Methods for treating cancer and methods for improving the effectiveness of T-cell redirection therapies

Abstract

The present invention provides a method for treating cancer and / or killing tumor cells in a given subject. [Solution] The present invention provides a method comprising administering a therapeutically effective amount of anti-CD38 antibody and a T-cell redirecting therapeutic agent to a subject to treat cancer. The present invention provides a method for improving the efficacy of a T-cell redirecting therapeutic agent in a subject having cancer, comprising administering an anti-CD38 antibody to the subject. The present invention also provides a method for treating multiple myeloma in a subject, comprising administering a therapeutically effective amount of BCMA×CDS bispecific antibody and anti-CD38 antibody to the subject to treat multiple myeloma. The present invention also provides a pharmaceutical combination comprising GPRC5D×CD3 bispecific antibody. The present invention also provides a kit comprising a pharmaceutical composition comprising BCMA×CD3 bispecific antibody and anti-CD38 antibody.

Description

[Technical Field]

[0001] Methods for treating cancer and methods for improving the effectiveness of T-cell redirection therapies are disclosed. ru. [Background technology]

[0002] T-cell redirection and killing is a desirable mode of action in many therapeutic areas. In T cell redirection molecules, one site binds to a surface antigen on the target cell, and the other site... The site is engineered to have at least two antigen-binding sites that bind to T cell surface antigens. Among T cell surface antigens, the human CD3 epsilon subunit of the TCR protein complex... The most targeted is to redirect T cell killing. Various bispecificities The antibody form mediates T cell redirection in both preclinical and clinical studies. This has been shown (May C et al., Biochem Pharmacol, 8 4:1105-12,2012, Frankel SR & Baeuerle P A,Curr Opin Chem Biol,17(3):385-92,2013) .

[0003] Tumors create an immunosuppressive tumor microenvironment (TME). Therefore, it evades immune recognition. In TME, under conditions of persistent antigen and inflammation, T cells, They become worn out or malfunction, and their effector functions and amplification capabilities are gradually diminished. Loss. The impaired function of available T cells involved in drug-mediated T cell redirection killing. The number and capacity of the drug may impair its antitumor efficacy. [Overview of the project]

Problems to be Solved by the Invention

[0004] Therefore, for the optimal efficacy of therapeutic agents that mediate T cell redirected killing, there is a need to improve T cell functionality.

Means for Solving the Problems

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

[0006] The present disclosure also provides a method for killing tumor cells in a subject, comprising administering to the subject an anti-CD38 antibody and a T cell redirected therapeutic agent that binds to an antigen on the tumor cells for a time sufficient to kill the tumor cells.

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

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

[0009] The present disclosure also provides a method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a BCMA× CD3 bispecific antibody to treat the cancer, wherein the subject has been treated with an anti-CD38 antibody prior to administration of the BCMA× CD3 bispecific antibody.

[0010] ​​​​​This disclosure also relates to a method for treating cancer in a subject, wherein the amount of BCMA effective for treatment is multiplied by The treatment of cancer involves administering a CD3 bispecific antibody to the target, and the target is a previously anti-cancer agent. We also provide methods for treating relapsed or refractory cases that have not responded to drug therapy.

[0011] This disclosure also relates to a method for treating multiple myeloma in a subject, wherein the amount is effective in treating the disease. BCMA x CD3 bispecific antibody and anti-CD38 antibody were administered to target multiple myeloma. We also provide methods, including treatment.

[0012] This disclosure also relates to a method for treating multiple myeloma in a subject, wherein the amount is effective in treating the disease. This includes administering a BCMA x CD3 bispecific antibody to treat multiple myeloma. The subjects were treated with an anti-CD38 antibody before administration of the BCMA x CD3 bispecific antibody. We also provide methods.

[0013] This disclosure also relates to a method for treating multiple myeloma in a subject, wherein the amount is effective in treating the disease. This includes administering a BCMA x CD3 bispecific antibody to treat multiple myeloma. The subjects are those whose multiple myeloma has relapsed or is refractory to previous treatment with other multiple myeloma medications, and the method is also provide.

[0014] This disclosure also includes BCMA-conjugated domains including VH of SEQ ID NO: 29 and VL of SEQ ID NO: 30. n, and CD3 binding domains including VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40 BCMA×CD3 bispecific antibody and anti-C2 antibody containing VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 We also provide pharmaceutical compositions containing D38 antibody.

[0015] This disclosure also relates to a method for treating cancer in a subject, wherein the treatment is bound to GPRC5D. The cancer was treated by administering effective amounts of T-cell redirecting drugs and anti-CD38 antibodies to the target. We also provide methods, including how to do so.

[0016] This disclosure also relates to a method for treating cancer in a subject, wherein the amount of GPRC5 effective for treatment is sufficient. The treatment of cancer involves administering a D×CD3 bispecific antibody to the target, and the target is a previous We also provide methods for treating cancer that has recurred or is refractory to anticancer drug therapy.

[0017] This disclosure also includes HCDR1 (SEQ ID NO: 43), HCDR2 (SEQ ID NO: 44), and SEQ ID NO: 45 HCDR3, LCDR1 of sequence number 46, LCDR2 of sequence number 47, and sequence number 4 8 GPRC5D binding domains including LCDR3, and HCDR1 of SEQ ID NO: 33, HCDR2 at column number 34, HCDR3 at sequence number 35, LCDR1 at sequence number 36, array Includes CD3 binding domains including LCDR2 (number 37) and LCDR3 (sequence number 38). GPRC5D×CD3 bispecific antibody, HCDR1 (SEQ ID NO. 6), and HCD (SEQ ID NO. 7) R2, HCDR3 (sequence number 8), LCDR1 (sequence number 9), LCDR2 (sequence number 10), We also provide a pharmaceutical combination that includes an anti-CD38 antibody containing LCDR3 of SEQ ID NO: 11. ru.

[0018] This disclosure also relates to a method for treating cancer in a subject, the treatment of which binds to CD19. The cancer is treated by administering effective doses of T-cell redirecting therapies and anti-CD38 antibodies to the target patient. We also provide methods that include this.

[0019] This disclosure also relates to CD19-binding T-cell redirecting therapeutics in subjects with cancer. A method to improve the effectiveness of a T cell redirection therapeutic drug that binds to CD19 The present invention also provides a method that includes administering an anti-CD38 antibody to the subject prior to administration.

[0020] This disclosure also relates to CD19×CD3 bispecific antibodies containing blinatumomab, SEQ ID NO: 53. And, HCDR1 of sequence number 6, HCDR2 of sequence number 7, HCDR3 of sequence number 8, sequence Includes LCDR1 with number 9, LCDR2 with sequence number 10, and LCDR3 with sequence number 11. We also offer drug combinations that include anti-CD38 antibodies.

[0021] This disclosure also provides a kit containing the pharmaceutical composition of this disclosure. [Brief explanation of the drawing]

[0022] [Figure 1] This study demonstrates JNJ-957-mediated lysis of the multiple myeloma (MM) cell line RPMI8226. Peripheral blood mononuclear cells (PB MNCs) from healthy donors were used as effector cells. [Figure 2] This study demonstrates JNJ-957-mediated lysis of the multiple myeloma (MM) cell line UM9. Peripheral blood mononuclear cells (PB MNCs) from healthy donors were used as effector cells. [Figure 3] This study demonstrates JNJ-957-mediated lysis of the multiple myeloma (MM) cell line U226. Peripheral blood mononuclear cells (PB MNCs) from healthy donors were used as effector cells. [Figure 4] This study demonstrates JNJ-957-mediated lysis of the multiple myeloma (MM) cell line MM1. Peripheral blood mononuclear cells (PB MNCs) from healthy donors were used as effector cells. [Figure 5]A representative example (n=2) of RPMI8226 cells incubated with healthy donor PB MNCs demonstrates that JNJ-957-mediated MM cell lysis is accompanied by CD4+ T cell activation and degranulation, determined by increased surface expression of CD25 (activated). [Figure 6] In a representative example (n=2) of RPMI8226 cells incubated with healthy donor PB MNCs, we demonstrate that JNJ-957-mediated MM cell lysis is accompanied by CD4+ T cell activation and degranulation, determined by increased surface expression of CD107a (degranulation). [Figure 7] A representative example (n=2) of RPMI8226 cells incubated with healthy donor PB MNCs demonstrates that JNJ-957-mediated MM cell lysis is accompanied by CD4+ T cell activation and degranulation, determined by the proportion of CD25 and CD107a double-positive CD4+ T cells. [Figure 8] In a representative example (n=2) of RPMI8226 cells incubated with healthy donor PB MNCs, we demonstrate that JNJ-957-mediated MM cell lysis is accompanied by CD8+ T cell activation and degranulation, which are determined by increased surface expression (activation) of CD25. [Figure 9] In a representative example (n=2) of RPMI8226 cells incubated with healthy donor PB MNCs, we demonstrate that JNJ-957-mediated MM cell lysis is accompanied by CD8+ T cell activation and degranulation, determined by increased surface expression of CD107a (degranulation). [Figure 10] In a representative example (n=2) of RPMI8226 cells incubated with healthy donor PB MNCs, we demonstrate that JNJ-957-mediated MM cell lysis is accompanied by CD8+ T cell activation and degranulation, determined by an increase in the proportion of CD25 and CD107a double-positive CD4+ T cells. [Figure 11]This shows in vitro daratumumab-mediated lysis of MM cells from newly diagnosed multiple myeloma (NDMM) and daratumumab-naive relapsed / refractory MM (RRMM) patients. Multiple myeloma cells from daratumumab-refractory RRMM patients were resistant to daratumumab-mediated lysis.*** *P<0.0001 [Figure 12] This report shows the dose-response of JNJ-957-mediated lysis of plasma cells, T cells, and NK cells in complete autologous bone marrow (BM) MNCs obtained from newly diagnosed multiple myeloma (NDMM) patients (n=8). The lysis rate was measured at various antibody concentrations (0.0064–4.0 μg / mL), as shown in the figure. Circles (top line): plasma cells, squares (center line): T cells, triangles (bottom line): NK cells. [Figure 13] This figure shows the dose-response of JNJ-957-mediated lysis of plasma, T cells, and NK cells in complete autologous bone marrow (BM) MNCs obtained from 15 patients with lenalidomide-refractory multiple myeloma (MM). The lysis rate was measured at various antibody concentrations (0.0064–4.0 μg / mL), as shown in the figure. Circles (top line): plasma cells, squares (center line): T cells, triangles (bottom line): NK cells. [Figure 14] This figure shows the dose-response of JNJ-957-mediated lysis of plasma, T cells, and NK cells in complete autologous bone marrow (BM) MNCs obtained from 11 refractory malformation myeloma (MM) patients who were refractory to lenalidomide and daratumumab treatment. The lysis rate was measured at various antibody concentrations (0.0064–4.0 μg / mL), as shown in the figure. Circles (top line): plasma cells, squares (center line): T cells, triangles (bottom line): NK cells. [Figure 15]This study demonstrates that JNJ-957-mediated MM cell lysis is accompanied by activation of CD4+ T cells (assessed by increased CD25 surface expression) in BM samples from patients with NDMM, daratumumab-naive RRMM (RRMM), and daratumumab-refractory RRMM (RRMM Dara R). 3930: Isotype control, BC3B4: BCMA × null bispecific antibody, 7008: null × CD3 bispecific antibody. [Figure 16] This study demonstrates that JNJ-957-mediated MM cell lysis is accompanied by degranulation of CD4+ T cells (assessed by increased CD107a surface expression) in BM samples from patients with NDMM, daratumumab-naive RRMM (RRMM), and daratumumab-refractory RRMM (RRMM DaraR). 3930: Isotype control, BC3B4: BCMA × null bispecific antibody, 7008: null × CD3 bispecific antibody. [Figure 17] The following shows the percentage of bipositive CD25+CD107a+ cells as the percentage of CD4+ T cells in BM samples from patients with NDMM, daratumumab naive RRMM (RRMM), and daratumumab-refractory RRMM (RRMM Daratumumab R) treated with the indicated concentrations of JNJ-957. 3930: Isotype control, BC3B4: BCMA × null bispecific antibody, 7008: null × CD3 bispecific antibody. Bipositive: CD25 and CD107a bipositive CD4+ T cells. [Figure 18] This study demonstrates that JNJ-957-mediated MM cell lysis is accompanied by activation of CD8+ T cells (assessed by increased CD25 surface expression) in BM samples from patients with NDMM, daratumumab-naive RRMM (RRMM), and daratumumab-refractory RRMM (RRMM Dara®). 3930: Isotype control, BC3B4: BCMA × null bispecific antibody, 7008: null × CD3 bispecific antibody. [Figure 19]This study demonstrates that JNJ-957-mediated MM cell lysis is accompanied by degranulation of CD8+ T cells (assessed by increased CD107a surface expression) in BM samples from patients with NDMM, daratumumab-naive RRMM (RRMM), and daratumumab-refractory RRMM (RRMM DaraR). 3930: Isotype control, BC3B4: BCMA × null bispecific antibody, 7008: null × CD3 bispecific antibody. [Figure 20] The following shows the percentage of bipositive CD25+CD107a+ cells as the percentage of CD8+ T cells in BM samples from patients with NDMM, daratumumab naive RRMM (RRMM), and daratumumab refractory RRMM (RRMM Daratumumab R) treated with the indicated concentrations of JNJ-957. 3930: Isotype control, BC3B4: BCMA × null bispecific antibody, 7008: null × CD3 bispecific antibody. Bipositive: CD25 and CD107a bipositive CD8+ T cells. [Figure 21] This shows the BCMA expression levels on MM cells (mean MFI±SEM) in NDMM, daratumumab-naive RRMM, and daratumumab-refractory RRMM patients. The P-values ​​between the groups shown were calculated using the Mann-Whitney U test. *P<0.05, ns: no significant difference. [Figure 22] This shows the PD-L1 expression levels on MM cells (mean MFI±SEM) in patients with NDMM, daratumumab-naive RRMM, and daratumumab-refractory RRMM. The P-values ​​between the groups shown were calculated using the Mann-Whitney U test. *P<0.05, ns: no significant difference. [Figure 23] This shows the baseline proportion of Tregs in BM MNCs for NDMM, daratumumab naive RRMM, and daratumumab refractory RRMM. **p<0.01, ns: no significant difference. [Figure 24] This shows the baseline percentage of activated T cells (assessed by HLA-DR positivity) in the BM MNC of NDMM, daratumumab naive RRMM, and daratumumab refractory RRMM. **p<0.01, ns: no significant difference. [Figure 25]This shows the baseline proportions of various T cell subsets in the BM MNC of NDMM, daratumumab-naive RRMM, and daratumumab-refractory RRMM. *p<0.05, **p<0.01, Ns: no significant difference. TEMRA: CD45RA+CCR7-T cells, EM: effector memory, CM: central memory, N: naive T cells. [Figure 26] This study demonstrates JNJ-957-mediated lysis of multiple myeloma cells (NDMM) from patients with NDMM mediated by autologous BM MNCs. Samples were bifurcated based on baseline Treg frequency (low ≤ 50th percentile, high > 50th percentile). Ns: No significant difference. [Figure 27] This study demonstrates JNJ-957-mediated lysis of multiple myeloma cells in daratum mab-naive RRMM patients, mediated by autologous BM MNCs. Samples were bifurcated based on baseline Treg frequency (low ≤50th percentile, high >50th percentile). *p<0.05, **p<0.01, Ns: no significant difference. [Figure 28] This study demonstrates JNJ-957-mediated lysis of multiple myeloma cells in daratumumab-refractory RRMM patients, mediated by autologous BM MNCs. Samples were bifurcated based on baseline Treg frequency (low ≤ 50th percentile, high > 50th percentile). *p<0.05, ns: no significant difference. [Figure 29] This shows JNJ-957-mediated lysis of MM cells in BM samples from patients with NDMM (n=9), daratumumab-naive RRMM (n=18), and daratumumab-refractory RRMM (n=13) after 48 hours of incubation. Data are shown as mean ± SEM, and p-values ​​were calculated using Student's t-test. **P<0.01. [Figure 30]This study shows that JNJ-957-mediated lysis of MM cells in bone marrow (BM) samples obtained from patients with relapsed / refractory multiple myeloma (RRMM) (n=8) was increased in samples from patients who received daratumumab ("Dara-exposed") compared to samples from the same patients before the initiation of daratumumab treatment ("Dara-naive"). Data are presented as mean ± SEM. P-values ​​were calculated using paired t-tests. ns: no significant difference. *P<0.05, **P<0.01. [Figure 31] This shows the percentage of Tregs in sequential BM aspirates in RRMM patients before daratumumab initiation (pre-daratumumab) and at the onset of daratumumab-refractory disease (daratumumab exposure). ns: no significant difference. [Figure 32] This shows the percentage of CD4+ cells in sequential BM aspirates from RRMM patients before daratumumab initiation (pre-daratumumab) and at the onset of daratumumab-refractory disease (daratumumab exposure). ns: no significant difference. [Figure 33] This shows the percentage of CD8+ T cells in sequential BM aspirates from RRMM patients before initiation of daratumumab (pre-daratumumab) and at the onset of daratumumab-refractory disease (daratumumab exposure). [Figure 34] This study shows that JNJ-957-mediated lysis of RPMI8226 multiple myeloma cells, using patient-derived PB MNCs as effector cells, was enhanced by PB MNCs from daratumumab-treated patients ("PBMNC Daratumumab-intermediate") compared to samples from the same patients before daratumumab treatment initiation ("PBMNC Daratumumab-naive") (n=5). Data are presented as mean ± SEM. P-values ​​were calculated using paired t-tests. ns: no significant difference. *P<0.05. [Figure 35] This shows the proportion of Tregs in PB-MNC samples from daratumumab-naive (pre-daratumumab) and daratumumab-refractory (daratumumab-interval) RRMM patients. [Figure 36] This shows the percentage of CD4+ T cells in PB-MNC samples from daratumumab-naive (pre-daratumumab) and daratumumab-refractory (daratumumab-interval) RRMM patients. ns: No significant difference. [Figure 37]This shows the percentage of CD8+ T cells in PB-MNC samples from daratumumab-naive (pre-daratumumab) and daratumumab-refractory (daratumumab-interval) RRMM patients. ns: No significant difference. [Figure 38] This study demonstrates that the addition of daratumumab increased JNJ-957-mediated MM cell lysis. BM mononuclear cells (MNCs) from NDMM (n=8) patients were treated for 48 hours with either JNJ-957 (0.032–0.8 μg / mL) alone or in combination with 10 μg / mL of daratumumab. Observed (Obs) lysis levels of MM cells by JNJ-957 and daratumumab were compared to expected (Exp) lysis levels, calculated assuming a combinatorial effect achieved through the additive effect described in the methods. Black bars indicate group mean ± SEM. P-values ​​were calculated using paired Student's t-tests. ns: no significant difference. [Figure 39] This study demonstrates that the addition of daratumumab increased JNJ-957-mediated MM cell lysis. BM MNCs from daratumumab-naive RRMM patients (n=17) were treated for 48 hours with JNJ-957 (0.032-0.8 μg / mL) alone or in combination with 10 μg / mL of daratumumab. Observed (Obs) lysis levels of MM cells by JNJ-957 and daratumumab were compared to expected (Exp) lysis levels, calculated assuming a combinatorial effect achieved through the additive effect described in the methods. Black bars indicate group mean ± SEM. P-values ​​were calculated using paired Student's t-tests. ns: no significant difference. [Figure 40]This study demonstrates that the addition of daratumumab increased JNJ-957-mediated MM cell lysis. BM MNCs in daratumumab-refractory RRMM patients (n=14) were treated for 48 hours with JNJ-957 (0.032-0.8 μg / mL) alone or in combination with 10 μg / mL daratumumab. Observed (O) lysis levels of MM cells by JNJ-957 and daratumumab were compared to expected (E) lysis levels, calculated assuming a combinatorial effect achieved through the additive effect shown in the method. Black bars indicate group mean ± SEM. P-values ​​were calculated using paired Student's t-tests. JNJ-957 is referred to as JNJ-7957 in the figures. Dara: daratumumab. ns: no significant difference. [Figure 41] Sequential PB samples from 11 RRMM patients were used as effector cells to demonstrate blinatumomab-mediated lysis of large cell lines (E:T in a 10:1 ratio). These were obtained directly before the initiation of daratumumab treatment (black, bottom line) and during daratumumab treatment (gray, top line). The median duration of treatment was 7 months (ranging from 2 to 14 months). Large cells were incubated with blinatumomab (0.01 to 10 g / mL) for 48 hours in the presence of these PB-MNCs, followed by a blinatumomoab-mediated cytotoxicity assay. Data represent mean ± SEM, and experiments were performed in double sequences. Statistical significance (P-value) between groups was calculated using nonlinear regression analysis. [Figure 42] This figure shows the dose-response of JNJ-957-mediated lysis of plasma, T cells, and NK cells obtained from six patients with primary plasma leukemia (pPCL). The lysis rate was measured at various antibody concentrations (0.0064–4.0 μg / mL), as shown in the figure. The upper line represents plasma cells, and the lower line represents overlapping lines for T cells and NK cells. JNJ-957 is referred to as JNJ-7957 in the figure. [Figure 43]Sequential PB samples from 11 RRMM patients were used as effector cells to demonstrate antibody-mediated lysis of MM cell lines using anti-GPRC5D×CD3 (E:T in a 10:1 ratio). These were obtained directly before the initiation of daratumumab treatment (bottom line) and during daratumumab treatment (top line). The median duration of treatment was 7 months (ranging from 2 to 14 months). Large cells were incubated with blinatumomab (0.01–10 μg / mL) for 48 hours in the presence of these PB-MNCs, followed by a blinatumomab-based cytotoxicity assay. Data represent mean ± SEM, and experiments were performed in double sequences. [Figure 44] This study demonstrates that the addition of daratumumab was additive to anti-GPRC5D×CD3 bispecific antibody (JNJ-7564)-mediated MM cell lysis. BM MNCs from daratumumab-naive RRMM patients (n=17) were treated for 48 hours with either anti-GPRC5D×CD3 bispecific antibody (0.00128~0.8 μg / mL) alone or in combination with 0.1 μg / mL of daratumumab. Observed (O) lysis levels of MM cells by anti-GPRC5D×CD3 bispecific antibody and daratumumab were compared to expected (E) lysis levels, calculated assuming a combinatorial effect achieved through the additive effect shown in the method. Black bars indicate group mean ± SEM. P-values ​​were calculated using paired Student's t-tests. ns: no significant difference. Dara: daratumumab. [Modes for carrying out the invention]

[0023] The methods disclosed are those made in connection with the attached drawings, which form part of this disclosure. It can be more easily understood by referring to the detailed explanation. The disclosed method is: Not limited to the specific methods described and / or illustrated herein, and furthermore, used herein The terms used are intended solely to illustrate specific embodiments and are not used in the claims. Please understand that this is not intended to be limited to the methods described herein. Published patent applications and publications are, by reference, described herein in their entirety. It is incorporated in the same way as other things that are already there.

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

[0025] Various terms relating to aspects thereof are used throughout this specification and the claims. Unless otherwise stated, such terms have their ordinary meaning in the art in question. Flavor shall be imparted. Other specifically defined terms are provided herein. It shall be interpreted in a manner consistent with the definition.

[0026] "Approximately" is used when referring to a numerical range, cutoff, or specific value, and is understood by those skilled in the art. This means that the specific value determined by this means is within the acceptable margin of error, and this is because The value of the measurement depends in part on the method used to measure or determine it, i.e., on the limitations of the measurement system. In the context of the assay, results, or embodiments, the examples or other parts of the specification may not be otherwise specified. Unless otherwise specified, “approximately” means one standard deviation or 5% in accordance with the practices of the art. This means it falls within the larger of the two ranges.

[0027] The term "antibody" is intended to be used in a broad sense, encompassing mouse, human, humanized, and chimeric monoclonal antibodies. Monoclonal antibodies, antigen-binding fragments, bispecific, triplicate, quadruplicate antibodies, etc. Multispecific antibodies, dimeric, tetrameric, or multimeric antibodies, single-chain antibodies, antibody domains any other modification of the immunoglobulin molecule, including the antigen-binding site of the required specificity. It contains immunoglobulin molecules that have been modified. "Full-length antibodies" have disulfide bonds. More interconnected, two heavy chains (HC) and two light chains It consists of LC, and their polymers (e.g., IgM). Each heavy chain has a heavy chain variable region (he Avy chain variable region (VH), and heavy chain constant region (domain CH1, hinge, Each light chain consists of CH2 and CH3. It consists of a variable region (VL) and a constant region (CL) of the light chain. The VH and VL regions are scattered with framework regions (FRs). This highly variable region is called the complementarity determining region (CDR). It can be further classified into regions. Each VH and VL is from the amino terminus to the carboxyl terminus. The following sequence is used for distribution: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. It consists of three CDR and four FR segments. Immunoglobulins are heavy Depending on the amino acid sequence of the chain's constant domain, there are five main classes: IgA, IgD, etc. It can be assigned to IgE, IgG, and IgM. IgA and IgG are isotypes. These are further subdivided into IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. The antibody light chain of any vertebrate species is based on the amino acid sequence of its constant domain. , one of two distinct types, namely kappa (κ) and lambda (λ) It can be assigned.

[0028] An "antigen-binding fragment" or "antigen-binding domain" refers to an immunoglobulin molecule that binds to an antigen. It means a part of the antigen-binding fragment is a synthetic polypeptide, an enzyme-mediated polypeptide D, or genetically modified polypeptides, VH, VL, VH and VL, Fab, F(ab')2, Fd and Fv fragments, one VH domain or one VL domain Domain antibody (dAb) consisting of a shark variable IgNAR domain mimics the CDR of antibodies, including the camelized VH domain and the FR3-CDR3-FR4 moiety. The smallest recognition unit consisting of amino acid residues, HCDR1, HCDR2, and / or HCDR 3, as well as LCDR1, LCDR2, and / or LCDR3. VH and VL The domains are linked to each other via synthetic linkers, forming various types of single-chain antibody designs. This is possible, and the VH and VL domains are expressed by individual single-chain antibody constructs. In combination, the VH / VL domains form intramolecular or intermolecular pairs, forming a monovalent antigen-binding site, for example. For example, it can form a single-chain Fv (scFv) or a diabody. These include, for example, International Publication No. 1998 / 44001 and International Publication No. 1988 / 01649. This is described in issues 1994 / 13804 and 1992 / 01047.

[0029] "BCMA" is CD269 or TNFRSF17 (UniProt Q02223) This refers to the human B cell maturation antigen, also known as BCMA. The extracellular domain of BCMA is Q0222. It includes residues 1-54 of sequence 3. Human BCMA contains the amino acid sequence of sequence number 2.

[0030] Sequence ID 2 MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQR YCNASVTNSVKGTNAILWTCLGLSLIISLAVFVLMFLLRK INSEPLKDEFKNTGSGLLGMANIDLEKSRTGDEIILPRGL EYTVEECTCEDCIKSKPKVDSDHCFPLPAMEEGATILVTT KTNDYCKSLPAALSATEIEKSISAR

[0031] "Bispecificity" refers to specificity in two different antigens, or two different epitopes within the same antigen. This refers to antibodies that bind heterospecifically. Bispecific antibodies can bind to other related antigens, such as human or monkey antigens. For example, Macaca cynomolgus (cyno) or Pan Troglodytes and other species (homologs) exhibit cross-reactivity to the same antigen. It may be able to bind to epitopes shared between two or more different antigens.

[0032] "Cancer" is a widespread disease characterized by the uncontrolled growth of abnormal cells in the body. This refers to a typical group. Uncontrolled cell division and growth result in the form of malignant tumors that invade adjacent tissues. It can cause growth and metastasize to distal parts of the body via the lymphatic system or bloodstream. "Cancer" or " "Cancer tissue" may include tumors.

[0033] "CD123" is a human interleukinose having the amino acid sequence shown in Sequence ID No. 57. This refers to the IR3RA receptor subunit alpha. It also refers to the extracellular domain or CD12 3 corresponds to residues 19-305 of sequence number 57.

[0034] CD123 (Sequence ID 57) MVLLWLTLLLLIALPCLLQTKEDPNPPITNLRMKAKAQQL TWDLNRNVTDIECVKDADYSMPAVNNSYCQFGAISLCEVT NYTVRVANPPFSTWILFPENSGKPWAGAENLTCWIHDVDF LSCSWAVGPGAPADVQYDLYLNVANRRQQYECLHYKTDAQ GTRIGCRFDDISRLSSGSQSSHILVRGRSAAFGIPCTDKF VVFSQIEILTPPNMTAKKCNKTHSFMHWKMRSHFNRKFRYE LQIQKRMQPVITEQVRDRTSFQLLNPGTYTVQIRARERVY EFLSAWSTPQRFECDQEEGANTRAWRTSLLIALGTLLALV CVFVICRRYLVMQRLFPRIPHMKDPIGDSFQNDKLVVWEA GKAGLEECLVTEVQVVQKT

[0035] "CD19" is the human B lymphocyte antigen CD19 having the amino acid sequence of SEQ ID NO: 58. It refers to the extracellular domain of CD19, which extends from residues 20 to 291 of sequence number 58.

[0036] CD19 (Sequence ID 58) MPPPRLFFLLFLTPMEVRPEEPLVVKVEEGDNAVLQCL KGTSDGPTQQLTWSRESPLKP FLKLSLGLPGLGIHMRPLAIWLFIFNVSQQMGGFYLCQP GPPSEKAWQPGWTVNVEGSGE LFRWNVSDLGGLGCGLKNRSSEGPSSPSGKLMSPKLYVW AKDRPEIWEGEPPCLPPRDSL NQSLSQDLTMAPGSTLWLSCGVPPDSVSRGPLSWTHVHP KGPKSLLSLELKDDRPARDMW VMETGLLLPRATAQDAGKYYCHRGNLTMSFHLEITARPV LWHWLLRTGGWKVSAVTLAYL IFCLCSLVGILHLQRALVLRRKRKRMTDPTRRFFKVTPP PGSGPQNQYGNVLSLPTPTSG LGRAQRWAAGLGGTAPSYGNPSSDVQADGALGSRSPPGV GPEEEEGEGYEEPDSEEDSEF YENDSNLGQDQLSQDGSGYENPEDEPLGPEDEDSFSNAE SYENEDEELTQPVARTMDFLS PHGSAWDPSREATSLGSQSYEDMRGILYAAPQLRSIRGQ PGPNHEEDADSYENMDNPDGP DPAWGGGGRMGTWSTR

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

[0038] Sequence ID 3 MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVS ISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDE DHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVC ENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKA KPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLY SGLNQRRI

[0039] Sequence ID 22 DGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQH NDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPR GSKPEDANFYLYLRARVCENCMEMD

[0040] "CD33" refers to the myeloid cell surface antigen CD33, which has the amino acid sequence of SEQ ID NO: 97. The extracellular domain of CD33 extends from residues 18 to 259 of sequence number 97.

[0041] CD33 (Sequence ID 97) MPLLLLLPLLWAGALAMDPNFWLQVQESVTVQEGLCVLV PCTFFHPIPYYDKNSPVHGYWFREGAIISRDSPVATNKLD QEVQEETQGRFRLLGDPSRNNCSLSIVDARRRDNGSYFFR MERGSTKYSYKSPQLSVHVTDLTHRPKILIPGTLEPGHSK NLTCSVSWACEQGTPPIFSWLSAAPTSLGPRTTHSSVLII TPRPQDHGTNLTCQVKFAGAGVTTERTIQLNVTYVPQNPT TGIFPGDGSGKQETRAGVVHGAIGGAGVTALLALCLCLIF FIVKTHRRKAARTAVGRNDTHPTTGSASPKHQKKSKLHGP TETSSCSGAAPTVEMDEELHYASLNFHGNMNPSKDTSTEYS EVRTQ

[0042] "CD38" refers to the human CD38 protein (UniProt acceptance number P28907) ( Synonyms: ADP-ribosylcyclase 1, cADPr hydrolase 1, cyclic ADP-ribo This refers to hydroxylase 1). Human CD38 has the amino acid sequence shown in Sequence ID No. 1. CD38 has amino acid residues 1-21 representing the cytoplasmic domain, and amino acid residues 22- Residue 42 represents the transmembrane domain, and residues 43-300 represent the extracellular domain, single path It is a type II transmembrane protein.

[0043] Sequence ID 1 MANCEFSPVSGDKPCCRLSRRAQLCLGVSILVLILVVVL AVVVPRWRQQWSGPGTTKRFPETVLARCVKYTEIHPEMRH VDCQSVWDAFKGAFISKHPCNITEEDYQPLMKLGTQTVPC NKILLWSRIKDLAHQFTQVQRDMFTLEDTLLGYLADDLTW CGEFNTSKINYQSCPDWRKDCSNNPVSVFWKTVSRRFAEA ACDVVHVMLNGSRSKIFDKNSTFGSVEVHNLQPEKVQTLE AWVIHGGREDSRDLCQDPTIKELESIISKRNIQFSCKNIY RPDKFLQCVKNPEDSSCTSEI

[0044] The "CH3 region" or "CH3 domain" refers to the CH3 region of immunoglobulins. (Human) The CH3 region of the IgG1 antibody corresponds to amino acid residues 341-446. However, The CH3 region may also be any of the other antibody isotypes described herein.

[0045] "Chimera antigen receptors" or "CARs" transfer ligands or antigen specificity onto T cells. Manipulated T cell receptors (e.g., naive T cells, central memory T cells, effervescent T cells) This refers to CAR memory T cells (or a combination thereof). CAR is also an artificial T cell receptor. Also known as CAR, chimeric T cell receptor, or chimeric immune receptor. CAR is an anti- Cells that can bind to the progenitor, transmembrane domain, and at least one intracellular domain. It includes the extradomain. The intracellular domain of CAR activates or inhibits intracellular biological processes. Polypeptides are known to function as domains that transmit harmful signals. Contains cydops. The transmembrane domain is known to extend to the cell membrane, and the extracellular domain and Contains any peptide or polypeptide capable of functioning to bind a signaling domain. Hmm. Chimeric antigen receptors optionally have a linker between the extracellular domain and the transmembrane domain and It may also include hinge domains that function in this way.

[0046] "Combination" refers to the use of two or more therapeutic agents together in a mixture form, or as a monotherapy. This means administering the drugs to the target subject in parallel or sequentially in any order, either as monotherapy or as separate agents.

[0047] The "complementarity-determining region (CDR)" is the region of an antibody that binds to an antigen. CDRs are... bat(Wu et al. J Exp Med132:211-50,1970)(K abat et al., Sequences of Proteins of Imm unological interest,5th Ed.Public Health Service,National Institutes of Health,B ethesda, Md., 1991), Chothia (Chothia et al. J Mol Biol 196:901-17,1987), IMGT (Lefranc et al. Dev Comp Immunol 27:55-77, 2003), and AbM(Martin and Thornton J Bmol Biol263:8 It can be defined using various descriptions such as (00-15, 1996). The correspondence with the numbering of the variable region is described (for example, Lefranc et a l.Dev Comp Immunol27:55-77,2003;Honegger and Pluckthun, J Mol Biol309:657-70,2001 International ImMunoGeneTics (IMGT) Database (See web source, http: / / www_imgt_org). UCL Using a business PLC with available programs such as abysis It can depict a CD-R. When used herein, "CDR" and "HCDR1" are used. "HCDR2", "HCDR3", "LCDR1", "LCDR2", and "LCD The term "R3" is used in accordance with the Kabat, C, and other terms as expressed herein, unless otherwise explicitly stated. Includes CDR as defined by either the hothia, IMGT, or AbM method.

[0048] The term "contains" is similar to the terms "essentially made from" and "consisting of". It is intended to include examples that are encompassed by the word. Similarly, the usage of "essentially becoming from" The word is intended to include examples that are encompassed by the term "consisting of". This is clear from the context. Unless otherwise intended, the word "includes" throughout the specification and claims shall not be interpreted in any other sense. Words like "comprise" and "comprising" have meanings that are in contrast to exclusive or exclusionary. In a general sense, it is interpreted as meaning "including but not limited to ~". It should.

[0049] "To improve" or "improved" refers to one of the test molecules compared to the control molecule. This refers to improvements in two or more functions, or the test results when compared to one or more control molecules. This refers to an improvement in one or more functions of a combination of children. Examples of measurable functions. This includes tumor cell killing, T cell activation, relative or absolute T cell count, and Fc-mediated effects. Receptor function (e.g., ADCC, CDC, and / or ADCP), or Fcγ receptor ( This refers to binding to FcγR) or FcRn. "Improved" means approximately 10%, 20%, 3%. 0%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more. This can be an improvement, or a statistically significant improvement.

[0050] The "Fc gamma receptor" (FcγR) is known as FcγRI, FcγRIIa, or FcγR This refers to IIb, or FcγRIII. Activated FcγR is FcγRI, FcγRIIa, and includes FcγRIII.

[0051] "GPRC5D" is a human G protein with the amino acid sequence shown in Sequence ID No. 98. This refers to member D of group C, family C, of ​​the binding receptor family.

[0052] GPRC5D (Sequence ID 98) MYKDCIESTGDYFLLCDAEGPWGIILESLAILGIVVTIL LLLAFLFLMRKIQDCSQWNVL PTQLLFLLSVLGLFGLAFAFIIELNQQTAPVRYFLFGVL FALCFSCLLAHASNLVKLVRG CVSFSWTTILCIAIGCSLLQIIIATEYVTLIMTRGMMFV NMTPCQLNVDFVVLLVYVLFL MALTFFVSKATFCGPCENWKQHGRLIFITVLFSIIIWVV WISMLLRGNPQFQRQPQWDDP VVCIALVTNAWVFLLLYIVPELCILYRSCRQECPLQGNA CPVTAYQHSFQVENQELSRAR DSDGAEEDVALTSYGTPIQPQTVDPTQECFIPQAKLSPQ QDAGGV

[0053] A "human antibody" is an antibody that is optimized to produce the minimum possible immune response when administered to a human subject. This refers to modified antibodies. The variable region of human antibodies is derived from the human immunoglobulin sequence. If the antibody contains a constant region or a portion of a constant region, that constant region is also human immunoglobulin It originates from the sequence. Human antibodies are derived from the variable region of human germline immunoglobulins or When obtained from a system using rearranged immunoglobulin genes, the human-derived sequence is " It includes the heavy chain variable region and light chain variable region derived from it. An example of such a system is F The human immunoglobulin gene library and human immunoglobulin gene presented on the page This includes non-human animals such as mice or rats that carry the gene locus. "Human antibodies" are Typically, this refers to the difference in the systems used to obtain human antibodies and human immunoglobulin gene loci. , introduction of somatic mutations, or replacement with a framework or CDR or both. The intentional introduction of this leads to differences in amino acids when compared to immunoglobulins expressed in humans. It contains. Typically, "human antibodies" are human germline immunoglobulins or rearranged For the amino acid sequence encoded by the immunoglobulin gene, The columns are at least approximately 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, They are 98% or 99% identical. In some cases, "human antibodies" are, for example, Knappi k et al. (2000) It is described in J Mol Biol 296:57-86. Consensus framework sequences, derived from human framework sequence analysis, or For example, Shi et al. (2010) J Mol Biol 397:385-9 6 and International Publication No. 2009 / 085462, the phage displayed The immunoglobulin gene library may also contain synthetic HCDR3 incorporated into it. Antibodies in which at least one CDR originates from a non-human species are not included in the definition of "human antibodies." stomach.

[0054] "Humanized antibodies" are those in which at least one CDR is derived from a non-human species and at least one F The framework refers to antibodies derived from human immunoglobulin sequences. Humanized antibodies are frameworks. Because the work can include substitutions, the framework expresses human immunoglobulins. Alternatively, it may not be an exact copy of the human immunoglobulin germline gene sequence.

[0055] "Isolated" means that molecules such as recombinant cells are extracted from other components of the system in which they are produced. A homogeneous group of molecules that are qualitatively separated and / or purified (e.g., synthetic polynucleotides) In addition to proteins such as antibodies or other substances, at least one purification or isolation step is performed. This refers to proteins. "Isolated antibodies" are those that substantially contain other cellular materials and / or chemical substances. This means no antibodies, and higher purity, e.g., 80%, 81%, 82%, 83%, 84%, 8 5%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 9 Includes antibodies isolated to a purity of 5%, 96%, 97%, 98%, 99%, or 100%. do.

[0056] A "monoclonal antibody" is a substantially homogeneous population of antibody molecules (i.e., a population composed of...) The individual antibodies that make up the body may undergo known modifications such as the removal of the C-terminal lysine from the antibody heavy chain. or amino acid isomerization or amide decomposition, methionine oxidation, or asparagine or glycerin This refers to antibodies obtained from (which are identical except for post-translational modifications such as lutamine adiposition). Noclonal antibodies typically bind to a single antigenic epitope. (Bispecific monoclonal antibodies) Monoclonal antibodies bind to two different antigenic epitopes. It may have heterogeneous glycosylation within a population. Monoclonal antibodies are monospecific. It may be monovalent, divalent, or polyvalent, and may be bivalent, divalent, or polyvalent. That's fine.

[0057] A "mutation" is a change in the polypeptide or polynucleotide sequence when compared to a reference sequence. This refers to an operation or a naturally occurring change. The change is one or more amino acids or polynucleotides. This may involve substitution, insertion, or deletion of cydos.

[0058] "Non-fixed combinations" refer to individual pharmaceuticals consisting of T-cell redirection therapies and anti-CD38 antibodies. The compositions, as individual entities, simultaneously, concurrently, or sequentially, without any limitations on specific intervening time. This refers to administration to the target body, and such administration brings the effective levels of the two compounds into the target body. To provide.

[0059] "Multispecificity" refers to an antibody that specifically binds to at least two different antigens, or the same antigen. This refers to antibodies that bind to at least two different epitopes within a single molecule. Examples of multispecific antibodies include... For example, two, three, four, or five different antigens, or different epitons within the same antigen. It can be combined with P.

[0060] "Pharmaceutical composition" refers to a composition containing an active ingredient and a pharmaceutically acceptable carrier.

[0061] A "medically acceptable carrier" or "excipient" is an active ingredient that is not toxic to the target substance. This refers to the components in a pharmaceutical composition.

[0062] "Philadelphia chromosome" or "Ph" is a constitutively active tyrosine kinase. A well-known oncogenic BCR-ABL gene fusion between chromosomes 9 and 22 results in sexually explicit oncogenic BCR-ABL gene fusions. This refers to a chromosomal translocation. This translocation causes a portion of the BCR gene on chromosome 22q11 to move to another chromosome. It is fused with a portion of the ABL gene at 9q34, which is part of the International Human Cytogenetics Nomenclature (International Human Cytogenetics Nomenclature). Under the International System for Human Cytogenetic Nomenclature (ISCN), t(9;2 2) It is named (q34;q11). Depending on the exact location of the fusion, the resulting fusion The molecular weight of the protein can be in the range of 185-210 kDa. "Chromoplasm" refers to all BCR-ABLs formed by the (9;22)(q34;q11) translocation. This refers to a fusion protein.

[0063] "PSMA" refers to the human prostate-specific membrane antigen having the amino acid sequence of SEQ ID NO: 99. The extracellular domain extends from residues 44 to 750 of sequence number 99.

[0064] PSMA (Sequence ID 99) MWNLLHETDSAVATARRPRWLCAGALVLAGGFFLLGFLF GWFIKSSNEATNITPKHNMKAFLDELKAENIKKFLYNFTQ IPHLAGTEQNFQLAKQIQSQWKEFGLDSVELAHYDVLLSY PNKTHPNYISIINEDGNEIFNTSLFEPPPPGYENVSDIVP PFSAFSPQGMPEGDLVYVNYARTEDFFKLERDMKINCSGK IVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADYFAPGV KSYPDGWNLPGGGVQRGNILNLNGAGDPLTPGYPANEYAY RRGIAEAVGLPSIPVHPIGYYDAQKLLEKMGGSAPPDSSW RGSLKVPYNVGPGFTGNFSTQKVKMHIHSTNEVTRIYNVI GTLRGAVEPDRYVILGGHRDSWVFGGIDPQSGAAVVHEIV RSFGTLKKEGWRPRRTILFASWDAEEFGLLGSTEWAEENS RLLQERGVAYINADSSIEGNYTLRVDCTPLMYSLVHNLTK ELKSPDEGFEGKSLYESWTKKSPSPEFSGMPRISKLGSGN DFEVFFQRLGIASGRARYTKNWETNKFSGYPLYHSVYETY ELVEKFYDPMFKYHLTVAQVRGGMVFELANSIVLPFDCRD YAVVLRKYADKIYSISMKHPQEMKTYSVSFDSLFSAVKNF TEIASKFSERLQDFDKSNPIVLRMMNDQLMFLERAFIDPL GLPDRPFYRHVIYAPSSHNKYAGESFPGIYDALFDIESKV DPSKAWGEVKRQIYVAAFTVQAAAETLSEVA

[0065] "Recombination" involves joining segments from different sources to create recombinant DNA, antibodies, or When generating proteins, they are prepared, expressed, produced, or isolated by recombinant means. This refers to DNA, antibodies, and other proteins.

[0066] "To reduce" or "reduced" means that one of the test molecules compared to the control molecule or Test molecules exhibiting reduction in two or more functions, or compared to one or more control molecules. This refers to a reduction in one or more functions of a combination of the following: Exemplary functions that can be measured are... tumor cell killing, T cell activation, relative or absolute T cell count, Fc-mediated effectors - Function (e.g., ADCC, CDC, and / or ADCP), or Fcγ receptor (F This refers to binding to cγR or FcRn. "Reduced" means approximately 10%, 20%, or 30%. 40%, 50%, 60%, 70%, 80%, 90%, 100%, or lower It may be a decrease or a statistically significant improvement.

[0067] "rHuPh20" is a recombinant hyaluronic acid described in International Publication No. 2004 / 078140. The amino acids in sequence number 105, which is lonidase (HYLENEX® recombinant). This refers to recombinant human hyaluronic acid that has a specific sequence.

[0068] rHuPH20 (Sequence ID 105) MGVLKFKHIFFRSFVKSSGVSQIVFTFLLIPCCLTLNFR APPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSP RINATGQGVTIFYVDRLGYYPYIDSITGVTVNGGIPQKIS LQDHLDKAKKDITFYMPVDNLGMAVIDWEEWRPTWARNWK PKDVYKNRSIELVQQQNVQLSLTEATEKAKQEFEKAGKDF LVETIKLGKLLRPNHLWGYYLFPDCYNHHYKKPGYNGSCF NVEIKRNDDLSWLWNESTALYPSIYLNTQQSPVAATLYVR NRVREAIRVSKIPDAKSPLPVFAYTRIVFTDQVLKFLSQD ELVYTFGETVALGASGIVIWGTLSIMRSMKSCLLLDNYME TILNPYIINVTLAAKMCSQVLCQEQGVCIRKNWNSSDYLH LNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSEKFYCSCYS TLSCKEKADVKDTDAVDVCIADGVCIDAFLKPPMETEEPQ IFYNASPSTLSATMFIVSILFLIISSVASL

[0069] "Refractory" means that the condition is not modifiable with surgical intervention and does not respond to therapy initially. It refers to cancer.

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

[0071] "Subject" includes any human or non-human animal. "Non-human animal" includes, for example, non-human animals. Mammals such as primates, sheep, dogs, cats, horses, cows, chickens, amphibians, and reptiles This includes all vertebrates, including non-mammals. Unless otherwise stated, "patient" and The terms "object" and "target" are used interchangeably.

[0072] "T-cell redirection therapeutic agents" refer to molecules containing two or more binding domains. One of the binding regions connects to a cell surface antigen (such as a tumor-associated antigen) on a target cell or tissue. The molecule binds specifically, and its second binding region specifically binds to T cell antigens (such as CD3). This dual / multiple target binding ability allows T cells to mobilize to target cells or tissues, and to target cells or This will lead to the eradication of the organization.

[0073] "TMEFF2" contains EGF-like and two folate statin-like domains (also known as Tomoregly). This refers to a human transmembrane protein having (2). The amino acid sequence of the full-length human TMEFF2 is As shown in SEQ ID NO: 101, the extracellular domain of TMEFF2 is from residue 40- of SEQ ID NO: 101. It totals 374.

[0074] TMEFF2 (Sequence ID 101) MVLWESPRQCSSWTLCEGFCWLLLLPVMLLIVARPKLA AFPTSLSDCQTPTGWNCSGYDDRENDLFLCDTNTCKFDGE CLRIGDTVTCVCQFKCNNDYVPVCGSNGESYQNECYLRQA ACKQQSEILVVSEGSCATDAGSGSGDGVHEGSGETSQKET STCDICQFGAECDEDAEDVWCVCNIDCSQTNFNPLCASDG KSYDNACQIKEASCQKQEKIEVMSLGRCQDNTTTTTKSED GHYARTDYAENANKLEESAREHHIPCPEHYNGFCMHKCE HSINMQEPSCRCDAGYTGQHCEKKDYSVLYVVPGPVRFQY VLIAAVIGTIQIAVICVVVLCITRKPRSNRIHRQKQNTG HYSSDNTTRASTRLI

[0075] "A therapeutically effective dose" is the amount that is effective in achieving the desired therapeutic outcome in the required dosage and duration. This refers to the effective dose for treatment, which depends on factors such as the individual's condition, age, sex, and weight, as well as the individual's individual health condition. The ability of a single drug or combination of drugs to elicit the desired response varies. This may be the case. Exemplary indicators of an effective single treatment or combination of treatments include: For example, improved patient health is one such benefit.

[0076] "To treat" or "treatment" refers to both therapeutic measures and preventive or protective measures. The purpose is to prevent or delay (mitigate) undesirable physiological changes or disorders. ) is the beneficial or desired clinical outcome, whether detectable or undetectable. Whether so, the goal is to alleviate symptoms, reduce the severity of the disease, and stabilize (i.e., prevent worsening) the disease condition. Condition, delay or slowing of disease progression, improvement or alleviation of disease state, and remission (whether partial or not) (or the whole) are examples of "treatment". "Treatment" also refers to cases where the subject has not received treatment. This may mean extending the survival time compared to the expected survival time. Those who are at risk include those who already have a condition or disease, and those who are prone to developing such a condition or disease. This includes individuals or those who seek to prevent a condition or disease.

[0077] "Tumor cells" or "cancer cells" are detected in vivo, ex vivo, or through tissue culture. Furthermore, cancerous, precancerous, or transformed cells with spontaneously occurring or introduced phenotypic changes. Refers to cells. These changes do not necessarily involve the incorporation of new genetic material. Transgenicity involves infection by a transformed virus, integration of new genomic nucleic acids, and removal of exogenous nucleic acids. It can also be caused by contamination, and can occur spontaneously or after exposure to carcinogens. This can also lead to mutations in endogenous genes. Transformation / cancer can be performed in vitro, in vitro. Morphological changes, cell immortalization, control of abnormal proliferation, and lesion shape in vo and ex vivo therapies. Growth, proliferation, malignant lesions, regulation of tumor-specific marker levels, invasiveness, and preference for nude mice, etc. This is exemplified by the growth of tumors in suitable animal hosts.

[0078] Throughout this specification, the numbering of amino acid residues in the constant region of antibodies is as specified herein. Unless otherwise explicitly stated, Kabat et al., Sequences of Proteins of Immunological Interest,5th E d.Public Health Service,National Institute EU Indicators of Health, Bethesda, MD. (1991) Follow DEX. Antibody constant chain numbering is, for example, ImMunoGeneTics's U On the website, in the IMGT Web Resources section of the IMGT Scientific charts... It can be found.

[0079] Substitution in the CH3 region is a modified position in the first CH3 domain of the first heavy chain. Position(s) / Modified position(s) in the second CH3 domain of the second heavy chain and It is expressed as follows. For example, F405L / K409R is F40 in the first CH3 region. This refers to the 5L mutation and the K09R mutation in the second CH3 region. L351Y_F405A_ Y407V / T394W is L351Y, F40FA, and Y in the first CH3 region. This refers to the 407V mutation and the T394W mutation in the second CH3 region. D399FHK RQ / K409AGRH may have D399 replaced by F, H, KR, or Q, K4 09 refers to a mutation in which it can be replaced by A, G, R, or H.

[0080] This specification uses the conventional one-letter and three-letter amino acid codes shown in Table 1.

[0081] [Table 1]

[0082] Combinations of anti-CD38 antibodies and T-cell redirecting therapies and their use The present invention relates to the killing of multiple myeloma cells when each of them is targeted and engaged on multiple myeloma cells. Wound-mediated therapeutic agents: JNJ-957 or GPRC5D×CD3 antibody and anti-CD38 antibody DARZALEX (registered trademark) (daratumumab) is competing for binding to MM cells. They do not antagonize each other in terms of their mechanism of action on MM cells or in terms of mutual downregulation of their targets, however This invention is at least partially based on the discovery that it is suitable for use as a combination therapy. Furthermore, previous treatment with DARZALEX (daratumumab) was found to be effective in many cases. JNJ-95 multiple myeloma cells obtained from patients with relapsed / refractory multiple myeloma who received treatment. This invention is at least partially based on the finding that it increased vector-mediated killing. ZALEX® (daratumumab) targets T cells that are non-multiple myeloma tumor cells. Cell redirection therapy increased the killing of tumor cells other than multiple myeloma cells. The discovery is at least partially based on this. Therefore, anti-CD38 antibody and T cell redirection therapy In combination with therapeutic drugs, and / or anti-CD38 antibodies before administration of T-cell redirection therapies Prior treatment for this target can improve the antitumor efficacy of monotherapy. Also, cancer is a common example. Considering that it is a heterogeneous disease in terms of type, some parts of cancer may benefit from combination therapy for deeper disease progression. It may exclusively have sufficient expression of one target versus another to aid in eradication.

[0083] CD38 has functions in receptor-mediated adhesion and signal transduction, and its e- It mediates calcium mobilization via type T enzyme activity, and cyclic ADP-ribose (cADPR) and CD38 is a multifunctional protein that catalyzes the formation of ADPR. It mediates secretion and the activation and proliferation of lymphocytes (Funaro et al., J Im munol 145:2390-6,1990;Terhorst et al.,Ce ll 771-80,1981;Guse et al.,Nature 398:70 (3,1999). CD38 also regulates through its NAD glycohydrolase activity. Extracellular NADs are thought to be involved in the regulation of sex T cell compartments. + Adjust the level (Adri ouch et al., Microbes infection14:1284-92,20 12;Chiarugi et al.,Nature Reviews 12:741 -52, 2012). Ca 2+ In addition to signal transduction via the mediated signaling pathway, CD38 signal transduction is , antigen receptor complexes or other types of receptor complexes on T and B cells (e.g., MHC molecules) This occurs through crosstalk with ), and in this way CD38 responds to several cellular responses. Furthermore, it is also involved in the switching and secretion of IgG1. In this specification, anti-CD38 antibodies DARZALEX® (daratumumab) is a T-cell redirection therapy for antitumor use. It has been identified as improving the effect. It is not constrained by any particular theory. Although it is not what we hope for, DARZALEX (registered trademark) (daratumumab) has been shown to be effective in human subjects. Immunomodulatory activity in (i.e., reducing the number of immunosuppressive Tregs, MDSCs, and Bregs) CD8 + T cell count and CD8 + Increase the ratio to Treg, CD8 + Central Me By promoting Molly cell formation and increasing the clonality of T cells, the target Even if it does not improve the immune response, it can lead to an improvement in T cell redirection therapy. It can be assumed that this can promote cell engagement.

[0084] This disclosure relates to a method for treating cancer in a subject, comprising a therapeutically effective amount of anti-CD38 antibody The present invention provides a method including administering a T-cell redirecting therapeutic agent to target cancer. do.

[0085] This disclosure also relates to a method for killing tumor cells in a subject, wherein the subject is subjected to anti-CD38 anti T cells bind to antigens on tumor cells for a sufficient amount of time to kill the body and tumor cells. The present invention also provides a method that includes administering a cytoplasmic redirecting therapeutic agent.

[0086] This disclosure also improves the efficacy of T-cell redirection therapies in patients with cancer. The present invention also provides a method that includes administering an anti-CD38 antibody to a subject.

[0087] In some embodiments, an anti-CD38 antibody is administered before the administration of a T-cell redirecting therapeutic agent. To be given.

[0088] T-cell redirection therapy is administered before the administration of anti-CD38 antibody, on days 1, 2, 3, 4, and 5. Day, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 2 months, 3 months It may be administered 4, 5, 6 months, or more prior to the treatment.

[0089] In some embodiments, T-cell redirecting therapeutics bind to antigens on tumor cells. .

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

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

[0092] In some embodiments, the T cell redirecting therapeutic agent binds to CD3 epsilon (CD3ε ).

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

[0094] In some embodiments, the T cell redirecting therapeutic agent binds to CD8, KI2L4, NKG 2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD 195, or binds to NKG2C. These antigens are specific to CD8+ T cells when compared to CD3 (see, for example, WO 2018 / 187215). + T cells (see, for example, WO 2018 / 187215). ).

[0095] In some embodiments, the T cell redirecting therapeutic agent comprises heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 33, HCDR2 of SEQ ID NO: 34, HCDR3 of SEQ ID NO: 35, light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 36, LCDR2 of SEQ ID NO: 37, and LCDR3 of SEQ ID NO: 38, heavy chain variable region (VH) of SEQ ID NO: 39 and light chain variable region (VL) of SEQ ID NO: 40, HCDR1 of SEQ ID NO: 74, HCDR2 of SEQ ID NO: 75, HCDR3 of SEQ ID NO: 76, LCDR1 of SEQ ID NO: 77, LCDR2 of SEQ ID NO: 78, and LCDR3 of SEQ ID NO: 79 , VH of SEQ ID NO: 80 and VL of SEQ ID NO: 81, , HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the CD3 binding domain of SEQ ID NO: 53, or VH and VL of the CD3 binding domain of SEQ ID NO: 53, and comprises a CD3 binding domain. In some embodiments, the T cell redirecting therapeutic agent binds to BCMA.

[0096] In some embodiments, the T cell redirecting therapeutic agent

[0097] comprises a BCMA binding domain comprising HCDR1 of SEQ ID NO: 23, HCDR2 of SEQ ID NO: 24, HCDR3 of SEQ ID NO: 25, LCDR1 of SEQ ID NO: 26, LCDR2 of SEQ ID NO: 27, and LCDR3 of SEQ ID NO: 28, and HCDR1 of SEQ ID NO: 33, HCD R2 of SEQ ID NO: 34, [[ID=​​R2, HCDR3 (sequence number 35), LCDR1 (sequence number 36), LCDR (sequence number 37) 2, and the CD3 binding domain including LCDR3 of Sequence ID No. 38, and / or BCMA binding domains including VH of SEQ ID NO: 29 and VL of SEQ ID NO: 30, and sequence It contains CD3-binding domains including VH (number 39) and VL (sequence number 40).

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

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

[0100] In some embodiments, the T cell redirecting therapeutic agent comprises any one of the BCMA binding domains described in International Publication No. 2017 / 031 104.

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

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

[0103] In some embodiments, T cell redirecting therapeutics that bind to GPRC5D are sequence HC1 with number 51, LC1 with sequence number 52, HC2 with sequence number 41, and sequence number 42 Includes LC2.

[0104] In some embodiments, T-cell redirecting therapeutics are used in Eureka Therap Contains GPRC5D antibody by eutics.

[0105] In some embodiments, T cell redirecting therapeutics are described in International Publication No. 2018 / 003 It contains one of the GPRC5D binding domains described in No. 7651.

[0106] In some embodiments, T-cell redirecting therapeutics bind to CD33.

[0107] In some embodiments, the T cell redirection therapeutic agent is HCDR1 of SEQ ID NO: 84, HCDR2 (sequence number 85), HCDR3 (sequence number 86), LCDR1 (sequence number 87), distribution CD33 binding domains including LCDR2 at column number 88 and LCDR3 at sequence number 89, Also, HCDR1 of sequence number 74, HCDR2 of sequence number 75, and HCDR of sequence number 76 3. LCDR1 of sequence number 77, LCDR2 of sequence number 78, and LCD of sequence number 79 CD3 binding domains including R3, and / or CD33 binding domains including VH of SEQ ID NO: 90 and VL of SEQ ID NO: 91, and sequence It contains CD3-binding domains including VH (number 80) and VL (sequence number 81).

[0108] In some embodiments, the T cell redirecting therapeutic agent that binds to CD33 is SEQ ID NO: HC1 of sequence number 92, LC1 of sequence number 93, HC2 of sequence number 82, and LC of sequence number 83 Includes 2.

[0109] In some embodiments, T-cell redirecting therapeutics that bind to CD33 are used by Shen CAR-T / TCR-T cell immunotherapy by zhen BinDeBio, AMG-33 0, AMV-564, JNJ-67571244, ICG-144, AMG-673, Z iopharm's CD33 CAR-T therapy INXN3004, huCD33-Bs Ab, VOR-33, HMBD-004A, GEM-333, TGB-3550, or C Includes D33.taNK

[0110] In some embodiments, T-cell redirecting therapeutics bind to CD123.

[0111] In some embodiments, T cell redirecting therapeutics are HCDR1 (sequence number 94), HCDR2 (sequence number 95), HCDR3 (sequence number 96), LCDR1 of sequence number 9, LCDR2 of sequence number 10, and LCDR3 of sequence number 59 Includes CD123 binding domain, as well as HCDR1 of SEQ ID NO: 33 and HCD of SEQ ID NO: 34 R2, HCDR3 (sequence number 35), LCDR1 (sequence number 36), LCDR (sequence number 37) 2, and the CD3 binding domain including LCDR3 of Sequence ID No. 38, and / or CD123 binding domains including VH of SEQ ID NO: 100 and VL of SEQ ID NO: 61, and It contains CD3-binding domains including VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40.

[0112] In some embodiments, T-cell redirecting therapeutics that bind to CD123 are sequence numbers HC1 of sequence number 102, LC1 of sequence number 63, HC2 of sequence number 41, and sequence number 42 Includes LC2.

[0113] In some embodiments, the T-cell redirecting therapeutic agent that binds to CD123 is the Therapy for acute myeloid leukemia with raVectys, APVO-437, Nanjing L Agend Biotech's anti-CD123 CAR-T cell therapy, APVO-43 6. CD123 CA by Hebei Senlang Biotechnology RT cell therapy, flotetuzumab, IM-23, JNJ-637091 78, MB-102, UCART-123, XmAb-1 by Mustang Bio 4045, or Sanofi's CD3-CD123 bispecific T cell engager Includes.

[0114] In some embodiments, T cell redirecting therapeutics are described in International Publication No. 2016 / 036 It contains one of the CD123 binding domains listed in No. 937.

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

[0116] In some embodiments, T cell redirecting therapeutics are CD19 binding domain of sequence number 53: HCDR1, HCDR2, HCDR3, LCD CD19 binding domains including R1, LCDR2, and LCDR3, and Sequence ID No. 53 CD3 binding domains HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and CD3 binding domains including LCDR3, and / or Contains the amino acid sequence of SEQ ID NO: 53.

[0117] In some embodiments, CD19-binding T-cell redirecting therapeutic agents are used in Axica Butagen shiroleucel, blinatumomab, tisagen leculeucel-t, AMG-562 AUTO-1 CAR by Cellular Biomedicine Group -T CD19, CD19 chimeric antigen receptor T cell therapy by Ziopharm, IOC CD19-CAR-T cell therapy by eltech Therapeutics, Mar CD19-CAR-T cell therapy by ino Biotechnology, Guang CD19-CAR-T2 cell therapy by dong Zhaotai InVivo, Ju CD19 / 4-1BBL-armed CAR T-cell therapy by no Therapeutics Law, CSG-CD19, DI-B4, ET-190, GC-007F, GC-022, H Human CD19 T-cell therapy by RAIN Biotechnology, Kite P Humanized anti-CD19 controlled CAR (3rd generation) by harma, Immune Cell ICAR-19 CAR-T cells, ICTCAR-003, Mar iPD1 CD19 eCAR T cells by ino Biotechnology, J WCAR029, PTG-01, PZ01, Senl_1904A, Senl_1904 B, UCART-19, UWC-19, AUTO-3, BinD-19, Shanghai i Unicar-Therapy Biomed's CAR-T cell therapy, Shen CAR-T / TCR-T cell immunotherapy by zhen BinDeBio, Milten CD-19 CAR-T cell therapy by yi Biotec, Shanghai University CD19 CAR-T cells by car-Therapy Biomed, Takara CD19-CAR T cell therapy by Bio, Shanghai Bioray La CD19-CART by boratory, CD19 target by Sinobioway Chimeric antigen receptor T cells, Shanghai Longyao Biotechnol CD19 / CD20 CAR-T cell therapy by ogy, CIK-CAR.CD19, I CTCAR-011, IM-19, JCAR-014, roncastuximabutecilin, M B-CART2019.1, OXS-1550, PBCAR-0191, PCAR-01 9, PCAR-119, Senl-001, TI-1007, XmAb-5871, rice Vilizumab, lisocabtagene maraleucel, XmAb- 5574, Eden BioCell's 3rd generation CD19-CART cells + mbIL 15, A-329, ALLO-501, Beijing Doing Biomedic Al Co-mediated anti-CD19 anti-CD20 bispecific CAR redirection autologous T cells, Al Anti-CD19 CAR NK cell therapy by life Medical Science, Anti-CD19 / BCMA CAR-T cells developed by Hrain Biotechnology Therapy, ATA-2431, ATA-3219.AVA-008.Celularity CD19 CAR-T cell therapy by Ziopharm, CD19 chimeric antigen receptor Third-generation T-cell therapy, CD19 dBiTE by Inovio, by Bellicum CD19 TCR cell therapy, CD19-ATAC by Wilex, Chineo M CD19 / 20 CAR-T therapy by ed(Beijing), Eureka The CD19 / CD22 dual-target therapy with rapeutics, Helix BioPha RMA-mediated chimeric antigen receptor T cell (CAR-T) therapy, CMD-502, CTX-1 10, CYAD-04, CYAD-221, ET-019002, FT-596, FT- 819, Gamma-delta CAR-T therapy by TC Biopharm, ICTCAR- 014, iDD-002, KITE-037, NI-2201, RB-1916, Sen l_002, TAC01-CD19, TC-110, TC-310, TCB-003, or This includes TI-7007.

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

[0119] In some embodiments, T cell redirecting therapeutics are HCDR1 (sequence number 54), HCDR2 (sequence number 55), HCDR3 (sequence number 56), LCDR1 of sequence number 9, LCDR2 of sequence number 10, and LCDR3 of sequence number 59 Includes PSMA-binding domain, as well as HCDR1 of SEQ ID NO: 33 and HCDR of SEQ ID NO: 34 2. HCDR3 (sequence number 35), LCDR1 (sequence number 36), LCDR2 (sequence number 37) , and the CD3 binding domain including LCDR3 of SEQ ID NO: 38, and / or PSMA-binding domains including VH of SEQ ID NO: 60 and VL of SEQ ID NO: 61, and sequence It contains CD3-binding domains including VH (number 39) and VL (sequence number 40).

[0120] In some embodiments, the T-cell redirecting therapeutic agent that binds to PSMA is SEQ ID NO: HC1 of sequence number 62, LC1 of sequence number 63, HC2 of sequence number 41, and LC of sequence number 42 Includes 2.

[0121] In some embodiments, T cell redirecting therapeutics bind to TMEFF2.

[0122] In some embodiments, T cell redirecting therapeutics are HCDR1 (sequence number 64), HCDR2 (sequence number 65), HCDR3 (sequence number 66), LCDR1 of sequence number 67, LCDR2 of sequence number 68, and LCDR3 of sequence number 69 The TMEFF2 binding domain, as well as HCDR1 of SEQ ID NO: 74, and H of SEQ ID NO: 75 CDR2, HCDR3 (sequence number 76), LCDR1 (sequence number 77), LC (sequence number 78) CD3 binding domains including DR2 and LCDR3 of SEQ ID NO: 79, and / or The TMEFF2 binding domains include VH of SEQ ID NO: 70 and VL of SEQ ID NO: 71, and It contains CD3-binding domains including VH of SEQ ID NO: 80 and VL of SEQ ID NO: 81.

[0123] In some embodiments, T cell redirecting therapeutics that bind to TMEFF2 are sequence HC1 number 72, LC1 number 73, HC2 number 82, and number 83 Includes LC2.

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

[0125] In some embodiments, T-cell redirecting therapeutics bind to CD22.

[0126] In some embodiments, T-cell redirecting therapeutics bind to CD25.

[0127] In some embodiments, T-cell redirecting therapeutics bind to CD52.

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

[0129] In some embodiments, T-cell redirecting therapeutics bind to HM1.24.

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

[0131] In some embodiments, the T-cell redirecting therapeutic agent is a multispecific antibody, a chimeric antigen. These are receptors (CARs) or T cells containing CARs.

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

[0133] In some embodiments, T cell redirecting therapeutics are T cells that express CARs. ru.

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

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

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

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

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

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

[0140] The multispecific antibody may be of any allotype. The allotype is conjugation or It is expected that this will not affect the properties of multispecific antibodies, such as Fc-mediated effector function. The immunogenicity of therapeutic antibodies is associated with an increased risk of infusion reactions and a shortened duration of the 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 is determined by the antibody's allotype. It can be partially determined by (Stickler et al., (2011) Ge NES and Immunity 12:213-21). Antibody allotypes are antibodies This relates to mutations in the amino acid sequence at specific positions within the constant region sequence. Table 2 shows the selected Ig G1, IgG2, and IgG4 allotypes are shown.

[0141] [Table 2]

[0142] In some embodiments, the multispecific antibody is the Fcγ receptor of the multispecific antibody (Fcγ The multispecific antibody contains one or more Fc substitutions that reduce binding to R). Substitutions that reduce binding to the multispecific antibodies ADCC, ADCP, and / or CDC are used. Reduces the function of any Fc effector. Specific substitutions include wild-type IgG1 (SEQ ID NO: 103). Alternatively, it can be performed by comparing it with wild-type IgG4 of sequence number 104.

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

[0144] In some embodiments, one or more Fc substitutions are F234A / on IgG4. It's L235A.

[0145] In some embodiments, one or more Fc substitutions are performed on IgG1, specifically L234A / It's L235A.

[0146] In some embodiments, one or more Fc substitutions are performed on IgG2, specifically V234A / These are the G237A / P238S / H268A / V309L / A330S / P331S models.

[0147] In some embodiments, one or more Fc substitutions are F234A / on IgG4. It's L235A.

[0148] In some embodiments, one or more Fc substitutions are performed on IgG4 with S228P / This is the F234A / L235A.

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

[0150] In some embodiments, one or more Fc substitutions are performed on IgG2, specifically V234A / It's a G237A.

[0151] In some embodiments, one or more Fc substitutions are performed on IgG1, such as K214T / E233P / L234V / L235A / G236 (missing) / A327G / P331A / D36 It is 5E / L358M.

[0152] In some embodiments, one or more Fc substitutions are performed on IgG2 with H268Q / The models are V309L / A330S / P331S.

[0153] In some embodiments, one or more Fc substitutions are performed on IgG1, such as S267E / It is L328F. In some embodiments, one or more Fc substitutions are IgG1 These are the L234F / L235E / D265A models shown above.

[0154] In some embodiments, one or more Fc substitutions are performed on IgG1, specifically L234A / These are L235A / G237A / P238S / H268A / A330S / P331S.

[0155] In some embodiments, one or more Fc substitutions are performed on IgG4 with S228P / F234A / L235A / G237A / P238S and S228P / F23 on IgG4 The values ​​are 4A / L235A / G236 (missing) / G237A / P238S.

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

[0157] In some embodiments, the multispecific antibody has a first CH3 domain or a second C In the H3 domain, or in both the first CH3 domain and the second CH3 domain, one or This includes two or more asymmetrical substitutions.

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

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

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

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

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

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

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

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

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

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

[0168] In some embodiments, one or more asymmetric substitutions are performed in T366W / T366S It is _L368A_Y407V.

[0169] In some embodiments, one or more asymmetric substitutions are performed in L351Y_F405A It is _Y407V / T394W.

[0170] In some embodiments, one or more asymmetric substitutions are performed as T366I_K392M It is _T394W / F405A_Y407V.

[0171] In some embodiments, one or more asymmetric substitutions are performed by T366L_K392M It is _T394W / F405A_Y407V.

[0172] In some embodiments, one or more asymmetric substitutions are performed in L351Y_Y407A It is / T366A_K409F.

[0173] In some embodiments, one or more asymmetric substitutions are performed in L351Y_Y407A It is / T366V_K409F.

[0174] In some embodiments, one or more asymmetric substitutions are performed in Y407A / T366A It is _K409F.

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

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

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

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

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

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

[0181] In some embodiments, multiple myeloma is high-risk multiple myeloma. Patients with myeloma are known to experience early relapses and have a poor prognosis and outcome. The target group includes individuals who may be classified as having high-risk multiple myeloma and who exhibit the following cytogenetic abnormalities. :t(4;14)(p16;q32), t(14;16)(q32;q23), del1 7p, 1qAmp, t(4;14)(p16;q32) and t(14;16)(q32; q23), t(4;14)(p16;q32) and del17p, t(14;16)(q 32;q23) and del17p, or t(4;14)(p16;q32), t(14; 16)(q32;q23), and del17p, having one or more of these. ru.

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

[0183] Various qualitative and / or quantitative methods are used to determine the recurrence or refractory nature of the disease. Related symptoms may include, for example, a decline or plateau in the patient's health, and solid The restoration or worsening of various symptoms associated with the tumor, and / or the transfer of tumors from one location to other organs, clusters. This refers to the spread of cancerous cells within the body to tissues or cells.

[0184] Cytogenetic abnormalities can be detected, for example, through fluorescence in situ hybridization (fluorescein It can be detected by in situ hybridization (FISH). Both chromosomal translocations are The oncogenes are translocated to the IgH region on chromosome 14q32, disrupting the regulation of these genes. The whole is brought about. t(4;14)(p16;q32) is fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain-containing protein (MMSET) (also known as, With the translocation of WHSC1 / NSD2, t(14;16)(q32;q23) is MAF This involves a translocation of the transcription factor C-MAF. 17p deletion (del17p) is a loss of the p53 locus. It involves loss.

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

[0186] In some embodiments, multiple myeloma relapses or It is refractory. In some embodiments, multiple myeloma is treated with lenalidomide. In contrast, it is relapsed or refractory. In some embodiments, multiple myeloma is treated with bortezomib It is relapsed or refractory to treatment with [the specified method]. In some embodiments, multiple myeloma is The condition is relapsed or refractory to treatment with pomalidomide. In some embodiments, multiple cases occur. Sexual myeloma is relapsed or refractory to treatment with carfilzomib. In terms of treatment patterns, multiple myeloma is relapsed or refractory to treatment with erotozumab. In some embodiments, multiple myeloma relapses or is resistant to treatment with ixazomib. It is curable. In some embodiments, multiple myeloma is treated with melphalan. It is recurrent or refractory. In some embodiments, multiple myeloma is treated with thalidomide. The condition is recurrent or refractory to treatment.

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

[0188] In some embodiments, AML is AML with at least one genetic abnormality, polymorphism AML with columnar dysplasia, therapy-associated AML, undifferentiated AML, most undifferentiated AML, differentiated AM L, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythrocytic leukemia, acute megakaryoblastic leukemia It is a hematological disease, acute basophilic leukemia, acute panmyelopathy with fibrosis, or myelosarcoma.

[0189] In some embodiments, AML is AML with at least one genetic abnormality. In some embodiments, AML is AML with polysequence dysplasia. In the context of administration, AML is therapy-related AML. In some embodiments, AML is not It is differentiated AML. In some embodiments, AML is the least differentiated AML. In some embodiments, AML is differentiated AML. In some embodiments, AM L is acute myelomonocytic leukemia. In some embodiments, AML is acute myelomonocytic leukemia. It is a blood disease. In some embodiments, AML is acute erythrocytic leukemia. In some embodiments, AML is acute megakaryoblastic leukemia. In some embodiments, A ML is acute basophilic leukemia. In some embodiments, AML is accompanied by fibrosis. It is acute panmyelopathy. In some embodiments, AML is myelosarcoma.

[0190] In some embodiments, at least one gene abnormality occurs on chromosomes 8 and 21. Translocation between chromosome 15 and chromosome 17, translocation or inversion of chromosome 16, between chromosome 15 and chromosome 17 Translocation, alteration of chromosome 11, or FMS-related tyrosine kinase 3 (FMS-related tyrosine kinase 3) kinase 3 (FLT3), nucleophosmin (NPM1), isocitane Acid dehydrogenase 1 (IDH1), isocitrate dehydrogenase Isocitrate dehydrogenase 2 (IDH2), DNA (cytosine-5)-methyl Chilltransferase 3 (DNA(cytosine-5)-methyltransferase 3, DNMT3A), CCAAT / enhancer binding protein a lpha, CEBPA), U2 small nuclear RNA auxiliary factor 1 (U2 small nuclear RNA auxiliary ry factor 1, U2AF1), zeste2 Polycomb inhibitory complex 2 subunit enhancement enhancer (enhancer of zeste 2 polycomb repressive complex 2 subunit, EZH2), Chromosome structure maintenance 1A (SMC1A), if In chromosome structure maintenance 3 (SMC3), This is a mutation.

[0191] In some embodiments, at least one gene abnormality occurs on chromosomes 8 and 21. This is a translocation between . In some embodiments, at least one gene abnormality is 16 This is a chromosomal translocation or inversion. In some embodiments, at least one gene abnormality is , a translocation between chromosome 15 and chromosome 17. In some embodiments, at least Another genetic abnormality is a change in chromosome 11. In some embodiments, at least Another genetic abnormality is a mutation in fms-related tyrosine kinase 3 (FLT3). In several embodiments, at least one gene abnormality is associated with nucleophosmin (NPM1). This is a mutation of isocitrate. In some embodiments, at least one gene abnormality is isocitrate This is a mutation in dehydrogenase 1 (IDH1). In some embodiments, at least 1 One of the gene abnormalities is a mutation in isocitrate dehydrogenase 2 (IDH2). In that embodiment, at least one gene abnormality is DNA(cytosine-5)-methyl This is a mutation in lanceferase 3 (DNMT3A). In some embodiments, at least Another gene abnormality is CCAAT / enhancer-binding protein alpha (CEBPA This is a mutation in ). In some embodiments, at least one gene abnormality is associated with low U2 nuclear density. This is a mutation in molecular RNA cofactor 1 (U2AF1). In some embodiments, at least Another gene abnormality is the zeste2 polycomb repression complex 2 subunit enhancer. This is a mutation in (EZH2). In some embodiments, at least one gene abnormality is This is a mutation in chromosome structure maintenance 1A (SMC1A). In some embodiments, at least One gene abnormality is a mutation in chromosome structure maintenance 3 (SMC3).

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

[0193] In some embodiments, at least one gene abnormality is translocation t(8;21)(q2 2;q22) In some embodiments, at least one gene abnormality is inverse i nv(16)(p13;q22). In some embodiments, at least one legacy The genetic anomaly is the translocation t(16;16)(p13;q22). In some embodiments, At least one gene abnormality is the translocation t(15;17)(q22;q12). In some embodiments, at least one gene abnormality is a mutation in FLT3-ITD. In some embodiments, at least one gene abnormality is R132 in IDH1. This is a mutation in H. In some embodiments, at least one gene abnormality is present in IDH1. These are mutations in R100Q / R104V / F108L / R119Q / I130V. In some embodiments, at least one gene abnormality is R140Q in IDH2 It is a mutation. In some embodiments, at least one gene abnormality is present in IDH2. This is a mutation of R172.

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

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

[0196] In some embodiments, ALL is B-cell lineage ALL. In some embodiments, ALL is T-cell lineage ALL. L is the case. In some embodiments, ALL is pediatric ALL.

[0197] In some embodiments, subjects having ALL have the Philadelphia chromosome. , or resistant to treatment with BCR-ABL kinase inhibitors or It possesses acquired resistance.

[0198] In some embodiments, subjects having ALL have the Philadelphia chromosome. In some embodiments, subjects having ALL are treated with BCR-ABL kinase inhibitors. They are resistant to treatment, or have acquired resistance to it.

[0199] The Ph chromosome is present in approximately 20% of adults with ALL and a small percentage of children with ALL. It exists and is associated with a poor prognosis. In patients with Ph+ positive ALL, tyrosine is present at the time of relapse. This can occur in kinase inhibitor (TKI) regimens, and therefore resistance to TKIs may develop. This can occur. Therefore, anti-CD38 antibodies are selective or partially selective BCR- It can also be administered to patients who have developed resistance to ABL inhibitors. An example of a BCR-ABL inhibitor is a BCR-ABL inhibitor. For example, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafeti These are nib, salakatinib, tozacertiveb, or danucertiveb.

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

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

[0202] Chromosome rearrangement is performed using well-known methods, such as fluorescence in situ hybridization, and nuclear They can be identified using type analysis, pulsed-field gel electrophoresis, or sequencing. .

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

[0204] In some embodiments, hematological malignancies are MGUS.

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

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

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

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

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

[0210] In some embodiments, hematological malignancies are characterized by Waldenström's hypergammaglobulinemia. It is a disease.

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

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

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

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

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

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

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

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

[0219] In some embodiments, hematological malignancies are HCLs.

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

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

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

[0223] In some embodiments, hematological malignancies are MZLs.

[0224] In some embodiments, hematological malignancies are MALTs.

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

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

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

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

[0229] In some embodiments, solid tumors include prostate cancer, lung cancer, and non-small cell lung cancer. ll lung cancer, NSCLC), liver cancer, cervical cancer, colon cancer, breast cancer, ovarian cancer, endometrial cancer, Pancreatic cancer, melanoma, esophageal cancer, gastric cancer, stomach cancer, kidney cancer, bladder Cancer, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, head and neck cancer, glioma, glioblastoma, colorectal cancer, It is thyroid cancer, epithelial carcinoma, adenocarcinoma, or an advanced solid tumor.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0256] In some embodiments, the solid tumor is a progressive solid tumor.

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

[0258] In some embodiments, the prostate cancer is recurrent prostate cancer. In some embodiments, prostate cancer is a refractory prostate cancer. It is prostate cancer. In some embodiments, the prostate cancer is castration-resistant prostate cancer.

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

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

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

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

[0263] Other anti-CD38 antibodies used in the method of the present invention are V of SEQ ID NOs. 14 and 15, respectively. Includes H sequence and VL sequence, such as mAb003 described in U.S. Patent No. 7,829,673. It may be a known antibody. VH and VL of mAb003 are expressed as IgG1 / κ. It may be; as described in U.S. Patent No. 7,829,673, Sequence ID Nos. 16 and 1, respectively. mAb024 containing the VH and VL sequences of 7. The VH and VL of mAb024 are IgG It can be expressed as 1 / κ; as described in U.S. Patent No. 8,088,896, each is distributed MOR-202 (MOR-03087) containing the VH and VL sequences in column numbers 18 and 19. ). (VH and VL of MOR-202 can be expressed as IgG1 / κ); or Isa Tuximab; as described in U.S. Patent No. 8,153,765, SEQ ID NOs. 20 and 20 respectively. It contains 21 VH and VL sequences. The VH and VL of isatuximab are IgG1 / κ and It can be expressed as follows.

[0264] Sequence ID 4 (Daratumumab VH) EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQ APGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVT VSS

[0265] Sequence ID 5 (Daratumumab VL) EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQK PGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLE PEDFAVYYCQQRSNWPPTFGQGTKVEIK

[0266] Sequence ID 6 (Daratumumab HCDR1) SFAMS

[0267] Sequence ID 7 (Daratumumab HCDR2) AISGSGGGTYYADSVKG

[0268] Sequence ID 8 (Daratumumab HCDR3) DKILWFGEPVFDY

[0269] Sequence ID 9 (Daratumumab LCDR1) RASQSVSSYLA

[0270] Sequence ID 10 (Daratumumab LCDR2) DASNRAT

[0271] Sequence ID 11 (Daratumumab LCDR3) QQRSNWPPTF

[0272] Sequence ID 12 (Daratumumab HC) EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQ APGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEL LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPS REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK

[0273] Sequence ID 13 (Daratumumab LC) EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQK PGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLE PEDFAVYYCQQRSNWPPTFGQGTKVEIKRTVAAPSVFIFP PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC

[0274] Sequence ID 14 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAFSWVRQ APGQGLEWMGRVIPFLGIANSAQKFQGRVTITADKSTSTA YMDLSSLRSEDTAVYYCARDDIAALGPFDYWGQGTLVTVS SAS

[0275] Sequence ID 15 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQK PEKAPKSLIYAASSLQSGVPSRFSGSGGSGTDFTLTISSLQ PEDFATYYCQQYNSYPRTFGQGTKVEIK

[0276] Sequence ID 16 EVQLVQSGAEVKKPGESLKISCKGSGYSFSNYWIGWVRQ MPGKGLEWMGIIYPHSDARYSPSFQGQVTFSADKSISTA YLQWSSLKASDTAMYYCARHVGWGSRYWYFDLWGRGTLVT VSS

[0277] Sequence ID 17 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQK PGQAPGLLIYDASNRASGIPARFSGSGSGTDFTLTISSLE PEDFAVYYCQQRSNWPLTFGGGTKVEIK

[0278] Sequence ID 18 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQ APGKGLEWVSGISGDPSNTYYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCARDLPLVYTGFAYWGQGTLVTVS S

[0279] Sequence ID 19 DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYWYQQKP GQAPVLVIYGDSKRPSGIPERFSGSNSGNTATLTISGTQA EDEADYYCQTYTGGASLVFGGGGTKLTVLGQ

[0280] Sequence ID 20 QVQLVQSGAEVAKPGTSVKLSCKASGYTFTDYWMQWVKQ RPGQGLEWIGTIYPGDGDTGYAQKFQGKATLTADKSSKTV YMHLSSLASEDSAVYYCARGDYYGSNSLDYWGQGTSVTVS S

[0281] Sequence ID 21 DIVMTQSHLSMSSTSLGDPVSITCKASQDVSTVVAWYQQK PGQSPRRLIYSASYRYIGVPDRFTGSGAGTDFTFTISSVQ AEDLAVYYCQQHYSPPYTFGGGTKLEIK

[0282] In some embodiments, the anti-CD38 antibody is used. VH of sequence number 14 and VL of sequence number 15, VH of sequence number 16 and VL of sequence number 17, VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or Includes VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

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

[0284] In some embodiments, T cell redirecting therapeutics are BCMA×CD3 bispecific. Antibody, GPRC5D×CD3 bispecific antibody, CD33×CD3 bispecific antibody, CD1 9×CD3 bispecific antibody, CD123×CD3 bispecific antibody, PSMA×CD3 bispecific antibody It is a specific antibody, or a TMEFF2 × CD3 bispecific antibody.

[0285] In some embodiments, T cell redirecting therapeutics are BCMA×CD3 bispecific. It is an antibody.

[0286] In some embodiments, the T cell redirection therapeutic agent is GPRC5D×CD3 dual-type These are heterozygous antibodies.

[0287] In some embodiments, T cell redirecting therapeutics are CD33×CD3 bispecific. It is an antibody, In some embodiments, T cell redirecting therapeutics are CD19×CD3 bispecific. It is an antibody.

[0288] In some embodiments, T cell redirecting therapeutics are CD123×CD3 bispecific It is a sex antibody.

[0289] In some embodiments, T cell redirecting therapeutics are PSMA×CD3 bispecific. It is an antibody.

[0290] In some embodiments, T cell redirecting therapeutics are TMEFF2×CD3 dual-type These are heterozygous antibodies.

[0291] In some embodiments, this method involves administering one or more anti-cancer treatments to the subject. It also includes.

[0292] In some embodiments, one or more anti-cancer treatments include autologous stem cell transplantation. US stem cell transplant (ASCT), radiation, surgery, chemotherapy agents, immunomodulatory agents, and The treatment is selected from a group consisting of targeted cancer therapies.

[0293] In some embodiments, one or more anti-cancer treatments include autologous stem cell transplantation (ASCT). ) In some embodiments, one or more anti-cancer treatments are radiation. In some embodiments, one or more anti-cancer treatments are surgeries. In this configuration, one or more anti-cancer treatments are chemotherapeutic agents. In some embodiments, One or more anticancer treatments are immunomodulators. In some embodiments, one or Two or more anti-cancer treatments constitute targeted cancer therapy.

[0294] In some embodiments, one or more anticancer treatments include lenalidomide, thalidomide, and lenalidomide. Do, pomalidomide, bortezomib, carfilzomib, erotozumab, ixazomib, me Ruphalan, Dexamethasone, Vincristine, Cyclophosphamide, Hydroxydauno Rubicin, prednisone, rituximab, imatinib, dasatinib, nilotinib, vostinib Nib, ponatinib, bafetinib, salakatinib, tozacertib, or danucertib Cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, Decitabine, Cladribine, Fludarabine, Topotecan, Etoposide 6-thioguanine, Corticosteroids, methotrexate, 6-mercaptopurine, azacitidine, trioxide Select from the group consisting of arsenic and all-trans retinoic acid, or any combination thereof. It will be selected.

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

[0296] In some embodiments, the anti-CD38 antibody is mixed with approximately 25 mM acetate and approximately 60 mM sodium chloride. Thorium, approximately 140 mannitol, and approximately 0.04% w / v polysorbate-20 (po Approximately 20 mg / mL to approximately 120 mg / mL of anti-CD38 anti-CD38 in lysorbate-20 (PS-20) A pharmaceutical composition containing a body and having a pH of approximately 5.5, which is administered or prepared for administration. To be served.

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

[0298] In some embodiments, the anti-CD38 antibody is approximately 120 mg / mL of anti-CD38 antibody and It is administered in a pharmaceutical composition containing approximately 2,000 U / mL of rHuPH20, or Provided for administration.

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

[0300] In some embodiments, the anti-CD38 antibody is used. Approximately 1,800 mg of anti-CD38 antibody, Approximately 30,000U of rHuPH20, Approximately 10 mM histidine, Approximately 300 mM sorbitol and PS-20 with approximately 0.04% (w / v), A pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6 is administered. It is either used or provided for administration.

[0301] In some embodiments, the anti-CD38 antibody is used. Approximately 120 mg / mL of anti-CD38 antibody, rHuPH20 at approximately 2,000 U / mL, Approximately 10 mM histidine, Approximately 300 mM sorbitol and PS-20 with approximately 0.04% (w / v), A pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6 is administered. It is either used or provided for administration.

[0302] Combination of anti-CD38 antibody and BCMA x CD3 bispecific antibody This disclosure also relates to a method for treating cancer in a subject, wherein the amount of BCMA effective for treatment is multiplied by This includes administering CD3 bispecific antibodies and anti-CD38 antibodies to target cancer. We will also provide the method.

[0303] This disclosure also relates to a method for treating cancer in a subject, wherein the amount of BCMA effective for treatment is multiplied by The treatment of cancer involves administering a CD3 bispecific antibody to the target, and the target is BCMA× We also provide a method in which treatment with an anti-CD38 antibody precedes the administration of a CD3 bispecific antibody.

[0304] This disclosure also relates to a method for treating cancer in a subject, wherein the amount of BCMA effective for treatment is multiplied by The treatment of cancer involves administering a CD3 bispecific antibody to the target, and the target is a previously anti-cancer agent. We also provide methods for treating relapsed or refractory cases that have not responded to drug therapy.

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

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

[0307] B-cell maturation antigen (BCMA) is a factor in the interaction of B cells with plasma cells. It is a member of the cell membrane-bound tumor necrosis factor receptor family involved in differentiation. Currently, it is limited to the B cell lineage, and in that lineage, it is mainly within the intrafollicular region of the germinal center, and It is expressed on differentiated plasma cells and plasmablasts. BCMA is expressed on naive and memory B cells. It is virtually absent on the cell (Tai and Anderson, Immunothe (rapy 7:1187-99, 2015).

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

[0309] In some embodiments, cancer is multiple myeloma, smoldering multiple myeloma, benign monochloromyeloma. B-cell γ-globulinemia (MGUS), B-cell acute lymphoblastic leukemia, diffuse large cell leukemia B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, mantle cell lymphoma, WALK Densestrome hypergammaglobulinemia, plasma cell leukemia, light chain amyloidosis, or This is non-Hodgkin lymphoma. An experienced physician will make the cancer diagnosis.

[0310] In some embodiments, the target is an anti-CD38 antibody or lenalidomide, or these The condition is relapsed or refractory to treatment with this combination.

[0311] In some embodiments, the subjects are patients who have relapsed or refractory to treatment with anti-CD38 antibodies. In some embodiments, the subject is a patient who has relapsed or has difficulty responding to treatment with lenalidomide. It is curable.

[0312] In some embodiments, the subject is used to treat multiple myeloma or other hematological malignancies. For patients whose cancer has relapsed or is refractory to treatment with previous anticancer drugs, such as the drugs used in this treatment. .

[0313] In some embodiments, the subject is THALOMID® (thalidomide), REVLIMID (registered trademark) (Lenalidomide), POMALYST (registered trademark) (Poma Lidomide, VELCADE (registered trademark) (bortezomib), NINLARO (Ixazol) MIB), KYPROLIS (registered trademark) (calfilzomib), FARADYK (registered trademark) (Panonostat), AREDIA (registered trademark) (Pamidronate), ZOMETA (Registered Trademark) (Zoledronic Acid), DARZALEX (Registered Trademark) (Daratumumab), Ero The condition is refractory or relapsed to treatment with tozumab or melphalan.

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

[0315] In some embodiments, the BCMA×CD3 bispecific antibody and the anti-CD38 antibody are anti These are proto-binding fragments. Exemplary antigen-binding fragments are Fab, F(ab')2, Fd, and Fv. It is a fragment.

[0316] In some embodiments, the BCMA×CD3 bispecific antibody is chimeric, humanized, or They are human.

[0317] In some embodiments, the BCMA×CD3 bispecific antibody is IgG1, IgG2, It is either an IgG3 or IgG4 isotype.

[0318] In some embodiments, the BCMA×CD3 bispecific antibody is IgG4 isotype That is the case.

[0319] In some embodiments, the BCMA×CD3 bispecific antibody is used in HCD of SEQ ID NO: 23. R1, HCDR2 (sequence number 24), HCDR3 (sequence number 25), LCDR (sequence number 26) 1. BCMA-conjugated domains including LCDR2 of SEQ ID NO: 27 and LCDR3 of SEQ ID NO: 28 In, as well as HCDR1 of sequence number 33, HCDR2 of sequence number 34, and H of sequence number 35. CDR3, LCDR1 of sequence number 36, LCDR2 of sequence number 37, and sequence number 38 Includes a CD3 binding domain containing LCDR3.

[0320] In some embodiments, the BCMA-binding domain is VH of SEQ ID NO: 29 and SEQ ID NO: It contains 30 VLs, and the CD3 binding domains are VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40 Includes.

[0321] In some embodiments, the BCMA×CD3 bispecific antibody is IgG4 isotype The first heavy chain (HC1) has phenylalanine at position 405 and arginine at position 409. Furthermore, the second heavy chain (HC2) contains leucine at position 405 and lysine at position 409, The numbering follows the EU index.

[0322] In some embodiments, the BCMA×CD3 bispecific antibody is used for both HC1 and HC2. It contains proline at position 228, alanine at position 234, and alanine again at position 235.

[0323] In some embodiments, the BCMA×CD3 bispecific antibody is used for HC1 of SEQ ID NO: 31. , the first light chain (LC1) of SEQ ID NO: 32, HC2 of SEQ ID NO: 41, and the first light chain of SEQ ID NO: 42 It contains two light chains (LC2).

[0324] In some embodiments, the BCMA×CD3 bispecific antibody is BI836909, P It is F-06863135, AMG-701, or CC-93269.

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

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

[0327] In some embodiments, the anti-CD38 antibody is the heavy chain (HC) and sequence number of SEQ ID NO. 12. Includes light chain (LC) No. 13.

[0328] In some embodiments, the anti-CD38 antibody is DARZALEX® (Dartz). It is a mumabu.

[0329] In some embodiments, the anti-CD38 antibody is used. VH of sequence number 14 and VL of sequence number 15, VH of sequence number 16 and VL of sequence number 17, VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or Includes VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

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

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

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

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

[0334] In some embodiments, the BCMA×CD3 bispecific antibody and the anti-CD38 antibody are statically It is administered by intravenous injection.

[0335] In some embodiments, BCMA × CD3 bispecific antibodies are administered by intravenous injection. The anti-CD38 antibody is administered by subcutaneous injection.

[0336] In some embodiments, a BCMA×CD3 bispecific antibody and an anti-CD38 antibody are used in the skin. It is administered by injection.

[0337] In some embodiments, this method involves administering one or more anti-cancer treatments to the subject. It also includes.

[0338] In some embodiments, one or more anti-cancer treatments include autologous stem cell transplantation (ASCT). ), selected from a group consisting of radiation, surgery, chemotherapy agents, immunomodulatory agents, and targeted cancer therapies. ru.

[0339] In some embodiments, one or more anticancer treatments include lenalidomide, thalidomide, and lenalidomide. Do, pomalidomide, bortezomib, carfilzomib, erotozumab, ixazomib, me Ruphalan, prednisone, or dexamethasone, or any combination thereof. Selected from the following group.

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

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

[0342] In some embodiments, the anti-CD38 antibody is approximately 120 mg / mL of anti-CD38 antibody and It is administered in a pharmaceutical composition containing approximately 2,000 U / mL of rHuPH20, or Provided for administration.

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

[0344] In some embodiments, the anti-CD38 antibody is used. Approximately 1,800 mg of anti-CD38 antibody, Approximately 30,000U of rHuPH20, Approximately 10 mM histidine, Approximately 300 mM sorbitol and PS-20 with approximately 0.04% (w / v), A pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6 is administered. It is either used or provided for administration.

[0345] In some embodiments, the anti-CD38 antibody is used. Approximately 120 mg / mL of anti-CD38 antibody, rHuPH20 at approximately 2,000 U / mL, Approximately 10 mM histidine, Approximately 300 mM sorbitol and PS-20 with approximately 0.04% (w / v), A pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6 is administered. It is either used or provided for administration.

[0346] BCMA x CD3 bispecific antibody administered to subjects with cancer such as multiple myeloma, and The dose of anti-CD38 antibody should alleviate the disease being treated, or at least partially alleviate it. Sufficient to block ("therapeutic dose"), approximately 0.005 mg to approximately 100 mg / kJ g, for example, approximately 0.05 mg to approximately 30 mg / kg or approximately 5 mg to approximately 25 mg / kg, Or approximately 4 mg / kg, approximately 8 mg / kg, approximately 16 mg / kg, or approximately 24 mg / kg Contains antibodies. Preferred doses include, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 1 0, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40 Examples include 50, 60, 70, 80, 90, or 100 mg / kg.

[0347] Fixed unit doses of BCMA x CD3 bispecific antibody and / or anti-CD38 antibody, for example, In some cases, 50, 100, 200, 500, or 1000 mg may be administered, or The dosage is determined based on the patient's surface area, for example, 500, 400, 300, 250, 200 , or 100 mg / m² 2 It is possible. Usually used to treat cancers such as multiple myeloma. A dose between 1 and 8 times (for example, 1, 2, 3, 4, 5, 6, 7, or 8 times) may be administered. However, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times, or In some cases, a higher dose may be administered.

[0348] Administration of BCMA x CD3 bispecific antibody and / or anti-CD38 antibody is on days 1, 2, and 3. Day, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 2 Treatment course may be repeated after months, 3 months, 4 months, 5 months, 6 months, or more. This can be repeated, and long-term administration is also possible. Repeated administration should be at the same dose. Even if the dosage is different, for example, BCMA × CD3 bispecific antibody and anti CD38 antibody is administered intravenously at a dose of 8 mg / kg or 16 mg / kg at one-week intervals. It is administered over a week, and then further doses of 8 mg / kg or 16 mg / kg every two weeks. The drug is administered over a 6-week period, followed by administration at 8 mg / kg or 16 mg / kg every 4 weeks. It is possible.

[0349] BCMA x CD3 bispecific antibody and anti-CD38 antibody are used for, for example, 6 months or longer. It can be administered as maintenance therapy, such as once a week, over a period of time. For example, BCMA×CD 3. Bispecific antibodies and anti-CD38 antibodies are administered as single doses every 24, 12, 8, 6, 4, or 2 hours. Use a single dose, divided dose, or a combination thereof, approximately 0.1 mg / For example, a daily dose of approximately 100 mg / kg, such as 0.5 or 0.9 per day. , 1.0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg / In kg, after the start of treatment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 2 7, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or On at least one day out of the 40 days, or on days 1, 2, 3, 4, 5, 6, 7, 8, 9, Among weeks 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 They may be offered at least once a week, or in combination of these.

[0350] BCMA x CD3 bispecific antibodies and anti-CD38 antibodies also treat cancers such as multiple myeloma. To reduce the risk of developing the disease, delay the onset of events in cancer progression, and / or It may be administered prophylactically to reduce the risk of recurrence when cancer goes into remission.

[0351] In some embodiments, a BCMA × CD3 bispecific antibody is used against an anti-CD38 antibody. It is administered to the subject after the administration of [another substance]. The BCMA x CD3 bispecific antibody is an anti-CD38 antibody. After administration, at 1 week, 2 weeks, 3 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 2 months, and 3 months. It may be administered after 4 months, 5 months, 6 months, or more. In some embodiments, Subjects treated with BCMA × CD3 antibody showed resistance to treatment with anti-CD38 antibody and / Or it is refractory.

[0352] The present invention also includes BCMA-conjugated domains, including VH of SEQ ID NO: 29 and VL of SEQ ID NO: 30. n, and CD3 binding domains including VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40 BCMA×CD3 bispecific antibody and anti-C2 antibody containing VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 We also provide pharmaceutical compositions containing D38 antibody.

[0353] In some embodiments, the pharmaceutical composition includes HC1 of SEQ ID NO: 31 and LC of SEQ ID NO: 32. 1. BCMA×CD3 bispecific antibody containing HC2 (SEQ ID NO: 41) and LC2 (SEQ ID NO: 42) The body contains anti-CD38 antibodies, including the HC of SEQ ID NO: 12 and the LC of SEQ ID NO: 13.

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

[0355] In some embodiments, the pharmaceutical composition contains about 25 mM acetic acid and about 60 mM sodium chloride. Um, approximately 140 mannitol, and approximately 0.04% w / v polysorbate-20 (PS- 20) Contains approximately 20 mg / mL to 120 mg / mL of anti-CD38 antibody, with a pH of approximately 5. The answer is 5.

[0356] BCMA x CD3 bispecific antibodies are antibodies with concentrations ranging from approximately 20 mg / mL to approximately 120 mg / mL. Acetic acid, histidine, sodium chloride, mannitol, and / or polysorbate-20 It can be formulated as a pharmaceutical composition containing it.

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

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

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

[0360] In some embodiments, one or more excipients include histidine, methionine, and so Rubitol, or polysorbate-20 (PS-20), or any combination thereof It is a waste.

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

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

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

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

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

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

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

[0368] This disclosure also relates to pharmaceutical compositions comprising a BCMA × CD3 bispecific antibody and an anti-CD38 antibody. We also offer kits that include this.

[0369] Treatment with BCMA x CD3 bispecific antibodies in patients with relapsed or refractory disease This disclosure also relates to a method for treating cancer in a subject, wherein the amount of BCMA effective for treatment is multiplied by The treatment of cancer involves administering a CD3 bispecific antibody to the target, and the target is a previously anti-cancer agent. We also provide methods for treating relapsed or refractory cases that have not responded to drug therapy.

[0370] In some embodiments, the BCMA×CD3 bispecific antibody is used in HCD of SEQ ID NO: 23. R1, HCDR2 (sequence number 24), HCDR3 (sequence number 25), LCDR (sequence number 26) 1. BCMA-conjugated domains including LCDR2 of SEQ ID NO: 27 and LCDR3 of SEQ ID NO: 28 In, as well as HCDR1 of sequence number 33, HCDR2 of sequence number 34, and H of sequence number 35. CDR3, LCDR1 of sequence number 36, LCDR2 of sequence number 37, and sequence number 38 Includes a CD3 binding domain containing LCDR3.

[0371] In some embodiments, the BCMA-binding domain is VH of SEQ ID NO: 29 and SEQ ID NO: It contains 30 VLs, and the CD3 binding domains are VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40 Includes.

[0372] In some embodiments, the BCMA×CD3 bispecific antibody is IgG4 isotype Therefore, phenylalanine is located at position 405 of HC1 and arginine at position 409, and HC2 It contains leucine at position 405 and lysine at position 409, and the residue numbering is based on the EU Index. Follow S.

[0373] In some embodiments, the BCMA×CD3 bispecific antibody is used for both HC1 and HC2. It contains proline at position 228, alanine at position 234, and alanine again at position 235.

[0374] In some embodiments, the BCMA×CD3 bispecific antibody is used for HC1 of SEQ ID NO: 31. This includes LC1 of sequence number 32, HC2 of sequence number 41, and LC2 of sequence number 42.

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

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

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

[0378] In some embodiments, subjects with high-risk multiple myeloma are t(4;14)(p16;q32); t(14;16)(q32;q23); del17p; 1qAmp; t(4;14)(p16;q32) and t(14;16)(q32;q23); t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23), and de Having one or more chromosomal abnormalities, including l17p, or any combination thereof. .

[0379] In some embodiments, the target is an anti-CD38 antibody, lenalidomide, bortezomib, and po Maridomide, carfilzomib, erotozumab, ixazomib, melphalan, or Relapsed or refractory to treatment with thalidomide or any combination thereof .

[0380] In some embodiments, the subjects are patients who have relapsed or refractory to treatment with lenalidomide. Yes. In some embodiments, the subjects are patients who have relapsed or refractory to treatment with bortezomib. It is sexual. In some embodiments, the subject is relapsed or in response to treatment with pomalidomide. It is refractory. In some embodiments, the subject is refractory to treatment with carfilzomib. The condition is relapsed or refractory. In some embodiments, the patient is refractory to treatment with erotozumab. The condition is relapsed or refractory. In some embodiments, the subject is treated with ixazomib. The condition is relapsed or refractory. In some embodiments, the subject is melphalan. The condition is relapsed or refractory to treatment. In some embodiments, the subject is thalidomide-induced The condition is relapsed or refractory to treatment.

[0381] In some embodiments, the subjects are relapsed in response to treatment with anti-CD38 antibodies.

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

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

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

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

[0386] In some embodiments, the anti-CD38 antibody is used. VH of sequence number 14 and VL of sequence number 15, VH of sequence number 16 and VL of sequence number 17, VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or Includes VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

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

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

[0389] In some embodiments, this method involves administering one or more anti-cancer treatments to the subject. It also includes.

[0390] In some embodiments, one or more anti-cancer treatments include autologous stem cell transplantation (ASCT). ), selected from a group consisting of radiation, surgery, chemotherapy agents, immunomodulatory agents, and targeted cancer therapies. ru.

[0391] In some embodiments, one or more anticancer treatments include lenalidomide, thalidomide, and lenalidomide. Do, pomalidomide, bortezomib, carfilzomib, erotozumab, ixazomib, me Ruphalan, prednisone, or dexamethasone, or any combination thereof. Selected from the following group.

[0392] Combination therapy with a T-cell redirecting agent that binds to GPRC5D and an anti-CD38 antibody. This disclosure also relates to a method for treating cancer in a subject, wherein the amount of GPRC5 effective for treatment is sufficient. The target of administration of a T-cell redirecting drug that binds to D and an anti-CD38 antibody is used to treat cancer. We also provide methods, including how to do so.

[0393] In some embodiments, the anti-CD38 antibody redirects T cells that bind to GPRC5D. It is administered to the target patient before administering the CT treatment drug.

[0394] In some embodiments, the subjects are those whose cancer has relapsed or is refractory to treatment with previous anticancer drugs. It is a sexual thing.

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

[0396] In some embodiments, GPRC5D-expressing cancers are hematological malignancies or solid tumors.

[0397] In some embodiments, hematological malignancies are leukemia, lymphoma, or multiple myeloma. ru.

[0398] In some embodiments, the hematological malignancy is leukemia. In some embodiments, Hematological malignancies include lymphomas. In some embodiments, hematological malignancies include multiple bone cancers. It is a myeloma.

[0399] In some embodiments, solid tumors include ovarian cancer, lung cancer, stomach cancer, prostate cancer, kidney cancer, liver cancer, The cancer is either pancreatic cancer, colon cancer, esophageal cancer, bladder cancer, cervical cancer, or malignant melanoma.

[0400] GPRC5D has been disclosed to be expressed in these tumors, for example, in countries Please refer to International Publication No. 2018 / 147245.

[0401] In some embodiments, the target is an anti-CD38 antibody, lenalidomide, bortezomib, and po Maridomide, carfilzomib, erotozumab, ixazomib, melphalan, or Relapsed or refractory to treatment with thalidomide or any combination thereof .

[0402] In some embodiments, the subjects are patients who have relapsed or refractory to treatment with lenalidomide. Yes. In some embodiments, the subjects are patients who have relapsed or refractory to treatment with bortezomib. It is sexual. In some embodiments, the subject is relapsed or in response to treatment with pomalidomide. It is refractory. In some embodiments, the subject is refractory to treatment with carfilzomib. The condition is relapsed or refractory. In some embodiments, the patient is refractory to treatment with erotozumab. The condition is relapsed or refractory. In some embodiments, the subject is treated with ixazomib. The condition is relapsed or refractory. In some embodiments, the subject is melphalan. The condition is relapsed or refractory to treatment. In some embodiments, the subject is thalidomide-induced The condition is relapsed or refractory to treatment with [specific treatment]. In some embodiments, the subject is anti-CD38 The disease is relapsed or refractory to antibody treatment.

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

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

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

[0406] In some embodiments, subjects with high-risk multiple myeloma are t(4;14)(p16;q32); t(14;16)(q32;q23); del17p; 1qAmp; t(4;14)(p16;q32) and t(14;16)(q32;q23); t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23), and de Having one or more chromosomal abnormalities, including l17p, or any combination thereof. .

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

[0408] In some embodiments, the T cell redirection therapeutic agent is HCDR1 of SEQ ID NO: 43, HCDR2 (sequence number 44), HCDR3 (sequence number 45), LCDR1 (sequence number 46), distribution GPRC5D coupled domain including LCDR2 at column number 47 and LCDR3 at sequence number 48 n, as well as HCDR1 of sequence number 33, HCDR2 of sequence number 34, and HC of sequence number 35 DR3, LCDR1 of sequence number 36, LCDR2 of sequence number 37, and L of sequence number 38 Includes CD3 binding domains, including CDR3.

[0409] In some embodiments, the GPRC5D binding domain is VH and sequence of sequence number 49. It contains VL number 50, and the CD3 binding domain is VH of SEQ ID NO: 39 and SEQ ID NO: 40 Includes VL.

[0410] In some embodiments, T cell redirecting therapeutics that bind to GPRC5C are multiple These are specific antibodies, CARs, or T cells that express CARs.

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

[0412] In some embodiments, the multispecific antibody is an IgG1 isotype. In this embodiment, the multispecific antibody is an IgG2 isotype. Therefore, the multispecific antibody is an IgG3 isotype. In some embodiments, multiple The specific antibody is the IgG4 isotype.

[0413] In some embodiments, the multispecific antibody is the Fcγ receptor of the multispecific antibody (Fcγ Includes one or more Fc substitutions that reduce binding to R).

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

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

[0416] In some embodiments, the multispecific antibody has a first CH3 domain or a second C In the H3 domain, or in both the first CH3 domain and the second CH3 domain, one or This includes two or more asymmetrical substitutions.

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

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

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

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

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

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

[0423] In some embodiments, the anti-CD38 antibody is used. VH of sequence number 14 and VL of sequence number 15, VH of sequence number 16 and VL of sequence number 17, VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or Includes VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

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

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

[0426] In some embodiments, T-cell redirecting therapeutics and anti-C cells that bind to GPRC5D The D38 antibody is administered by intravenous injection.

[0427] In some embodiments, T-cell redirecting therapeutics that bind to GPRC5D are used in veins. The drug is administered by internal injection, while the anti-CD38 antibody is administered by subcutaneous injection.

[0428] In some embodiments, T-cell redirecting therapeutics and anti-C cells that bind to GPRC5D The D38 antibody is administered by subcutaneous injection.

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

[0430] In some embodiments, a T-cell redirecting therapeutic agent that binds to GPRC5D is GP This is a bispecific antibody for RC5D × CD3.

[0431] In some embodiments, this method involves administering one or more anti-cancer treatments to the subject. It also includes.

[0432] In some embodiments, one or more anti-cancer treatments include autologous stem cell transplantation (ASCT). ), selected from a group consisting of radiation, surgery, chemotherapy agents, immunomodulatory agents, and targeted cancer therapies. ru.

[0433] In some embodiments, one or more anticancer treatments include lenalidomide, thalidomide, and lenalidomide. Do, pomalidomide, bortezomib, carfilzomib, erotozumab, ixazomib, me The following are selected from the group consisting of ruphalan, dexamethasone, or prednisone.

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

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

[0436] In some embodiments, the anti-CD38 antibody is approximately 120 mg / mL of anti-CD38 antibody and It is administered in a pharmaceutical composition containing approximately 2,000 U / mL of rHuPH20, or Provided for administration.

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

[0438] In some embodiments, the anti-CD38 antibody is used. Approximately 1,800 mg of anti-CD38 antibody, Approximately 30,000U of rHuPH20, Approximately 10 mM histidine, Approximately 300 mM sorbitol and PS-20 with approximately 0.04% (w / v), A pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6 is administered. It is either used or provided for administration.

[0439] In some embodiments, the anti-CD38 antibody is used. Approximately 120 mg / mL of anti-CD38 antibody, rHuPH20 at approximately 2,000 U / mL, Approximately 10 mM histidine, Approximately 300 mM sorbitol and PS-20 with approximately 0.04% (w / v), A pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6 is administered. It is either used or provided for administration.

[0440] This disclosure also includes HCDR1 (SEQ ID NO: 43), HCDR2 (SEQ ID NO: 44), and SEQ ID NO: 45 HCDR3, LCDR1 of sequence number 46, LCDR2 of sequence number 47, and sequence number 4 8 GPRC5D binding domains including LCDR3, and HCDR1 of SEQ ID NO: 33, HCDR2 at column number 34, HCDR3 at sequence number 35, LCDR1 at sequence number 36, array Includes CD3 binding domains including LCDR2 (number 37) and LCDR3 (sequence number 38). GPRC5D×CD3 bispecific antibody, HCDR1 (SEQ ID NO. 6), and HCD (SEQ ID NO. 7) R2, HCDR3 (sequence number 8), LCDR1 (sequence number 9), LCDR2 (sequence number 10), We also provide a pharmaceutical combination that includes an anti-CD38 antibody containing LCDR3 of SEQ ID NO: 11. ru.

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

[0442] In some embodiments, the GPRC5D×CD3 bispecific antibody is H of SEQ ID NO: 51 Contains C1, LC1 of SEQ ID NO: 52, HC2 of SEQ ID NO: 41, and LC2 of SEQ ID NO: 42, anti The CD38 antibody includes HC (SEQ ID NO: 12) and LC (SEQ ID NO: 13).

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

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

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

[0446] In some embodiments, the drug combination includes approximately 120 mg / mL of anti-CD38 antibody and It contains approximately 2,000 U / mL of rHuPH20.

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

[0448] In some embodiments, one or more excipients include histidine, methionine, and so Rubitol, or polysorbate-20 (PS-20), or any combination thereof It is a waste.

[0449] In some embodiments, the pharmaceutical composition is Anti-CD38 antibody at approximately 100 mg / mL to approximately 120 mg / mL, Approximately 5 mM to approximately 15 mM histidine, Sorbitol in a concentration of approximately 100 mM to 300 mM, PS-20 with approximately 0.01% w / v to approximately 0.04% w / v, It contains approximately 1 mg / mL to 2 mg / mL of methionine and has a pH of approximately 5.5 to 5.6. .

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

[0451] In some embodiments, the pharmaceutical combination contains approximately 300 mM sorbitol.

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

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

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

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

[0456] This disclosure also relates to GPRC5D-binding T-cell redirecting therapeutics and anti-CD38 antibodies. We also offer combinations of pharmaceuticals that include these.

[0457] Treatment with GPRC5D × CD3 bispecific antibody in patients with relapsed or refractory disease This disclosure also relates to a method for treating cancer in a subject, wherein the amount of GPRC5 effective for treatment is sufficient. The treatment of cancer involves administering a D×CD3 bispecific antibody to the target, and the target is a previous We also provide methods for treating cancer that has recurred or is refractory to anticancer drug therapy.

[0458] In some embodiments, the GPRC5D×CD3 bispecific antibody is H of SEQ ID NO: 43 CDR1, HCDR2 (sequence number 44), HCDR3 (sequence number 45), LC (sequence number 46) GPRC5D includes DR1, LCDR2 (sequence number 47), and LCDR3 (sequence number 48). The binding domain, as well as HCDR1 of SEQ ID NO: 33, HCDR2 of SEQ ID NO: 34, SEQ ID NO: HCDR3 at 35, LCDR1 at sequence number 36, LCDR2 at sequence number 37, and sequence number Contains a CD3 binding domain including LCDR3 of type 38.

[0459] In some embodiments, the GPRC5D binding domain is VH and sequence of sequence number 49. It contains VL number 50, and the CD3 binding domain is VH of SEQ ID NO: 39 and SEQ ID NO: 40 Includes VL.

[0460] In some embodiments, the GPRC5D×CD3 bispecific antibody is used as an IgG4 isota It is a type of polyp, with phenylalanine at position 405 and arginine at position 409 of HC1, and H C2 contains leucine at position 405 and lysine at position 409, and the residue numbering is based on the EU index. Follow the rules.

[0461] In some embodiments, the GPRC5D×CD3 bispecific antibody is used for HC1 and HC2 Both contain proline at position 228, alanine at position 234, and alanine at position 235. .

[0462] In some embodiments, the GPRC5D×CD3 bispecific antibody is H of SEQ ID NO: 51 Includes C1, LC1 of SEQ ID NO: 52, HC2 of SEQ ID NO: 41, and LC2 of SEQ ID NO: 42. .

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

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

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

[0466] In some embodiments, subjects with high-risk multiple myeloma are t(4;14)(p16;q32); t(14;16)(q32;q23); del17p; 1qAmp; t(4;14)(p16;q32) and t(14;16)(q32;q23); t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23), and de Having one or more chromosomal abnormalities, including l17p, or any combination thereof. .

[0467] In some embodiments, the target is an anti-CD38 antibody, lenalidomide, bortezomib, and po Maridomide, carfilzomib, erotozumab, ixazomib, melphalan, or Refractory or relapsing to treatment with thalidomide or any combination thereof .

[0468] In some embodiments, the subjects are patients who have relapsed or refractory to treatment with anti-CD38 antibodies. That is the case.

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

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

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

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

[0473] In some embodiments, the anti-CD38 antibody is used. VH of sequence number 14 and VL of sequence number 15, VH of sequence number 16 and VL of sequence number 17, VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or Includes VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

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

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

[0476] In some embodiments, this method involves administering one or more anti-cancer treatments to the subject. It also includes.

[0477] In some embodiments, one or more anti-cancer treatments include autologous stem cell transplantation (ASCT). ), selected from a group consisting of radiation, surgery, chemotherapy agents, immunomodulatory agents, and targeted cancer therapies. ru.

[0478] In some embodiments, one or more anticancer treatments include lenalidomide, thalidomide, and lenalidomide. Do, pomalidomide, bortezomib, carfilzomib, erotozumab, ixazomib, me Ruphalan, Dexamethasone, Vincristine, Cyclophosphamide, Hydroxydauno Rubicin, prednisone, rituximab, imatinib, dasatinib, nilotinib, vostinib Nib, ponatinib, bafetinib, salakatinib, tozacertib, or danucertib Cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, Decitabine, Cladribine, Fludarabine, Topotecan, Etoposide 6-thioguanine, Corticosteroids, methotrexate, 6-mercaptopurine, azacitidine, trioxide Select from the group consisting of arsenic and all-trans retinoic acid, or any combination thereof. It will be selected.

[0479] Combination therapy with a CD19-binding T-cell redirecting agent and an anti-CD38 antibody. This disclosure also relates to a method for treating cancer in a subject, wherein a therapeutically effective amount of CD19 is used. The target is administered a binding T-cell redirecting drug and an anti-CD38 antibody to treat cancer. We also provide methods that include this.

[0480] In some embodiments, the subject is the administration of a CD19-binding T-cell redirecting therapeutic agent. The patient had been treated with anti-CD38 antibody prior to administration.

[0481] This disclosure also relates to CD19-binding T-cell redirecting therapeutics in subjects with cancer. A method to improve the effectiveness of a T cell redirection therapeutic drug that binds to CD19 The present invention also provides a method that includes administering an anti-CD38 antibody to the subject prior to administration.

[0482] In some embodiments, the subjects are those whose cancer has relapsed or is refractory to treatment with previous anticancer drugs. It is a sexual thing.

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

[0484] In some embodiments, hematological malignancies include lymphoma, B-cell malignancy, and Hodgkin's lymphoma. Parkinson's disease, non-Hodgkin lymphoma, DLBLC, FL, MCL, marginal zone B-cell lymphoma (MZL) ), mucosal-associated lymphoid lymphoma (MALT), CLL, ALL, AML, Waldenst It is either Rhehm's hypergammaglobulinemia or T-cell lymphoma.

[0485] In some embodiments, solid tumors include lung cancer, liver cancer, cervical cancer, colon cancer, breast cancer, and ovarian cancer. These include pancreatic cancer, melanoma, glioblastoma, prostate cancer, esophageal cancer, or gastric cancer. International Publication No. 2019 Case No. / 057124(A1) is a treatment using a CD19-binding T-cell redirecting drug. It discloses cancers that are suitable for this treatment.

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

[0487] In some embodiments, the CD19-binding T-cell redirecting therapeutic agent is blina Momab, Axicaptagensiloleucel, Tisagenlecleucel-t, Rinebilizumab Lithocab-Butagen-Maral-Ucel, XmAb-5574, CIK-CAR.CD19, I CTCAR-011, IM-19, JCAR-014, roncastuximabutecilin, M B-CART2019.1, OXS-1550, PBCAR-0191, PCAR-01 9, PCAR-119, Senl-001, TI-1007, XmAb-5871, PT G-01, PZ01, Senl_1904A, Senl_1904B, UCART-19 , CSG-CD19, DI-B4, ET-190, GC-007F, or GC-022 Includes CD19 binding domain.

[0488] In some embodiments, the CD19-binding T-cell redirecting therapeutic agent is blina Momab, Axicaptagensiloleucel, Tisagenlecleucel-t, Rinebilizumab Lithocab-Butagen-Maral-Ucel, XmAb-5574, CIK-CAR.CD19, I CTCAR-011, IM-19, JCAR-014, roncastuximabutecilin, M B-CART2019.1, OXS-1550, PBCAR-0191, PCAR-01 9, PCAR-119, Senl-001, TI-1007, XmAb-5871, PT G-01, PZ01, Senl_1904A, Senl_1904B, UCART-19 , CSG-CD19, DI-B4, ET-190, GC-007F, or GC-022 include.

[0489] In some embodiments, T-cell redirecting therapeutics that bind to CD19 are multispecific These are sex antibodies, CARs, or T cells that express CARs.

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

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

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

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

[0494] In some embodiments, the anti-CD38 antibody is used. VH of sequence number 14 and VL of sequence number 15, VH of sequence number 16 and VL of sequence number 17, VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or Includes VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

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

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

[0497] In some embodiments, T-cell redirecting therapeutics that bind to CD19 and anti-CD3 The 8 antibodies are administered by intravenous injection.

[0498] In some embodiments, CD19-binding T-cell redirecting therapeutics are administered intravenously. It is administered by injection, and the anti-CD38 antibody is administered by subcutaneous injection.

[0499] In some embodiments, T-cell redirecting therapeutics that bind to CD19 and anti-CD3 The 8 antibodies are administered by subcutaneous injection.

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

[0501] In some embodiments, a T-cell redirecting therapeutic agent that binds to CD19 is CD19 This is a bispecific antibody for CD3.

[0502] In some embodiments, this method involves administering one or more anti-cancer treatments to the subject. It also includes.

[0503] In some embodiments, one or more anti-cancer treatments include autologous stem cell transplantation (ASCT). ), selected from a group consisting of radiation, surgery, chemotherapy agents, immunomodulatory agents, and targeted cancer therapies. ru.

[0504] This disclosure also relates to CD19×CD3 bispecific antibodies containing blinatumomab, SEQ ID NO: 53. , HCDR1 of sequence number 6, HCDR2 of sequence number 7, HCDR3 of sequence number 8, sequence number Anti- We also offer drug combinations that include CD38 antibodies.

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

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

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

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

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

[0510] In some embodiments, the drug combination includes approximately 120 mg / mL of anti-CD38 antibody and It contains approximately 2,000 U / mL of rHuPH20.

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

[0512] In some embodiments, one or more excipients include histidine, methionine, and so Rubitol, or polysorbate-20 (PS-20), or any combination thereof It is a waste.

[0513] In some embodiments, the drug combination is Anti-CD38 antibody at approximately 100 mg / mL to approximately 120 mg / mL, Approximately 5 mM to approximately 15 mM histidine, Sorbitol in a concentration of approximately 100 mM to 300 mM, PS-20 with approximately 0.01% w / v to approximately 0.04% w / v, It contains approximately 1 mg / mL to 2 mg / mL of methionine and has a pH of approximately 5.5 to 5.6. .

[0514] In some embodiments, the drug combination is It contains approximately 10 mM histidine.

[0515] In some embodiments, the pharmaceutical combination contains approximately 300 mM sorbitol.

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

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

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

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

[0520] In some embodiments, the pharmaceutical combination includes citric acid monohydrate (3.35 mg), salt Lysine acid (23.23 mg), polysorbate 80 (0.64 mg), trehalose dihydrate Formulated with the Japanese compound (95.5 mg) and sodium hydroxide, and the pH was adjusted to 7.0. It contains 35 mcg of blinatumomab.

[0521] In some embodiments, blinatumomab is administered in 3 mL of sterile water for injection without preservatives. This is a reconstruction by USP.

[0522] Blinatumomab (SEQ ID NO: 53), HCDR1 (SEQ ID NO: 6), HCDR2 (SEQ ID NO: 7) HCDR3 of sequence number 8, LCDR1 of sequence number 9, LCDR2 of sequence number 10, and A kit containing a drug combination including an anti-CD38 antibody containing LCDR3 in column number 11.

[0523] T-cell redirection therapy multispecific antibodies T-cell redirection therapies may also be multispecific molecules such as bispecific antibodies. Various multispecific and / or bispecific forms include the forms and recombinant I described herein. γ-like dual-target molecule (each of the two sides of the molecule is a Fab fragment of at least two different antibodies) (or containing part of a Fab fragment), IgG fusion molecule (full-length IgG antibody, with extra Fa (fused to a portion of the b fragment or Fab fragment), Fc fusion molecule (single-chain Fv molecule or stabilizing) The resulting diabody is fused to the heavy chain constant domain, the Fc region, or a part thereof), F ab fusion molecules (where different Fab fragments are fused into one), based on ScFv and diabodies. Antibodies and heavy chain antibodies (e.g., domain antibodies, nanobody antibodies) (different single-chain Fv molecules or This is when different diabodies or different heavy chain antibodies (e.g., domain antibodies, nanobodies) interact with each other. It is fused to, or produced by another protein or carrier molecule, or by arm exchange. This includes (fused to the resulting multispecific antibodies). Exemplary multispecific and / or bispecific antibodies. The specificity form includes dual-target molecules, such as Dual Targeting (DT)-Ig(GS) K / Domantis), 2-in-1 (Two-in-one) antibody (Genentech), and m Ab2(F-Star), Dual Variable Domain (DVD)-Ig(Abbott), Ts2 Ab (MedImmune / AZ), and BsAb (Zymogenetics), HE RCULES (Biogen Idec), and TvAb (Roche), ScFv / F c Fusion (Academic Institution), SCORPION (Emer gent BioSolutions / Trubion, Zymogenetics / B MS), and Dual Affinity Retargeting Technology (Fc-D ART)(MacroGenics), F(ab)2(Medarex / AMGEN), Dual activity or Bis-Fab (Genentech), Dock-and-Lock (D NL) (ImmunoMedics), divalent bispecificity (Biotecnol), and F ab-Fv (UCB-Celltech), Bispecific T cell Engager (Bispecif ic T Cell Engineer, BITE) (Micromet), Tandem Diabody (Tandem Diabody, Tandab) (Affimed), Dual Affinity Retargeting Technology (DART) (M acroGenics), single-stranded diabody (Academic), TCR-like antibody (A IT, ReceptorLogics), Human serum albumin ScFv fusion (Merr imack), and COMBODY (Epigen Biotech), dual-target nanobo Di (Ablynx) includes dual-target heavy chain-only domain antibodies. Various forms of dual specificity. Antibodies include, for example, Chames and Baty (2009) Curr Opin D rug Disc Dev 12:276 and Nunez-Prado et al., (2015)Drug Discovery Today 20(5):588-594 It is described there.

[0524] Method for generating antibodies used in the present invention The antibodies used in the method of the present invention that bind to a specific antigen are, for example, phage displays. A new phage may be selected from the library, in which case the phage is human immunoglobulin. or a part thereof (Fab, single-chain antibody (scFv), or unpaired or paired) The antibody is manipulated to express a variable region (such as an antibody variable region) (Knappik et al., J Mol Biol296:57-86,2000, Krebs et al., JI mmunol Meth 254:67-84,2001, Vaughan et al. .,Nature Biotechnology14:309-14,1996, She ets et al., PITAS (USA) 95:6157-62, 1998, Hoo genboom and Winter, J Mol Biol 227:381,19 91, Marks et al., J Mol Biol 222:581, 1991). Shi et al (2010) J.Mol.Biol.397:385-96 and International The bacteriophage pIX coat protein described in Publication No. 2009 / 085462 and Phage display proteins that express antibody heavy chain and light chain variable regions as fusion proteins. Blur. Antibody library: BCMA, CD3, CD38, CD123, CD19, CD3 3. Regarding binding to desired antigens such as PSMA or the TMEFF2 extracellular domain, Lean the lysate, further characterize the resulting positive clones, and extract Fab from the clone lysates. After isolation, it can be cloned as a full-length antibody. To isolate human antibodies... Such phage display methods are well-established in the field. For example, in the United States Japanese Patent No. 5,223,409, U.S. Patent No. 5,403,484, U.S. Patent No. 557 US Patent No. 1,698, US Patent No. 5,427,908, US Patent No. 5,580,717, US Japanese Patent No. 5,969,108, U.S. Patent No. 6,172,197, U.S. Patent No. 5,88 US Patent No. 5,793, US Patent No. 6,521,404, US Patent No. 6,544,731, US Japanese Patent No. 6,555,313, U.S. Patent No. 6,582,915, and U.S. Patent No. 6, Please refer to issue 593,081.

[0525] The T cell redirecting bispecific antibody is described in International Publication No. 2011 / 131746. According to the method, in a cell-free environment, in vitro, two monospecific homodimeric antibodies Different (asymmetrical) mutations are introduced into each CH3 region, and the disulfide bonds are altered. Under reducing conditions that induce sexualization, two parent monospecific homodimer antibodies produce a bispecific heterogen. It may also be produced by forming a heterodimer antibody. In this method, the heterodimer is stable. Two monospecific bivalent antibodies having specific substitutions in the CH3 domain to facilitate qualitative analysis. These antibodies are genetically engineered. In these antibodies, the cysteine ​​in the hinge region is disulfide bonded. They are incubated together under reducing conditions sufficient to isomerize F Bispecific antibodies are generated by AB arm exchange. The optimal incubation conditions are: The conditions can be returned to non-reducing conditions. A typical reducing agent that can be used is 2-mercaptoethylamine. (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), Lutathione, Tris(2-carboxyethyl)phosphine (TCEP), L-cysteine , and β-mercaptoethanol, preferably 2-mercaptoethylamine, di Select from the group consisting of thiothreitol and tris(2-carboxyethyl)phosphine. It is a reducing agent that is used at a temperature of at least 20°C and at least 25 mM 2-M In the presence of EA or at least 0.5 mM dithiothreitol, pH 5-8, For example, use an incubation period of at least 90 minutes at pH 7.0 or pH 7.4. It is possible.

[0526] Representative CH3 mutations that can be used in the first and second heavy chains of bispecific antibodies are: This is K409R and / or F405L.

[0527] Additional CH3 mutations that may be used include the Duobody(registered trademark) mutation (Genmab). ), knob-in-hole mutation (Genentech), electrostatic match mutation (Chugai, A mgen, NovoNordisk, Oncomed), chain exchange operation domain body (S EED body) (EMD Serono), and other asymmetric mutations (e.g., Zymewo This includes technologies such as RKS.

[0528] The Duobody® mutation (Genmab) is, for example, U.S. Patent No. 91506 Disclosed in Patent No. 63 and U.S. Patent Application Publication No. 2014 / 0303356, for example, F405L / K409R, wild type / F405L_R409K, T350I_K370T_ F405L / K409R, K370W / K409R, D399AFGHILMNRSTV WY / K409R, T366ADEFGHILMQVY / K409R, L368ADEG HNRSTVQ / K409AGRH, D399FHKRQ / K409AGRH, F405 The mutations IKLSTVW / K409AGRH and Y407LWQ / K409AGRH are included. Born.

[0529] The nobu-in-hole mutation is disclosed, for example, in International Publication No. 1996 / 027011. Then, an amino acid with a small side chain (hole) is introduced into the first CH3 region, and the large side chain An amino acid containing a (knob) is introduced into the second CH3 region, and the first CH3 region and the second C This includes an interface mutation in the CH3 region that leads to preferential interaction with the H3 region. Exemplary CH3 region mutations that form knobs and holes include T366Y / F405A and T36 6W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y 407A, T366W / T394S, F405W / T394S, and T366W / T36 It is 6S_L368A_Y407V.

[0530] Heavy chain heterodimer formation is described in U.S. Patent Application Publication No. 2010 / 0015133, and the same patent application publication No. 20 Issues 09 / 0182127, 2010 / 028637, or 2011 / 0123 As described in No. 532, the positively charged residue on the first CH3 region and the second CH3 region By substituting the negatively charged residue above, the process is facilitated by utilizing electrostatic interactions. It is possible.

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

[0532] SEED body mutations are as described in U.S. Patent Application Publication No. 2007 / 0287170. Furthermore, by substituting selected IgG residues with IgA residues, heavy chain heterodimerization is promoted. It is accompanied by.

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

[0534] Additional bispecific or multispecific structures that can be used as T-cell redirection therapies This is a dual variable domain immunoglobulin (DVD) (International Publication No. 2009 / 134776). DVD has a heavy chain with a VH1-linker-VH2-CH structure and a VL1-linker- A full-length antibody containing a light chain having a VL2-CL structure, with an optional linker. Two antibodies with different specificities, such as an isine zipper or a collagen dimerization domain. Structure containing various dimerization domains for connecting arms (International Publication No. 2012 / 022) (Patent No. 811, U.S. Patent No. 5,932,448, U.S. Patent No. 6,833,441), together Two or more domain antibodies (dAbs), diabodies, and ra conjugates Heavy chain only antibodies such as camelid antibodies and modified camelid antibodies, dual target (DT)-Ig( GSK / Domantis), 2in1 antibody (Genentech), cross-linked Mab (Ka rmanos Cancer Center), mAb2 (F-Star), and Cov X-body (CovX / Pfizer), IgG-like bispecificity (InnClone / Eli Lilly), Ts2Ab(MedImmune / AZ), and BsAb(Zymog enetics), HERCULES (Biogen Idec), and TvAb (Ro che), ScFv / Fc fusion (Academic Institution), SC ORPION(Emergent BioSolutions / Trubion, Zym ogenetics / BMS), dual affinity retargeting technology (Fc-DART) (Macro Genics), and Dual (ScFv)2-Fab (National Research) h Center for Antibody Medicine--China), 2 Heavy activity or Bis-Fab (Genentech), Dock-and-Lock (DN L) (ImmunoMedics), divalent bispecificity (Biotecnol), and Fa Contains b-Fv (UCB-Celltech). Based on ScFv antibody and diabody. Antibodies and domain antibodies include bispecific T cell engagers (BiTEs) (Mic romet), tandem diabody (Tandab) (Affimed), dual affinity Retargeting technology (DART) (MacroGenics), single-strand diamond body (Acade mic), TCR-like antibody (AIT, ReceptorLogics), human serum albumin ScFv fusion (Merrimack), and COMBODY (Epigen Bio (tech), dual-target nanobody (Ablynx), dual-target heavy chain-only domain antibody These are rare, but not limited to them.

[0535] Fc manipulation of antibodies T-cell redirection therapy using bispecific or multispecific antibodies or anti-CD38 antibodies. The Fc region of the drug binds to the activated Fcγ receptor (FcγR) of T cell redirecting therapeutics. Reduces C1q binding and / or complement-dependent cytotoxicity. oxicity (CDC), antibody-dependent cell-mediated cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (CDC); d cytotoxicity (ADCC), or phagocytosis (antibody-dependent cell-mediated p Reduces Fc effect functions such as hagocytosis (ADCP), and reduces the Fc region. It may contain at least one substitution.

[0536] After reducing the binding of Fc to activated FcγR, it is replaced to reduce its effector function. Possible Fc locations are L234A / L235A on IgG1, V234A / on IgG2 G237A / P238S / H268A / V309L / A330S / P331S, IgG4 F234A / L235A above, S228P / F234A / L235A above IgG4, all N297A on Ig isotype, V234A / G237A on IgG2, and on IgG1 K214T / E233P / L234V / L235A / G236 (missing) / A327G / P3 31A / D365E / L358M, H268Q / V309L / A330S / on IgG2 P331S, S267E / L328F on IgG1, L234F / L235 on IgG1 E / D265A, L234A / L235A / G237A / P238S / H2 on IgG1 68A / A330S / P331S, S228P / F234A / L235A / on IgG4 G237A / P238S, and S228P / F234A / L235A / G2 on IgG4 This is a substitution of deletion 36 / G237A / P238S.

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

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

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

[0540] Sequence ID 103: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPSRD ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPGK

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

[0542] Sequence ID 104: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTK TYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYV DGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPSQEEMT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQK SLSLSLGK

[0543] "Antibody-dependent cytotoxicity", "Antibody-dependent cell-mediated cytotoxicity", or "ADCC" The Fcγ receptor (FcγR) expressed in effector cells affects antibody-coated target cells. , the lytic activity of natural killer cells (NK), monocytes, macrophages, and neutrophils This mechanism induces cell death depending on the interaction with effector cells it possesses. NK cells express FcγRIIIa, while monocytes express FcγRI, FcγRII, and It expresses FcγRIIIa. The ADCC activity of the antibody is determined by the expression of the protein to which the antibody binds. In vitro, using cells as target cells and NK cells as effector cells. It can be evaluated using an assay. Cell lysis is the labeling of lysed cells (for example) If detected, it may be detected by the release of a radioactive substrate, fluorescent dye, or natural intracellular protein. This can be done. In an example assay, target cells are divided into 1 target cell and 4 effector cells. The ratio used is as follows: Target cells are pre-labeled with BATDA, and effector cells and test antibodies are used together. Combine the samples. Incubate the samples for 2 hours and measure the BATDA released into the supernatant. Cell lysis was measured by using 0.67% Triton X-100 (Sigm The data was normalized to the maximum cytotoxicity caused by Aldrich, and also to any antibody. Determine the minimum control by the natural release of BATDA from target cells in the absence of

[0544] "Antibody-dependent cell phagocytosis" ("ADCP") refers to a mechanism for eliminating antibody-coated target cells by uptake by phagocytic cells such as macrophages or dendritic cells. AD CP can be evaluated by using monocyte-derived macrophages as effector cells and target cells engineered to express a protein to which the antibody binds to express GFP or another labeling molecule. In an exemplary assay, the effector :target cell ratio can be, for example, 4:1. The effector cells may be incubated with the target cells for 4 hours with or without the addition of the antibody of the present invention. After incubation , the cells can be detached using trypsin. Macrophages can be identified by anti-CD11b antibody and anti-CD14 antibody conjugated to a fluorescent label, and the percentage of phagocytosis can be determined using a standard method based on the percentage of GFP fluorescence in CD11 and CD14 macrophages. After incubation, the cells can be detached using trypsin. Macrophages can be identified by anti-CD11b antibody and anti-CD14 antibody conjugated to a fluorescent label, and the percentage of phagocytosis can be determined using a standard method based on the percentage of GFP fluorescence in CD11 and CD14 macrophages. + and CD14 + in macrophages. The percentage of GFP fluorescence in macrophages can be determined based on the percentage of GFP fluorescence in CD11

[0545] "Complement-dependent cytotoxicity", i.e., "CDC", refers to a mechanism for inducing cell death in which the Fc effector domain of a target-binding antibody binds to and activates complement component C1q, and such complement component C1q then activates the complement cascade to cause cell death of the target cell. Activation of the complement can also result in the deposition of complement components on the surface of the target cell, facilitating CDC by binding of complement receptors (e.g., CR3) on leukocytes. CDC of cells can be induced, for example, by incubating Daudi cells in RPMI-B (RPMI supplemented with 1% BSA) with the antibody of the present invention, and the cell death can be detected by measuring the release of a fluorescent dye or other marker from the cells. Activation of the complement can also result in the deposition of complement components on the surface of the target cell, facilitating CDC by binding of complement receptors (e.g., CR3) on leukocytes. CDC of cells can be induced, for example, by incubating Daudi cells in RPMI-B (RPMI supplemented with 1% BSA) with the antibody of the present invention, and the cell death can be detected by measuring the release of a fluorescent dye or other marker from the cells. 1 x 10 per shell 5 Plate with individual cells (50 μL / well), 50 μL Add the test antibody to the wells at a final concentration of 0-100 μg / mL, and allow the reaction to stand at room temperature for 15 minutes. Incubate in , add 11 μL of pooled human serum to the wells, and react for 45 minutes. The percentage of lysed cells can be measured by incubation at 37°C. (%) represents the percentage of propidium iodide-stained cells in a FACS assay using the standard method. It may be detected as a percentage.

[0546] The binding of antibodies to FcγR or FcRn is determined by flow cytometry for each receptor. This can be evaluated in cells modified to express [the gene]. In the example binding assay, 2 x 10⁶ per well in a 96-well plate 5 Seed individual cells, BSA Stain 4°C in Buffer (BD Biosciences, San Jose, USA) The cells were blocked for 30 minutes. The cells were incubated with the test antibody on ice at 4°C for 1.5 hours. After washing twice with BSA staining buffer, the cells are subjected to R-PE labeled anti-human IgG secondary staining. Antibodies (Jackson Immunoresearch Laboratories) and Incubate both at 4°C for 45 minutes. Wash the cells twice with staining buffer, and then... DRAQ7 live / dead cell staining reagent (Cell Signaling T) diluted 1:200 150 μL of Stain B containing (ecology, Danvers, USA) Resuspend in uffer. PE and DRAQ7 signals from stained cells are measured in Mild. enyi MACSQuant Flow Cytometer (Miltenyi Biotec) Auburn (USA) uses B2 and B4 channels for detection, respectively. Gated live cells with DRAQ7 exclusion, and at least 10,000 live cell events were collected. For the test, the geometric mean fluorescence signal is determined. FlowJo software is used for the analysis. Use Tree Star. The data is the logarithm of antibody concentration relative to the mean fluorescence signal. Plot it as follows. Perform a nonlinear regression analysis.

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

[0548] CARs typically have an extracellular domain that binds to an antigen (e.g., prostate prostatic antigen). Any linker, transmembrane domain, and costimulatory domain and / or signaling domain It contains a cytoplasmic domain that includes n.

[0549] The extracellular domain of CAR binds to any desired antigen (e.g., prostate prostatic antigen). It may contain polypeptides. The extracellular domain is a part of the antibody or an alternative scaffold. It may include scFv. CAR is also arranged in tandem and separated by a linker array. It may be manipulated to bind to two or more desired antigens. For example, 1 One or more domain antibodies, scFv, Rama VHH antibodies, or other VH-only antibody fragments. This is configured in tandem via a linker to provide the CAR with dual or multiple specificity. That's fine.

[0550] The transmembrane domain of CAR is the transmembrane domain of CD8, and the alpha and base of the T cell receptor. CD28, CD3 epsilon, CD45, CD4, CD5, CD 8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86 , CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, LFA-1 (CDI la, CD18), ICOS (CD278), 4-1BB (CD1 37), 4-1BBL, GITR, CD40, BAFFR, HVEM(LIGHTR), SLAMF7, NKp80(KLRFI), CD160, CD19, IL2R Beta, I L2R Gamma, IL7R a, ITGA1, VLA1, CD49a, ITGA4, IA4 , CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDI ID, IT GAE, CD103, ITGAL, CDI la, LFA-1, ITGAM, CDI l b, ITGAX, CDI lc, ITGB1, CD29, ITGB2, CD18, LFA -1, ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244 , 2B4), CD84, CD96 (tactile), CEACAM1, CRT AM, Ly9(C D229), CD160(BY55), PSGL1, CD100(SEMA4D), SL AMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO- 3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​PAG / By Cbp, NKp44, NKp30, NKp46, NKG2D, and / or NKG2C It is possible.

[0551] The intracellular co-stimulatory domain of CAR is located within the intracellular domain of one or more co-stimulatory molecules. It may originate from this. Co-stimulatory molecules are essential for the efficient activation and function of T lymphocytes when they bind to antigens. A well-known cell surface molecule other than an antigen receptor or Fc receptor that provides a crucial second signal. Yes. Exemplary co-stimulatory domains that can be used in CAR are 4-1BB, CD2, CD7, CD27, CD28, CD30, CD40, CD54(ICAM), CD83, CD13 4 (OX40), CD150 (SLAMF1), CD152 (CTLA4), CD223 (LAG3), CD270(HVEM), CD278(ICOS), DAP10, LAT These are the intracellular domains of NKD2C SLP76, TRIM, and ZAP70.

[0552] The intracellular signaling domains of CAR include, for example, O'O3ζ, CD3ε, CD22, It may originate from the signaling domains of CD79a, CD66d, or CD39. The "signaling domain" is effective against target antigens in order to induce effector cell function. The CAR binding message is involved in the transduction of immune effector cells into the interior. Effector cell functions, e.g., activation, cytokine production, proliferation, and cytotoxic activity ( Release of cytotoxic factors to CAR-bound target cells, or antigen binding to extracellular CAR domains. This refers to a portion of CAR polypeptides that elicit other cellular responses (including those that are subsequently triggered).

[0553] Any linker of a CAR located between the extracellular domain and the transmembrane domain is It can be a polypeptide with a length of approximately 2 to 100 amino acids. The linker is adjacent to the protein. The main components contain flexible residues such as glycine and serine, allowing them to move freely relative to each other. It can be seen, or can be composed of. Two adjacent domains interfere with each other in three dimensions. If it is desirable to ensure that the linker is long, a longer linker can be used. Linkers may be cleavable or incleavable. An example of a cleavable linker is... , 2A linker (e.g., T2A), 2A-like linker, or functional equivalents thereof and These combinations are included. The linker also includes any immunoglobulin hinge region or It may originate from a part of the hinge region.

[0554] An exemplary CAR that may be used is, for example, an extracellular drug that binds to the prostate-derived antigen of the present invention. A CAR containing a main, CD8 transmembrane domain, and CD3ζ signaling domain There is. Other exemplary CARs include the extracellular domain that binds to the prostate-prostatic antigen of the present invention, CD. 8 or CD28 transmembrane domain, CD28, 41BB, or OX40 co-stimulatory domain, and It contains the CD3ζ signaling domain.

[0555] CARs are generated using standard molecular biological techniques. These are cells that bind to the desired antigen. The outer domain is the antibody or antigen binding cleavage of antibodies produced using the techniques described herein. It can be derived from a piece.

[0556] Although the present invention has been described in general terms, embodiments of the present invention are within the scope of the claims. Further disclosures in the following embodiments should not be interpreted as limiting.

[0557] Further embodiments of the present invention Further embodiments of the invention, as disclosed elsewhere in this specification, are described below. The features of the embodiments of the present invention described above as relating to the present invention disclosed herein are This also relates to each of these numbered further embodiments.

[0558] Embodiment 1. Used in combination with a T-cell redirecting therapeutic agent for the treatment of patients with cancer. Anti-CD38 antibody for this purpose

[0559] Embodiment 2. Used to improve the efficacy of T-cell redirection therapeutics in subjects with cancer. An anti-CD38 antibody for this purpose.

[0560] Embodiment 3. A combination of a T-cell redirection therapy drug and a method for treating patients with cancer. Use of anti-CD38 antibodies for preparing drugs or pharmaceutical compositions.

[0561] Embodiment 4. Use of an anti-CD38 antibody in combination with a T-cell redirecting therapeutic agent. Therefore, it is useful in developing combinations for treating cancer patients who need it. A use characterized by functioning to produce.

[0562] Embodiment 5. An anti-CD38 antibody is administered before the administration of a T-cell redirecting therapeutic agent. An anti-CD38 antibody for use in one of the four administration methods (1-4).

[0563] Embodiment 6. The T-cell redirection therapeutic agent is BCMA, GPRC5D, CD33, CD Embodiments 1-5, coupled to 123, CD19, PSMA, TMEFF2, or CD20. An anti-CD38 antibody for use by any one of the following means.

[0564] Embodiment 7. The T cell redirection therapeutic agent is CD3, CD3 epsilon (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, Any of Embodiments 1 to 6, coupled to BTNL8, PD-1, CD195, or NKG2C Anti-CD38 antibody for use by one of the following:

[0565] Embodiment 8. A T-cell redirecting therapeutic agent is Heavy chain complementarity determination region 1 (HCDR1) of SEQ ID NO: 33, HCDR2 of SEQ ID NO: 34, HCDR3 at sequence number 35, light chain complementarity determination region 1 (LCDR1) at sequence number 36, sequence number LCDR2 of number 37, and LCDR3 of sequence number 38, The heavy chain variable region (VH) of sequence number 39 and the light chain variable region (VL) of sequence number 40, HCDR1 (sequence number 74), HCDR2 (sequence number 75), HCDR3 (sequence number 76), LCDR1 of sequence number 77, LCDR2 of sequence number 78, and LCDR3 of sequence number 79 , VH of sequence number 80 and VL of sequence number 81, CD3 binding domains of sequence number 53: HCDR1, HCDR2, HCDR3, LCDR 1, LCDR2, and LCDR3, or CD3 binding domains including VH and VL of the CD3 binding domain of sequence number 53, An anti-CD38 antibody for use according to any one of Embodiments 1 to 7.

[0566] Embodiment 9. A T-cell redirecting therapeutic agent is HCDR1 (sequence number 23), HCDR2 (sequence number 24), HCDR3 (sequence number 25), LCDR1 of sequence number 26, LCDR2 of sequence number 27, and LCDR3 of sequence number 28 This includes the BCMA binding domain, as well as HCDR1 of SEQ ID NO: 33 and HCD of SEQ ID NO: 34. R2, HCDR3 (sequence number 35), LCDR1 (sequence number 36), LCDR (sequence number 37) 2, and the CD3 binding domain including LCDR3 of Sequence ID No. 38, and / or BCMA binding domains including VH of SEQ ID NO: 29 and VL of SEQ ID NO: 30, and sequence Embodiments 1 to 40 include CD3-binding domains including VH number 39 and VL number 40. An anti-CD38 antibody for use by any one of the eight methods.

[0567] Embodiment 10. The T cell redirection therapeutic agent is 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 sequence Use according to any one of Embodiments 1 to 9, including the second light chain (LC2) number 42. Anti-CD38 antibody.

[0568] Embodiment 11. A T cell redirecting therapeutic agent is HCDR1 (sequence number 43), HCDR2 (sequence number 44), HCDR3 (sequence number 45), LCDR1 of sequence number 46, LCDR2 of sequence number 47, and LCDR3 of sequence number 48 The GPRC5D binding domain, as well as HCDR1 of SEQ ID NO: 33 and H of SEQ ID NO: 34 CDR2, HCDR3 (sequence number 35), LCDR1 (sequence number 36), LC (sequence number 37) CD3 binding domains including DR2 and LCDR3 of Sequence ID No. 38, and / or The GPRC5D binding domain includes VH of SEQ ID NO: 49 and VL of SEQ ID NO: 50, and Embodiments including CD3 binding domains, VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40 Anti-CD38 antibody for use in any one of the following categories: 1-10.

[0569] Embodiment 12. T cell redirection therapy involves HC1 of SEQ ID NO: 51, L of SEQ ID NO: 52 Embodiment 111 includes C1, HC2 of SEQ ID NO: 41, and LC2 of SEQ ID NO: 42 Anti-CD38 antibody for use by one of the following:

[0570] Embodiment 13. A T cell redirecting therapeutic agent is HCDR1 (sequence number 84), HCDR2 (sequence number 85), HCDR3 (sequence number 86), LCDR1 of sequence number 87, LCDR2 of sequence number 88, and LCDR3 of sequence number 89 CD33 binding domains including HCDR1 of SEQ ID NO: 74, and HCD of SEQ ID NO: 75 R2, HCDR3 (sequence number 76), LCDR1 (sequence number 77), LCDR (sequence number 78) 2, and the CD3 binding domain including LCDR3 of Sequence ID No. 79, and / or CD33 binding domains including VH of SEQ ID NO: 90 and VL of SEQ ID NO: 91, and sequence Embodiments 1 to 80 include CD3-binding domains including VH (number 80) and VL (sequence number 81). Anti-CD38 antibody for use by any one of 12 methods.

[0571] Embodiment 14. T cell redirection therapy involves HC1 of SEQ ID NO: 92, L of SEQ ID NO: 93 Embodiments 1 to 13 include C1, HC2 of SEQ ID NO: 82, and LC2 of SEQ ID NO: 83. Anti-CD38 antibody for use by one of the following agents.

[0572] Embodiment 15. A T-cell redirecting therapeutic agent is HCDR1 (sequence number 94), HCDR2 (sequence number 95), HCDR3 (sequence number 96), LCDR1 of sequence number 9, LCDR2 of sequence number 10, and LCDR3 of sequence number 59 Includes CD123 binding domain, as well as HCDR1 of SEQ ID NO: 33 and HCD of SEQ ID NO: 34 R2, HCDR3 (sequence number 35), LCDR1 (sequence number 36), LCDR (sequence number 37) 2, and the CD3 binding domain including LCDR3 of Sequence ID No. 38, and / or CD123 binding domains including VH of SEQ ID NO: 100 and VL of SEQ ID NO: 61, and Embodiments including CD3 binding domains, VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40 An anti-CD38 antibody for use in any one of the following cases: 1-14.

[0573] Embodiment 16. T cell redirection therapy is performed using HC1 of SEQ ID NO: 102, SEQ ID NO: 63 Embodiments 1 to 15 include LC1, HC2 of SEQ ID NO: 41, and LC2 of SEQ ID NO: 42 Anti-CD38 antibody for use by any one of the following means.

[0574] Embodiment 17. A T cell redirecting therapeutic agent is CD19 binding domain of sequence number 53: HCDR1, HCDR2, HCDR3, LCD CD19 binding domains including R1, LCDR2, and LCDR3, and Sequence ID No. 53 CD3 binding domains HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and CD3 binding domains including LCDR3, and / or Use according to any one of Embodiments 1 to 16, including the amino acid sequence of Sequence ID No. 53 Anti-CD38 antibody.

[0575] Embodiment 18. A T-cell redirecting therapeutic agent is HCDR1 (sequence number 54), HCDR2 (sequence number 55), HCDR3 (sequence number 56), LCDR1 of sequence number 9, LCDR2 of sequence number 10, and LCDR3 of sequence number 59 Includes PSMA-binding domain, as well as HCDR1 of SEQ ID NO: 33 and HCDR of SEQ ID NO: 34 2. HCDR3 (sequence number 35), LCDR1 (sequence number 36), LCDR2 (sequence number 37) , and the CD3 binding domain including LCDR3 of SEQ ID NO: 38, and / or PSMA-binding domains including VH of SEQ ID NO: 60 and VL of SEQ ID NO: 61, and sequence Embodiments 1 to 40 include CD3-binding domains including VH number 39 and VL number 40. Anti-CD38 antibody for use by any one of 17.

[0576] Embodiment 19. T cell redirection therapy involves HC1 of SEQ ID NO: 62, L of SEQ ID NO: 63 Embodiments 1 to 18 include C1, HC2 of SEQ ID NO: 41, and LC2 of SEQ ID NO: 42. Anti-CD38 antibody for use by one of the following agents.

[0577] Embodiment 20. A T cell redirecting therapeutic agent is HCDR1 (sequence number 64), HCDR2 (sequence number 65), HCDR3 (sequence number 66), LCDR1 of sequence number 67, LCDR2 of sequence number 68, and LCDR3 of sequence number 69 The TMEFF2 binding domain, as well as HCDR1 of SEQ ID NO: 74, and H of SEQ ID NO: 75 CDR2, HCDR3 (sequence number 76), LCDR1 (sequence number 77), LC (sequence number 78) CD3 binding domains including DR2 and LCDR3 of SEQ ID NO: 79, and / or The TMEFF2 binding domains include VH of SEQ ID NO: 70 and VL of SEQ ID NO: 71, and Embodiments including CD3 binding domains including VH of SEQ ID NO: 80 and VL of SEQ ID NO: 81 An anti-CD38 antibody for use in any one of the following cases: 1-19.

[0578] Embodiment 21. T cell redirection therapy involves HC1 of SEQ ID NO: 72, L of SEQ ID NO: 73 Embodiments 1 to 20 include C1, HC2 of SEQ ID NO: 82, and LC2 of SEQ ID NO: 83. Anti-CD38 antibody for use by one of the following agents.

[0579] Embodiment 22. The T cell redirection therapeutic agent is a multispecific antibody, a chimeric antigen receptor (C T cells containing AR, or CAR, used in any one of Embodiments 1 to 21 Anti-CD38 antibody for this purpose.

[0580] Embodiment 23. The multispecific antibody is IgG1, IgG2, IgG3, or IgG4. A sotype of anti-CD38 antibody for use according to Embodiment 22.

[0581] Embodiment 24. Multispecific antibody binding to Fcγ receptor (FcγR) Use according to Embodiment 22 or 23, which includes one or more Fc substitutions to reduce the amount Anti-CD38 antibody.

[0582] Embodiment 25. One or more Fc substitutions are performed on IgG4, F234A / L235A L234A / L235A on IgG1, V234A / G237A / P23 on IgG2 8S / H268A / V309L / A330S / P331S, F234A / L on IgG4 235A, S228P / F234A / L235A on IgG4, all Ig isotypes N297A on top, V234A / G237A on IgG2, K214T / E2 on IgG1 33P / L234V / L235A / G236 Missing / A327G / P331A / D365E / L358M, H268Q / V309L / A330S / P331S on IgG2, IgG S267E / L328F on 1, L234F / L235E / D265A on IgG1, I L234A / L235A / G237A / P238S / H268A / A330S on gG1 / P331S, S228P / F234A / L235A / G237A / P23 on IgG4 8S, and S228P / F234A / L235A / G236 deletion / G237 on IgG4 Selected from the group consisting of A / P238S, the residue numbering follows the EU index. An anti-CD38 antibody for use according to any one of embodiments 22 to 24.

[0583] Embodiment 26. A multispecific antibody further comprising the S228P substitution, as in Embodiment 25. Anti-CD38 antibody for use.

[0584] Embodiment 27. A multispecific antibody has a first CH3 domain or a second CH3 domain In the first CH3 domain, or in both the first and second CH3 domains, one or more Anti-CD38 for use by any one of embodiments 22-26, including asymmetric substitution of antibody.

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

[0586] Embodiment 29. The subject has newly diagnosed cancer, and one of Embodiments 1 to 28 Anti-CD38 antibody for use by [unspecified]

[0587] Embodiment 30. The subject is a patient whose cancer has relapsed or is refractory to previous anti-cancer treatment, as described in Embodiment 1~ An anti-CD38 antibody for use by any one of the 29 specified agents.

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

[0589] Embodiment 32. Hematological malignancies include multiple myeloma, smoldering multiple myeloma, and benign monochloromyeloma. Lymphatic gamma globulinemia (MGUS), acute lymphoblastic leukemia (ALL), diffuse large cell carcinoma B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), follicular lymphoma (FL) ), mantle cell lymphoma (MCL), Waldenström's hypergammaglobulinemia, morphology Plasma cell leukemia, light chain amyloidosis (AL), precursor B-cell lymphoblastic leukemia, progenitor Somatic B-cell lymphoblastic leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) ), chronic lymphocytic leukemia (CLL), B-cell malignancy, chronic myeloid leukemia (CML), Ally cell leukemia (HCL), blastic plasmacytoid dendritic cell neoplasm, Hodgkin lymphoma, non-H. Dikin lymphoma, marginal zone B-cell lymphoma (MZL), or mucosal-associated lymphoid tissue lymphoma ( MALT), plasma cell leukemia, anaplastic large cell lymphoma (ALCL), leukemia, or lymph An anti-CD38 antibody for use according to any one of embodiments 1 to 31.

[0590] Embodiment 33. Multiple myeloma is a newly diagnosed multiple myeloma, as in Embodiment 1~ Anti-CD38 antibody for use by any one of 32.

[0591] Embodiment 34. Multiple myeloma is relapsed or refractory multiple myeloma, as in Embodiments 1-3. An anti-CD38 antibody for use by either of the following two methods.

[0592] Embodiment 35. Multiple myeloma is a high-risk multiple myeloma, as in Embodiments 1-34. Anti-CD38 antibody for use by one of the following agents.

[0593] Embodiment 36. A subject with high-risk multiple myeloma, t(4;14)(p16;q32); t(14;16)(q32;q23); del17p; 1qAmp; t(4;14)(p16;q32) and t(14;16)(q32;q23); t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23), and de Having one or more chromosomal abnormalities, including l17p, or any combination thereof. an anti-CD38 antibody for use according to Embodiment 35.

[0594] Embodiment 37. Multiple myeloma is treated with anti-CD38 antibody, lenalidomide, bortezomib, and poma. Lidomide, carfilzomib, erotozumab, ixazomib, melphalan, or sa For patients who have relapsed or refractory to treatment with lidomide or any combination thereof, An anti-CD38 antibody for use according to any one of embodiments 1 to 36.

[0595] Embodiment 38. The solid tumor is prostate cancer, lung cancer, liver cancer, cervical cancer, Colon cancer, breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, melanoma, glioblastoma, esophageal cancer, gastric cancer (gastri c cancer), stomach cancer, kidney cancer, colon cancer, bladder cancer, cervical cancer Cinoma, melanoma, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, head and neck cancer, glioma, or glioblastoma An anti-CD38 antibody for use according to any one of embodiments 1 to 37.

[0596] Embodiment 39. Prostate cancer is recurrent, refractory, malignant, or castration-resistant prostate cancer, These are any combination of anti-CD38 antibodies for use according to Embodiment 38.

[0597] Embodiment 40. AML is characterized by AML with at least one gene abnormality, polyseries dysplasia. Accompanying AML, therapy-related AML, undifferentiated AML, most undifferentiated AML, differentiated AML, acute bone AML Melanomonocytic leukemia, acute monocytic leukemia, acute erythrocytic leukemia, acute megakaryoblastic leukemia, acute According to Embodiment 32, the disease is basophilic leukemia, acute panmyelopathy with fibrosis, or myelosarcoma. Anti-CD38 antibody for use.

[0598] Embodiment 41. At least one gene abnormality causes translocation between chromosome 8 and chromosome 21. locus, translocation or inversion of chromosome 16, translocation between chromosome 15 and chromosome 17, 11 Changes in chromosome 3, or fms-related tyrosine kinase 3 (FLT3), nucleophosmin (NPM1), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase DNA methyltransferase 2 (IDH2), DNA (cytosine-5)-methyltransferase 3 (DNM T3A), CCAAT / enhancer-binding protein alpha (CEBPA), U2 nucleus Small RNA cofactor 1 (U2AF1), zeste2 Polycomb repression complex 2 subunit Chromosome enhancer (EZH2), chromosome structure maintenance 1A (SMC1A), or chromosome structure Anti-CD38 for use in embodiment 40, which is a mutation in structural maintenance 3 (SMC3). antibody.

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

[0600] Embodiment 43. ALL is B-cell lineage ALL, T-cell lineage ALL, adult ALL, or small An anti-CD38 antibody for use in infant ALL, according to Embodiment 32.

[0601] Embodiment 44. A subject having ALL has the Philadelphia chromosome, or BC Resistance to or acquired tolerance to R-ABL kinase inhibitors An anti-CD38 antibody having properties for use according to Embodiment 43.

[0602] Embodiment 45. The anti-CD38 antibody is HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7 , HCDR3 of SEQ ID NO: 8, LCDR1 of SEQ ID NO: 9, LCDR2 of SEQ ID NO: 10, and For use in any one of Embodiments 1 to 44, including LCDR3 of Sequence ID No. 11 Anti-CD38 antibody.

[0603] Embodiment 46. An anti-CD38 antibody comprising VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 An anti-CD38 antibody for use in one of the application methods 1 to 45.

[0604] Embodiment 47. The anti-CD38 antibody is of the IgG1 isotype, as in Embodiments 1-46. Anti-CD38 antibody for use by any one of the following means.

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

[0606] Embodiment 49. The anti-CD38 antibody is VH of sequence number 14 and VL of sequence number 15, VH of sequence number 16 and VL of sequence number 17, VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or Any one of Embodiments 1 to 44, including VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21 Anti-CD38 antibody for use by [unspecified].

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

[0608] Embodiment 51. The T cell redirection therapeutic agent is a BCMA x CD3 bispecific antibody, GP RC5D×CD3 bispecific antibody, CD33×CD3 bispecific antibody, CD19×CD3 Bispecific antibody, CD123×CD3 bispecific antibody, PSMA×CD3 bispecific antibody , or a TMEFF2×CD3 bispecific antibody, one of any one of Embodiments 1 to 50 Anti-CD38 antibody for use by [unspecified].

[0609] Embodiment 52. Embodiment 1 further includes administering one or more anti-cancer treatments to the subject. Anti-CD38 antibody for use by ~51

[0610] Embodiment 53. One or more anti-cancer treatments include autologous stem cell transplantation (ASCT), radiation therapy, etc. The implementation is selected from the group consisting of surgery, chemotherapy agents, immunomodulators, and targeted cancer therapies. An anti-CD38 antibody for use in any one of states 1-52.

[0611] Embodiment 54. One or more anticancer treatments include lenalidomide, thalidomide, and pomaline. Domido, bortezomib, carfilzomib, erotozumab, ixazomib, melphalan Dexamethasone, vincristine, cyclophosphamide, hydroxydaunorubicin, Prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponad Tinib, bafetinib, salakatinib, tozacertive, or danucertive, sitarab Daunorubicin, Idarubicin, Mitoxanthrone, Hydroxyurea, Decitabine Cladribine, fludarabine, topotecan, etoposide 6-thioguanine, corticos Teroids, methotrexate, 6-mercaptopurine, azacitidine, arsenic trioxide, and Selected from the group consisting of all trans retinoic acids, or any combination thereof. An anti-CD38 antibody for use according to any one of Embodiments 1 to 53.

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

[0613] Embodiment 56. Anti-CD38 antibody is mixed with approximately 25 mM acetic acid and approximately 60 mM sodium chloride. Approximately 140 mannitol and approximately 0.04% w / v polysorbate-20 (PS-20) It contains approximately 20 mg / mL to 120 mg / mL of anti-CD38 antibody and has a pH of approximately 5.5. Embodiments 1 to 55, which are administered or provided for administration in a pharmaceutical composition. An anti-CD38 antibody for use by any one of the following means.

[0614] Embodiment 57. The anti-CD38 antibody is approximately 1,800 mg of anti-CD38 antibody and approximately 30,0 A pharmaceutical composition containing 00U of rHuPH20 is administered or provided for administration. An anti-CD38 antibody for use according to any one of embodiments 1 to 53.

[0615] Embodiment 58. The anti-CD38 antibody is approximately 120 mg / mL of anti-CD38 antibody and approximately 2,0 A pharmaceutical composition containing 00 U / mL of rHuPH20 is administered, or for the purpose of administration. An anti-CD38 antibody provided for use according to Embodiment 57.

[0616] Embodiment 59. Anti-CD38 antibody, Approximately 5 mM to approximately 15 mM histidine, Sorbitol in a concentration of approximately 100 mM to 300 mM, PS-20 with approximately 0.01% w / v to approximately 0.04% w / v, It contains approximately 1 mg / mL to 2 mg / mL of methionine and has a pH of approximately 5.5 to 5.6. Embodiments 57-58, which are administered in a pharmaceutical composition or provided for administration. An anti-CD38 antibody for use by any one of the following means.

[0617] Embodiment 60. The anti-CD38 antibody is Approximately 1,800 mg of anti-CD38 antibody, Approximately 30,000U of rHuPH20, Approximately 10 mM histidine, Approximately 300 mM sorbitol and PS-20 with approximately 0.04% (w / v), A pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6 is administered. Use by any one of Embodiments 57-59, which is either used or provided for administration. Anti-CD38 antibody for this purpose.

[0618] Embodiment 61. The anti-CD38 antibody is Approximately 120 mg / mL of anti-CD38 antibody, rHuPH20 at approximately 2,000 U / mL, Approximately 10 mM histidine, Approximately 300 mM sorbitol and PS-20 with approximately 0.04% (w / v), A pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6 is administered. Use by any one of Embodiments 57-60, which is either used or provided for administration. Anti-CD38 antibody for this purpose.

[0619] Embodiment 62. For use in the treatment of subjects with cancer, in combination with an anti-CD38 antibody. This is a BCMA x CD3 bispecific antibody.

[0620] Embodiment 63. The subject was subjected to an anti-CD38 antibody before administration of a BCMA×CD3 bispecific antibody. A BCMA×CD3 bispecific antibody for use according to Embodiment 62, which is being treated.

[0621] Embodiment 64. BCMA × CD3 bispecific antibody, sequence of HCDR1 of SEQ ID NO: 23 HCDR2 with number 24, HCDR3 with sequence number 25, LCDR1 with sequence number 26, sequence number BCMA-binding domains including LCDR2 of sequence number 27 and LCDR3 of sequence number 28, and HCDR1 (sequence number 33), HCDR2 (sequence number 34), HCDR3 (sequence number 35), LCDR1 (sequence number 36), LCDR2 (sequence number 37), and LCDR3 (sequence number 38) BCMA× for use according to Embodiment 62 or 63, including a CD3 binding domain. CD3 bispecific antibody.

[0622] Embodiment 65. The BCMA binding domain is VH of SEQ ID NO: 29 and VL of SEQ ID NO: 30 The CD3 binding domain includes VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40, A BCMA × CD3 bispecific antibody for use in any one of the application methods 62-64.

[0623] Embodiment 66. The BCMA×CD3 bispecific antibody is of the IgG4 isotype, H Phenylalanine is at position 405 of C1 and arginine is at position 409, and at position 405 of HC2 It contains leucine and lysine at position 409, and the residue numbering follows the EU index. BCMA×CD3 bispecific antibody for use according to any one of embodiments 62-65 .

[0624] Embodiment 67. The BCMA×CD3 bispecific antibody is 228 for both HC1 and HC2. Embodiment 62 further comprises proline at position 234, alanine at position 234, and alanine at position 235. BCMA × CD3 bispecific antibody for use in any of the following cases (~66).

[0625] Embodiment 68. The BCMA×CD3 bispecific antibody is HC1 of SEQ ID NO: 31, SEQ ID NO: Embodiment 62 includes LC1 of 32, HC2 of SEQ ID NO: 41, and LC2 of SEQ ID NO: 42. BCMA x CD3 bispecific antibody for use in any of the following cases (~67).

[0626] Embodiment 69. The cancer is a BCMA-expressing cancer, according to any one of Embodiments 62 to 68. BCMA x CD3 bispecific antibody for use.

[0627] Embodiment 70. The cancer is a hematological malignancy, according to any one of Embodiments 62 to 69. BCMA x CD3 bispecific antibody for use.

[0628] Embodiment 71. The subject is an anti-CD38 antibody, lenalidomide, bortezomib, and pomalidomide. Carfilzomib, erotozumab, ixazomib, melphalan, or thalidomyne The embodiment is one in which the patient is relapsed or refractory to treatment with D, or any combination thereof. A BCMA x CD3 bispecific antibody for use in one of the following categories: 62-70.

[0629] Embodiment 72. The subject is a patient whose condition has relapsed or is refractory to treatment with an anti-CD38 antibody. A BCMA × CD3 bispecific antibody for use in any one of the application methods 62 to 71.

[0630] Embodiment 73. Hematological malignancies include multiple myeloma, myeloma, DLBLC, CLL, and Walde. Embodiment 62~ is characterized by Ström's hypergammaglobulinemia or non-Hodgkin lymphoma. BCMA × CD3 bispecific antibody for use by any one of 72.

[0631] Embodiment 74. Embodiment 73, in which the multiple myeloma is a newly diagnosed multiple myeloma. BCMA × CD3 bispecific antibody for use by [unspecified method].

[0632] Embodiment 75. Multiple myeloma is relapsed or refractory multiple myeloma, as in Embodiment 74. BCMA x CD3 bispecific antibody for use by [unspecified method].

[0633] Embodiment 76. Multiple myeloma is a high-risk multiple myeloma, and the method used in Embodiment 74 is used. BCMA x CD3 bispecific antibody for use.

[0634] Embodiment 77. A subject with high-risk multiple myeloma, t(4;14)(p16;q32); t(14;16)(q32;q23); del17p; 1qAmp; t(4;14)(p16;q32) and t(14;16)(q32;q23); t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23), and de Having one or more chromosomal abnormalities, including l17p, or any combination thereof. , BCMA×CD3 bispecific antibody for use according to Embodiment 76.

[0635] Embodiment 78. The anti-CD38 antibody is HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7 , HCDR3 of SEQ ID NO: 8, LCDR1 of SEQ ID NO: 9, LCDR2 of SEQ ID NO: 10, and For use in any one of embodiments 62 to 77, including LCDR3 of sequence number 11 BCMA x CD3 bispecific antibody.

[0636] Embodiment 79. An anti-CD38 antibody comprising VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 A BCMA × CD3 bispecific antibody for use in any one of the application methods 62-78.

[0637] Embodiment 80. Embodiments 62-79, in which the anti-CD38 antibody is of the IgG1 isotype. A BCMA x CD3 bispecific antibody for use by one of the following means.

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

[0639] Embodiment 82. The anti-CD38 antibody VH of sequence number 14 and VL of sequence number 15, VH of sequence number 16 and VL of sequence number 17, VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or Any one of embodiments 62 to 77, including VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21 BCMA x CD3 bispecific antibody for use by [unspecified method].

[0640] Embodiment 83. The anti-CD38 antibody is of the IgG1 isotype, according to Embodiment 82. BCMA x CD3 bispecific antibody for use.

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

[0642] Embodiment 85. BCMA x CD3 bispecific antibody and anti-CD38 antibody administered by intravenous injection. Therefore, BCMA×C for use according to any one of embodiments 62 to 84 is administered. D3 bispecific antibody.

[0643] Embodiment 86. BCMA × CD3 bispecific antibody is administered by intravenous injection, anti The CD38 antibody is administered by subcutaneous injection, according to any one of embodiments 62 to 84. BCMA x CD3 bispecific antibody for use.

[0644] Embodiment 87. Use according to any one of Embodiments 62 to 86, wherein the subject is a human. A BCMA x CD3 bispecific antibody for this purpose.

[0645] Embodiment 88. Embodiment 6, further comprising administering one or more anti-cancer treatments to the subject. A BCMA x CD3 bispecific antibody for use in any of the following categories: 2-87.

[0646] Embodiment 89. One or more anti-cancer treatments include autologous stem cell transplantation (ASCT), radiation therapy, etc. The implementation is selected from the group consisting of surgery, chemotherapy agents, immunomodulators, and targeted cancer therapies. BCMA × CD3 bispecific antibody for use in state 88.

[0647] Embodiment 90. One or more anticancer treatments include lenalidomide, thalidomide, and pomaline. Domido, bortezomib, carfilzomib, erotozumab, ixazomib, melphalan , prednisone, or dexamethasone, or any combination thereof BCMA×CD3 for use by any one of embodiments 88-89, selected from the above. Bispecific antibodies.

[0648] Embodiment 91. Anti-CD38 antibody is mixed with approximately 25 mM acetic acid and approximately 60 mM sodium chloride. Approximately 140 mannitol and approximately 0.04% w / v polysorbate-20 (PS-20) It contains approximately 20 mg / mL to 120 mg / mL of anti-CD38 antibody and has a pH of approximately 5.5. Embodiments 62-9, which are administered or provided for administration in a pharmaceutical composition. BCMA×CD3 bispecific antibody for use with either 0 or 1.

[0649] Embodiment 92. The anti-CD38 antibody is approximately 1,800 mg of anti-CD38 antibody and approximately 30,0 A pharmaceutical composition containing 00U of rHuPH20 is administered or provided for administration. BCMA×CD3 dual special for use by any one of embodiments 62 to 90 Heterogeneous antibodies.

[0650] Embodiment 93. The anti-CD38 antibody is approximately 120 mg / mL of anti-CD38 antibody and approximately 2,0 A pharmaceutical composition containing 00 U / mL of rHuPH20 is administered, or for the purpose of administration. A BCMA×CD3 bispecific antibody provided for use according to Embodiment 92.

[0651] Embodiment 94. The anti-CD38 antibody is Approximately 5 mM to approximately 15 mM histidine, Sorbitol in a concentration of approximately 100 mM to 300 mM, PS-20 with approximately 0.01% w / v to approximately 0.04% w / v, It contains approximately 1 mg / mL to 2 mg / mL of methionine and has a pH of approximately 5.5 to 5.6. , in the pharmaceutical composition, which is administered or provided for administration, as in Embodiments 92-93 A BCMA x CD3 bispecific antibody for use with either one of the following:

[0652] Embodiment 95. Anti-CD38 antibody, Approximately 1,800 mg of anti-CD38 antibody, Approximately 30,000U of rHuPH20, Approximately 10 mM histidine, Approximately 300 mM sorbitol and PS-20 with approximately 0.04% (w / v), A pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6 is administered. Use by any one of Embodiments 92-94, which is either used or provided for administration. BCMA x CD3 bispecific antibody for this purpose.

[0653] Embodiment 96. The anti-CD38 antibody is Approximately 120 mg / mL of anti-CD38 antibody, rHuPH20 at approximately 2,000 U / mL, Approximately 10 mM histidine, Approximately 300 mM sorbitol and PS-20 with approximately 0.04% (w / v), A pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6 is administered. Use by any one of Embodiments 92-95, which is either used or provided for administration. BCMA x CD3 bispecific antibody for this purpose.

[0654] Embodiment 97. BCMA×CD3 bispecific antibody for use in the treatment of subjects with cancer The body, and the subject, has relapsed or is refractory to previous treatment with anticancer drugs, BC MA×CD3 bispecific antibody.

[0655] Embodiment 98. BCMA × CD3 bispecific antibody, sequence of HCDR1 of SEQ ID NO: 23, HCDR2 with number 24, HCDR3 with sequence number 25, LCDR1 with sequence number 26, sequence number BCMA-binding domains including LCDR2 of sequence number 27 and LCDR3 of sequence number 28, and HCDR1 (sequence number 33), HCDR2 (sequence number 34), HCDR3 (sequence number 35), LCDR1 (sequence number 36), LCDR2 (sequence number 37), and LCDR3 (sequence number 38) BCMA×CD3 for use according to Embodiment 97, including a CD3 binding domain Heavy specific antibody.

[0656] Embodiment 99. The BCMA binding domain is VH of SEQ ID NO: 29 and VL of SEQ ID NO: 30 The CD3 binding domain includes VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40, BCMA × CD3 bispecific antibody for use according to application method 97 or 98.

[0657] Embodiment 100. The BCMA×CD3 bispecific antibody is of the IgG4 isotype, Phenylalanine is located at position 405 of HC1 and arginine at position 409, and at position 405 of HC2. It contains leucine at position 409 and lysine at position 409, and the residue numbering follows the EU index. , BCMA×CD3 bispecific antibody for use according to any one of embodiments 97 to 99 body.

[0658] Embodiment 101. The BCMA×CD3 bispecific antibody is 22% specific to both HC1 and HC2. Embodiment 1 further comprises proline at position 8, alanine at position 234, and alanine at position 235. BCMA × CD3 bispecific antibody for use by 00.

[0659] Embodiment 102. The BCMA×CD3 bispecific antibody is HC1 of SEQ ID NO. 31, sequence number Embodiment 9 includes LC1 of number 32, HC2 of sequence number 41, and LC2 of sequence number 42. A BCMA × CD3 bispecific antibody for use in any of the following categories: 7-101.

[0660] Embodiment 103. The cancer is a hematological malignancy, according to any one of Embodiments 97 to 102. BCMA x CD3 bispecific antibody for use by [unspecified method].

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

[0662] Embodiment 105. Multiple myeloma is a high-risk multiple myeloma, according to Embodiment 104. BCMA x CD3 bispecific antibody for use.

[0663] Embodiment 106. A subject with high-risk multiple myeloma, t(4;14)(p16;q32); t(14;16)(q32;q23); del17p; 1qAmp; t(4;14)(p16;q32) and t(14;16)(q32;q23); t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23), and de Having one or more chromosomal abnormalities, including l17p, or any combination thereof. BCMA×CD3 bispecific antibody for use according to Embodiment 105.

[0664] Embodiment 107. The target is anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide. Carfilzomib, erotozumab, ixazomib, melphalan, or thalidomide In practice, treatment with id, or any combination thereof, is refractory or relapsed. A BCMA × CD3 bispecific antibody for use in any one of states 97-106.

[0665] Embodiment 108. Embodiment in which the subject is relapsed in response to treatment with an anti-CD38 antibody. A BCMA x CD3 bispecific antibody for use in any one of the following categories: 97-107.

[0666] Embodiment 109. Anti-CD38 antibody is HCDR1 of SEQ ID NO: 6, HCDR of SEQ ID NO: 7 2. HCDR3 of sequence number 8, LCDR1 of sequence number 9, LCDR2 of sequence number 10, and Use according to any one of embodiments 97 to 108, including LCDR3 of sequence number 11. A BCMA x CD3 bispecific antibody for this purpose.

[0667] Embodiment 110. The anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 BCMA×CD3 bispecific antimicrobial for use according to any one of embodiments 97-109 body.

[0668] Embodiment 111. Embodiments 97-1, in which the anti-CD38 antibody is of the IgG1 isotype. BCMA × CD3 bispecific antibody for use by any one of the 10 methods.

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

[0670] Embodiment 113. Anti-CD38 antibody, VH of sequence number 14 and VL of sequence number 15, VH of sequence number 16 and VL of sequence number 17, VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or Any of embodiments 97 to 108, including VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21 A BCMA x CD3 bispecific antibody for single-use applications.

[0671] Embodiment 114. The anti-CD38 antibody is of the IgG1 isotype, as in Embodiment 113. BCMA x CD3 bispecific antibody for use by [unspecified method].

[0672] Embodiment 115. The subject is a human, and the method is used according to any one of Embodiments 97 to 114. BCMA x CD3 bispecific antibody for use.

[0673] Embodiment 116. An embodiment further comprising administering one or more anti-cancer treatments to the subject. A BCMA x CD3 bispecific antibody for use with one of the following antibody counts: 97-115.

[0674] Embodiment 117. One or more anti-cancer treatments include autologous stem cell transplantation (ASCT), radiation therapy, etc. The following are selected from the group consisting of radiotherapy, surgery, chemotherapy, immunomodulatory agents, and targeted cancer therapies. BCMA × CD3 bispecific antibody for use according to Form 116.

[0675] Embodiment 118. One or more anticancer treatments include lenalidomide, thalidomide, and poma. Lidomide, Bortezomib, Carfilzomib, Elotozumab, Ixazomib, Melphala A group consisting of , prednisone, or dexamethasone, or any combination thereof. A BCMA×CD3 bispecific antibody selected from, for use according to Embodiment 116.

[0676] Embodiment 119. BCMA-conjugated domain containing VH of SEQ ID NO: 29 and VL of SEQ ID NO: 30 It contains the in, as well as CD3 binding domains including VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40. This product contains a BCMA x CD3 bispecific antibody and an antibody containing VH (SEQ ID NO: 4) and VL (SEQ ID NO: 5). A pharmaceutical composition containing a CD38 antibody.

[0677] Embodiment 120. The BCMA×CD3 bispecific antibody is HC1 of Sequence ID No. 31, sequence number Includes LC1 of sequence number 32, HC2 of sequence number 41, and LC2 of sequence number 42, anti-CD38 The pharmaceutical composition of Embodiment 119, wherein the antibody comprises the HC of SEQ ID NO: 12 and the LC of SEQ ID NO: 13. thing.

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

[0679] Embodiment 122. Approximately 25 mM acetic acid, approximately 60 mM sodium chloride, approximately 140 mannitol , and approximately 20 mg / in polysorbate-20 (PS-20) at approximately 0.04% w / v Embodiment 12 contains approximately 120 mg / mL of anti-CD38 antibody and has a pH of approximately 5.5. A pharmaceutical composition of type 1.

[0680] Embodiment 123. Approximately 1,800 mg of anti-CD38 antibody and approximately 30,000 U of rHuP A pharmaceutical composition of Embodiment 121, comprising H2O.

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

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

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

[0684] Embodiment 127. The pharmaceutical composition is Anti-CD38 antibody at approximately 100 mg / mL to approximately 120 mg / mL, Approximately 5 mM to approximately 15 mM histidine, Sorbitol in a concentration of approximately 100 mM to 300 mM, PS-20 with approximately 0.01% w / v to approximately 0.04% w / v, It contains approximately 1 mg / mL to 2 mg / mL of methionine and has a pH of approximately 5.5 to 5.6. , a pharmaceutical composition of embodiment 126.

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

[0686] Embodiment 129. The medical device of Embodiment 127 or 128, comprising approximately 300 mM sorbitol. A pharmaceutical composition.

[0687] Embodiment 130. Embodiments 127-12, containing approximately 0.04% (w / v) of PS-20. One of the nine pharmaceutical compositions.

[0688] Embodiment 131. Containing approximately 1 mg / mL of methionine, any of Embodiments 127-130 Any one of the following pharmaceutical compositions.

[0689] Embodiment 132. Approximately 1,800 mg of anti-CD38 antibody, Approximately 30,000U of rHuPH20, Approximately 10 mM histidine, Approximately 300 mM sorbitol and PS-20 with approximately 0.04% (w / v), Embodiments 127-131 contain approximately 1 mg / mL of methionine and have a pH of approximately 5.6. Any one of the following pharmaceutical compositions.

[0690] Embodiment 133. Approximately 120 mg / mL of anti-CD38 antibody, rHuPH20 at approximately 2,000 U / mL, Approximately 10 mM histidine, Approximately 300 mM sorbitol and PS-20 with approximately 0.04% (w / v), Embodiments 127-132 contain approximately 1 mg / mL of methionine and have a pH of approximately 5.6. Any one of the following pharmaceutical compositions.

[0691] Embodiment 134. A kit comprising any one of the pharmaceutical compositions from Embodiments 119 to 133. .

[0692] Embodiment 135. For use in the treatment of subjects with cancer, in combination with an anti-CD38 antibody. Therefore, it is a T-cell redirection therapy that binds to GPRC5D.

[0693] Embodiment 136. Anti-CD38 antibody is used in T-cell redirection therapy that binds to GPRC5D. Conjugated to GPRC5D for use according to Embodiment 135, administered to the subject before drug administration. A therapeutic agent that redirects T cells.

[0694] Embodiment 137. The subject is a patient whose cancer has relapsed or is refractory to treatment with previous anticancer drugs. , T cell redirection conjugated to GPRC5D for use according to Embodiment 135 or 136 A drug for treating ulcers.

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

[0696] Embodiment 139. Embodiment in which GPRC5D-expressing cancer is a hematological malignancy or a solid tumor. T cell redemption that binds to GPRC5D for use by any one of 135-138 Lectotherapy drug.

[0697] Embodiment 140. The hematological malignancy is leukemia, lymphoma, or multiple myeloma. A T-cell redirecting therapeutic agent that binds to GPRC5D for use according to Form 139.

[0698] Embodiment 141. The solid tumor is ovarian cancer, lung cancer, stomach cancer, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, Intestinal cancer, esophageal cancer, bladder cancer, cervical cancer, or malignant melanoma, as used in Embodiment 139 A T-cell redirection therapy that binds to GPRC5D.

[0699] Embodiment 142. The target is anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide. Carfilzomib, erotozumab, ixazomib, melphalan, or thalidomide Relapsed or refractory to treatment with iodine, or any combination thereof, T cell leader that binds to GPRC5D for use by any one of states 135-141 Irect medication.

[0700] Embodiment 143. The subject is relapsed or refractory to treatment with an anti-CD38 antibody. T-fine element coupled to GPRC5D for use according to any one of Embodiments 135 to 142 Cellular redirection therapy drug.

[0701] Embodiment 144. Embodiment 1, where the multiple myeloma is a newly diagnosed multiple myeloma. T cell redirection to GPRC5D for use by any one of 40-143 A drug for treating ulcers.

[0702] Embodiment 145. Embodiment 14, in which the multiple myeloma is relapsed or refractory multiple myeloma. T cell redirection that binds to GPRC5D for use by any one of 0-143 A drug for treating toxins.

[0703] Embodiment 146. Multiple myeloma is a high-risk multiple myeloma, Embodiments 140-1 T-cell redirection therapy that binds to GPRC5D for use by any one of 45 medicine.

[0704] Embodiment 147. A subject with high-risk multiple myeloma, t(4;14)(p16;q32); t(14;16)(q32;q23); del17p; 1qAmp; t(4;14)(p16;q32) and t(14;16)(q32;q23); t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23), and de Having one or more chromosomal abnormalities, including l17p, or any combination thereof. , a T-cell redirecting therapeutic agent that binds to GPRC5D for use according to Embodiment 146 .

[0705] Embodiment 148. The T cell redirection therapeutic agent is CD3, CD3 epsilon (CD3ε ), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD18 Embodiments 135~ coupled to 6, BTNL8, PD-1, CD195, or NKG2C T cell redirection therapy that binds to GPRC5D for use by any one of 147 Therapeutic medicine.

[0706] Embodiment 149. The T cell redirection therapeutic agent is HCDR1 of SEQ ID NO: 43, SEQ ID NO: HCDR2 at 44, HCDR3 at 45, LCDR1 at 46, and HCDR3 at 45. GPRC5D binding domains including LCDR2 of 7 and LCDR3 of sequence number 48, and HCDR1 (sequence number 33), HCDR2 (sequence number 34), HCDR3 (sequence number 35), LCDR1 (sequence number 36), LCDR2 (sequence number 37), and LCDR3 (sequence number 38) Use by any one of embodiments 135 to 148, including a CD3 binding domain A T-cell redirection therapy that binds to GPRC5D.

[0707] Embodiment 150. The GPRC5D binding domain is VH of SEQ ID NO: 49 and SEQ ID NO: 50 It contains VL, and the CD3 binding domain contains VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40 Hmm, coupled to GPRC5D for use according to any one of embodiments 135 to 149. T-cell redirection therapy drug.

[0708] Embodiment 151. A T cell redirecting therapeutic agent that binds to GPRC5C is a multispecific anti A body, a CAR, or a T cell expressing a CAR, any one of embodiments 135 to 150 A T-cell redirecting therapeutic agent that binds to GPRC5D for use by [unspecified].

[0709] Embodiment 152. The multispecific antibody is IgG1, IgG2, IgG3, or IgG4 Isotype, T cell receptors that bind to GPRC5D for use according to Embodiment 151 Direct-acting treatment.

[0710] Embodiment 153. A multispecific antibody interacts with the Fcγ receptor (FcγR). Any of embodiments 151 to 152, including one or more Fc substitutions that reduce bonding. A T-cell redirecting therapeutic agent that binds to GPRC5D for use by one agent.

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

[0712] Embodiment 155. The multispecific antibody further comprises an S228P substitution, according to Embodiment 154. A T-cell redirecting therapeutic agent that binds to GPRC5D for use.

[0713] Embodiment 156. A multispecific antibody has a first CH3 domain or a second CH3 domain In, or in both the first and second CH3 domains, one or more GP for use by any one of embodiments 151 to 155, including the asymmetric substitution described above. A therapeutic agent that redirects T cells by binding to RC5D.

[0714] Embodiment 157. One or more asymmetric substitutions are performed on F450L / K409R, wild type. / F409L_R409K, T366Y / F405A, T366W / F405W, F40 5W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T 394S, F405W / T394S and T366W / T366S_L368A_Y407 V, L351Y_F405A_Y407V / T394W, T366I_K392M_T3 94W / F405A_Y407V, T366L_K392M_T394W / F405A_ Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407 A / T366V_K409F, Y407A / T366A_K409F, and T350V _L351Y_F405A_Y407V / T350V_T366L_K392L_T39 A coupling to GPRC5D for use according to Embodiment 156, selected from the group consisting of 4W. A therapeutic agent that redirects T cells.

[0715] Embodiment 158. The multispecific antibody is HC1 of SEQ ID NO: 51, LC1 of SEQ ID NO: 52, Embodiments 151 to 157 include HC2 of SEQ ID NO: 41 and LC2 of SEQ ID NO: 42. A T-cell redirecting therapeutic agent that binds to GPRC5D for use by either one of the following means.

[0716] Embodiment 159. Anti-CD38 antibody is HCDR1 of SEQ ID NO: 6, HCDR of SEQ ID NO: 7 2. HCDR3 of sequence number 8, LCDR1 of sequence number 9, LCDR2 of sequence number 10, and Use by any one of embodiments 135 to 158, including LCDR3 of sequence number 11. A T-cell redirecting therapeutic agent that binds to GPRC5D.

[0717] Embodiment 160. The anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 T-fine element coupled to GPRC5D for use according to any one of Embodiments 135 to 159 Cellular redirection therapy drug.

[0718] Embodiment 161. Embodiment 135~, in which the anti-CD38 antibody is of the IgG1 isotype. T cell redirection therapy that binds to GPRC5D for use by any one of 160 Therapeutic medicine.

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

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

[0721] Embodiment 164. The anti-CD38 antibody is of the IgG1 isotype, as in Embodiment 163. A T-cell redirecting therapeutic agent that binds to GPRC5D for use.

[0722] Embodiment 165. Anti-CD38 antibody is administered at a dose of approximately 8 mg / kg to approximately 16 mg / kg. Coupled to GPRC5D for use according to any one of embodiments 135 to 164. A therapeutic agent that redirects T cells.

[0723] Embodiment 166. T-cell redirecting therapeutic agent and anti-CD38 anti-binding therapeutic agent that binds to GPRC5D The body is administered by intravenous injection, according to any one of embodiments 135 to 165. A T-cell redirecting therapeutic agent that binds to GPRC5D for use.

[0724] Embodiment 167. A T-cell redirecting therapeutic agent that binds to GPRC5D is administered by intravenous injection. Therefore, the anti-CD38 antibody is administered by subcutaneous injection, in Embodiments 135-1 T-cell redirection therapy that binds to GPRC5D for use by any one of 65 medicine.

[0725] Embodiment 168. The subject is a human, and the method is one of Embodiments 135 to 167. A T-cell redirecting therapeutic agent that binds to GPRC5D for use.

[0726] Embodiment 169. A T cell redirection therapeutic agent that binds to GPRC5D ×CD3 bispecific antibody, used according to any one of embodiments 135 to 168. A T-cell redirection therapy that binds to GPRC5D.

[0727] Embodiment 170. An embodiment further comprising administering one or more anti-cancer treatments to the subject. T cell redemption that binds to GPRC5D for use by any one of 135-170 Lectotherapy drug.

[0728] Embodiment 171. One or more anti-cancer treatments include autologous stem cell transplantation (ASCT), radiation therapy, etc. The following are selected from the group consisting of radiotherapy, surgery, chemotherapy, immunomodulatory agents, and targeted cancer therapies. A T-cell redirecting therapeutic agent that binds to GPRC5D for use according to Form 170.

[0729] Embodiment 172. One or more anticancer treatments include lenalidomide, thalidomide, and poma. Lidomide, Bortezomib, Carfilzomib, Elotozumab, Ixazomib, Melphala According to Embodiment 170, a drug selected from the group consisting of , dexamethasone, or prednisone A T-cell redirecting therapeutic agent that binds to GPRC5D for use.

[0730] Embodiment 173. Anti-CD38 antibody in approximately 25 mM acetic acid and approximately 60 mM sodium chloride. Approximately 140 mannitol and approximately 0.04% w / v polysorbate-20 (PS-20) It contains approximately 20 mg / mL to 120 mg / mL of anti-CD38 antibody, and has a pH of approximately 5.5. Embodiment 135, in which a pharmaceutical composition is administered or provided for administration. T cell redirection to GPRC5D for use by any one of ~172 A therapeutic drug.

[0731] Embodiment 174. The anti-CD38 antibody is approximately 1,800 mg of anti-CD38 antibody and approximately 30, In a pharmaceutical composition containing 000U of rHuPH20, it is administered or prepared for administration. Provided for use in any one of embodiments 135 to 172, connected to GPRC5D A therapeutic agent that combines to redirect T cells.

[0732] Embodiment 175. The anti-CD38 antibody is approximately 120 mg / mL of anti-CD38 antibody and approximately 2, In a pharmaceutical composition containing rHuPH20 at 000U / mL, or for administration A T cell leader that binds to GPRC5D for use according to Embodiment 174 is provided for this purpose. Irect medication.

[0733] Embodiment 176. Anti-CD38 antibody, Anti-CD38 antibody at approximately 100 mg / mL to approximately 120 mg / mL, Approximately 5 mM to approximately 15 mM histidine, Sorbitol in a concentration of approximately 100 mM to 300 mM, PS-20 with approximately 0.01% w / v to approximately 0.04% w / v, It contains approximately 1 mg / mL to 2 mg / mL of methionine and has a pH of approximately 5.5 to 5.6. Embodiment 174 or A T-cell redirecting therapeutic agent that binds to GPRC5D for use by 175.

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

[0735] Embodiment 178. Anti-CD38 antibody, Approximately 120 mg / mL of anti-CD38 antibody, rHuPH20 at approximately 2,000 U / mL, Approximately 10 mM histidine, Approximately 300 mM sorbitol and PS-20 with approximately 0.04% (w / v), A pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6 is administered. This is done or provided for administration, according to any one of Embodiments 174 to 177. A T-cell redirecting therapeutic agent that binds to GPRC5D for use.

[0736] Embodiment 179. GPRC5D×CD3 dual-type for use in the treatment of subjects with cancer Heterozygous antibodies, in which the patient has relapsed or is refractory to treatment with previous anticancer drugs. , GPRC5D×CD3 bispecific antibody.

[0737] Embodiment 180. A bispecific antibody of GPRC5D×CD3 corresponds to HCDR1 of SEQ ID NO: 43. , HCDR2 (sequence number 44), HCDR3 (sequence number 45), LCDR1 (sequence number 46), GPRC5D-bound domains including LCDR2 (sequence number 47) and LCDR3 (sequence number 48) In, as well as HCDR1 of sequence number 33, HCDR2 of sequence number 34, and H of sequence number 35. CDR3, LCDR1 of sequence number 36, LCDR2 of sequence number 37, and sequence number 38 GPR for use according to Embodiment 179, including a CD3 binding domain including LCDR3. C5D×CD3 bispecific antibody.

[0738] Embodiment 181. The GPRC5D binding domain is VH of SEQ ID NO: 49 and SEQ ID NO: 50 It contains VL, and the CD3 binding domain contains VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40 GPRC5D×CD3 bispecific antibody for use according to Embodiment 179 or 180 .

[0739] Embodiment 182. The GPRC5D×CD3 bispecific antibody is of the IgG4 isotype. Phenylalanine is located at position 405 of HC1 and arginine at position 409, and 4 of HC2 It contains leucine at position 05 and lysine at position 409, and the residue numbering is in line with the EU index. Accordingly, GPRC5D×CD3 for use according to any one of embodiments 179-181 Bispecific antibodies.

[0740] Embodiment 183. The GPRC5D×CD3 bispecific antibody is effective for both HC1 and HC2. Proline is ranked 228th, alanine 234th, and alanine is further included at 235th, in the implementation form. GPRC5D×CD3 bispecific antibody for use in state 182.

[0741] Embodiment 184. The GPRC5D×CD3 bispecific antibody is used with HC1 of SEQ ID NO: 51, Implementation form including LC1 in column number 52, HC2 in sequence number 41, and LC2 in sequence number 42. GPRC5D×CD3 bispecific antibody for use in any one of states 179-183 body.

[0742] Embodiment 185. The cancer is a hematological malignancy or a solid tumor, as in Embodiments 179-184. A GPRC5D×CD3 bispecific antibody for use with either one of the following:

[0743] Embodiment 186. Cancer is multiple myeloma, lymphoma, melanoma, breast cancer, endometrial cancer, ovarian cancer , lung cancer, stomach cancer, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, colon cancer, esophageal cancer, bladder cancer, or cervical cancer. A GPRC5D×CD3 bispecific antibody for use according to one embodiment 185.

[0744] Embodiment 187. Multiple myeloma is a high-risk multiple myeloma, according to Embodiment 186. GPRC5D×CD3 bispecific antibody for use.

[0745] Embodiment 188. A subject with high-risk multiple myeloma, t(4;14)(p16;q32); t(14;16)(q32;q23); del17p; 1qAmp; t(4;14)(p16;q32) and t(14;16)(q32;q23); t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23), and de Having one or more chromosomal abnormalities, including l17p, or any combination thereof. GPRC5D×CD3 bispecific antibody for use according to Embodiment 187.

[0746] Embodiment 189. The subject is anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide. Carfilzomib, erotozumab, ixazomib, melphalan, or thalidomide In practice, treatment with id, or any combination thereof, is refractory or relapsed. GPRC5D×CD3 bispecific antibody for use in any one of states 179-188 body.

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

[0748] Embodiment 191. Anti-CD38 antibody is HCDR1 of SEQ ID NO: 6, HCDR of SEQ ID NO: 7 2. HCDR3 of sequence number 8, LCDR1 of sequence number 9, LCDR2 of sequence number 10, and Use by any one of embodiments 179 to 190, including LCDR3 of sequence number 11 GPRC5D×CD3 bispecific antibody for this purpose.

[0749] Embodiment 192. An anti-CD38 antibody comprising VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 GPRC5D×CD3 Dual for use according to any one of Embodiments 179-191 Heterogeneous antibodies.

[0750] Embodiment 193. Embodiment 179~, in which the anti-CD38 antibody is of the IgG1 isotype. GPRC5D×CD3 bispecific antibody for use by any one of 192.

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

[0752] Embodiment 195. Anti-CD38 antibody, VH of sequence number 14 and VL of sequence number 15, VH of sequence number 16 and VL of sequence number 17, VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or Any of embodiments 179 to 190, including VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21 A GPRC5D×CD3 bispecific antibody for use by one person.

[0753] Embodiment 196. The anti-CD38 antibody is of the IgG1 isotype, as in Embodiment 195. GPRC5D×CD3 bispecific antibody for use by [unspecified user].

[0754] Embodiment 197. The subject is a human, and the method is one of Embodiments 179 to 196. GPRC5D×CD3 bispecific antibody for use.

[0755] Embodiment 198. An embodiment further comprising administering one or more anti-cancer treatments to the subject. GPRC5D×CD3 bispecific antibody for use in any one of the following cases (179-197): .

[0756] Embodiment 199. One or more anti-cancer treatments include autologous stem cell transplantation (ASCT), radiation therapy, etc. The following are selected from the group consisting of radiotherapy, surgery, chemotherapy, immunomodulatory agents, and targeted cancer therapies. GPRC5D×CD3 bispecific antibody for use according to form 198.

[0757] Embodiment 200. One or more anticancer treatments include lenalidomide, thalidomide, and poma. Lidomide, Bortezomib, Carfilzomib, Elotozumab, Ixazomib, Melphala Dexamethasone, vincristine, cyclophosphamide, hydroxydaunorubicin Prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, po Natinib, bafetinib, salakatinib, tozacertib, or danucertib, citara Bin, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine Cladribine, fludarabine, topotecan, etoposide 6-thioguanine, cortico Steroids, methotrexate, 6-mercaptopurine, azacitidine, arsenic trioxide, and Selected from the group consisting of all-trans retinoic acid, or any combination thereof. GPRC5D×CD3 bispecific antibody for use according to Embodiment 198.

[0758] Embodiment 201. HCDR1 of SEQ ID NO: 43, HCDR2 of SEQ ID NO: 44, SEQ ID NO: 4 HCDR3 of 5, LCDR1 of sequence number 46, LCDR2 of sequence number 47, and sequence number GPRC5D binding domain containing 48 LCDR3, and HCDR1 of sequence number 33, HCDR2 (sequence number 34), HCDR3 (sequence number 35), LCDR1 (sequence number 36), Includes CD3 binding domains including LCDR2 at column number 37 and LCDR3 at sequence number 38. The GPRC5D×CD3 bispecific antibody, along with HCDR1 (SEQ ID NO: 6) and HC (SEQ ID NO: 7). DR2, HCDR3 (sequence number 8), LCDR1 (sequence number 9), LCDR2 (sequence number 10) A pharmaceutical combination comprising, and an anti-CD38 antibody containing LCDR3 of SEQ ID NO: 11.

[0759] Embodiment 202. The GPRC5D binding domain is VH of SEQ ID NO: 49 and SEQ ID NO: 50 It contains VL, and the CD3 binding domain contains VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40 Embodiment 201 includes an anti-CD38 antibody comprising VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5. A combination of medicines.

[0760] Embodiment 203. The GPRC5C×CD3 bispecific antibody is used with HC1 of SEQ ID NO: 51, Includes LC1 in column number 52, HC2 in sequence number 41, and LC2 in sequence number 42, anti-CD Embodiment 201 or 2 includes antibody 38, comprising HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13. 02 drug combinations.

[0761] Embodiment 204. A non-fixed combination of any one of Embodiments 201 to 203 Combinations of pharmaceuticals.

[0762] Embodiment 205. Approximately 25 mM acetic acid, approximately 60 mM sodium chloride, approximately 140 mannitol , and approximately 20 mg / in polysorbate-20 (PS-20) at approximately 0.04% w / v Embodiment 20 contains approximately 120 mg / mL of anti-CD38 antibody and has a pH of approximately 5.5. 4 drug combinations.

[0763] Embodiment 206. Approximately 1,800 mg of anti-CD38 antibody and approximately 30,000 U of rHuP A pharmaceutical combination of Embodiment 204, including H2O.

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

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

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

[0767] Embodiment 210. A pharmaceutical composition is Anti-CD38 antibody at approximately 100 mg / mL to approximately 120 mg / mL, Approximately 5 mM to approximately 15 mM histidine, Sorbitol in a concentration of approximately 100 mM to 300 mM, PS-20 with approximately 0.01% w / v to approximately 0.04% w / v, It contains approximately 1 mg / mL to 2 mg / mL of methionine and has a pH of approximately 5.5 to 5.6. , the pharmaceutical combination of Embodiment 209.

[0768] Embodiment 211. The pharmaceutical combination of Embodiment 209 or 210, comprising approximately 10 mM histidine. Matching.

[0769] Embodiment 212. A mixture containing approximately 300 mM sorbitol, according to Embodiments 209-211. Any one combination of medications.

[0770] Embodiment 213. Embodiments 209-21, containing approximately 0.04% (w / v) of PS-20. One of the two combinations of medications.

[0771] Embodiment 214. Containing approximately 1 mg / mL of methionine, according to Embodiments 209-213 Any one combination of medications.

[0772] Embodiment 215. Approximately 1,800 mg of anti-CD38 antibody, Approximately 30,000U of rHuPH20, Approximately 10 mM histidine, Approximately 300 mM sorbitol and PS-20 with approximately 0.04% (w / v), Embodiments 209-214 contain approximately 1 mg / mL of methionine and have a pH of approximately 5.6. Any one of the following combinations of medications.

[0773] Embodiment 216. Approximately 120 mg / mL of anti-CD38 antibody, rHuPH20 at approximately 2,000 U / mL, Approximately 10 mM histidine, Approximately 300 mM sorbitol and PS-20 with approximately 0.04% (w / v), Embodiments 209-215 contain approximately 1 mg / mL of methionine and have a pH of approximately 5.6. Any one of the following combinations of medications.

[0774] Embodiment 217. A combination of pharmaceuticals comprising any one of Embodiments 201 to 215. .

[0775] Embodiment 218. For use in the treatment of subjects with cancer, in combination with an anti-CD38 antibody. Therefore, it is a T-cell redirection therapy that binds to CD19.

[0776] Embodiment 219. CD19-binding T cell redirection therapy in subjects with cancer An anti-CD38 antibody for use in improving the efficacy of drugs, wherein the target is bound to CD19. Before administering the T-cell redirection therapy, the patient has been treated with an anti-CD38 antibody, and an anti-CD3 antibody has been used. 8 antibodies.

[0777] Embodiment 220. The subject is refractory or recurrent in response to treatment with previous anticancer drugs. , T cell redirecting therapeutic or anti-CD3 for use according to Embodiment 218 or 219 8 antibodies.

[0778] Embodiment 221. The cancer is a hematological malignancy or a solid tumor, as in Embodiments 218-221. A T-cell redirecting therapeutic agent or an anti-CD38 antibody for use by either one of the following means.

[0779] Embodiment 222. Hematological malignancies include lymphoma, B-cell malignancy, Hodgkin lymphoma, and non- Hodgkin lymphoma, DLBLC, FL, MCL, Marginal Zone B-cell Lymphoma (MZL), Mucosa Associated lymphoid tissue lymphoma (MALT), CLL, ALL, AML, Waldenström's disease For use according to Embodiment 221, gammaglobulinemia or T-cell lymphoma T-cell redirection therapy or anti-CD38 antibody

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

[0781] Embodiment 224. The T cell redirection therapeutic agent is CD3 epsilon (CD3εε), C D8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, B Embodiments 218-223, coupled to TNL8, PD-1, CD195, or NKG2C. A T-cell redirecting therapeutic agent or an anti-CD38 antibody for use by either of the following means.

[0782] Embodiment 225. A T-cell redirecting therapeutic agent that binds to CD19 is blinatumomab, Akisikabutogensiloleucel, tisagenlecleucel-t, ricebilizumab, lysoka Butagenmaralucel, XmAb-5574, CIK-CAR.CD19, ICTCA R-011, IM-19, JCAR-014, Longasutuximabutecilin, MB-CA RT2019.1, OXS-1550, PBCAR-0191, PCAR-019, PC AR-119, Senl-001, TI-1007, XmAb-5871, PTG-01 , PZ01, Senl_1904A, Senl_1904B, UCART-19, CSG -CD19, DI-B4, ET-190, GC-007F, or GC-022 CD19 T cells for use according to any one of embodiments 218-224, including a binding domain Redirecting therapeutic agents or anti-CD38 antibodies.

[0783] Embodiment 226. A T-cell redirecting therapeutic agent that binds to CD19 is blinatumomab, Akisikabutogensiloleucel, tisagenlecleucel-t, ricebilizumab, lysoka Butagenmaralucel, XmAb-5574, CIK-CAR.CD19, ICTCA R-011, IM-19, JCAR-014, Longasutuximabutecilin, MB-CA RT2019.1, OXS-1550, PBCAR-0191, PCAR-019, PC AR-119, Senl-001, TI-1007, XmAb-5871, PTG-01 , PZ01, Senl_1904A, Senl_1904B, UCART-19, CSG - Including CD19, DI-B4, ET-190, GC-007F, or GC-022, actual T-cell redirecting therapeutic agents for use in any one of the application methods 218-225 or Anti-CD38 antibody.

[0784] Embodiment 227. A T cell redirecting therapeutic agent that binds to CD19 is a multispecific antibody, One of embodiments 218 to 226 is a CAR, or a T cell expressing a CAR. T-cell redirecting therapeutic agents or anti-CD38 antibodies for use by [unspecified].

[0785] Embodiment 228. Anti-CD38 antibody is HCDR1 of SEQ ID NO: 6, HCDR of SEQ ID NO: 7 2. HCDR3 of sequence number 8, LCDR1 of sequence number 9, LCDR2 of sequence number 10, and Use by any one of embodiments 218 to 227, including LCDR3 of sequence number 11 T-cell redirecting therapeutic agents or anti-CD38 antibodies for this purpose.

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

[0787] Embodiment 230. The anti-CD38 antibody is of the IgG1 isotype, as in Embodiments 218~ T-cell redirecting therapeutic agents or anti-CD38 antibodies for use by any one of the following 229 .

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

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

[0790] Embodiment 233. The anti-CD38 antibody is of the IgG1 isotype, as in Embodiment 232. T-cell redirecting therapeutic agents or anti-CD38 antibodies for use by [unspecified].

[0791] Embodiment 234. Anti-CD38 antibody is administered at a dose of approximately 8 mg / kg to approximately 16 mg / kg. T cell redirection for use according to any one of embodiments 218-233. A therapeutic agent or an anti-CD38 antibody.

[0792] Embodiment 235. A T cell redirecting therapeutic agent that binds to CD19 and an anti-CD38 antibody , administered by intravenous injection, as used in any one of embodiments 218 to 234 T-cell redirecting therapeutic agents or anti-CD38 antibodies for this purpose.

[0793] Embodiment 236. A T-cell redirecting therapeutic agent that binds to CD19 is administered by intravenous injection. Embodiments 218-234 describe the administration of anti-CD38 antibodies by subcutaneous injection. A T-cell redirecting therapeutic agent or an anti-CD38 antibody for use by either of the following means.

[0794] Embodiment 237. The subject is a human, and the embodiment is one of Embodiments 218 to 236. T-cell redirecting therapeutic agents or anti-CD38 antibodies for use.

[0795] Embodiment 238. A T cell redirecting therapeutic agent that binds to CD19, CD19×CD3 A bispecific antibody, for use according to any one of embodiments 218 to 237. Cellular redirection therapy or anti-CD38 antibody.

[0796] Embodiment 239. An embodiment further comprising administering one or more anti-cancer treatments to the subject. T-cell redirecting therapeutic or anti-CD therapy for use by any one of 218-238 38 antibodies.

[0797] Embodiment 240. One or more anti-cancer treatments include autologous stem cell transplantation (ASCT), radiation therapy, etc. The following are selected from the group consisting of radiotherapy, surgery, chemotherapy, immunomodulatory agents, and targeted cancer therapies. A T-cell redirecting therapeutic agent or anti-CD38 antibody for use according to Form 238.

[0798] Embodiment 241. CD19×CD3 bispecific antibody containing blinatumomab of SEQ ID NO: 53 Body, HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7, HCDR3 of SEQ ID NO: 8, sequence Includes LCDR1 with number 9, LCDR2 with sequence number 10, and LCDR3 with sequence number 11. A combination of drugs including an anti-CD38 antibody.

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

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

[0801] Embodiment 244. A non-fixed combination of any one of Embodiments 241 to 243 Combinations of pharmaceuticals.

[0802] Embodiment 245. Approximately 25 mM acetic acid, approximately 60 mM sodium chloride, approximately 140 mannitol , and approximately 20 mg / in polysorbate-20 (PS-20) at approximately 0.04% w / v Embodiment 24 contains approximately 120 mg / mL of anti-CD38 antibody and has a pH of approximately 5.5. One of 1 to 244 drug combinations.

[0803] Embodiment 246. Approximately 1,800 mg of anti-CD38 antibody and approximately 30,000 U of rHuP A pharmaceutical combination from any one of embodiments 241 to 243, including H2O.

[0804] Embodiment 247. Approximately 120 mg / mL of anti-CD38 antibody and approximately 2,000 U of rHuP A pharmaceutical combination of Embodiment 246, including H2O.

[0805] Embodiment 248. The embodiment of Embodiment 246 or 257, further comprising one or more excipients. Combinations of pharmaceuticals.

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

[0807] Embodiment 250. A combination of pharmaceuticals, Anti-CD38 antibody at approximately 100 mg / mL to approximately 120 mg / mL, Approximately 5 mM to approximately 15 mM histidine, Sorbitol in a concentration of approximately 100 mM to 300 mM, PS-20 with approximately 0.01% w / v to approximately 0.04% w / v, It contains approximately 1 mg / mL to 2 mg / mL of methionine and has a pH of approximately 5.5 to 5.6. or any one of the pharmaceutical combinations from Embodiments 246 to 249.

[0808] Embodiment 251. Any of Embodiments 246 to 250, containing approximately 10 mM histidine. One combination of medications.

[0809] Embodiment 252. A mixture containing approximately 300 mM sorbitol, according to Embodiments 246-251. Any one combination of medications.

[0810] Embodiment 253. Embodiments 246-25, containing approximately 0.04% (w / v) of PS-20. One of the two combinations of medications.

[0811] Embodiment 254. Containing approximately 1 mg / mL of methionine, according to Embodiments 246-253 Any one combination of medications.

[0812] Embodiment 255. Approximately 1,800 mg of anti-CD38 antibody, Approximately 30,000U of rHuPH20, Approximately 10 mM histidine, Approximately 300 mM sorbitol and PS-20 with approximately 0.04% (w / v), Embodiments 246-254 contain approximately 1 mg / mL of methionine and have a pH of approximately 5.6. Any one of the following combinations of medications.

[0813] Embodiment 256. Approximately 120 mg / mL of anti-CD38 antibody, rHuPH20 at approximately 2,000 U / mL, Approximately 10 mM histidine, Approximately 300 mM sorbitol and PS-20 with approximately 0.04% (w / v), Embodiments 246-255 contain approximately 1 mg / mL of methionine and have a pH of approximately 5.6. Any one of the following pharmaceutical compositions.

[0814] Embodiment 257. A kit comprising any one of the pharmaceutical compositions from Embodiments 241 to 256. . [Examples]

[0815] To further illustrate some of the embodiments disclosed herein, the following examples are provided. These embodiments are for illustrative purposes only and do not limit the embodiments of the present disclosure. No.

[0816] General materials and methods Antibodies and reagents Anti-BCMA / anti-CD3 antibody JNJ-957 (International Publication No. 2017 / 031104 (A1 (as described in issue) and daratumumab are manufactured by Janssen Pharmaceuticals. It was all Janssen Pharmaceuticals' CNTO7008. (CD3×null), BC3B4(BCMA×null), and 3930(IgG eye) A sotype control was used as the control antibody. JNJ-957 is also known as JNJ-7957. be.

[0817] JNJ-957 uses BCMA coupling arm BCMB69 and CD3 coupling arm CD3B2 It includes 19, and their amino acid sequences are shown in Tables 3 and 4, respectively.

[0818] [Table 3]

[0819] [Table 4]

[0820] Bone marrow and peripheral blood mononuclear cells Peripheral blood mononuclear cells (PBMCs) from healthy donors and MM patients, as well as BM aspirates from MM patients. Bone marrow mononuclear cells (BM-MNCs) are obtained by Ficoll-Hypaque density gradient centrifugation. And then it was isolated.

[0821] Cell lines and cultures Multiple myeloma cell lines UM9 and R, transduced with luciferase (LUC). PMI8226, U266, and MM1.S, as well as the untransduced multiple myeloma cell line NC. I-H929 and RPMI8226 were tested in 10% fetal bovine serum (F). BS, Lonza) and antibiotics (penicillin at 100 units / mL, 100 μg / mL) RPMI1 supplemented with streptomycin (both from Life Technologies) The cells were cultured in 640 (Invitrogen).

[0822] Flow cytometry analysis of bone marrow and blood samples from MM patients Identify BM-localized MM cells, 1.0 × 10 6 Cells / mL, HuMax-003 (CD 38) FITC (This antibody is different from the epitope that is bound by daratumumab) Binds to pitopes, Janssen Pharmaceuticals, CD138 PE, CD56 PC7, CD45 Krome Orange (all Beckman) Coulter), CD269 (BCMA) APC (Biolegend), CD27 4(PD-L1)BV421, and CD19 APC-H7 (both Becton Dic Cell surface marker expression levels were analyzed by staining with Kinson's solution. Identify BM or PB immune cell subsets and measure 1.0 × 10⁶ 6 cells / mL, CD45 Krome Orange, CD56 PC7 (both Beckman Coulter) , CD14 APC-H7, CD19 APC-H7, CD3 V450, CD4 AP C-H7 or PE, CD8 FITC, CD45-RA APC, CD127 PE.C y7, CD62L PE, CD274(PD-1)BV421, CD16 APC, HL A-DR APC-H7 (all Becton Dickinson), and CD25 P Cell surface marker expression levels were analyzed by staining with E(Dako). All BM samples were analyzed within 24 hours of sample collection.

[0823] Flow cytometry is performed using the 7 laser LSRFORTESSA (Becton Dic This was performed using Kinson. Fluorescently labeled beads (CS&T beads, Becton) I use Dickinson daily to monitor the performance of the flow cytometer and the optical path and The flow rate was verified. This procedure allows for controlled and standardized results and a flow cytometer. Enables the determination of long-term drift and accidental changes within the system. Changes that may affect the outcome. It was not observed. Using compensation beads, spectral overlap was determined, and the compensation was Di Calculated automatically using VA software. FACS Diva software was used. Then, the flow cytometry data was analyzed.

[0824] Ex vivo lysis analysis based on flow cytometry in BM-MNC Not only BM-MNC derived from MM patients containing tumor cells, but also homemade effect pedals The cells were also used in the lysis assay. Sample viability during incubation was 7 -When evaluated using AAD (Becton Dickinson), it was over 98% For the dissolution assay, BM-MNC was used in a 96-well U-bottom plate as a control. Antibody or JNJ-957 (0.0064~4.0 μg / mL) and / or Daratum Incubation for 48 hours in fetal bovine serum with RPMI+10% containing 10 μg / mL It was done. Primary CD138 in BM-MNC + The survival of MM cells has been described previously. Sea urchin (van der Veers et al.,Haematologica.20 11;96(2):284-290, van der Veer MS et al. Blood CancerJ.2011;1(10):e41, Nijhof IS e t al., Leukemia2015;29(10):2039-2049, Nijh of IS,et al.,Blood2016;128(7):959-970.), Determined by flow cytometry. In both assays, viable MM cells were identified as F low-Count Fluorospheres (Beckman Coulter) and LIVE / DEAD Fixable Dead Cell Stain Near - CD138 in the presence of IR fluorescent dye (Invitrogen) + A single cell The number of viable MM cells was counted by platform flow cytometry analysis. The logarithm was determined. Then, the dissolution rate induced by JNJ-957 was expressed using the following formula: Lysified MM cells %=1-(Survival CD138 in the presence of JNJ-957) + Absolute number of cells / Unknown Survival CD138 in the processing well + The calculation was performed using (absolute number of cells) × 100%.

[0825] CD4 + and CD8 + JNJ-957-induced activation and degranulation of T cells, respectively, are controlled by CD. Cell surface expression of 25 and CD107a was analyzed by flow cytometry detection.

[0826] Flow cytometry in MM cell lines using PB MNCs as effector cells A dissolution assay based on -. BCMA-positive MM cell lines were subjected to control antibody or JNJ- in a 96-well U-bottom plate. In the presence of 957 (0.00256~4.0 μg / mL), with an effector-to-target ratio of 9:1. The MM cells were then co-cultured for 48 hours with PB MNCs from healthy donors or MM patients. The existence was determined by the flow cytometry described above.

[0827] Bioluminescence imaging using MM cell lines transduced with LUC. Dissolution assay based on imaging (BLI) MM cell lines transduced with LUC were obtained from newly diagnosed MM patients (n=12). In the presence or absence of pooled BM stromal cells (BMSCs), at 16:00 After inter-culture, effector cells (from healthy donors or target cells) are cultured in a 9:1 effector-to-target ratio. (Then, newly isolated PBMCs) were incubated together in a 96-well flat-bottom plate (Gre In iner-Bio-One, JNJ-957 (0.00256~4.0μg / The substrate luciferin (150 μg) or control antibody was continuously diluted for 48 hours. Then, the substrate luciferin (150 μg) was added. 10 minutes after adding LUC (Promega / mL), + - MM cell survival in BLI Therefore, it was determined that the lysis of MM cells was determined by the following formula: lysis % = 1 - (effector cells and J Mean BLI signaling / effector cells and untreated antibodies in the presence of NJ-957 The determination was made using (average BLI signal under normal conditions) × 100%.

[0828] In vivo daratumumab monotherapy for the efficacy of JNJ-957 in PB MNC To evaluate the effect of prior treatment, LUC-transduced MM cell line 4 was also used in the evaluation of daratum Data obtained from MM patients before initiating daratumumab monotherapy and at the time of best response to daratumumab monotherapy. Co-cultured with PB MNC (effector-to-target ratio of 9:1). BLI assay was performed. I did as described above.

[0829] Cytogenetic analysis Fluorescence in situ hybridization (FISH) and single nucleotide polymorphism (SI cytogenetic abnormalities can be detected by a ngle nucleotide polymorphism (SNP) array, and purified M Evaluation was performed in M ​​cells. High-risk diseases included del(17p), del(1p), and amp. Defined by the existence of l(1q), t(4;14), or t(14;16). 2 .

[0830] Soluble BCMA assay MSD GOLD (trademark) 96-well Small Spot Streptavidi n SECTOR plates (Meso Scale Diagnostics) are manufactured by Use according to the protocol recommended by the user, soluble BCMA in the cell culture supernatant (soluble BCMA and sBCMA were measured.

[0831] Granzyme B assay MSD R-Plex Granzyme B Assay Plate (Meso Scale Di Using agnostics) according to the manufacturer's protocol, in the cell culture supernatant, Nzyme B was measured.

[0832] Multiple cytokine assay V-Plex Pro-inflammatory Panel 1 Human Kit (Meso Scale Diagnos) Using tics) according to the manufacturer's protocol, cytokines in the cell culture supernatant [ Interferon-gamma (IFN-γ), interleukin (inte rleukin, IL-2, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha We analyzed tumor necrosis factor-alpha (TNF-α).

[0833] Statistical data If the data does not follow a normal distribution, comparisons between variables should be made using a two-sided (paired) Study. t-test, or Mann-Whitney U test, or Wilcoxon matched pair signed rank The analysis was performed using statistical tests. Correlations between variables were calculated using Spearman's rank correlation coefficient. A p-value less than 0.05 was considered statistically significant. The combination of JNJ-957 and daratumumab... In real treatment, calculate the expected dissolution value and use the following formula as described above: (JNJ-9 Dissolution by 57% + Dissolution by daratumumab% - (Dissolution by JNJ-957% × Daratumumab) Using tumumab solubility, an additive effect was observed between JNJ-957 and daratumumab. We tested the null hypothesis that only exists. 20、23、24 The observed value was greater than the expected value. If the value was significantly higher (P<0.05), the null hypothesis for "additive effect" was rejected.

[0834] Example 1 BCMA +JNJ-957, an anti-BCMA / anti-CD3 antibody for multiple myeloma cell lines. T-cell activation and degranulation are associated with mediated lysis. Using peripheral blood mononuclear cells from a healthy donor (HD) as effector cells, JNJ-9 RPMI8226( across a concentration range of 57 (0.00128~4.0 μg / mL) Figure 1), UM9 (Figure 2), U226 (Figure 3), and MM1.S (Figure 4) are mediated by dissolution. The effect of JNJ-957 was evaluated. JNJ-957-mediated lysis was observed in a dose-dependent manner. This mediated the lysis of all tested cell lines, as seen in Figures 1, 2, 3, and 4. Depending on the cell line, nearly 100% maximum efficacy was achieved at an antibody concentration of approximately 0.1 μg / ml. Ta.

[0835] BMSCs are resistant to various anti-MM agents, including daratumumab and MM-reactive T cells, and are MM-metabolized. It has been previously shown to protect the cells. Therefore, the efficacy of JNJ-957 The potential effects of BMSC-MM cell interactions were evaluated. MM cell line RPMI-8226, The activity of JNJ-957 against UM9 and U266 is affected by the presence of BMSC. Did not receive (data not shown). JNJ-957-mediated MM cell lysis occurs at low concentrations in MM 1. In S cells, BMSC was moderately inhibited (P<0.0001), but this effect The effect was completely suppressed by increasing the dose of JNJ-7957.

[0836] T cell activation was evaluated in the RPMI8226 cell line. Treatment with JNJ-957. These are due to increased cell surface expression of CD25 and CD107a, respectively, or double-positive C CD107a cells, as evidenced by the proportion of D25 and CD107a cells, in a dose-dependent manner 4 + and CD8+ This resulted in both activation and degranulation of T cells. Figure 5 shows CD25+C Figure 6 shows a JNJ-957-mediated increase in the proportion of D4 T cells. CD107a+CD4 Figure 7 shows a JNJ-957-mediated increase in the proportion of T cells. Figure 7 shows double-positive CD25+CD1 Figure 8 shows a JNJ-957-mediated increase in the proportion of O7+CD4 T cells. Figure 9 shows a JNJ-957-mediated increase in the proportion of D8 T cells. CD107a+CD8 Figure 10 shows a JNJ-957-mediated increase in the proportion of T cells. Double-positive CD25+ CD This shows a JNJ-957-mediated increase in the proportion of 107+CD8 T cells.

[0837] Example 2: Daratumumab improved the efficacy of a T-cell redirecting antibody. patient BCMA expression levels, composition of immune cell subsets, and ex vivo exposure of JNJ-957 Efficacy was observed in 11 newly diagnosed MM patients and 21 patients with daratum mab naive relapse / refractory disease. Sexual MM patients, and 17 daratumumab-refractory relapsed / refractory MM patients (daratumumab relapsed / For patients with refractory disease, all-trans retinoic acid (ATRA) and Enrolled in Phase 1 and Phase 2 trials of the combined daratumumab; Clinical trial identifier NCT0 2751255), and 55BM obtained from primary plasma cell leukemia (pPCL; n=6). Evaluation was performed in the aspirated fluid. Progression occurred immediately before the initiation of daratumumab monotherapy and during daratumumab treatment. At the time of sexually transmitted disease, sequential BM samples were taken from 8 patients treated in the DARA / ATRA trial. We obtained. In the same study, we achieved the following immediately before initiating daratumumab monotherapy and with daratumumab. Peripheral blood samples were obtained sequentially from 10 patients at the point of maximum response.

[0838] In the DARA / ATRA trial (NCT02751255), patients required systemic treatment. You have MM and have relapsed after two or three or more previous treatments, or you have difficulty with them. It was curable. The patient was 18 or 19 years of age or older, with a life expectancy of 3 or 4 months or more. Alternatively, they had an activity index of 1 or less, and a measurable disease.

[0839] During the Phase 1 trial, the recommended dose and schedule (16 mg / kg per week for 8 weeks) Subsequently, daratumumab was administered every two weeks for 16 weeks, and every four weeks until the period of progression (PD). The ethics committee or institutional review board of the research site approves the protocol, and this is declared. tion of Helsinki, International Conference e on Harmonization, and Guidelines for Good The procedure followed the principles of Clinical Practice. All patients provided written documentation. I submitted informed consent.

[0840] The baseline characteristics of patients enrolled in the Phase 1 and Phase 2 trial NCT02751255 were as follows: This is shown in Tables 5 and 6. RRMM patients had previously received an average of 5 (range 1-9) treatments. RMM DaraR patients had previously received an average of 6 (range 3-12) treatments. Table 7 shows the results. This section presents an updated summary of baseline characteristics of patients enrolled in Phase 1 and Phase 2 trials.

[0841] [Table 5]

[0842] [Table 6]

[0843] [Table 7] * High-risk diseases include del(17p), del(1p), ampl(1q), t(4; 14) or defined by the existence of t(14;16). ** Intractable diseases are assessed according to the internationally unified criteria for evaluating the effectiveness of treatment for multiple myeloma, and the progression of the disease during therapy is monitored. It is defined as a sexually transmitted disease, no response (less than PR), or a progressive disease within 60 days of discontinuation of treatment. ru. #BM aspirate was obtained immediately upon the onset of progressive disease during daratumumab monotherapy (n=1 5) However, the two BM samples were daratumumab monotherapy after 3 and 5 cycles of other treatment, respectively. The results were obtained 22 and 48 months after the onset of the progression of the disease. Furthermore, one of the 19 patients is intolerant to lenalidomide. Furthermore, four of the 17 patients were intolerant to bortezomib. Furthermore, three of the 16 patients were intolerant to bortezomib. Abbreviations: MM, Multiple Myeloma, NDMM, Newly Diagnosed MM, RRMM, Relapsed / Refractory Sexual MM, Dara: daratumumab, pPCL, primary plasma cell leukemia, n, number, IgG, immunity Globulin G, IgA, immunoglobulin A, FLC, free light chain, del, deletion, amp, Amplification, t, translocation, PI, proteasome inhibitor, IMiD, immunomodulator,

[0844] result Daratumumab is used in newly diagnosed (NDMM) patients and in patients with relapsed / refractory daratumumab. It mediated efficient lysis of MM cells in Eev patients, but in RRMM daratumumab refractory patients. The cells were resistant to lysis (Figure 11).

[0845] In a newly diagnosed (ND)MM patient sample (n=8), JNJ-957 4.0 The average lysis of MM cells with μg / mL was 79% (range: 66-92%, Figure 12). ). Although similar, MM dissolution exhibits greater variability, which is intractable with lenalidomide (LEN). Sexually transmitted patient samples (n=15, mean dissolution rate at 4.0 μg / mL: 69%, range: 24-98) %, achieved in Figure 13), these patients also received bortezomib (73%), pomación Domide (82%) and carfilzomib (9%) were refractory. JNJ-957 Furthermore, a sample of MM patients with daratumumab (DARA) refractory disease (n=11, 4.0 μg) It was also effective at an average dissolution rate of 83% at / mL, with a range of 52-99% (Figure 14). NK and T cell frequencies were not affected in any of the samples tested.

[0846] When comparing CD3×null and BCMA×null control antibodies with JNJ-957... In addition, it showed significantly lower activity in different patient samples, which is due to MM cells and ephedra. This demonstrates the necessity of crosslinking with Kutar T cells and the absence of a direct effect of BCMA blocking. Ta.

[0847] JNJ-957-mediated lysis of primary MM cells is evaluated by the expression of CD25-activating antigen. If valued, activate CD4 + and CD8 + This was associated with a dose-dependent increase in the proportion of T cells. JNJ-957 treatment is also determined by the cell surface expression of CD107a, and CD4 + and CD8 + This resulted in T cell degranulation. NDMM patients and daratum mab naive® There is a difference in T cell activation and degranulation between RMM patients and daratumumab-refractory RRMM patients. There was no significant difference in degree. Figure 15 shows the proportion of CD25+CD4 T cells mediated by JNJ-957. It shows an increase in sex. Figure 16 shows the JNJ-957-mediated increase in the proportion of CD107a+CD4 T cells. It shows an increase. Figure 17 shows the percentage of double-positive CD25+CD107+CD4 T cells in JNJ. -957 shows increased mediated activity. Figure 18 shows the percentage of JNJ-95 CD25+CD8 T cells. 7 shows a mediated increase. Figure 19 shows the percentage of CD107a+CD8 T cells in JNJ-957. It shows a mediated increase. Figure 20 shows the percentage of double-positive CD25+CD107+CD8 T cells. It shows increased transmission by JNJ-957.

[0848] JNJ-957 treats naive patients with daratumumab and refractory RRMM with daratumumab. The levels of granzyme B and various cytokines in the supernatant of the treated BM-MNC were also evaluated. It was worthwhile. JNJ-957-mediated T cell activation involves granzyme B, IFN-γ, IL-2, This results in a dose-dependent increase in the levels of IL-6, IL-8, IL-10, and TNF-α. (Data not shown).

[0849] The efficacy of JNJ-957 in mediating MM cell killing is related to tumor characteristics (BCMA or PD). -L1 expression, presence of standard or high-risk cytogenetic abnormalities) also applies to all BM samples. Effectors across the range: target ratio, T cell system composition, or PD-1 / HLA- on T cells It was not associated with patient characteristics such as DR expression. However, when analyzing patient classifications individually... In that case, the expression levels of BCMA (Figure 21) and PD-L1 (Figure 22) are affected by daratumumab exposure. Regardless of the cause, the risk was significantly higher in RRMM patients compared to NDMM patients. Although the number of participants was small, the activity of JNJ-957 was observed in daratum mab naive RRMM patients. Furthermore, it was inversely correlated with PD-L1 expression levels (P=0.045).

[0850] BM Aspirate NDMM, Daratumumab Naive RRMM, and Daratumumab RRMM Sun The composition of immune cells during the pull was evaluated in samples obtained from three patient subgroups. We gained an understanding of the differential effect of JNJ-957. In the combined patient group, high T-cell density was observed. Cell frequency (P=0.034) and high E:T ratio (P=0.029) suggest that MM cells are JNJ- It was associated with improved 7957-mediated lysis. Other immune parameters (T cells, Treg, PD- 1 + T cells, HLA-DR + The number of T cells, or naive T cells, is measured by the JNJ-7957 medium. It did not affect the lysis of intermediated MM cells.

[0851] In the subgroup analysis, RRMM patients showed a higher Treg rate compared to NDMM patients. (Figure 23) and significant changes in activated T cells (defined by HLA-DR expression) (Figure 24) This resulted in a higher frequency and a lower frequency of naive T cells. In addition, daratumumab The refractory patient sample showed significantly more TEMRA than the daratum mab naive sample. It contained T cells (Figure 25). However, activation, naive, central memory ( The frequency of CM, Effector Memory (EM), or TEMRA T cells is in this subgroup. Loop analysis did not show any correlation with the response to JNJ-7957. The line ratio is related to JNJ-957-mediated MM cell lysis in RRMM patient samples. It showed negative effects, which were overcome by optimal medication. Treg baseline NDMM mediated by autologous effector cells, divided into two groups based on their proportion (Figure 26) , daratumumab naive RRMM (Figure 27), and daratumumab refractory RRMM (Figure 28) The JNJ-597-mediated solubility of patient samples was evaluated. The 50th percentile was used. The samples were then classified as "low" or "high" in terms of Treg content. NDMM: Low: ≤7.34%, High:>7.34%. Daratum mabu naive RRMM: Low ≤15.57%, High > 15.57%. Daratumumab-refractory RRMM: Low ≤ 11.24%, High > 11.24% Higher Treg concentrations are used in daratumumab naive RRMM and daratumumab refractory RR. It weakened JNJ-957-mediated lysis of MM cells in MM samples. The Treg effect was, It was suppressed at higher JNJ-957 concentrations.

[0852] PD-1 + The percentage of T cells and the E:T ratio were similar across the three patient groups. NDM In M patients only, low frequency of T cells (P=0.010) and high frequency of PD-1 + T cells (P=0.048) However, it impaired JNJ-957-mediated lysis of MM cells (data not shown). ).

[0853] The efficacy of daratumumab treatment against the effectiveness of JNJ-957 was evaluated in a 48-hour incubation period. After the procedure, NDMM (n=9), Daratum mab naive RRMM (n=18), and Da JNJ-957-mediated BM samples from patients with latumumab-refractory RRMM (n=13) The solubility was evaluated by assessing the properties of JNJ-957 (0.0064) at relatively low concentrations. At ~0.032 μg / mL, daratum mab naive patients with RRMM and NDMM Compared to both groups, tumor cell lysis was significantly better in patients exposed to daratumumab. (Figure) 29 shows the rate of dissolution in the patient population. Data are shown as mean ± SEM, and the p-value is shown. This is calculated using a Student's t-test.

[0854] The improvement in tumor reduction can be aided by the recently discovered immunostimulatory effect of DARA. Therefore, sequential BM aspirates from MM patients were analyzed before and after DARA treatment (n=5). Therefore, we compared samples obtained after disease progression during DARA with samples obtained before the start of DARA. In the sample, BCMA expression was equivalent, but MM cell lysis by JNJ-957 was improved. We observed that it improved (average dissolution at 4.0 μg / mL: 93 vs 74%, Figure 30). In the BM aspirate, Treg (Figure 31) and CD4 + The proportion of cells (Figure 32) is small. Although it decreased, the percentage of CD8+ cells (Figure 33) was higher compared to the daratumumab-exposed patient sample. And it increased in daratum mab naive patient samples. In this study, patients with daratum mab Samples were taken from patients whose median duration of treatment with mumab monotherapy was 3 months (1-7 months). Obtained. In a follow-up study of a sample of 8 RRMM patients, CD38 + Treg and B The proportion of reg was compared between daratum mab naive patient samples and daratum refractory patient samples. This was significantly reduced (data not shown).

[0855] JNJ-957-mediated lysis of the RPMI8226 multiple myeloma cell line, treated with daratumumab. Sequential PB MNC samples from RRMM patients before and during treatment were used as effector cells. The study used daratumumab exposure PB MNC was the median duration of daratumumab treatment at 11 months. A value (range 7-14 months) indicates a good response (partial response, very good partial response, or complete response). Obtained from patients with either of the above conditions during daratumumab treatment. Figure 34 shows RPMI822. The lysis of 6 via JNJ-957 was improved using PB MNC in Dara-exposed patients. This shows the proportion of Treg (Figure 35) and CD4+ cells in the PB-MNC sample (Figure 35). 6) was slightly decreased, but the percentage of CD8+ cells (Figure 37) was higher in daratumumab-exposed patients. Compared to the sample, the levels increased in the daratum mab naive patient sample. In this study, From patients where the median duration of daratumumab treatment in the patient is 3 months (1-7 months), I got a pull.

[0856] The combination of JNJ-957 and daratumumab is also NDMM or RRMM daratumumab. The effectiveness of killing MM cells obtained from patients was tested. Figure 38 shows JNJ-95. 7 (0.032~0.8 μg / mL) alone, or in combination with daratumumab 10 μg / mL BM M in newly diagnosed MM (NDMM) (n=8) patients treated with Waseda for 48 hours. This shows the lysis rate of NC. Observation of MM cells with JNJ-957 and daratumumab (ob s) Compare the dissolution level with the expected (exp) dissolution level, and these are expressed as shown in the method. The calculation was based on the assumption that the combinatorial effect is achieved through the effect. The black bars represent the Gunpei The mean ± SEM is shown. The p-value is calculated using a paired Student's t-test. Figure Figure 39 shows the percentage of BM MNC dissolution rates in RRNN daranave patients. Figure 40 This shows the rate of BM MNC lysis in RRMM daratumumab-refractory patients.

[0857] Therefore, this study investigated whether JNJ-957 was present in newly diagnosed MM patient samples, and It demonstrated effectiveness in a large number of previously treated MM patient samples. Alternatively, regulatory T cells may negatively affect the efficacy of low doses of JNJ-957, but this negative impact The hibiki was overcome by increasing the dose of JNJ-957. Prior to in vivo daratumumab treatment. This improved the efficacy of JNJ-957 against MM cells.

[0858] The combination of JNJ-957 and daratumumab in ex vivo therapy showed additive efficacy. Furthermore, prior treatment with daratumumab in vivo is ex vivo with BCMA x CD3 It increased the effectiveness.

[0859] Example 3: Daratumumab treatment improved the ex vivo efficacy of blinatumomab. To evaluate whether daratumumab treatment is beneficial in addition to other T-cell redirection therapies. Therefore, in pairs of 11 MM patients, daratumumab naive and daratumumab-exposed PB- Using MNC, CD19 + Raji cells for the treatment of acute lymphoblastic leukemia (FD) The patient was treated with blinatumomab, an A-approved CD19 x CD3 BiTE. (JNJ-957) Similar to the observations made by [unclear], the activity of blinatumomab was compared with daratumumab naive PB-MNC. When this was done, co-incubation with daratumumab-exposed PB-MNCs showed significant improvement. The result was obtained (P<0.0001, Figure 41). Blinatumomab is the amino acid sequence of Sequence ID No. 53. Includes.

[0860] Sequence ID 53 DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNW YQQIPGQPPKL LIYDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAAT YHCQQSTEDPW TFGGGTKLEIKGGGGGSGGGGSGGGGSQVQLQQSGAELVR PGSSVKISCKA SGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGK FKGKATLTADE SSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDY WGQGTTVTVSS GGGGSDIKLQQSGAELARPGASVKMSCKTSGYTFTRYTM HWVKQRPGQGL EWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLS SLTSEDSAVYY CARYYDDHYCLDYWGQGTTLTVSSVEGGSGGSGGSGSG GVDDIQLTQSP AIMSASPGEKVTMTCRASSSVSYMNWYQQKSGTSPKRWI YDTSKVASGVP YRFSGSGGSTSYSLTISSMEAEDAATYYCQQWSSNPLTF GAGTKLELKHH HHHH

[0861] Example 4: JNJ-957 effectively kills primary pPCL cells. The ex vivo activity of JNJ-957 is being investigated in newly diagnosed cases characterized by invasive clinical behavior. This was evaluated in BM samples from 6 patients with pPCL. JNJ-957-mediated tumor cell lysis during pull is observed in NDMM and daratum mab naive RR. The lysis observed in MM samples was similar to that observed in daratumumab-refractory RRMM patients. The pPCL sample was lower than that observed in the pull sample (P=0.0014) (Figure 42). The median E:T ratio in the region was lower than approximately 8 times, but CD4 + (P=0.0040) and CD8 + The degree of activation of both T cells (P<0.0001) and CD8 + T cells The degree of degranulation (P=0.0141) was superior in pPCL compared to NDMM. CD4 + T cell degranulation was similar to that observed in NDMM.

[0862] BM-MNC was obtained from 6 pPCL patients, and JNJ-957 (0.0064~4.0μ (g / mL) or together with control antibodies 3930, BC3B4, and 7008 (4.0 μg / mL) After incubation for 48 hours, viable CD138 + Tumor cells, as well as T cells and NK cells Cells were counted using flow cytometry analysis. Data were obtained by comparing cells ± the mean lysis of SEM cells. The results were expressed as a percentage. All experiments were performed in pairs.

[0863] Example 5: Combination of GPRC5D×CD3 bispecific antibody and daratumumab To further evaluate whether daratumumab treatment is beneficial in addition to other T-cell redirection therapies. In addition, 11 pairs of daratumumab naive and daratu...

Claims

1. A method for treating cancer in a target, comprising an effective amount of anti-CD38 antibody and T cells. A method comprising administering a redirecting therapeutic agent to the subject to treat the cancer.

2. A method for improving the efficacy of T-cell redirection therapeutics in subjects with cancer. a method comprising administering an anti-CD38 antibody to the subject.

3. The claim states that the anti-CD38 antibody is administered before the administration of the T-cell redirecting therapeutic agent. The method described in 1 or 2.

4. The aforementioned T-cell redirecting therapeutic agents include BCMA, GPRC5D, CD33, CD123, Any of claims 1 to 3, which involves coupling to CD19, PSMA, TMEFF2, or CD20. The method described in item 1.

5. The aforementioned T-cell redirecting therapeutic agents include CD3, CD3 epsilon (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL 8. To be bound to PD-1, CD195, or NKG2C, according to any one of claims 1 to 4 Method of description.

6. The aforementioned T cell redirection therapeutic agent, a) Heavy chain complementarity determination region 1 (HCDR1) of SEQ ID NO: 33, HCDR2 of SEQ ID NO: 34 , HCDR3 of SEQ ID NO: 35, light chain complementarity determination region 1 (LCDR1) of SEQ ID NO: 36, LCDR2 in column number 37, and LCDR3 in sequence number 38, b) The heavy chain variable region (VH) of SEQ ID NO: 39 and the light chain variable region (VL) of SEQ ID NO: 40, c) HCDR1 of SEQ ID NO: 74, HCDR2 of SEQ ID NO: 75, HCDR of SEQ ID NO: 76 3. LCDR1 of Sequence ID No. 77, LCDR2 of Sequence ID No. 78, and LCD of Sequence ID No. 79 R3, d) VH of SEQ ID NO: 80 and VL of SEQ ID NO: 81 e) HCDR1, HCDR2, HCDR3, LC of the CD3 binding domain of Sequence ID No. 53 DR1, LCDR2, and LCDR3, or f) CD3 binding domain including VH and VL of the CD3 binding domain of Sequence ID No. 53 The method according to claim 5.

7. The aforementioned T cell redirection therapeutic agent, a) HCDR1 of SEQ ID NO: 23, HCDR2 of SEQ ID NO: 24, HCDR of SEQ ID NO: 25 3. LCDR1 of Sequence ID No. 26, LCDR2 of Sequence ID No. 27, and LCD of Sequence ID No. 28 BCMA-binding domain including R3, and HCDR1 of SEQ ID NO: 33, H of SEQ ID NO: 34 CDR2, HCDR3 (sequence number 35), LCDR1 (sequence number 36), LC (sequence number 37) CD3 binding domains including DR2 and LCDR3 of Sequence ID No. 38, and / or b) BCMA binding domains including VH of SEQ ID NO: 29 and VL of SEQ ID NO: 30, and Claim 5, comprising a CD3 binding domain including VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40 Methods used.

8. The T cell redirection therapeutic agent is the first heavy chain (HC1) of SEQ ID NO: 31, SEQ ID NO: 3 The first light chain of 2 (LC1), the second heavy chain of SEQ ID NO: 41 (HC2), and SEQ ID NO: 42 The method according to claim 7, comprising a second light chain (LC2).

9. The aforementioned T cell redirection therapeutic agent, a) HCDR1 of SEQ ID NO: 43, HCDR2 of SEQ ID NO: 44, HCDR of SEQ ID NO: 45 3. LCDR1 of sequence number 46, LCDR2 of sequence number 47, and LCD of sequence number 48 GPRC5D binding domain including R3, and HCDR1 of SEQ ID NO: 33, SEQ ID NO: 34 HCDR2 of sequence number 35, HCDR3 of sequence number 36, LCDR1 of sequence number 37 CD3-binding domains including LCDR2 and LCDR3 of Sequence ID No. 38, and / or b) GPRC5D binding domains including VH of SEQ ID NO: 49 and VL of SEQ ID NO: 50, The claim includes a CD3 binding domain including VH of sequence number 39 and VL of sequence number 40. The method described in item 5.

10. The T cell redirection therapeutic agent is HC1 of SEQ ID NO: 51, LC1 of SEQ ID NO: 52, The method according to claim 9, comprising HC2 of row number 41 and LC2 of sequence number 42.

11. The aforementioned T cell redirection therapeutic agent, a) HCDR1 of SEQ ID NO: 84, HCDR2 of SEQ ID NO: 85, HCDR of SEQ ID NO: 86 3. LCDR1 of Sequence ID No. 87, LCDR2 of Sequence ID No. 88, and LCD of Sequence ID No. 89 CD33 binding domain including R3, and HCDR1 of SEQ ID NO: 74, H of SEQ ID NO: 75 CDR2, HCDR3 (sequence number 76), LCDR1 (sequence number 77), LC (sequence number 78) CD3-binding domains including DR2 and LCDR3 of Sequence ID No. 79, and / or b) CD33 binding domains including VH of SEQ ID NO: 90 and VL of SEQ ID NO: 91, and Claim 5, comprising a CD3 binding domain including VH of SEQ ID NO: 80 and VL of SEQ ID NO: 81 Methods used.

12. The T cell redirection therapeutic agent is HC1 of SEQ ID NO: 92, LC1 of SEQ ID NO: 93, The method according to claim 11, comprising HC2 of row number 82 and LC2 of sequence number 83.

13. The aforementioned T cell redirection therapeutic agent, a) HCDR1 of SEQ ID NO: 94, HCDR2 of SEQ ID NO: 95, HCDR of SEQ ID NO: 96 3. LCDR1 of Sequence ID 9, LCDR2 of Sequence ID 10, and LCDR of Sequence ID 59 CD123 binding domain including 3, and HCDR1 of SEQ ID NO: 33, H of SEQ ID NO: 34 CDR2, HCDR3 (sequence number 35), LCDR1 (sequence number 36), LC (sequence number 37) CD3 binding domains including DR2 and LCDR3 of Sequence ID No. 38, and / or b) CD123 binding domains including VH of SEQ ID NO: 100 and VL of SEQ ID NO: 61, The claim includes a CD3 binding domain including VH of sequence number 39 and VL of sequence number 40. The method described in item 5.

14. The aforementioned T cell redirection therapeutic agent is HC1 of SEQ ID NO: 102, LC1 of SEQ ID NO: 63, The method according to claim 13, comprising HC2 of sequence number 41 and LC2 of sequence number 42.

15. The aforementioned T cell redirection therapeutic agent, a) HCDR1, HCDR2, HCDR3, L of the CD19 binding domain of Sequence ID No. 53 CD19 binding domains including CDR1, LCDR2, and LCDR3, and Sequence ID No. 5 3 CD3 binding domains HCDR1, HCDR2, HCDR3, LCDR1, LCDR 2, and CD3-binding domains including LCDR3, and / or b) The method according to claim 5, comprising the amino acid sequence of SEQ ID NO:

53.

16. The aforementioned T cell redirection therapeutic agent, a) HCDR1 of SEQ ID NO: 54, HCDR2 of SEQ ID NO: 55, HCDR of SEQ ID NO: 56 3. LCDR1 of Sequence ID 9, LCDR2 of Sequence ID 10, and LCDR of Sequence ID 59 PSMA-binding domain including 3, and HCDR1 of SEQ ID NO: 33, HC of SEQ ID NO: 34 DR2, HCDR3 (sequence number 35), LCDR1 (sequence number 36), LCD (sequence number 37) R2, and the CD3-binding domain including LCDR3 of Sequence ID No. 38, and / or b) PSMA-binding domains including VH of SEQ ID NO: 60 and VL of SEQ ID NO: 61, and Claim 5, comprising a CD3 binding domain including VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40 Methods used.

17. The aforementioned T cell redirection therapeutic agent is HC1 of SEQ ID NO: 62, LC1 of SEQ ID NO: 63, The method according to claim 16, comprising HC2 of column number 41 and LC2 of sequence number 42.

18. The aforementioned T cell redirection therapeutic agent, a) HCDR1 of SEQ ID NO: 64, HCDR2 of SEQ ID NO: 65, HCDR of SEQ ID NO: 66 3. LCDR1 of Sequence ID No. 67, LCDR2 of Sequence ID No. 68, and LCD of Sequence ID No. 69 The TMEFF2 binding domain including R3, and HCDR1 of SEQ ID NO: 74, SEQ ID NO: 75 HCDR2, HCDR3 of SEQ ID NO: 76, LCDR1 of SEQ ID NO: 77, HCDR3 of SEQ ID NO: 78 CD3-binding domains including LCDR2 and LCDR3 of Sequence ID No. 79, and / or b) A TMEFF2 binding domain including VH of SEQ ID NO: 70 and VL of SEQ ID NO: 71, The claim includes a CD3 binding domain including VH of sequence number 80 and VL of sequence number 81. The method described in item 5.

19. The aforementioned T cell redirection therapeutic agent is HC1 of SEQ ID NO: 72, LC1 of SEQ ID NO: 73, The method according to claim 18, comprising HC2 of row number 82 and LC2 of sequence number 83.

20. The aforementioned T cell redirection therapeutic agent is a multispecific antibody, a chimeric antigen receptor (CAR), and The method according to any one of claims 1 to 19, wherein is a T cell containing the CAR.

21. The multispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype. A method according to claim 20.

22. The multispecific antibody reduces the binding of the multispecific antibody to the Fcγ receptor (FcγR). The method according to claim 21, comprising one or more Fc substitutions to reduce.

23. The one or more Fc substitutions mentioned above are F234A / L235A on IgG4, IgG1 Upper L234A / L235A, IgG2 upper V234A / G237A / P238S / H2 68A / V309L / A330S / P331S, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N29 on all Ig isotypes 7A, V234A / G237A on IgG2, K214T / E233P / L on IgG1 234V / L235A / G236 Missing / A327G / P331A / D365E / L358 M, H268Q / V309L / A330S / P331S on IgG2, S2 on IgG1 67E / L328F, L234F / L235E / D265A on IgG1, on IgG1 L234A / L235A / G237A / P238S / H268A / A330S / P331 S, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236 deletion / G237A / P23 on IgG4 Claim 22, selected from the group consisting of 8S, wherein the numbering of residues follows the EU index. Methods used.

24. The method according to claim 23, wherein the multispecific antibody further comprises an S228P substitution.

25. The multispecific antibody is located in the first CH3 domain or the second CH3 domain, or Both the first CH3 domain and the second CH3 domain contain one or more The method according to any one of claims 20 to 24, including asymmetric substitution.

26. The one or more asymmetric substitutions mentioned above are F450L / K409R, wild-type / F409L _R409K, T366Y / F405A, T366W / F405W, F405W / Y40 7A, T394W / Y407T, T394S / Y407A, T366W / T394S, F 405W / T394S and T366W / T366S_L368A_Y407V, L351 Y_F405A_Y407V / T394W, T366I_K392M_T394W / F4 05A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366 V_K409F, Y407A / T366A_K409F, and T350V_L351Y It consists of _F405A_Y407V / T350V_T366L_K392L_T394W The method according to claim 25, selected from the group.

27. The subject is a person according to any one of claims 1 to 26 who has been newly diagnosed with cancer. Law.

28. The subject is relapsed or refractory to previous anticancer drug therapy, according to any of claims 1 to 27. The method described in any one of the items.

29. The cancer is a hematological malignancy or a solid tumor, according to any one of claims 1 to 28. method.

30. The aforementioned hematological malignancies include multiple myeloma, smoldering multiple myeloma, and benign monoclonal gamma globulin. Robulinemia (MGUS), acute lymphoblastic leukemia (ALL), diffuse large B cell lymphocyte leukemia Lymphoma (DLBCL), Burkitt lymphoma (BL), follicular lymphoma (FL), mantle MCL (major cell lymphoma), Waldenström's hypergammaglobulinemia, plasma cell leukemia Disease, light chain amyloidosis (AL), precursor B-cell lymphoblastic leukemia, precursor B-cell lymphoblastic leukemia Panpablastic leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic leukemia CLL, B-cell malignancy, chronic myeloid leukemia (CML), hairy cells Leukemia (HCL), blastic plasmacytoid dendritic cell neoplasm, Hodgkin lymphoma, non-Hodgkin lymphoma Parkinson's disease, marginal zone B-cell lymphoma (MZL), or mucosal-associated lymphoid tissue lymphoma (MALT) Plasma cell leukemia, anaplastic large cell lymphoma (ALCL), leukemia, or lymphoma. The method according to claim 29.

31. The method according to claim 30, wherein the multiple myeloma is a newly diagnosed multiple myeloma. 。

32. The method according to claim 30, wherein the multiple myeloma is relapsed or refractory multiple myeloma.

33. The method according to claim 31 or 32, wherein the multiple myeloma is a high-risk multiple myeloma. 。

34. The subject having high-risk multiple myeloma, a) t(4;14)(p16;q32), b) t(14;16)(q32;q23), c) del17p, d) 1qAmp, e) t(4;14)(p16;q32) and t(14;16)(q32;q23), f) t(4;14)(p16;q32) and del17p, g) t(14;16)(q32;q23) and del17p, or h) t(4;14)(p16;q32), t(14;16)(q32;q23) and d Having one or more chromosomal abnormalities, including EL17P, or any combination thereof. The method according to claim 33.

35. The aforementioned multiple myeloma is treated with the aforementioned anti-CD38 antibody, lenalidomide, bortezomib, and pomalidomide. D, carfilzomib, elotozumab, ixazomib, melphalan, young Relapse or refractory to treatment with thalidomide or any combination thereof The method according to claim 32.

36. The aforementioned solid tumors include prostate cancer, lung cancer, liver cancer, cervical cancer, colon cancer, and breast cancer. Cancer, ovarian cancer, endometrial cancer, pancreatic cancer, melanoma, glioblastoma, esophageal cancer, gastric cancer , stomach cancer, kidney cancer, colon cancer, bladder cancer, cervical cancer, If you have melanoma, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, head and neck cancer, glioma, or glioblastoma, please contact us. The method described in item 29.

37. The aforementioned prostate cancer is recurrent, refractory, malignant, or castration-resistant prostate cancer, or these The method according to claim 36, which is any combination.

38. The AML is an AML with at least one gene abnormality, and an AML with the formation of multiple gene dysplasia. Therapy-related AML, undifferentiated AML, most undifferentiated AML, differentiated AML, acute myelomonocytic white blood cell carcinoma Blood diseases, acute monocytic leukemia, acute erythrocytic leukemia, acute megakaryoblastic leukemia, acute basophilic leukemia The method according to claim 30, wherein the disease is leukemia, acute panmyelopathy with fibrosis, or myelosarcoma.

39. The aforementioned at least one gene abnormality is a translocation between chromosome 8 and chromosome 21, and chromosome 16. Chromosomal translocations or inversions, translocations between chromosome 15 and chromosome 17, and translocations between chromosome 11 Changes, or fms-related tyrosine kinase 3 (FLT3), nucleophosmine (NPM1 ), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 ( IDH2), DNA (cytosine-5)-methyltransferase 3 (DNMT3A), CCAAT / enhancer-binding protein alpha (CEBPA), U2 nuclear small molecule RN A cofactor 1 (U2AF1), zeste 2 Polycomb inhibitory complex 2 subunit enzyme Hanser (EZH2), chromosome structure maintenance 1A (SMC1A), or chromosome structure maintenance 3 The method according to claim 38, wherein the mutation is in (SMC3).

40. The aforementioned at least one gene abnormality is a translocation t(8;21)(q22;q22), inversion i nv(16)(p13;q22), translocation t(16;16)(p13;q22), translocation t( 15;17) (q22;q12), mutations in FLT3-ITD, R132 in IDH1 H or R100Q / R104V / F108L / R119Q / I130V mutation, The method according to claim 39, wherein the mutation is R140Q or R172 in IDH2.

41. The aforementioned ALL is B-cell lineage ALL, T-cell lineage ALL, adult ALL, or pediatric ALL. A method according to claim 30.

42. The subject having ALL has either the Philadelphia chromosome or BCR-ABL They are resistant to or have acquired resistance to kinase inhibitor treatment. The method according to claim 41.

43. The aforementioned anti-CD38 antibody is HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7, SEQ ID NO: HCDR3 of 8, LCDR1 of SEQ ID NO: 9, LCDR2 of SEQ ID NO: 10, and SEQ ID NO: 1 The method according to any one of claims 1 to 42, comprising 1 LCDR3.

44. Claims 1 to 4, wherein the anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 The method described in any one of item 3.

45. The anti-CD38 antibody is an IgG1 isotype, any one of claims 1 to 44. Methods used.

46. Claim 1, wherein the anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO:

13. The method described in any one of items ~45.

47. The aforementioned anti-CD38 antibody, a) VH of sequence number 14 and VL of sequence number 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) Any one of claims 1 to 42, comprising VH of sequence number 20 and VL of sequence number 21 The method described in section [section number].

48. The method according to claim 47, wherein the anti-CD38 antibody is an IgG1 isotype.

49. The aforementioned T-cell redirection therapeutic agent is a BCMA x CD3 bispecific antibody, GPRC5D x CD3 bispecific antibody, CD33 x CD3 bispecific antibody, CD19 x CD3 bispecific Antibodies, CD123 x CD3 bispecific antibodies, PSMA x CD3 bispecific antibodies, or TM The method according to any one of claims 1 to 48, wherein the antibody is an EFF2 × CD3 bispecific antibody.

50. Claims 1 to 49 further include administering one or more anticancer drug therapies to the subject. The method described in any one of the items.

51. The aforementioned one or more anticancer drug therapies include autologous stem cell transplantation (ASCT), radiation therapy, surgery, A selected from the group consisting of chemotherapeutic agents, immunomodulators, and targeted cancer therapies, as described in claim 50. Method of loading.

52. The aforementioned one or more anticancer drug therapies include lenalidomide, thalidomide, pomalidomide, Bortezomib, carfilzomib, erotozumab, ixazomib, melphalan, dexa Metazone, vincristine, cyclophosphamide, hydroxydaunorubicin, predni Zon, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, salakatinib, tozacertib, or danucertib, cytarabine, dow Norbicin, Idarubicin, Mitoxantrone, Hydroxyurea, Decitabine, Clado Livin, fludarabine, topotecan, etoposide-6-thioguanine, corticosteroids Methotrexate, 6-mercaptopurine, azacitidine, arsenic trioxide, and total tran Claim 5 The method described in 1.

53. The anti-CD38 antibody is administered in a dose of approximately 8 mg / kg to approximately 16 mg / kg, The method described in any one of items 1 to 52.

54. The aforementioned anti-CD38 antibody is mixed with approximately 25 mM acetic acid, approximately 60 mM sodium chloride, and approximately 140 mM Nitol, and about 20% w / v polysorbate-20 (PS-20) A medical solution containing the aforementioned anti-CD38 antibody in a concentration of mg / mL to approximately 120 mg / mL, with a pH of approximately 5.

5. Any of claims 1 to 53, which is administered or provided for administration in a pharmaceutical composition. The method described in item 1.

55. The anti-CD38 antibody consists of approximately 1,800 mg of the anti-CD38 antibody and approximately 30,000 U. A pharmaceutical composition containing rHuPH20 that is administered or provided for administration. The method according to any one of claims 1 to 52.

56. The anti-CD38 antibody is approximately 120 mg / mL of the anti-CD38 antibody and approximately 2,000 U A pharmaceutical composition containing rHuPH20 at a concentration of / mL is administered or provided for administration. The method according to claim 55.

57. The aforementioned anti-CD38 antibody, a) Histidine at approximately 5 mM to approximately 15 mM, b) Sorbitol in a concentration of approximately 100 mM to approximately 300 mM, c) PS-20 with a concentration of approximately 0.01% w / v to approximately 0.04% w / v, d) Contains approximately 1 mg / mL to approximately 2 mg / mL of methionine, with a pH of approximately 5.5 to 5.

6. A pharmaceutical composition that is administered or provided for administration, as described in claim 56. Method of loading.

58. The aforementioned anti-CD38 antibody, a) Approximately 1,800 mg of the anti-CD38 antibody, b) Approximately 30,000 U of rHuPH20, c) Approximately 10 mM histidine, d) Approximately 300 mM sorbitol, e) PS-20 at approximately 0.04% (w / v), f) A pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6 The method according to claim 57, which is administered or provided for administration.

59. The aforementioned anti-CD38 antibody, a) The anti-CD38 antibody in a concentration of approximately 120 mg / mL, b) rHuPH2O at approximately 2,000 U / mL, c) Approximately 10 mM histidine, d) Approximately 300 mM sorbitol, e) PS-20 at approximately 0.04% (w / v), f) A pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6 The method according to claim 58, which is administered or provided for administration.

60. A method for treating cancer in a target, wherein the effective amount of BCMA × CD3 bispecific A method comprising administering a sex antibody and an anti-CD38 antibody to the subject to treat the cancer.

61. The subject was treated with an anti-CD38 antibody before administration of the BCMA x CD3 bispecific antibody. The method according to claim 60.

62. The BCMA x CD3 bispecific antibody is HCDR1 of SEQ ID NO: 23, and SEQ ID NO:

24. HCDR2, HCDR3 (SEQ ID NO: 25), LCDR1 (SEQ ID NO: 26), L (SEQ ID NO: 27) CDR2 and the BCMA-binding domain including LCDR3 of Sequence ID No. 28, and Sequence ID No. HCDR1 of 33, HCDR2 of SEQ ID NO: 34, HCDR3 of SEQ ID NO: 35, SEQ ID NO: 3 CD containing LCDR1 of 6, LCDR2 of sequence number 37, and LCDR3 of sequence number 38. The method according to claim 60 or 61, comprising a three-joint domain.

63. The BCMA binding domain includes VH of SEQ ID NO: 29 and VL of SEQ ID NO: 30, Claim 6, wherein the CD3 binding domain includes VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40 The method described in 2.

64. The BCMA x CD3 bispecific antibody is of the IgG4 isotype, and HC1 is 40 Phenylalanine is at position 5, arginine at position 409, and leucine is at position 405 of HCl2. and containing lysine at position 409, wherein the residue numbering follows the EU index, claim 60 The method described in any one of paragraphs 62.

65. The BCMA×CD3 bispecific antibody is located at position 228 of both HC1 and HC2. Claim 64 further comprises proline, alanine at position 234, and alanine at position 235. Method of loading.

66. The BCMA x CD3 bispecific antibody is HC1 of SEQ ID NO: 31, and LC of SEQ ID NO:

32.

1. The method according to claim 65, comprising HC2 of sequence number 41 and LC2 of sequence number 42. 。

67. The method according to any one of claims 60 to 66, wherein the cancer is a BCMA-expressing cancer.

68. The method according to any one of claims 60 to 67, wherein the cancer is a hematological malignancy.

69. The aforementioned targets are anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, and calfy. Luzomib, erotozumab, ixazomib, melphalan, or thalidomide, or The condition is relapsed or refractory to any combination of these treatments, according to claims 60 to 68. The method described in any one of the items.

70. Claim 6, wherein the subject is relapsed or refractory to treatment with the anti-CD38 antibody. The method described in 9.

71. The aforementioned hematological malignancies include multiple myeloma, myeloma, DLBLC, CLL, and Waldenstler's disease. The method according to claim 68, wherein the patient has hypergammaglobulinemia or non-Hodgkin lymphoma.

72. The method according to claim 71, wherein the multiple myeloma is a newly diagnosed multiple myeloma. 。

73. The method according to claim 71, wherein the multiple myeloma is relapsed or refractory multiple myeloma.

74. Any one of claims 71 to 73, wherein the multiple myeloma is a high-risk multiple myeloma. Methods used.

75. The subject having high-risk multiple myeloma, a) t(4;14)(p16;q32), b) t(14;16)(q32;q23), c) del17p, d) 1qAmp, e) t(4;14)(p16;q32) and t(14;16)(q32;q23), f) t(4;14)(p16;q32) and del17p, g) t(14;16)(q32;q23) and del17p, or h) t(4;14)(p16;q32), t(14;16)(q32;q23) and d Having one or more chromosomal abnormalities, including EL17P, or any combination thereof. The method according to claim 74.

76. The aforementioned anti-CD38 antibody is HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7, SEQ ID NO: HCDR3 of 8, LCDR1 of SEQ ID NO: 9, LCDR2 of SEQ ID NO: 10, and SEQ ID NO: 1 The method according to any one of claims 60 to 75, comprising 1 LCDR3.

77. Claims 60 to 60, wherein the anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 The method described in any one of paragraphs 76.

78. The anti-CD38 antibody is an IgG1 isotype, as per any one of claims 60 to 77. The method described in section [section number].

79. Claim 6, wherein the anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13 The method described in any one of items 0 to 78.

80. The aforementioned anti-CD38 antibody, a) VH of sequence number 14 and VL of sequence number 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) Any of claims 60 to 75, comprising VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21 The method described in item 1.

81. The method according to claim 80, wherein the anti-CD38 antibody is an IgG1 isotype.

82. The anti-CD38 antibody is administered in a dose of approximately 8 mg / kg to approximately 16 mg / kg, The method described in any one of paragraphs 60 to 81.

83. The BCMA x CD3 bispecific antibody and the anti-CD38 antibody are administered by intravenous injection. The method according to any one of claims 60 to 82, which is administered.

84. The BCMA x CD3 bispecific antibody is administered by intravenous injection, and the anti-CD3 The method according to any one of claims 60 to 82, wherein the antibody is administered by subcutaneous injection. 。

85. The method according to any one of claims 60 to 84, wherein the subject is a human.

86. Claims 60 to 8 further include administering one or more anticancer drug therapies to the subject. The method described in any one of item 5.

87. The aforementioned one or more anticancer drug therapies include autologous stem cell transplantation (ASCT), radiation therapy, surgery, A selected from the group consisting of chemotherapeutic agents, immunomodulators, and targeted cancer therapies, as described in claim 86. Method of loading.

88. The aforementioned one or more anticancer drug therapies include lenalidomide, thalidomide, pomalidomide, Bortezomib, carfilzomib, erotozumab, ixazomib, melphalan, prednisolone Selected from the group consisting of dizone, dexamethasone, or any combination thereof. The method according to claim 86.

89. The aforementioned anti-CD38 antibody is mixed with approximately 25 mM acetic acid, approximately 60 mM sodium chloride, and approximately 140 mM Nitol, and about 20% w / v polysorbate-20 (PS-20) A medical solution containing the aforementioned anti-CD38 antibody in a concentration of mg / mL to approximately 120 mg / mL, with a pH of approximately 5.

5. Any of claims 60 to 88, which is administered or provided for administration in a pharmaceutical composition. The method described in any one of the items.

90. The anti-CD38 antibody consists of approximately 1,800 mg of the anti-CD38 antibody and approximately 30,000 U. A pharmaceutical composition containing rHuPH20 that is administered or provided for administration. or the method according to any one of claims 60 to 88.

91. The anti-CD38 antibody is approximately 120 mg / mL of the anti-CD38 antibody and approximately 2,000 U A pharmaceutical composition containing rHuPH20 at a concentration of / mL is administered or provided for administration. The method according to claim 90.

92. The aforementioned anti-CD38 antibody, a) Histidine at approximately 5 mM to approximately 15 mM, b) Sorbitol in a concentration of approximately 100 mM to approximately 300 mM, c) PS-20 with a concentration of approximately 0.01% w / v to approximately 0.04% w / v, d) Contains approximately 1 mg / mL to approximately 2 mg / mL of methionine, with a pH of approximately 5.5 to 5.

6. A pharmaceutical composition that is administered or provided for administration, as described in claim 91. Method of loading.

93. The aforementioned anti-CD38 antibody, a) Approximately 1,800 mg of the anti-CD38 antibody, b) Approximately 30,000 U of rHuPH20, c) Approximately 10 mM histidine, d) Approximately 300 mM sorbitol, e) PS-20 at approximately 0.04% (w / v), f) A pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6 The method according to claim 92, which is administered or provided for administration.

94. The aforementioned anti-CD38 antibody, a) The anti-CD38 antibody in a concentration of approximately 120 mg / mL, b) rHuPH2O at approximately 2,000 U / mL, c) Approximately 10 mM histidine, d) Approximately 300 mM sorbitol, e) PS-20 at approximately 0.04% (w / v), f) A pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6 The method according to claim 93, which is administered or provided for administration.

95. BCMA-binding domains including VH of SEQ ID NO: 29 and VL of SEQ ID NO: 30, and sequence BCMAxCD containing CD3 binding domains including VH (number 39) and VL (sequence number 40).

3. Bispecific antibodies and anti-CD38 antibodies including VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 Includes pharmaceutical compositions.

96. The BCMA x CD3 bispecific antibody is HC1 of SEQ ID NO: 31, and LC of SEQ ID NO:

32.

1. The anti-CD38 antibody comprises HC2 of SEQ ID NO: 41 and LC2 of SEQ ID NO: 42, The pharmaceutical composition according to claim 95, comprising the HC of SEQ ID NO: 12 and the LC of SEQ ID NO:

13.

97. A pharmaceutical composition according to claim 95 or 96, which is a non-fixed combination.

98. Approximately 25 mM acetic acid, approximately 60 mM sodium chloride, approximately 140 mM mannitol, and approximately 0. Approximately 20 mg / mL to approximately 120 mg in 0.4% w / v polysorbate-20 (PS-20) The pharmaceutical compound according to claim 97, comprising the anti-CD38 antibody in g / mL and having a pH of approximately 5.5 Finished product.

99. It contains approximately 1,800 mg of the anti-CD38 antibody and approximately 30,000 U of rHuPH20. The pharmaceutical composition according to claim 97.

100. Approximately 120 mg / mL of the aforementioned anti-CD38 antibody and approximately 2,000 U / mL of rHuPH20 A pharmaceutical composition according to claim 99, comprising:

101. The pharmaceutical composition according to claim 100, further comprising one or more excipients.

102. The one or more excipients mentioned above are histidine, methionine, sorbitol, or Claim 1, which is polysorbate-20 (PS-20), or any combination thereof. The pharmaceutical composition described in 01.

103. The aforementioned pharmaceutical composition a) The anti-CD38 antibody in a concentration of approximately 100 mg / mL to approximately 120 mg / mL, b) Histidine at approximately 5 mM to approximately 15 mM, c) Sorbitol in a concentration of approximately 100 mM to approximately 300 mM, d) PS-20 with a concentration of approximately 0.01% w / v to approximately 0.04% w / v, e) Contains approximately 1 mg / mL to approximately 2 mg / mL of methionine, with a pH of approximately 5.5 to 5.

6. A pharmaceutical composition according to claim 102.

104. The pharmaceutical composition according to claim 103, comprising approximately 10 mM histidine.

105. The pharmaceutical composition according to claim 103 or 104, comprising approximately 300 mM sorbitol.

106. Any one of claims 103 to 105, comprising approximately 0.04% (w / v) of PS-20 The pharmaceutical composition described.

107. A medical device according to any one of claims 103 to 106, containing approximately 1 mg / mL of methionine. A pharmaceutical composition.

108. a) Approximately 1,800 mg of the anti-CD38 antibody, b) Approximately 30,000 U of rHuPH20, c) Approximately 10 mM histidine, d) Approximately 300 mM sorbitol, e) PS-20 at approximately 0.04% (w / v), f) A solution containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6, claims 103-10 A pharmaceutical composition according to any one of item 7.

109. a) The anti-CD38 antibody in a concentration of approximately 120 mg / mL, b) rHuPH2O at approximately 2,000 U / mL, c) Approximately 10 mM histidine, d) Approximately 300 mM sorbitol, e) PS-20 at approximately 0.04% (w / v), f) A solution containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6, claims 103-10 A pharmaceutical composition according to any one of item 9.

110. A kit comprising the pharmaceutical composition described in any one of claims 95 to 109.

111. A method for treating cancer in a target, comprising T100, which binds to GPRC5D in an effective amount for treatment. The cancer is treated by administering a cell redirection therapy drug and an anti-CD38 antibody to the subject. A method that includes [this].

112. The administration of the anti-CD38 antibody that binds to GPRC5D, and the T-cell redirection therapeutic agent. The method according to claim 111, wherein the subject is administered the preceding dose.

113. Claim 11, wherein the subject is relapsed or refractory to treatment with a previous anticancer drug. The method described in 1 or 112.

114. The cancer is a GPRC5D-expressing cancer, according to any one of claims 111 to 113. method.

115. The GPRC5D-expressing cancer is a hematological malignancy or a solid tumor, according to claim 114. method.

116. Claim 115 states that the aforementioned hematological malignancy is leukemia, lymphoma, or multiple myeloma. Method of loading.

117. The aforementioned solid tumors include ovarian cancer, lung cancer, stomach cancer, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, colon cancer, and esophageal cancer. The method according to claim 116, wherein the patient is bladder cancer, cervical cancer, or malignant melanoma.

118. The aforementioned subjects are the anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, and cal. Filzomib, erotozumab, ixazomib, melphalan, or thalidomide, The patient is relapsed or refractory to treatment with any combination of these, claims 111- The method described in any one of paragraphs 117.

119. Claim 1, wherein the subject is relapsed or refractory to treatment with the anti-CD38 antibody. The method described in 18.

120. The person according to claim 117, wherein the multiple myeloma is a newly diagnosed multiple myeloma. Law.

121. The method according to claim 117, wherein the multiple myeloma is relapsed or refractory multiple myeloma. 。

122. The multiple myeloma described in claim 120 or 121 is a high-risk multiple myeloma. method.

123. The subject having high-risk multiple myeloma, a) t(4;14)(p16;q32), b) t(14;16)(q32;q23), c) del17p, d) 1qAmp, e) t(4;14)(p16;q32) and t(14;16)(q32;q23), f) t(4;14)(p16;q32) and del17p, g) t(14;16)(q32;q23) and del17p, or h) t(4;14)(p16;q32), t(14;16)(q32;q23) and d Having one or more chromosomal abnormalities, including EL17P, or any combination thereof. The method according to claim 122.

124. The aforementioned T-cell redirecting therapeutic agents include CD3, CD3 epsilon (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL 8. Any of claims 111 to 123, which binds to PD-1, CD195, or NKG2C. The method described in item 1.

125. The aforementioned T-cell redirection therapeutic agents include HCDR1 (SEQ ID NO: 43) and HCD (SEQ ID NO: 44). R2, HCDR3 (sequence number 45), LCDR1 (sequence number 46), LCDR (sequence number 47) 2, and the GPRC5D binding domain containing LCDR3 of Sequence ID No. 48, and Sequence ID No. 3 HCDR1 of 3, HCDR2 of SEQ ID NO: 34, HCDR3 of SEQ ID NO: 35, SEQ ID NO: 36 CD3 including LCDR1 of sequence number 37, LCDR2 of sequence number 37, and LCDR3 of sequence number 38. The method according to any one of claims 111 to 124, comprising a binding domain.

126. The GPRC5D binding domain includes VH of SEQ ID NO: 49 and VL of SEQ ID NO: 50 The claim states that the CD3 binding domain includes VH of SEQ ID NO: 39 and VL of SEQ ID NO:

40. The method described in any one of paragraphs 111 to 126.

127. The T-cell redirecting therapeutic agent that binds to GPRC5C is a multispecific antibody, CAR, Or, the T cell expressing the CAR, according to any one of claims 111 to 126. method.

128. The multispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype. A method according to claim 127.

129. The multispecific antibody reduces the binding of the multispecific antibody to the Fcγ receptor (FcγR). The method according to claim 128, comprising one or more Fc substitutions to reduce.

130. The one or more Fc substitutions mentioned above are F234A / L235A on IgG4, IgG1 Upper L234A / L235A, IgG2 upper V234A / G237A / P238S / H2 68A / V309L / A330S / P331S, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N29 on all Ig isotypes 7A, V234A / G237A on IgG2, K214T / E233P / L on IgG1 234V / L235A / G236 Missing / A327G / P331A / D365E / L358 M, H268Q / V309L / A330S / P331S on IgG2, S2 on IgG1 67E / L328F, L234F / L235E / D265A on IgG1, on IgG1 L234A / L235A / G237A / P238S / H268A / A330S / P331 S, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236 deletion / G237A / P23 on IgG4 Claim 12, selected from the group consisting of 8S, wherein the numbering of residues follows the EU index. The method described in 9.

131. The method according to claim 130, wherein the multispecific antibody further comprises an S228P substitution.

132. The multispecific antibody is located in the first CH3 domain or the second CH3 domain, or Both the first CH3 domain and the second CH3 domain contain one or more The method according to any one of claims 127 to 131, including asymmetric substitution.

133. The one or more asymmetric substitutions mentioned above are F450L / K409R, wild-type / F409L _R409K, T366Y / F405A, T366W / F405W, F405W / Y40 7A, T394W / Y407T, T394S / Y407A, T366W / T394S, F 405W / T394S and T366W / T366S_L368A_Y407V, L351 Y_F405A_Y407V / T394W, T366I_K392M_T394W / F4 05A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366 V_K409F, Y407A / T366A_K409F, and T350V_L351Y It consists of _F405A_Y407V / T350V_T366L_K392L_T394W The method according to claim 132, selected from the group.

134. The multispecific antibodies are HC1 of SEQ ID NO: 51, LC1 of SEQ ID NO: 52, and SEQ ID NO: 41 The following is a description of any one of claims 111 to 133, including HC2 of and LC2 of Sequence ID No.

42. Method of loading.

135. The aforementioned anti-CD38 antibody is HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7, SEQ ID NO: HCDR3 of 8, LCDR1 of SEQ ID NO: 9, LCDR2 of SEQ ID NO: 10, and SEQ ID NO: 1 The method according to any one of claims 111 to 134, comprising 1 LCDR3.

136. Claim 111, wherein the anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 The method described in any one of items ~135.

137. The anti-CD38 antibody is an IgG1 isotype, as per any of claims 111 to 136. The method described in item 1.

138. Claim 1, wherein the anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO:

13. The method described in any one of items 11 to 137.

139. The aforementioned anti-CD38 antibody, a) VH of sequence number 14 and VL of sequence number 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) Any of claims 111 to 138, including VH of sequence number 20 and VL of sequence number 21 The method described in any one of the items.

140. The method according to claim 139, wherein the anti-CD38 antibody is an IgG1 isotype.

141. The anti-CD38 antibody is administered in a dose of approximately 8 mg / kg to approximately 16 mg / kg, The method described in any one of items 111 to 140.

142. The T-cell redirecting therapeutic agent and the anti-CD38 antibody that bind to GPRC5D are static The method according to any one of claims 111 to 141, administered by intravascular injection.

143. The T-cell redirecting therapeutic agent that binds to GPRC5D is administered by intravenous injection. The anti-CD38 antibody is administered by subcutaneous injection, according to claims 111 to 142. The method described in any one of the items.

144. The method according to any one of claims 111 to 143, wherein the subject is a human.

145. The T-cell redirecting therapeutic agent that binds to GPRC5D is GPRC5D×CD3 dual The method according to any one of claims 111 to 144, wherein the antibody is specific.

146. Claims 111 to 111 further include administering one or more anticancer drug therapies to the subject. The method described in any one of paragraphs 145.

147. The aforementioned one or more anticancer drug therapies include autologous stem cell transplantation (ASCT), radiation therapy, surgery, A selected agent from the group consisting of chemotherapeutic agents, immunomodulators, and targeted cancer therapies, as in claim 146. Method of description.

148. The aforementioned one or more anticancer drug therapies include lenalidomide, thalidomide, pomalidomide, Bortezomib, carfilzomib, erotozumab, ixazomib, melphalan, dexa The method according to claim 146, selected from the group consisting of metazone or prednisone.

149. The aforementioned anti-CD38 antibody is mixed with approximately 25 mM acetic acid, approximately 60 mM sodium chloride, and approximately 140 mM Nitol, and about 20% w / v polysorbate-20 (PS-20) A medical solution containing the aforementioned anti-CD38 antibody in a concentration of mg / mL to approximately 120 mg / mL, with a pH of approximately 5.

5. Claims 111 to 148, which are administered or provided for administration in a pharmaceutical composition The method described in any one of the items.

150. The anti-CD38 antibody consists of approximately 1,800 mg of the anti-CD38 antibody and approximately 30,000 U. A pharmaceutical composition containing rHuPH20 that is administered or provided for administration. The method according to any one of claims 111 to 149.

151. The anti-CD38 antibody is approximately 120 mg / mL of the anti-CD38 antibody and approximately 2,000 U A pharmaceutical composition containing rHuPH20 at a concentration of / mL is administered or provided for administration. The method according to claim 150.

152. The aforementioned anti-CD38 antibody, a) The anti-CD38 antibody in a concentration of approximately 100 mg / mL to approximately 120 mg / mL, b) Histidine at approximately 5 mM to approximately 15 mM, c) Sorbitol in a concentration of approximately 100 mM to approximately 300 mM, d) PS-20 with a concentration of approximately 0.01% w / v to approximately 0.04% w / v, e) Contains approximately 1 mg / mL to approximately 2 mg / mL of methionine, with a pH of approximately 5.5 to 5.

6. Claim 151, a pharmaceutical composition that is administered or provided for administration Method of description.

153. The aforementioned anti-CD38 antibody, a) Approximately 1,800 mg of the anti-CD38 antibody, b) Approximately 30,000 U of rHuPH20, c) Approximately 10 mM histidine, d) Approximately 300 mM sorbitol, e) PS-20 at approximately 0.04% (w / v), f) A pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6 The method according to claim 152, which is administered or provided for administration.

154. The aforementioned anti-CD38 antibody, a) The anti-CD38 antibody in a concentration of approximately 120 mg / mL, b) rHuPH2O at approximately 2,000 U / mL, c) Approximately 10 mM histidine, d) Approximately 300 mM sorbitol, e) PS-20 at approximately 0.04% (w / v), f) A pharmaceutical composition containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6 The method according to claim 153, which is administered or provided for administration.

155. HCDR1 of sequence number 43, HCDR2 of sequence number 44, HCDR3 of sequence number 45, LCDR1 of sequence number 46, LCDR2 of sequence number 47, and LCDR3 of sequence number 48 The GPRC5D binding domain, as well as HCDR1 of SEQ ID NO: 33 and H of SEQ ID NO: 34 CDR2, HCDR3 (sequence number 35), LCDR1 (sequence number 36), LC (sequence number 37) GPRC5C× containing CD3 binding domains including DR2 and LCDR3 of Sequence ID No. 38 CD3 bispecific antibody, HCDR1 (SEQ ID NO: 6), HCDR2 (SEQ ID NO: 7), SEQ ID NO: HCDR3 of 8, LCDR1 of SEQ ID NO: 9, LCDR2 of SEQ ID NO: 10, and SEQ ID NO: 1 A pharmaceutical combination comprising an anti-CD38 antibody containing LCDR3 (1).

156. The GPRC5D binding domain includes VH of SEQ ID NO: 49 and VL of SEQ ID NO: 50 The CD3 binding domain includes VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40, Claim 155, wherein the anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 A combination of medicines.

157. The GPRC5C×CD3 bispecific antibody is HC1 of SEQ ID NO: 51, and SEQ ID NO:

52. The anti-CD38 antibody comprises LC1, HC2 of SEQ ID NO: 41, and LC2 of SEQ ID NO:

42. However, the pharmaceutical combination according to claim 156 includes HC of sequence number 12 and LC of sequence number 13. Match.

158. A non-fixed combination of pharmaceuticals according to any one of claims 155 to 157 height.

159. Approximately 25 mM acetic acid, approximately 60 mM sodium chloride, approximately 140 mM mannitol, and approximately 0. Approximately 20 mg / mL to approximately 120 mg in 0.4% w / v polysorbate-20 (PS-20) The pharmaceutical product according to claim 158, comprising g / mL of the anti-CD38 antibody and having a pH of approximately 5.

5. combination.

160. It contains approximately 1,800 mg of the anti-CD38 antibody and approximately 30,000 U of rHuPH20. , the pharmaceutical combination according to claim 158.

161. Approximately 120 mg / mL of the aforementioned anti-CD38 antibody and approximately 2,000 U / mL of rHuPH20 The pharmaceutical composition according to claim 159, comprising:

162. The pharmaceutical combination according to claim 161, further comprising one or more excipients.

163. The one or more excipients mentioned above are histidine, methionine, sorbitol, or Claim 1, which is polysorbate-20 (PS-20), or any combination thereof. The drug combinations listed in 62.

164. The aforementioned pharmaceutical composition a) The anti-CD38 antibody in a concentration of approximately 100 mg / mL to approximately 120 mg / mL, b) Histidine at approximately 5 mM to approximately 15 mM, c) Sorbitol in a concentration of approximately 100 mM to approximately 300 mM, d) PS-20 with a concentration of approximately 0.01% w / v to approximately 0.04% w / v, e) Contains approximately 1 mg / mL to approximately 2 mg / mL of methionine, with a pH of approximately 5.5 to 5.

6. A combination of pharmaceuticals as described in claim 163.

165. The pharmaceutical combination according to claim 164, comprising approximately 10 mM histidine.

166. The pharmaceutical combination according to claim 164 or 165, comprising approximately 300 mM sorbitol. 。

167. A compound comprising approximately 0.04% (w / v) PS-20, according to any one of claims 163 to 166. The listed combination of medications.

168. A medical device according to any one of claims 163 to 167, containing approximately 1 mg / mL of methionine. Drug combinations.

169. a) Approximately 1,800 mg of the anti-CD38 antibody, b) Approximately 30,000 U of rHuPH20, c) Approximately 10 mM histidine, d) Approximately 300 mM sorbitol, e) PS-20 at approximately 0.04% (w / v), f) A solution containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6, claims 163-16 A combination of medicines as described in any one of item 8.

170. a) The anti-CD38 antibody in a concentration of approximately 120 mg / mL, b) rHuPH2O at approximately 2,000 U / mL, c) Approximately 10 mM histidine, d) Approximately 300 mM sorbitol, e) PS-20 at approximately 0.04% (w / v), f) A solution containing approximately 1 mg / mL of methionine and having a pH of approximately 5.6, claims 164-16 A combination of medicines listed in any one of item 9.

171. A kit comprising the pharmaceutical combination described in any one of claims 155 to 171.

172. A method for treating cancer in a target, comprising T cells that bind to a therapeutically effective amount of CD19. The cancer is treated by administering a redirecting therapeutic agent and an anti-CD38 antibody to the subject. Includes, method.

173. The subject, prior to administration of the T-cell redirecting therapeutic agent that binds to CD19, has an anti-CD38 The method according to claim 172, wherein the treatment is performed with an antibody.

174. Improving the efficacy of CD19-binding T-cell redirection therapies in patients with cancer. A method for causing the T cell redirection therapeutic agent that binds to CD19 to be administered before the administration of the T cell redirection therapeutic agent. A method comprising administering an anti-CD38 antibody to a subject.

175. Claim 1, the subject is refractory or recurrent in response to treatment with previous anticancer drugs. The method described in any one of items 72 to 174.

176. The cancer is a hematological malignancy or a solid tumor, according to any one of claims 172 to 175. Method of description.

177. The aforementioned hematological malignancies include lymphoma, B-cell malignancy, Hodgkin lymphoma, and non-Hodgkin lymphoma. Parkinson's disease, DLBLC, FL, MCL, marginal zone B-cell lymphoma (MZL), mucosa-associated lymphoma Medial lymphoma (MALT), CLL, ALL, AML, Waldenström high gamma globulin The method according to claim 176, wherein the patient has phosphatemia or T-cell lymphoma.

178. The aforementioned solid tumors include lung cancer, liver cancer, cervical cancer, colon cancer, breast cancer, ovarian cancer, pancreatic cancer, melanoma, and nerve cancer. The method according to claim 176, wherein the cancer is glioblastoma, prostate cancer, esophageal cancer, or gastric cancer.

179. The aforementioned T-cell redirection therapeutic agents include CD3 epsilon (CD3ε), CD8, and KI2L. 4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD -1, bonded to CD195, or NKG2C, according to any one of claims 172 to 178 Method of description.

180. The T-cell redirecting therapeutic agents that bind to CD19 include blinatumomab and axicabuta. Gensyloleucel, tisagenlecleucel-t, ricebilizumab, lysokabutagenmara lisocabtagene maraleucel, XmAb-5574, CIK-CAR. CD 19. ICTCAR-011, IM-19, JCAR-014, Longasutsukishimabuteshi Linn, MB-CART2019.1, OXS-1550, PBCAR-0191, PCA R-019, PCAR-119, Senl-001, TI-1007, XmAb-587 1, PTG-01, PZ01, Senl_1904A, Senl_1904B, UCAR T-19, CSG-CD19, DI-B4, ET-190, GC-007F, or GC- The person according to any one of claims 172 to 179, which includes the CD19 binding domain of 022. Law.

181. The T-cell redirecting therapeutic agents that bind to CD19 include blinatumomab and axicabuta. Gensyloleucel, tisagenlecleucel-t, ricebilizumab, lysokabutagenmara Luyucel, XmAb-5574, CIK-CAR. CD19, ICTCAR-011, IM-19, JCAR-014, Longasutuximabutecilin, 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, Claims 172 to include DI-B4, ET-190, GC-007F, or GC-022. The method described in any one of paragraphs 180.

182. The T-cell redirecting therapeutic agent that binds to CD19 is a multispecific antibody, CAR, or The method according to any one of claims 172 to 181, wherein the T cell expresses the CAR. 。

183. The aforementioned anti-CD38 antibody is HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7, SEQ ID NO: HCDR3 of 8, LCDR1 of SEQ ID NO: 9, LCDR2 of SEQ ID NO: 10, and SEQ ID NO: 1 The method according to any one of claims 172 to 182, comprising 1 LCDR3.

184. Claim 172, wherein the anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 The method described in any one of items ~183.

185. The anti-CD38 antibody is an IgG1 isotype, as per any of claims 172 to 184. The method described in item 1.

186. Claim 1, wherein the anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO:

13. The method described in any one of items 72 to 185.

187. The aforementioned anti-CD38 antibody, a) VH of sequence number 14 and VL of sequence number 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) Any of claims 172 to 182, including VH of sequence number 20 and VL of sequence number 21 The method described in any one of the items.

188. The method according to claim 187, wherein the anti-CD38 antibody is an IgG1 isotype.

189. The anti-CD38 antibody is administered in a dose of approximately 8 mg / kg to approximately 16 mg / kg, The method described in any one of paragraphs 172 to 188.

190. The T-cell redirecting therapeutic agent that binds to CD19 and the anti-CD38 antibody are administered intravenously. The method according to any one of claims 172 to 189, administered by injection.

191. The T-cell redirecting therapeutic agent that binds to CD19 is administered by intravenous injection. The anti-CD38 antibody is administered by subcutaneous injection, as per any one of claims 172 to 189. The method described in item 1.

192. The method according to any one of claims 172 to 191, wherein the subject is a human.

193. The T cell redirection therapeutic agent that binds to CD19 is a CD19 x CD3 bispecific anti- The method according to any one of claims 172 to 192, wherein the body is...

194. Claim 172 further comprises administering one or more anticancer drug therapies to the subject. The method described in any one of paragraphs 193.

195. The aforementioned one or more anticancer drug therapies include autologous stem cell transplantation (ASCT), radiation therapy, surgery, A selected from the group consisting of chemotherapeutic agents, immunomodulators, and targeted cancer therapies, as in claim 194. Method of description.

196. CD19 x CD3 bispecific antibody containing blinatumomab (SEQ ID NO: 53), SEQ ID NO: 6 HCDR1, HCDR2 (SEQ ID NO: 7), HCDR3 (SEQ ID NO: 8), LCDR (SEQ ID NO: 9) 1. An anti-CD38 antibody containing LCDR2 of SEQ ID NO: 10 and LCDR3 of SEQ ID NO: 11 Includes, combination of pharmaceuticals.

197. Claim 196, wherein the anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 The drug combinations listed.

198. Claim 1, wherein the anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO:

13. The drug combinations listed in item 97.

199. A non-fixed combination of pharmaceutical combinations according to any one of claims 196 to 198 height.

200. Approximately 25 mM acetic acid, approximately 60 mM sodium chloride, approximately 140 mM mannitol, and approximately 0. Approximately 20 mg / mL to approximately 120 mg in 0.4% w / v polysorbate-20 (PS-20) The pharmaceutical product according to claim 199, comprising g / mL of the anti-CD38 antibody and having a pH of approximately 5.

5. combination.

201. It contains approximately 1,800 mg of the anti-CD38 antibody and approximately 30,000 U of rHuPH20. , the pharmaceutical combination according to claim 199.

202. Approximately 120 mg / mL of the aforementioned anti-CD38 antibody and approximately 2,000 U / mL of rHuPH20 The pharmaceutical combination according to claim 201, including the above.

203. The pharmaceutical combination according to claim 202, further comprising one or more excipients.

204. The one or more excipients mentioned above are histidine, methionine, sorbitol, or Claim 2, which is polysorbate-20 (PS-20), or any combination thereof. The drug combinations listed in 03.

205. The aforementioned combination of pharmaceuticals a) The anti-CD38 antibody in a concentration of approximately 100 mg / mL to approximately 120 mg / mL, b) Histidine at approximately 5 mM to approximately 15 mM, c) Sorbitol in a concentration of approximately 100 mM to approximately 300 mM, d) PS-20 with a concentration of approximately 0.01% w / v to approximately 0.04% w / v, e) Contains approximately 1 mg / mL to approximately 2 mg / mL of methionine, with a pH of approximately 5.5 to 5.

6. A combination of pharmaceuticals according to claim 204.

206. The pharmaceutical combination according to claim 205, comprising approximately 10 mM histidine.

207. The pharmaceutical combination according to claim 205 or 206, comprising approximately 300 mM sorbitol. 。

208. Any one of claims 205 to 207, comprising approximately 0.04% (w / v) of PS-20 The listed combination of medications.

209. A medical device according to any one of claims 205 to 208, containing approximately 1 mg / mL of methionine. Drug combinations.

210. a) Approximately 1,800 mg of the anti-CD38 antibody, b) Approximately 30,000 U of rHuPH20, c) Approximately 10 mM histidine, d) Approximately 300 mM sorbitol, e) PS-20 at approximately 0.04% (w / v), f) A solution comprising approximately 1 mg / mL of methionine and having a pH of approximately 5.6, claims 205-20 A combination of medicines listed in any one of item 9.

211. a) The anti-CD38 antibody in a concentration of approximately 120 mg / mL, b) rHuPH2O at approximately 2,000 U / mL, c) Approximately 10 mM histidine, d) Approximately 300 mM sorbitol, e) PS-20 at approximately 0.04% (w / v), f) A solution comprising approximately 1 mg / mL of methionine and having a pH of approximately 5.6, claims 205-21 A pharmaceutical composition according to any one of the items in paragraph 0.

212. A kit comprising the pharmaceutical composition according to any one of claims 196 to 211.

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