Immunomodulation and treatment of solid tumors using antibodies that specifically bind CD38

Abstract

To provide methods of immunomodulation and treating patients having solid tumors with antibodies that specifically bind CD38.SOLUTION: The present invention provides a method of treating a patient having a solid tumor, including administering to a patient in need thereof a therapeutically effective amount of an antibody that specifically binds CD38 for a time sufficient to treat the solid tumor.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention relates to immunomodulation using an antibody that specifically binds CD38 and to a method for treating solid tumors. To relate to. [Background technology]

[0002] The immune system is strictly controlled by a network of co-stimulatory and co-inhibitory ligands and receptors. These molecules are controlled. They emit secondary signals for T cell activation, both positive and negative. This results in a balanced network of signals, leading to immunity against infection and tumors. Maximizing the epidemic response while limiting self-immunity (Wang et al., (Epub Mar.7,2011)J Exp Med 208(3):577~92 , Lepenies et al.,(2008) Endocr Metab Immu ne Disord Drug Targets 8:279~288).

[0003] Immunotherapy checkpoints for treating solid tumors promote an anti-tumor immune response. It targets co-inhibitory pathways in T cells and is an anti-CTLA-4 and anti-PD-1 antibody, Y ERVOY (registered trademark) (ipilimumab), KEYTRUDA (registered trademark) (pembrolizolite) The approval of zumab and OPDIVO (registered trademark) (nivolumab) has enabled clinical care for cancer patients. This has led to advancements in A. Anti-PD-1 / PD-L1 antibodies are used in patients with multiple solid tumors. Although favorable clinical responses have been observed in some individuals, the response rate remains considerably low. In patients who had received prior treatment, the rate was approximately 15% to 20% (Swaika et al., (2015) Mol Immunol doi:10.1016 / j.molimm.2 (015.02.009).

[0004] Natural killer cells (NK), dendritic cells (DC), and effector T cells are strong anti- While it can trigger a tumor response, tumor cells often possess an immunosuppressive microenvironment. Myelin-derived suppressor cells (MDSCs), regulatory T cells (Tregs), or regulatory B cells Because it is favorable for the development of immunosuppressive populations of immune cells such as cysts (Bregs), tumor immune tolerance This contributes to the failure of immunotherapy regimens in cancer patients and experimental tumor models. [Overview of the project] [Problems that the invention aims to solve]

[0005] Therefore, it is necessary to induce an adaptive immune response against tumors or to target immunosuppressive immune cells. Therefore, there remains a need to develop new cancer immunotherapies. [Means for solving the problem]

[0006] The present invention provides an antibody that specifically binds a therapeutically effective amount of CD38, which is required The present invention provides a method for treating patients with solid tumors, including administering the treatment to the patient.

[0007] The present invention also provides an antibody that specifically binds a therapeutically effective amount of CD38, which is necessary for... This includes administering the drug to patients who have regulatory T cell (Treg)-mediated diseases. We also provide treatment methods.

[0008] The present invention also provides an antibody that specifically binds a therapeutically effective amount of CD38, which is necessary for... This includes administering it to patients with myeloid-derived suppressor cell (MDSC)-mediated diseases. We also provide methods to treat patients who are experiencing these symptoms.

[0009] The present invention also provides an antibody that specifically binds a therapeutically effective amount of CD38, which is necessary for... This includes administering the drug to patients who have regulatory B-cell (Breg)-mediated diseases. We also provide treatment methods.

[0010] The present invention also involves contacting regulatory T cells (Tregs) with an antibody that specifically binds CD38. The present invention also provides methods for suppressing Treg activity, including the following:

[0011] This invention also specifically binds CD38 to bone marrow-derived suppressor cells (MDSCs). The invention also provides methods for suppressing the activity of MDSCs, including contact with antibodies.

[0012] The present invention also involves contacting regulatory B cells (Bregs) with an antibody that specifically binds CD38. The invention also provides methods for suppressing Breg activity, including [specific method / method].

[0013] The present invention also includes administering to a patient an antibody that specifically binds to CD38. The report also provides methods for enhancing the immune response.

[0014] The present invention also involves administering an antibody that specifically binds CD38 to a patient, thereby enabling the patient to... A method for treating patients with solid tumors, including reducing the number of Treg cells in the body. We also offer this.

[0015] The present invention also involves administering an antibody that specifically binds CD38 to a patient, thereby enabling the patient to... This includes reducing the number of bone marrow-derived suppressor cells (MDSCs) in solid tumors. We also provide methods for treating patients who have this condition.

[0016] This invention also specifically binds CD38 to immunosuppressing cells. The present invention also provides a method for suppressing the activity of immune suppressor cells, which includes contacting them with antibodies. ru.

[0017] The present invention also involves administering an antibody that specifically binds to CD38 to a patient who needs it. The system also provides methods for treating patients with viral infections, including the treatment of the virus. [Brief explanation of the drawing]

[0018] [Figure 1] The median lymphocyte count increased over time in patients treated with DARZALEX™ (daratumumab) at doses of 8 mg / kg (upper line) or 16 mg / kg (lower line), indicating that lymphocyte counts returned to normal after treatment completion. Study name: SIRIUS. The X-axis represents the treatment cycle and the administration day within each treatment cycle (C1D1: Cycle 1, Day 1; C1D4: Cycle 1, Day 4, etc.). SCR: Normal value, EOT: End of treatment, WK: Weeks, POST-WK: Weeks after treatment, post-PD FU: Follow-up after exacerbation. The areas highlighted in gray shade indicate the 25-27% interquartile range (IQR) for each responder's outpatient data point. [Figure 2] For individual patients (light gray line), the graph shows the percentage change (%) in the absolute number of CD3+ T cells in peripheral blood relative to the normal range in patients treated with DARZALEX (daratumumab). Study name: SIRIUS (MMY2002). The X-axis represents the treatment cycle and the administration day within each treatment cycle (C1D1: Cycle 1, Day 1; C1D4: Cycle 1, Day 4, etc.). WK: Weeks, POST-WK: Weeks after treatment, POST-PD FU: Follow-up after exacerbation. The black line shows the median percentage change for all patients. [Figure 3]For individual patients (light gray line), the graph shows the percentage change (%) in the absolute number of CD4+ T cells in peripheral blood relative to the reference value in patients treated with DARZALEX (daratumumab). Study name: SIRIUS. The X-axis represents the treatment cycle and the administration day within each treatment cycle (C1D1: Cycle 1, Day 1; C1D4: Cycle 1, Day 4, etc.). WK: Weeks, POST-TMT: Post-Treatment. The black line shows the median percentage change for all patients. [Figure 4] For individual patients (light gray line), the graph shows the percentage change (%) in the absolute number of CD8+ T cells in peripheral blood of patients treated with DARZALEX (daratumumab) relative to the normal range. Study name: SIRIUS. The X-axis represents the treatment cycle and the administration day within each treatment cycle (C1D1: Cycle 1, Day 1; C1D4: Cycle 1, Day 4, etc.). WK: Weeks, Pre-PDFU: Follow-up before exacerbation, Post-PDFU: Follow-up after exacerbation. The black line shows the median percentage change for all patients. [Figure 5] This graph shows that the number of CD45+CD3+ cells (measured as a percentage of lymphocytes) in bone marrow aspirate increased over time during treatment with DARZALEX® (daratumumab) at doses of 8 mg / kg or 16 mg / kg. As shown, this graph includes both responders and non-responders. Study name: SIRIUS. The X-axis represents the treatment cycle and the administration day within each treatment cycle (e.g., C2D22: cycle 2, day 22). SCR: normal value, Post-PD FU1: follow-up after exacerbation. The areas highlighted in gray shade show the 25-27% interquartile range (IQR) for outpatient data points for non-responders at the 8 mg / kg dose, responders at the 16 mg / kg dose, or non-responders at the 16 mg / kg dose, respectively. NR: non-responder, R: responder. [Figure 6]This graph shows that the CD45+CD3+CD8+ cell count (measured as a percentage of lymphocytes) in bone marrow aspirate increased over time during treatment with DARZALEX® (daratumumab) at doses of 8 mg / kg or 16 mg / kg. As shown, this graph includes both responders and non-responders. Study name: SIRIUS. The X-axis represents the treatment cycle and the administration day within each treatment cycle (e.g., C2D22: cycle 2, day 22). SCR: normal value, Post-PD FU1: follow-up after exacerbation. The gray highlighted areas represent the 25-27% interquartile range (IQR) for outpatient data points for non-responders at the 8 mg / kg dose, responders at the 16 mg / kg dose, or non-responders at the 16 mg / kg dose, respectively. NR: non-responder, R: responder. [Figure 7A] This shows that the median CD8+ / Treg and CD8+ / CD4+ cell ratios in peripheral blood, expressed as the median for all treated patients, increased over time during DARZALEX (daratumumab) treatment. Time points: C1D1: Cycle 1, Day 1; C3D1: Cycle 3, Day 1; C4D1: Cycle 4, Day 1. Study name: SIRIUS. SCR: Reference values. [Figure 7B] This shows that the CD8+ / Treg cell ratio in bone marrow aspirate, expressed as the median for all treated patients, increased over time during DARZALEX® (daratumumab) treatment. Time points: C1D1: Cycle 1, Day 1; C3D1: Cycle 3, Day 1; C4D1: Cycle 4, Day 1. Study name: SIRIUS. [Figure 8A] When measured using the percentage change in the abundance (CIA) of specific clonal cells, responders showed increased CD8+ T cell clonality compared to non-responders. Study name: GEN501, a subset of 17 patients. [Figure 8B]This chart shows the fold change in CD8+ T cell clonality of individual patients before and after DARZALEX (daratumumab) treatment. Responders are indicated with an asterisk. Clonality was measured by the fold change in the abundance of specific clonal cells (CIA). Study name: GEN501, a subset of 17 patients. [Figure 8C] Compared to non-responders (Group B), responders (Group A) showed a greater total proliferation of the TCR repertoire, as measured by CIA (change in abundance). P=0.037. Study name: GEN501, a subset of 17 patients. [Figure 8D] The sum of the absolute values ​​of the change in T cell abundance (CIA) between responders and non-responders for each proliferated T cell clone is shown. P=0.035 between responders (Group A) and non-responders (Group B). Study name: GEN501, a subset of 17 patients. [Figure 8E] This shows the maximum CIA of single T cell clones in responders (Group A) and non-responders (Group B). Study name: GEN501, a subset of 17 patients. [Figure 8F] Compared to non-responders (Group B), responders (Group A) showed a greater maximum single-clonal growth rate, as measured using maximum CIA%. P=0.0477. Study name: GEN501, a subset of 17 patients. [Figure 9A] This shows the percentage of CD8+ naive cells in peripheral blood of non-responders (NR, black square) and patients showing at least minimal response (MR, white square) to DARZALEX® (daratumumab) at baseline, or at weeks 2, 4, or 8 of treatment, or after relapse. Study name: GEN501, a subset of 17 patients. **p=1.82×10⁻⁴. [Figure 9B]This shows the percentage of CD8+ central memory cells (Tem) in the peripheral blood of non-responders (NR, black square) and patients showing at least minimal response (MR, white square) to DARZALEX® (daratumumab) at baseline, or at weeks 2, 4, or 8 of treatment, or after relapse. Study name: GEN501, subset of 17 patients. *p=4.88×10⁻². [Figure 9C] This indicates the percentage increase in HLA class I-bound CD8+ T cells in peripheral blood, compared to baseline, or at weeks 1, 4, or 8 of treatment, or after relapse. Study name: GEN501, a subset of 17 patients. [Figure 9D] The baseline (bassline) or treatment-dependent state indicates low levels of CD38 expression in peripheral blood CD8+ naive T cells and CD8+ central memory cells (TEM). Study name: GEN501, a subset of 17 patients. MFI: Mean fluorescence intensity. [Figure 10A] The histograms from FACS analysis show the frequency of Treg cells (CD3+CD3+CD4+CD25+CD127dim) in patients with reference values ​​(upper histogram, P4 cell population) and the frequency of CD38+Treg cells within the Treg population (lower histogram, P5 cell population). Study name: GEN501, subset of 17 patients. [Figure 10B] The histograms from FACS analysis show the frequency of Tregs (CD3+CD3+CD4+CD25+CD127dim) in multiple myeloma patients after DARZALEX (daratumumab) treatment (upper histogram, P4 cell population) and the frequency of CD38+ Tregs within the Treg population (lower histogram, P5 cell population). CD38+ Tregs were depleted after DARZALEX (daratumumab) treatment. Study name: GEN501, subset of 17 patients. [Figure 10C]This shows the frequency of CD38highCD3+CD4+CD25+CD127dim Tregs in patients treated with DARZALEX® (daratumumab) at baseline, or at week 1, week 4, week 8, post-relapse, or end-of-treatment (EOT) at 6 months. The frequency of CD38high Tregs decreased with DARZALEX® (daratumumab) treatment and returned to baseline at EOT. Y-axis: % of CD38highCD3+CD4+CD25+CD127dim Tregs (CD3+ T cell origin). Study name: GEN501, subset of 17 patients. [Figure 10D] The CD8+ / Treg cell ratios for responders and non-responders are shown for baseline, weeks 1, 4, and 8 of treatment. At week 8 of treatment, the CD8+ / Treg cell ratio was significantly higher in responders compared to non-responders (p=0.00955). Study name: GEN501, a subset of 17 patients. [Figure 10E] This shows that the proliferation of effector cells is more effectively inhibited in the presence of CD38+ Tregs compared to CD38-Tregs or negative controls. Error bars represent the standard error. Asterisks indicate significant changes. Samples were obtained from multiple healthy donors. Cell proliferation was assessed by dilution of carboxyfluorescein succinimidyl ester (CFSE). [Figure 11] The graph shows that bone marrow-derived suppressor cells (MDSCs) are present in patients with multiple myeloma (upper graph, cells enclosed in squares), and approximately half of these cells expressed CD38 (middle graph, cells enclosed in squares). The CD38-high MDSC population was depleted in patients treated with a single infusion of DARZALEX (daratumumab) (lower graph, cells enclosed in squares). Study name: GEN501, a subset of 17 patients. [Figure 12]The number of CD38high MDSCs (CD11b+HLADR-CD14-CD33+CD15+) was lower in patients at weeks 1, 4, or 8 of DARZALEX® (daratumumab) treatment compared to the normal range, and returned to near the normal range after end of treatment (EOT). Patients who relapsed still showed a decrease in CD38high MDSCs. Black squares: Non-responders; White squares: Patients who showed at least minimal response to DARZALEX® (daratumumab) treatment. Vertical lines show the median in each group. Patients 2, 4, 15, 16, and 17 showed high initial values ​​in the CD38high MDSC population. Study name: GEN501, a subset of 17 patients. [Figure 13] The patients with the highest CD38 high MDSC (Patients 2, 4, 15, 16, and 17) had the longest progression-free survival (PFS). These patients achieved either a partial response (PR) or minimal response (MR) to DARZALEX® (daratumumab) treatment. SD: stable; PD: progressive. The X-axis shows PFS for each numbered patient. [Figure 14] This study demonstrates that MDSCs are sensitive to DARZALEX® (daratumumab)-induced ADCC. Daudi cells were used as a positive control for target cells in the assay. Cell lysis percentage was measured. [Figure 15A] This study shows that CD38+ Breg was depleted at weeks 1, 4, and 8 of treatment in patients treated with DARZALEX (daratumumab). [Figure 15B] This shows that CD38+ Breg secretes IL-10 in response to stimulation. [Figure 16A]This shows the antiviral response, measured by CMV, EBV, and influenza virus-specific (CEF) IFN-γ production in PBMCs derived from patients treated with DARZALEX (daratumumab) who were VGPR at the reference values ​​and indicated time points during treatment. OD: Optical density. White bars: Negative control; Black bars: CEF added; Shaded bars: Allogeneic PBMCs only. Asterisks indicate statistically significant changes. Pre 4, 8, 10 = Week 4, Week 8, or Week 10 of treatment. [Figure 16B] This shows the antiviral response, measured by CMV, EBV, and influenza virus-specific (CEF) IFN-γ production in PBMCs derived from patients treated with DARZALEX (daratumumab) who achieved complete response (CR) at the reference values ​​and indicated time points during treatment. OD: Optical density. White bars: Negative control; Black bars: CEF added; Shaded bars: Allogeneic PBMCs only. Asterisks indicate statistically significant changes. Pre 4, 8, 10 = Week 4, Week 8, or Week 10 of treatment. [Figure 16C] This shows the antiviral response, measured by CMV, EBV, and influenza virus-specific (CEF) IFN-γ production in privately-derived microorganisms (PBMCs) from patients treated with DARZALEX (daratumumab) who were PD (pathogenic disease) at the reference values ​​and indicated time points during treatment. OD: Optical density. White bars: Negative control; Black bars: CEF added; Shaded bars: Allogeneic PBMCs only. Ns: No significant difference. Pre 4, 8 = Week 4 or Week 8 of treatment. [Figure 16D] This shows the antiviral response, measured by CMV, EBV, and influenza virus-specific (CEF) IFN-γ production in privately-derived PBMCs (PBMCs) from patients treated with DARZALEX (daratumumab) who had MR (metazoidal reduction) during treatment and at the indicated time points. OD: Optical density. White bars: Negative control; Black bars: CEF added; Shaded bars: Allogeneic PBMCs only. Ns: No significant difference. Pre 4, 8 = Week 4 or Week 8 of treatment. [Figure 16E]This table shows the percentage (%) of proliferative virus-reactive T cells in patient-derived PBMCs (PBMCs) treated with DARZALEX (daratumumab) that were VGPR (vigorous viral reactivity) during treatment and at the indicated time points. White bars: negative control; black bars: CEF added. Asterisks indicate statistically significant changes. Pre 4, 8, 10 = week 4, week 8, or week 10 of treatment. [Figure 16F] This table shows the percentage (%) of proliferative virus-reactive T cells in patient-derived PBMCs (PBMCs) treated with DARZALEX (daratumumab) that achieved complete response (CR) at the reference values ​​and the indicated time points during treatment. White bars: negative control; black bars: CEF added. Asterisks indicate statistically significant changes. Pre 4, 8, 10 = week 4, week 8, or week 10 of treatment. [Figure 17A] This shows histograms of FACS analysis results indicating CD38 expression levels in natural killer (NK), monocytes, B cells, and T cells derived from healthy donors. [Figure 17B] This shows histograms of FACS analysis results indicating CD38 expression levels in plasma cells, natural killer cells (NK), monocytes, B cells, and T cells derived from multiple myeloma patients. [Figure 17C] This report compares the mean fluorescence intensity (MFI) of CD38 in CD38+ Treg, Breg, NK, B cells, and T cells derived from patients with relapsed and refractory multiple myeloma. CD38 was expressed at lower levels in B cells and T cells compared to CD38+ Treg, Breg, and NK cells. [Figure 18] This shows that PD-L1 protein is downregulated in responder (R) PBMC samples and upregulated in non-responder (NR) samples over time. SD: stable. C1D1: Cycle 1, Day 1; C3D1: Cycle 3, Day 1. The Y-axis shows log2 protein concentration values. [Modes for carrying out the invention]

[0019] When used in this specification and the attached "Claims", the singular form "a", "n" and "the" refer to multiple objects unless otherwise explicitly indicated. It includes. Therefore, for example, the reference "a cell" can mean two or more cells. This includes combinations of the above, and similar combinations.

[0020] "CD38" is the human CD38 protein (synonym: ADP-ribosylcyclase 1, c This refers to ADPr hydrolase 1 (cyclic ADP-ribose hydrolase 1). Human CD38 is , as shown in GenBank acceptance number NP 001766 and sequence number 1, ami It has an amino acid sequence. CD38 has amino acid sequences 1-21 that represent the cytoplasmic domain and transmembrane. The amino acid sequence 22-42 represents the domain, and residues 43- represent the extracellular domain of CD38. It is well known that it is a single-pass type II membrane protein having 300.

[0021] Sequence ID 1 MANCEFSPVSGDKPCCRLSRRAQLCLGVSILVLILVVVL AVVVPRWRQQWSGPGTTKRFPETVLARCVKYTEIHPEMRH VDCQSVWDAFKGAFISKHPCNITEEDYQPLMKLGTQTVPC NKILLWSRIKDLAHQFTQVQRDMFTLEDTLLGYLADDLTW CGEFNTSKINYQSCPDWRKDCSNNPVSVFWKTVSRRFAEA ACDVVHVMLNGSRSKIFDKNSTFGSVEVHNLQPEKVQTLE AWVIHGGREDSRDLCQDPTIKELESIISKRNIQFSCKNIY RPDKFLQCVKNPEDSSCTSEI

[0022] As used herein, “antibody” is intended to be in a broad sense, including mouse, human, humanized, and Monoclonal antibodies, antibody fragments, bispecific antibodies, or multiplexes containing bichimeric monoclonal antibodies Specific antibodies, dimers, tetramers, or polymers, single-chain antibodies, domain antibodies, and Any other modified immunoglobulin molecule containing the antigen-binding site of the required specificity This includes the composition, including immunoglobulin molecules.

[0023] Immunoglobulins are classified into five major classes based on the amino acid sequence of their heavy chain constant domain. These can be assigned to IgA, IgD, IgE, IgG, and IgM. IgA and I IgG is an isotype of IgA1, IgA2, IgG1, IgG2, IgG3, and IgG It is further subdivided into 4. The antibody light chains of any vertebrate species have their constant domains Based on the amino acid sequence, there are two distinctly different types: kappa (κ) and lambda (λ). ) can be classified into one of the following categories.

[0024] "Antibody fragment" refers to the heavy chain and / or light chain antigen-binding sites, for example, the heavy chain complementarity-determining region. HCDR)1, 2, and 3, Light Chain Complementarity Determination Region (LCDR)1, 2, and 3, Heavy Chain Variable This refers to a portion of an immunoglobulin molecule that possesses a region (VH) or a light chain variable region (VL). The antibody fragment is a monovalent fragment consisting of the VL, VH, CL, and CH1 domains. A divalent Fab fragment containing one piece and two Fab fragments linked by disulfide bridges in the hinge region The F(ab)2 fragment, the Fd fragment consisting of the VH and CH1 domains, and one of the antibodies The Fv fragment consists of the VL and VH domains of this arm, and the domain consists of the VH domain. dAb (antibody) fragment (Ward et al., Nature 341:544~6, (1989) and includes. The VH domain and VL domain are manipulated and linked via a synthetic linker. By linking them together, various types of single-chain antibody designs can be formed, and here VH / V The L domain either pairs within the molecule, or the VH and VL domains are separate single strands. When expressed by antibody constructs, they pair intermolecules to form single-stranded Fv(scFv) or These form monovalent antigen-binding sites such as diabodies. These are, for example, described in International Publication No. 19. Issues 98 / 44001, 1988 / 01649, 1994 / 13804, and It is described in the same publication No. 1992 / 01047. These antibody fragments are well known to those skilled in the art. These fragments were obtained using the same method as for full-length antibodies, and their usefulness was assessed in the same manner. It will be cleaned.

[0025] "Isolated antibody" is an antibody or antibody that substantially does not contain other antibodies with different antigen specificity. This refers to a fragment (for example, an isolated antibody that specifically binds to CD38 other than human CD38). (It contains virtually no antibodies that specifically bind to the antigen.) However, it specifically binds to human CD38. The isolated antibody to bind is Macaca fascicularis (cynomolgus monkey) CD3. There is a possibility of cross-reactivity with other antigens, such as human CD38 orthologs, including 8. Yes, in the case of bispecific antibodies, they specifically bind to two target antigens. Furthermore, it contains virtually no antibodies that specifically bind to antigens other than these two target antigens. Isolated antibodies may also be substantially free of other cellular material and / or chemical substances. "Antibodies" are antibodies isolated with high purity, for example, 80%, 81%, 82%, 83%, 84% purity. %, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% comprising antibodies that are 90%, 95%, 96%, 97%, 98%, 99% or 100%.

[0026] "Specific binding" or "specifically binds" or "binds" refers to an antibody that binds to an antigen or an epitope within an antigen with a higher affinity than other antigens. Typically, an antibody has an equilibrium dissociation constant (K<00,00594>,

[0026] , , , , , , , ) of about 1×10 -8 M or less, such as about 1×10 -9 M or less, about 1×10 - 10 M or less, about 1×10 -11 M or less, or about 1×10 -12 M or less and binds to an antigen or an epitope within an antigen, and typically this K is at least 100-fold smaller than the K D for binding to a non-specific antigen (e.g., BSA, casein ). The dissociation constant can be measured using standard techniques. However, an antibody that specifically binds to an antigen or an epitope within an antigen may cross-react with the same antigen (homolog) from other species, such as human or monkey, such as Macaca fascicularis (cynomolgus monkey, cyno), Pan troglodytes (chimpanzee, chimp) or [[ID=2,9]]<0S00009>Callithrix jacchus (common marmoset, marmoset). A monospecific antibody specifically binds to one type of antigen or one type of epitope, while a bispecific antibody specifically binds to two different antigens or two different epitopes. The antibody variable region consists of "framework" regions separated by three "antigen-binding sites". The antigen-binding sites are defined using various terms: three in VH (HCDR1, HC DR2, HCDR3) and three in VL (LCDR1, LCDR2, LCDR3), which together form the antigen-binding site. The "framework" regions are relatively conserved regions that maintain the overall structure of the variable region, while the "antigen-binding sites" are hypervariable regions that determine the specificity and affinity of the antibody for the antigen. A monospecific antibody binds specifically to one type of antigen or one type of epitope, while a bispecific antibody binds specifically to two different antigens or two different epitopes.

[0027] The antibody variable region consists of "framework" regions separated by three "antigen-binding sites". The antigen-binding sites are defined using various terms: three in VH (HCDR1, HC DR2, HCDR3) and three phases within VL (LCDR1, LCDR2, LCDR3) Complementary Determination Regions (CDRs) are based on sequence variability (Wu and Kabat (1970) )J Exp Med 132:211~50;Kabatet al Sequenc es of Proteins of Immunological Interest ,5th Ed,Public Health Service,National I Institutes of Health, Bethesda, Md., 1991), V There are three within H (H1, H2, H3) and three within VL (L1, L2, L3), which are "super variable" "Region", "HVR", or "HV" refers to Chothia and Lesk (Choth According to ia and Lesk (1987) MolBiol 196:901~17) This refers to the region of the antibody variable domain that is structurally hypervariable as defined. , “IMGT-CDR” (Lefranc et al., (2003) Dev Com parat Immunol 27:55~77) and “specificity-determining residue use” (SDR U)(Almagro(2004)Mol Recognit 17:132~43) International ImMunoGeneTics (IMGT) can be cited. The database (http: / / www_imgt_org) is a standardized number of antigen-binding sites. Numbering and definitions are provided. The correspondence between CDR, HV, and IMGT notations is as follows: , Lefrancet al., (2003) Dev Comparat Immuno It is described in 27:55~77.

[0028] When used herein, "Chotia residue" refers to Al-Lazikani(Al -Lazikani et al.,(1997)J MolBiol 273:927 These are antibody VL and VH residues numbered according to ~48).

[0029] A "framework" or "framework sequence" is defined as an antigen-binding site. This is the remaining sequence of the variable region, excluding the specified part. The antigen-binding site is referred to by various terms as described above. Therefore, the exact amino acid sequence of the framework can be defined as how the antigen-binding site is It depends on how it's defined.

[0030] A "humanized antibody" is one in which the antigen-binding site originates from a species other than human, and the variable region framework is used. This refers to antibodies derived from human immunoglobulin sequences. Humanized antibodies are within the framework region. Because it may include substitutions, this framework is for expressed human immunoglobulins. It does not have to be a complete replica of the germline gene sequence.

[0031] "Human antibodies" are those in which both the framework and antigen-binding site are derived from human sequences. This refers to antibodies that have a heavy chain variable region and a light chain variable region. If the antibody contains a constant region, then the constant region is called a constant region. The regions also originate from human-derived sequences.

[0032] Human antibodies are antibodies whose variable region is human germline immunoglobulin or rearranged immunoglobulin. The heavy chain variable region "derived" from a human sequence when obtained from a system using the brin gene. This includes a region or light chain variable region. Such a system is a human immunoglobulin presented on a phage. The gene library and the transgender mice possessing the human immunoglobulin gene locus. Includes genetically modified non-human animals. "Human antibodies" are, for example, naturally occurring somatic mutations. Or the introduction of intended substitutions in the framework or antigen-binding site, or both. When compared to human germline immunoglobulins or rearranged immunoglobulin genes This may include differences in amino acids. Typically, "human antibodies" are human germline immunoglobulins. or an amino acid sequence encoded by a rearranged immunoglobulin gene, and amino acids In the sequence, at least approximately 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, They are 97%, 98%, 99%, or 100% identical. In some cases, "human antibodies" are, for example, For example, Knappik et al., (2000) J Mol Biol 296:57 Consensus framework obtained from human framework sequence analysis described in ~86 k sequence, or for example Shi et al., (2010) J MolBiol 397: Presentation on phages, as described in 385-96 and International Publication No. 2009 / 085462. It may contain synthetic HCDR3 incorporated into a human immunoglobulin gene library. .

[0033] Human antibodies derived from human immunoglobulin sequences are phage-presenting integrated synthetic CDRs and / or it can be produced using a system such as a synthetic framework, or to improve antibody properties To achieve this, it can undergo in vitro mutagenesis and in vivo human antibodies It brings antibodies that do not naturally exist within the reproductive system repertoire.

[0034] Antibodies whose antigen-binding sites originate from species other than humans are not included in the definition of human antibodies.

[0035] "Recombinant antibodies" are transgenic or chromosomal derivatives of human immunoglobulin genes. Entered animals (e.g., mice or rats) or hybridomas prepared therefrom (hereinafter) (Detailed below) Antibodies isolated from, and antibodies isolated from host cells transformed to express antibodies. Antibodies extracted, antibodies isolated from recombinant combinatorial antibody libraries, and human immunoassay By any other means involving splicing a globulin gene sequence with another DNA sequence Antibodies prepared, expressed, manufactured, or isolated, or antibodies used with Fab arm exchange, are used in v Antibodies produced in ITR, such as bifunctional antibodies, are prepared, expressed, and processed by recombinant means. Includes all antibodies produced or isolated.

[0036] The term "monoclonal antibody" refers to a preparation of an antibody molecule with a single molecular composition. The monochromic antibody composition exhibits a single binding specificity and affinity for a specific epitope, and In the case of a bispecific monoclonal antibody, it exhibits double binding specificity to two distinct epitopes. It indicates the opposite sex. Therefore, "monoclonal antibodies" are those in which the C-terminal lysine is removed from the antibody heavy chain. Except for potential well-known alternatives, each heavy chain and each light chain has a single This refers to a population of antibodies that contain amino acid compositions. Monoclonal antibodies contain heterologous glycosidic compounds within the antibody population. It may have a compounding effect. Monoclonal antibodies are monospecific or multispecific, or monovalent, bivalent, Alternatively, they may be polyvalent. Bivalent antibodies are included in the term monoclonal antibodies.

[0037] An "epitope" refers to the part of an antigen to which an antibody specifically binds. , the chemically active (polar, nonpolar, or hydrophobic, etc.) of sites such as amino acids or polysaccharide side chains. ) Consists of surface groups and may have specific three-dimensional structural properties and specific charge properties. Epitope is It can consist of adjacent and / or non-adjacent amino acids that form conformational spatial units. For non-adjacent epitopes, amino acids from different regions of the linear sequence of the antigen are: Protein molecules come into close proximity in three-dimensional space through folding.

[0038] A "variant" is a variant of a standard formed by one or more modifications, such as substitution, insertion, or deletion. A polypeptide or polynucleotide different from a standard polypeptide. It refers to.

[0039] "In combination with ~" means that two or more therapeutic drugs are used together in a mixture form on the target. Each drug may be administered simultaneously as a separate drug, or sequentially in any order. This means that. Generally, each drug is prescribed for the specified dosage and / or pre-treatment. It is administered at regular intervals.

[0040] "To treat" or "to treat" means that the purpose is to prevent undesirable physiological changes or disease progression. To delay (reduce), for example, to delay the development or spread of a tumor or tumor cells. This could be by providing beneficial or desirable clinical outcomes during treatment. It refers to therapeutic procedures that may or may not be present. Beneficial or desired clinical outcomes are detectable. Whether present or undetectable, relief of symptoms, reduction of disease severity, and stabilization (that is, (No worsening of the disease state), delayed or slowed progression of the disease, absence of metastases, improvement of the disease state or This includes relief and remission (whether partial or complete). "Treatment" is Furthermore, the survival time was extended compared to the expected survival time if the subjects had not received treatment. This can mean causing unwanted physiological changes or diseases. Those requiring treatment include unwanted physiological changes or diseases. This includes individuals who already have a disease, as well as individuals who have a tendency to undergo physiological changes or develop diseases. It can be done.

[0041] "A therapeutically effective dose" is the dose and duration required to achieve the desired therapeutic outcome. This refers to an effective dose. The therapeutically effective dose depends on factors such as the individual's condition, age, sex, and weight. Furthermore, by the ability of a therapeutic agent or combination of therapeutic agents to elicit a desired response in an individual There may be various types. Examples of indicators showing effective treatments or combinations of treatments include, for example, If so, improvement in the patient's health, reduction in tumor volume, cessation or slowing of tumor growth, and / or One notable finding is the absence of metastasis of cancer cells to other parts of the body.

[0042] "Inhibiting proliferation" (for example, with respect to tumor cells) is a treatment or combination of drugs. Compared to the absence of the same tumor cells or tumor tissue, the reduction or delay in the growth of the treatment or treatment or in vitro or in vivo when in contact with a combination of therapeutic drugs This refers to a measurable decrease or delay in the proliferation of tumor cells or tumor tissue, in vitro or in vitro. Inhibition of tumor cell or tumor tissue proliferation in vivo is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%, or 100% It is possible.

[0043] "Regulatory T cells" or "Tregs" affect the activity of other T cells and / or other immune cells. Treg usually refers to T lymphocytes whose activity is controlled by suppressing it. + CD4 + CD25 +CD127 dim T cells are possible. Treg cells are completely in this phenotype. It is recognized that Foxp3 can be expressed, and is not limited to this.

[0044] "Effector T cells" or "Teff" are responsible for killing tumor cells and / or Functions of the immune response, such as activation of the anti-tumor immune response which can lead to the elimination of tumor cells from the body. This refers to T lymphocytes that perform this function. Teff stands for CD3 + CD4 + or CD8 + It may be accompanied by. Teff secretes and contains markers such as IFN-γ, granzyme B, and ICOS, These can be expressed. Teff is recognized as not being entirely limited to these phenotypes. ru.

[0045] "Treg function" or "Treg function" modulates the host immune response and / or autoimmunity. This refers to the inhibitory function of Tregs in preventing CD8 + T cells, natural NK cells,

[0046]

number

[0047] "Inhibition of Treg function" or "Inhibition of Treg function" refers to in animals or humans. Measurements taken in vitro or in vivo using conventional methods known in the art. This refers to a decrease in the level of function of Tregs. For example, at least about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, It can decrease by 70%, 80%, 90%, 95%, 99%, or 100%. "Treg function "Inhibition" includes, for example, antibody-dependent cell-mediated cytotoxicity (ADCC) and other antibody effector functions. This involves reducing the number of Tregs by killing them.

[0048] "Bone marrow-derived suppressor cells" or "MDSCs" are hematopoietic cells, and macrophages / CD11b, a marker for monocytes, and Gr-1 / Ly-6G, a marker for granulocytes. It refers to a specialized population of cells that express a specific gene. The phenotype of MDSCs is, for example, CD11b + HLA -DR - CD14 - CD33 + CD15 + It is possible. MDSCs are mature antigen-presenting cells. The expression of the markers, MHC class II and F480, is low or undetectable. DSCs are immature cells of the myeloid lineage, including macrophages, neutrophils, dendritic cells, monocytes, or granules. MDSCs can further differentiate into several cell types, such as globules. MDSCs are derived from the normal bone marrow of adults and adult animals. Alternatively, it can be found spontaneously in normal hematopoietic sites such as the spleen.

[0049] "Inhibition of MDSC function" or "Inhibition of MDSC function" refers to in animals or humans. Measurements taken in vitro or in vivo using conventional methods known in the art. This refers to a decrease in the level of MDSC functionality. The level of MDSC functionality is For example, at least about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, It may decrease by 70%, 80%, 90%, 95%, 99%, or 100%. "The function of MDSC "Inhibition" involves killing MDSCs through antibody effector functions such as ADCC. This includes reducing the number of MDSCs. MDSCs are reactive oxygen species, peroxy The generation of night light, the improvement of arginase metabolism due to high levels of arginase, and Through various mechanisms such as an increase in nitric oxide synthase, proliferation, clonal proliferation, or cy MDSCs can suppress T cell responses such as tokine production. MDSCs can suppress IFN-γ and IL-4 It can also respond to several cytokines, such as IL-13. IFN-γ reacts to nitrate monoxide. It may activate MDSCs that induce the activity of Nosozyme Synthase 2 (NOS2). Alternating between, inter Th2 cytokines such as leukin-4 (IL-4) and IL-13 are arginase- It may activate MDSCs that can induce 1(ARG1) activity. NOS2 or AR Metabolism of L-arginine by any of the G1 cells may cause inhibition of T cell proliferation. Furthermore, the activity of both of these enzymes is related to the production of reactive nitrogen oxide species, which leads to T cell apoptosis. This could cause problems.

[0050] "Treg-related diseases" refer to diseases or disorders associated with T regulatory cells (Tregs). Treg-related diseases involve Treg function, such as suppression of the antitumor response, or effector Tregs. This can be caused by the suppression of cell proliferation. Treg-mediated diseases can be cancerous. "Treg-related diseases" The terms "Treg-mediated disease" and "Treg-mediated disease" are used interchangeably in this specification.

[0051] "Enhancement of effector T cell response" or "enhancement of T cell response" refers to animal or human subjects. To maintain or amplify biological functions in vitro or in vivo, Alternatively, effectors for regenerating or reactivating depleted or inactive T cells. - Refers to the enhancement or stimulation of T cells. Typical T cell responses include proliferation and γ-interferon CD8 + This enhancement is measured by secretion from T cells, antigen response, or clonal proliferation. The method is known to those skilled in the art.

[0052] "MDSC-related diseases" are diseases associated with bone marrow-derived suppressor cells (MDSCs) or It refers to a disorder. MDSC-related diseases affect MDSC function, such as the antitumor response or effector. This may be due to the suppression of T cell proliferation. MDSC-mediated diseases can be cancerous. The terms "patient" and "MDSC-mediated disease" are used interchangeably in this specification.

[0053] "Regulatory B cells" or "Breg" refer to B lymphocytes that suppress the immune response. g is CD19 + CD24 + CD38 + It can be a cell and is secreted by Breg. By inhibiting T cell proliferation mediated by -10, the immune response can be suppressed. e.g., subsets exist, for example Ding et al., (2015) Human I It is recognized as being described in mmunology 76:615~621.

[0054] "Breg-related diseases" refer to diseases or disorders associated with regulatory B cells. The disease is caused, for example, by Breg-mediated suppression of the antitumor response or effector T cell proliferation. Obtain. Breg-mediated diseases can be cancerous. "Breg-related diseases" and "Breg-mediated The term "disease" is used interchangeably in this specification.

[0055] "Patient" includes all humans and non-human animals. "Non-human animals" include all vertebrates. For example, non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, and reptiles. This includes mammals and non-mammals. "Patient" and "Subject" are used interchangeably in this specification. It will be done.

[0056] This invention specifically binds CD38 regardless of whether tumor cells express CD38 or not. The present invention provides a method for treating patients with solid tumors using antibodies. Dominant T cells (Treg), bone marrow-derived suppressor cells (MDSCs), or regulatory B cells (B The present invention provides a method for treating patients with reg-mediated diseases. The present invention further provides a method for treating Treg, It modulates MDSC or Breg activity and suppresses CD38-positive and / or high levels of these immunosuppressions. This provides a method for treating solid tumors associated with sex cells.

[0057] This invention is at least in part an anti-CD38 antibody called DARZALEX (trademark) (Dara Tummumab exhibits immunomodulatory activity in patients, affecting immunosuppressive Tregs and MDSCs. And reduce the number of Bregs, CD8 + T cell count and CD8 + Increase the proportion of Tregs CD8 + It promotes central memory cell formation and increases T cell clonality. It is based on that discovery.

[0058] DARZALEX (trademark) (daratumumab) and other anti-CD38 antibodies are ADCC, C CD38 positivity of antibodies due to antibody effector functions such as DC, ACDP, and apoptosis. Due to its cell elimination ability, it is used in the treatment of hematological malignancies such as multiple myeloma and plasma cell disorders. Although its effectiveness has been clinically evaluated, regarding its immunomodulatory activity in promoting adaptive immune responses... This has not been observed. Other immunomodulatory antibodies (anti-PD1, anti-CTLA4) do not elicit an antitumor response. It works by targeting components of the immune system that it suppresses. For example, anti-PD1 antibodies It increases T cell proliferation, stimulates antigen-specific memory responses, and in vitro, It has been shown that it partially releases Treg-mediated suppression of effector T cells (e.g.) For example, see U.S. Patent No. 8,779,105. Two types of anti-PD for the treatment of melanoma. -1 antibody, OPDIVO® (nivolumab) and KEYTRUDA® (Pembrolizumab) is currently approved, and these antibodies are used for various solid tumors, for example Non-small cell lung cancer, prostate, head and neck, gastrointestinal, stomach, prostate, fallopian tube, ovarian, pancreatic, breast, and brain cancer, It is currently in clinical development for kidney, bladder, urethra, esophagus, and colorectal cancer. Anti-CTLA-4 antibody YERVOY (registered trademark) (ipilimumab) is approved for the treatment of melanoma. Yes. YERVOY(registered trademark) (ipilimumab) and another anti-CTLA-4 antibody Remelimumab is also used for prostate, non-small cell lung cancer, ovarian, gastrointestinal, stomach, colorectal, kidney, esophageal, and It is currently under development for genitourinary cancers.

[0059] While not bound by any particular theory, DARZA as described herein Based on the immunomodulatory effects observed with LEX (trademark) (daratumumab), DAR ZALEX (trademark) (daratumumab) and other anti-CD38 antibodies are effective in treating solid tumors. There is a possibility of this occurring. This is observed in patients treated with DARZALEX (trademark) (daratumumab). Due to the general activation of the immune response, patients with CD38-negative solid tumors are susceptible to anti-C It can similarly respond to D38 antibody therapy.

[0060] The present invention provides a method for treating a patient having a solid tumor, comprising administering to a patient in need thereof, for a sufficient period of time, a therapeutically effective amount of an antibody that specifically binds CD38 for the treatment of the solid tumor.

[0061] The present invention also provides a method for treating a patient having a regulatory T cell (Treg)-mediated disease, comprising administering to a patient in need thereof, for a sufficient period of time, a therapeutically effective amount of an antibody that specifically binds CD38 for the treatment of the Treg-mediated disease.

[0062] The present invention also provides a method for treating a patient having a myeloid-derived suppressor cell (MDSC)-mediated disease, comprising administering to a patient in need thereof, for a sufficient period of time, a therapeutically effective amount of an antibody that specifically binds CD38 for the treatment of the MDSC-mediated disease.

[0063] The present invention also provides a method for treating a patient having a regulatory B cell (Breg)-mediated disease, comprising administering to a patient in need thereof, for a sufficient period of time, a therapeutically effective amount of an antibody that specifically binds CD38 for the treatment of the Breg-mediated disease.__

[0064] The present invention also provides a method for suppressing the activity of regulatory T cells (Tregs), comprising contacting the regulatory T cells with an antibody that specifically binds CD38.

[0065] The present invention also provides a method for suppressing the activity of myeloid-derived suppressor cells (MDSCs), comprising contacting the MDSCs with an antibody that specifically binds CD38.

[0066] The present invention also provides a method for suppressing the activity of regulatory B cells (Bregs), comprising contacting the regulatory B cells with an antibody that specifically binds CD38. The invention also provides methods for suppressing Breg activity, including [specific method / method].

[0067] The present invention also involves administering an antibody that specifically binds CD38 to a patient, thereby enabling the patient to... Patients with solid tumors who have a condition that includes reducing the number of regulatory T cells (Tregs) in the following areas We also provide treatment options.

[0068] The present invention also involves administering an antibody that specifically binds CD38 to a patient, thereby enabling the patient to... This includes reducing the number of bone marrow-derived suppressor cells (MDSCs) in solid tumors. We also provide methods for treating patients who have this condition.

[0069] The present invention also involves administering an antibody that specifically binds CD38 to a patient, thereby enabling the patient to... Patients with solid tumors who have a history of having a disease that includes reducing the number of regulatory B cells (Bregs) in the body. We also provide treatment options.

[0070] The present invention also provides an antibody that specifically binds CD38 for a period of time sufficient to enhance the immune response. The invention also provides methods for enhancing a patient's immune response, including administering it to patients who require it.

[0071] In some embodiments, the patient has a viral infection.

[0072] The present invention also provides an antibody that specifically binds CD38 for a sufficient period of time to treat a viral infection. The method also includes administering it to patients who need it, as a way to treat the viral infection in patients. To provide.

[0073] In some embodiments, the immune response is an effector T cell (Teff) response.

[0074] In some embodiments, the Teff response is CD4 +T cells or CD8 + mediated by T cells through.

[0075] In some embodiments, the Teff response is mediated by CD4 + T cells.

[0076] In some embodiments, the Teff response is mediated by CD8 + T cells.

[0077] In some embodiments, the Teff response is an increase in CD8 + T cell number, an increase in CD8 + T cell proliferation, an increase in T cell clonal expansion, an increase in CDVIII + memory cell formation, an increase in antigen-dependent antibody production, or an increase in cytokine, chemokine or interleukin production is.

[0078] T cell proliferation can be evaluated, for example, by measuring the rate of DNA synthesis using tritiated thymidine , or by measuring the in vitro production of interferon-γ (IFN-γ), or by measuring the absolute number or percentage of T cells in a cell population derived from a patient sample using a known method thereby.

[0079] Clonal expansion can be evaluated, for example, by sequencing the TCR derived from a T cell pool using a known method thereby.

[0080] Memory cell formation can be evaluated, for example, by using FACS to measure the ratio of naive T cells (CD45RO - / C D62L + ) to memory T cells (CD45RO + / CD62L high ) by measurement.

[0081] Cytokine, chemokine, or interleukin production, e.g., interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), IL-1, IL-2, IL-3, I L-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-16, IL The production of -18 and IL-23, MIP-1α, MIP-1β, Lantes, and CCL4 is E Evaluation can be performed using standard methods such as the LISA or ELLISPOT assay.

[0082] Antigen-specific antibody production is performed using ELISA or radioimmunoassay from patient-derived samples. It can be evaluated using standard methods such as (RIA).

[0083] The meaning of various Teff responses being "increased" or "increasing" is easily understood. When a test sample or subject is treated with an anti-CD38 antibody, for example, compared to a control, In patients who underwent treatment, when compared to the same patient before treatment, or the response to anti-CD38 antibody treatment In patients or groups of patients, compared to patients or groups of patients who were unresponsive to the same treatment, At least approximately 5%, at least approximately 10%, 25%, 50%, 51%, 52%, 53% %, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63 %, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73 %, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83 %, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 110%, 120% 130%, 140%, 150%, 200%, 250%, 300%, 350%, 400% Or it may be an increase of more than that. Typically, this increase is statistically significant.

[0084] Similarly, the number of Treg, MDSC and / or Breg cells "decreases" or "declines". Alternatively, the meaning of "decrease" or "to decline" is easily understood. Decrease refers to the test sample. Or, in the case of subjects, when compared with the control, for example, in patients treated with anti-CD38 antibodies When compared to the same patient before treatment, or in patients who responded to anti-CD38 antibody treatment or In the patient group, compared to patients or the patient group that were unresponsive to the same treatment, at least Approximately 10%, 25%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57% %, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67 %, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77 %, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87 %, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97 %, 98%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, The decrease may be 200%, 250%, 300%, 350%, 400%, or more. Typically, this decline is statistically significant.

[0085] In some embodiments, antibodies that specifically bind CD38 are used to target immunosuppressor cells. It inhibits the function.

[0086] In some embodiments, immune suppressor cells are regulatory T cells (Treg), bone marrow These are derived suppressor cells (MDSCs) or regulatory B cells (Bregs).

[0087] In some embodiments, Treg is CD3 + CD4 + CD25 + CD127 dim These are T cells.

[0088] In some embodiments, CD3 + CD4 + CD25 + CD127 dim Cells are Fo It expresses xp3.

[0089] In some embodiments, CD3 + CD4 + CD25 + CD127 dim T cells It expresses CD38.

[0090] Treg function, for example, the ability to suppress Teff cells, is related to the reaction of Treg cells to mixed lymphocytes. This can be evaluated using known methods for assessing Teff proliferation inhibition in MLR.

[0091] The Treg function, for example, measures the relative number of Tregs compared to Teff (e.g., CD8). + / An increase in the ratio of Treg cells, or a subpopulation of Treg cells, e.g., CD38 + T's Reg It can be inhibited by reducing its numbers through direct killing.

[0092] In some embodiments, Treg function is inhibited by killing Treg cells.

[0093] In some embodiments, Treg killing is performed by antibodies that specifically bind CD38. More induced, antibody-induced antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell phagocytosis It is mediated by ADCP, complement-dependent cell-mediated cytotoxicity (CDC), or apoptosis.

[0094] In some embodiments, the killing of Tregs is mediated by ADCC.

[0095] In some embodiments, CD38 + Treg is killed or injured.

[0096] In some embodiments, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, or 60% The Treg is killed.

[0097] CD38 is expressed only in Tregs and some MDSCs, therefore solid tumor patients Treatment does not lead to systemic depletion of Tregs and MDSCs, and there is a possibility of improving safety. It is expected.

[0098] In some embodiments, the MDSC is CD11b + HLA-DR - CD14 - CD3 3 + CD15 + It is a cell.

[0099] In some embodiments, CD11b + HLA-DR - CD14 - CD33 + CD15 + MDSCs express CD38.

[0100] MDSC function involves, for example, reducing the number of MDSCs by directly killing cells. This can be inhibited.

[0101] In some embodiments, the MDSC function is CD38 + Inhibited by MDSC killing It can be done.

[0102] In some embodiments, MDSCs are killed by antibodies that specifically bind CD38. Induced, antibody-induced antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell phagocytosis ( It is mediated by ADCP, complement-dependent cell-mediated cytotoxicity (CDC), or apoptosis.

[0103] In some embodiments, the killing of MDSCs is mediated by ADCCs.

[0104] In some embodiments, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, or 60% MDSCs are killed or injured.

[0105] In some embodiments, Breg is CD19 + CD24 + CD38 + It is a cell.

[0106] The Breg function reduces the number of Bregs by directly killing them, for example. Therefore, it may be inhibited.

[0107] In some embodiments, the Breg function is CD38 + Inhibited by Breg's killing It can be done.

[0108] In some embodiments, Breg is killed by an antibody that specifically binds to CD38. Induced, antibody-induced antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell phagocytosis ( It is mediated by ADCP, complement-dependent cell-mediated cytotoxicity (CDC), or apoptosis.

[0109] In some embodiments, the killing of Breg is mediated by ADCC.

[0110] In some embodiments, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, or 60% Breg is killed.

[0111] Treg plays an important role in maintaining peripheral self-tolerance. Naturally occurring CD 4 + CD25 hi Tregs are produced in the thymus, and the identity and inhibitory function of the Treg system are confirmed. It expresses Foxp3, a transcription factor necessary for establishment and maintenance. Tregs are located at the disease site (e.g.) For example, it can accumulate in tumors and suppress the effector function of tumor antigen-specific T cells. This leads to an insufficient antitumor response. Foxp3 infiltrating the tumor + Treg Increased density is associated with a poor prognosis in various solid tumors, including pancreatic, ovarian, and hepatocellular carcinoma. In mouse models, Treg depletion has been shown to improve antitumor immunity and tumor rejection. While it can be beneficial, it can also lead to the progression of autoimmune diseases.

[0112] Myeloid-derived suppressor cells (MDSCs) are early myeloid progenitor cells at various stages of differentiation. These are heterogeneous populations of cells, immature granulocytes, macrophages, and dendritic cells. It accumulates in large quantities in individuals and has a strong immunosuppressive function, affecting natural killer cells (NK) and na Cytotoxic activity of natural killer T cells (NKT), and CD8 + Mediated by T cells It inhibits both adaptive immune responses. The mechanism of NK cell inhibition is not yet well understood. However, it does not produce arginase 1 / ARG1, and nitric oxide synthase 2 (NOS2). Multiple pathways, including pharmacokinetic regulation, are responsible for MDSC-mediated T cell suppression. ARG1 and NOS2 metabolizes L-arginine and, together or separately, inhibits the translation of T cell CD3ζ chains. It stops T cell proliferation and promotes T cell apoptosis. In addition, MDSCs are immune It secretes inhibitory cytokines and induces the growth of regulatory T cells.

[0113] MDSCs are induced by inflammatory cytokines and play a significant role in infectious and inflammatory conditions. These are found to increase in number. They accumulate in the blood, bone marrow, and secondary lymphoid organs of tumor-bearing mice. Furthermore, the presence of these in the tumor microenvironment plays a role in promoting tumor-associated immunosuppression. It is said that they will fulfill their promise.

[0114] MDSC includes colon cancer, melanoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, non-small cell lung cancer, and renal cell carcinoma. This has been described in patients with pancreatic adenocarcinoma and breast cancer (Mandruzzato et al. l.,(2009)J Immunol 182:6562~6568;Liu et al. al.,(2009)J Cancer Res Clin Oncol 136:35 ~45;Ko et al.,(2009)Clin Cancer Res 15:2 148~2157;Morse et al.,(2009)Expert OpinB iol Ther 9:331~339;Diaz-Montero et al.,( 2009) Cancer Immunol Immunother 58:49~59; Corzo et al.,(2009)J Immunol 182:5693~57 01). In cancer patients, Diaz et al. (Diaz-Montero et al., (2 009) Cancer Immunol Immunother 58:49~59) They propose that the accumulation of MDSCs correlates with further disease progression and a poor prognosis.

[0115] Tumor-invasive Bregs have been identified in solid tumors, and Bregs are involved in various mechanisms. For example, CD8 + By suppressing the antitumor activity of T cells and NK cells, tumor growth It may promote proliferation and metastasis (e.g., Ding et al., (2015) Human (Described in Immunology 76:615-62).

[0116] “Antibody-dependent cytotoxicity”, “antibody-dependent cell-mediated cytotoxicity”, or “ADCC” The antibody-coated target cells are targeted via the Fc gamma receptor (FcγR) expressed in phenotype cells. Cells possess lytic activity against natural killer cells, monocytes, macrophages, and neutrophils. This is a mechanism for inducing cell death that depends on the interaction with effector cells. NK cells express FcγRIIIa, while monocytes express FcγRI, FcγRII, and It expresses FcγRIIIa. Death of antibody-coated target cells such as CD38-expressing cells occurs through membrane pores. As a result of effector cell activity through the secretion of formation proteins and proteases, To evaluate the ADCC activity of antibodies that specifically bind CD38, the antibody is used in immunotherapy. These can be added to CD38-expressing cells in combination with effector cells, but these may be antigen-resistant. When activated by the complex, it can lead to cell lysis of target cells. Cell lysis is a process Typically, labels are used from lysed cells (e.g., radioactive substrates, fluorescent dyes, or natural intracellular proteins). It is detected by the release of (quality). Effector cells for such assays include terminal Peripheral blood mononuclear cells (PBMCs) and NK cells are examples. CD38 is a representative target cell. Examples include Treg or MDSCs that express [the specified gene]. In an exemplary assay, the target cells are , 20 μCurie 51 It is labeled with Cr for 2 hours and then washed over a wide area. The cell concentration of the target cells is 1 × 10⁻⁶ 6 Anti-CD38 antibodies can be adjusted to cells / mL, but they vary. It is added at a certain concentration. The assay involves adding target cells with an effector:target cell ratio of 40:1. The assay is initiated by incubating at 37°C for 3 hours, then centrifuging the assay. The separation stopped the lysis from the lysed cells. 51 The release of Cr inside the scintillation counter The cytotoxicity percentage is measured by adding 3% perchloric acid to the target cells. This can be calculated as the maximum dissolution percentage that can be induced by the cause.

[0117] "Antibody-dependent cell phagocytosis" ("ADCP") refers to, for example, macrophages or dendritic cells. This refers to the mechanism of antibody-coated target cell elimination through intracellular translocation by phagocytic cells such as cysts. ADCPs are genetically engineered to express GFP or other labeled molecules. Evaluation can be performed by using Treg or MDSC cells that express CD38 as target cells. The effector-to-target cell ratio can be, for example, 4:1. Effector cells are Incubate target cells with or without anti-CD38 antibody for 4 hours. It can be done. After incubation, the cells can be detached using Accutase. Macrophages are identified by fluorescently labeled anti-CD11b and anti-CD14 antibodies. It is possible, but the percentage of phagocytosis is determined using standard methods, CD11 + and CD14 + This can be determined based on the percentage of GFP fluorescence in macrophages.

[0118] "Complement-dependent cell injury" or "CDC" refers to the Fc effector domain of a target-binding antibody. It binds to complement component C1q and activates it, and complement component C1q then activates the complement cascade. This refers to the mechanism that induces cell death, which involves sexualization and leads to the death of target cells. (Complement) Activation can also lead to the deposition of complement components on the surface of target cells, which in turn can lead to leukocytes The binding of complement receptors (e.g., CR3) to ADCC facilitates ADCC.

[0119] The ability of monoclonal antibodies to induce ADCC is due to their oligosaccharide components It can be enhanced by genetic manipulation. Human IgG1 or IgG3 is A N-glycosylation occurs in sn297. Here, the majority of glycans are well known as It is in the branched form G0, G0F, G1, G1F, G2, or G2F. It has been genetically modified. Antibodies produced by non-CHO cells typically contain at least approximately 85% glycan. It has a cous content. Core fucose from a bifurcated complex oligosaccharide bound to the Fc region. Removal of the antigen improves FcγRIIIa binding without altering antigen binding or CDC activity. It enhances the ADCC of antibodies through synthesis. Such mAbs control the osmolality of the culture medium. (Konno et al.,(2012)Cytotechnology 64:24 9-65), Application of mutant CHO system Lec13 as a host cell system (Shields e et al., (2002) J Biol Chem 277:26733~26740) Application of the mutant CHO line EB66 as a host cell line (Olivier et al., (2010)MAbs 2(4),Epub ahead of print;PMID (20562582), suitability of rat hybridoma cell line YB2 / 0 as a host cell line (Shinkawa et al., (2003) J Biol Chem 278: 3466~3473), against the α1,6-fucosyltransferase (FUT8) gene This involves the introduction of specific small interfering RNAs (Mori et al., (2004) Biot echnol Bioeng 88:901~908), or β-1,4-N-acetyl Luglucosaminyltransferase III and Golgi α-mannosidase II or Co-expression of kifunensin, a potent α-mannosidase I inhibitor (Ferrara e t al.,(2006)J Biol Chem 281:5032~5036;Fe rrara et al.,(2006)Biotechnol Bioeng 93: 851~861;Xhou et al.,(2008)Biotechnol Bio Defucosilamines possessing a bifurcated complex form of Fc oligosaccharides such as eng 99:652~65) It has been reported that this results in relatively high expression of oxidized antibodies, achieved using various methods. This may be done. In the method of the present invention, and in the numbered embodiments listed below, A, which is induced by the anti-CD38 antibody used in each of several embodiments. DCC may also be enhanced by certain substitutions in the antibody Fc. (Examples) The substitution is, for example, at amino acid position 25, as described in U.S. Patent No. 6,737,056. 6, 290, 298, 312, 356, 330, 333, 334, 360, 378, or This is a substitution at 430 (residue numbering according to the EU index).

[0120] In some embodiments, the antibody that specifically binds CD38 is a substitution in antibody Fc. Includes.

[0121] In some embodiments, the antibody that specifically binds CD38 is 256 in antibody Fc, 290, 298, 312, 356, 330, 333, 334, 360, 378 or 430 Includes substitutions at the nth amino acid (residue numbering follows the EU index).

[0122] In some embodiments, the antibody that specifically binds CD38 has a fucose content of approximately 0% ~Approximately 15%, for example 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7 It has a branched glycan structure, which is %, 6%, 5%, 4%, 3%, 2%, 1%, or 0%. .

[0123] In some embodiments, the antibody that specifically binds CD38 has a fucose content of approximately 50 %, 40%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 14%, 13 %, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% It has a branched glycan structure, or it is 0%.

[0124] Substitutions and reduced fucose content in Fc are found in ADCs of antibodies that specifically bind CD38. It can enhance C activity.

[0125] "Fucose content" refers to the amount of fucose monosaccharides in the sugar chain of Asn297. The relative amount of fucose is the ratio of fucose-containing structures to the total sugar structure. The construction can be done in several ways, for example, 1) as described in International Publication No. 2008 / 077546 In addition, MALDI-TOF (for example, complex, hybrid) of N-glycosidase F treated samples 1) Use of glycans (and oligosaccharides and high mannose structures), 2) Enzymatic release of Asn297 glycans HPLC (UPLC) and / or HPLC- Detection / quantification by MS (UPLC-MS), 3) Between the first and second GlcNAc monosaccharides The fucose is cleaved and bound to the first GlcNAc by Endo S or other enzymes. With or without the treatment of Asn297 glycans, natural or reduced mAbs Intact protein analysis, 4) Digestion using enzymes (e.g., trypsin or endopeptide) After digestion of mAbs into component peptides by dase Lys-C, HPLC-MS (UPL) is performed. Separation, detection, and quantification by C-MC) or 5) PNGase F with Asn297 mAb oligosaccharides converted to mAb proteins through specific deglycosylation by enzymes using [a specific enzyme / method]. Separation from can be characterized and quantified. The released oligosaccharides are fluorophosphate. Labeled with a ferrite, various supplementary techniques enable detailed characterization of the glycan structure. It is possible to separate and identify these by comparing experimental mass with theoretical mass. Matrix-assisted laser desorption / ionization (MALDI) mass spectrometry, ion exchange HPLC ( Determination of the degree of sialylation by GlycoSep C, normal-phase HPLC (GlycoSep C) Separation and quantification of oligosaccharide types in accordance with the hydrophilicity criteria of N), and high-performance capillary Separation and quantification of oligosaccharides by Lie electrophoresis-laser-induced fluorescence (HPCE-LIF) ru.

[0126] As used herein, "low fucose" or "low fucose content" means that the antibody is approximately 0% This refers to having a fucose content of approximately 15%.

[0127] As used herein, "normal fucose" or "normal fucose content" means Antibodies exceeding approximately 50%, typically exceeding approximately 60%, 70%, 80%, or exceeding 85% This refers to having a fucose content.

[0128] In some embodiments, antibodies that specifically bind CD38 are used by apoptosis. It can induce the killing of Treg, MDSC, and / or Breg. Evaluate apoptosis. The methods for this are well known, for example, staining with Annexin IV using standard methods. The anti-CD38 antibody used in the method of the present invention is present in approximately 20%, 25%, and 30% of cells. %, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80 Apoptosis can be induced in %, 85%, 90%, 95%, or 100% of cells.

[0129] In some embodiments, Teff or immunosuppressor cells are present in the bone marrow or peripheral blood. exist.

[0130] In some embodiments, Teff or immunosuppressor cells are present in the bone marrow.

[0131] In some embodiments, Teff or immunosuppressor cells are present in the peripheral blood. .

[0132] In some embodiments, the antibody that specifically binds CD38 is CD8 + T cell Tr Increase the ratio to eg.

[0133] In some embodiments, the antibody that specifically binds CD38 is CD8 + Central Me CD8 in Molly cells + Increase the ratio to naive cells. CD8 + Central Memory The cells are CD45RO + / CD62L +high It can be identified as a cell. CD8 + Naive Bu cells are CD45RO- / CD62L + It can be identified as a cell.

[0134] In some embodiments, the antibody that specifically binds CD38 is a non-agonist antibody. ru.

[0135] Non-agonist antibodies that specifically bind to CD38, when they bind to CD38, in v An antibody for which the proliferation of a sample of peripheral blood mononuclear cells in vitro is not significantly induced as compared to the proliferation induced by an isotype control antibody or by the medium alone.

[0136] In some embodiments, a non-agonist antibody that specifically binds CD38 induces the proliferation of peripheral blood mononuclear cells (PBMCs) in a statistically insignificant manner. PBMC proliferation can be evaluated by isolating PBMCs from healthy donors and culturing them at 1 × 10 cells / well in a flat-bottom 96-well plate in 200 μL of RPMI, in the presence or absence of the test antibody. After incubation at 37 °C for 4 days, 30 μL of H-thymidine (16. 7 μCi / mL) can be added and the culture continued overnight. <00OO089>The incorporation of H-thymidine can be evaluated using a Packard Cobra gamma counter (Packard Instruments 3 (Meriden, CT, USA)) according to the manufacturer's instructions. The data can be calculated as the mean cpm (±SEM) of PBMCs obtained from several donors. The statistical significance or non-significance between samples cultured in the presence or absence of the test antibody is calculated using standard 3 methods. A representative anti-CD38 antibody that can be used in the methods of the invention is DARZALEX™ (daratumumab). DARZALEX™ (daratumumab) has the amino acid sequences of the heavy chain variable region (VH) and the light chain variable region (VL) shown in SEQ ID NOs 4 and 5, respectively, the heavy chain complementarity determining regions 1 (HCDR1), HCDR2, and H CDR3 of SEQ ID NOs 6, 7, and 8, respectively, and the light chain complementarity determining regions 1 (LCDR

[0137] 1), LCDR2, and LCDR3 of SEQ ID NOs 9, 10, and 11, respectively. [[ID=U3]] 1) Includes LCDR2 and LCDR3, and daratumumab is of the IgG1 / κ subtype. It is described in U.S. Patent No. 7,829,693. DARZALEX (trademark) The amino acid sequence of the (daratumumab) heavy chain is shown in SEQ ID NO: 12, and the amino acid sequence of the light chain is This is shown in sequence number 13.

[0138] In some embodiments, the antibody that specifically binds CD38 is the heavy chain variable of SEQ ID NO: 4. An antibody containing the region (VH) and the light chain variable region (VL) of SEQ ID NO: 5, and binding to CD38 They compete in this regard.

[0139] In some embodiments, the antibody that specifically binds CD38 is human CD38 (sequence number Region SKRNIQFSCKNIYR (SEQ ID NO: 2) and region EKVQTLEA (Sequence ID: 1) It binds to WVIHGG (sequence number 3) at least.

[0140] Sequence ID 1 MANCEFSPVSGDKPCCRLSRRAQLCLGVSILVLILVVVL AVVVPRWRQQWSGPGTTKRFPETVLARCVKYTEIHPEMRH VDCQSVWDAFKGAFISKHPCNITEEDYQPLMKLGTQTVPC NKILLWSRIKDLAHQFTQVQRDMFTLEDTLLGYLADDLTW CGEFNTSKINYQSCPDWRKDCSNNPVSVFWKTVSRRFAEA ACDVVHVMLNGSRSKIFDKNSTFGSVEVHNLQPEKVQTLE AWVIHGGREDSRDLCQDPTIKELESIISKRNIQFSCKNIY RPDKFLQCVKNPEDSSCTSEI

[0141] Sequence ID 2 SKRNIQFSCKNIYR

[0142] Sequence ID 3 EKVQTLEAWVIHGG

[0143] Sequence ID 4 EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQ APGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVT VSS

[0144] Sequence ID 5 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQK PGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLE PEDFAVYYCQQRSNWPPTFGQGTKVEIK

[0145] Sequence ID 6 SFAMS

[0146] Sequence ID 7 AISGSGGGTYYADSVKG

[0147] Sequence ID 8 DKILWFGEPVFDY

[0148] Sequence ID 9 RASQSVSSYLA

[0149] Sequence ID 10 DASNRAT

[0150] Sequence ID 11 QQRSNWPPTF

[0151] Sequence ID 12 EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQ APGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEL LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPS REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK

[0152] Sequence ID 13 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQK PGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLE PEDFAVYYCQQRSNWPPTFGQGTKVEIKRTVAAPSVFIFP PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC

[0153] The antibody, using a well-known in vitro method, was found to bind to CD38 as shown in SEQ ID NO: 4. DARZALEX (trademark) (daratumumab), which has VH and VL of SEQ ID NO: 5, etc. Competition with a reference antibody can be evaluated. A typical method involves recombinant expression of CD38. The CHO cells were incubated with an unlabeled reference antibody at 4°C for 15 minutes, and then the excess was... The fluorescently labeled test antibody may be incubated with the antibody in PBS / BSA for 45 minutes at 4°C. After washing, fluorescence can be measured by flow cytometry using a standard method. Another typical method involves the extracellular portion of human CD38 being filtered onto the surface of an ELISA plate. It can be coated. An excess of unlabeled reference antibody can be added for about 15 minutes, after which biotin Biotinylation test antibody can be added. After washing in PBS / Tween, test biotinylation Antibody binding was performed using horseradish peroxidase (HRP)-conjugated streptavidin and standard It can be detected using a signal detected by a specific method. In a competitive assay, It is readily apparent that the retinoantibody may be labeled while the test antibody is not. The reference antibody inhibits the binding of the test antibody, or the test antibody inhibits the binding of the reference antibody to CD38. The ratio should be at least 80%, for example, 81%, 82%, 83%, 84%, 85%, 86%, 8 7%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 9 When inhibiting by 7%, 98%, 99%, or 100%, the test antibody competes with the reference antibody. The epitopes of the test antibodies can be identified, for example, by peptide mapping or by using known methods. It may be further defined by a hydrogen / deuterium protection assay or by crystal structure determination.

[0154] The region SKRNIQFSCKNIYR (Sequence ID 2) of human CD38 (SEQ ID NO: 1) and Antibodies that bind to region EKVQTLEAWVIHGG (SEQ ID NO: 3) are, for example, standard methods and Using the materials described herein, mice can be given the amino acid combination shown in SEQ ID NOs: 2 and 3. Immunizing with peptides having columns, for example, using ELISA or mutagenesis studies. It can be generated by characterizing the antibody obtained to bind to the tide.

[0155] The present invention also relates to the region SKRNIQFSCKNIYR (distributed) of human CD38 (SEQ ID NO: 1). Anti-CD38 bound to column number 2) and region EKVQTLEAWVIHGG (sequence number 3) Treating patients with solid tumors, including administering antibodies to patients who need them. The method is also provided. The antibody epitope used in the method of the present invention is Sequence ID No. 2 or Sequence No. It includes some or all of the residues having the sequence shown in No. 3. In some embodiments, the antibody The epitope is the region SKRNIQFSCKNIYR (sequence number 1) of human CD38. Number 2) at least one amino acid and region EKVQTLEAWVIHGG (distributed It includes at least one amino acid in column 3). In some embodiments, the antibody The epitope is the region SKRNIQFSCKNIYR (sequence number 1) of human CD38. At least two amino acids in number 2), and region EKVQTLEAWVIHGG (distributed It includes at least two amino acids in column 3). In some embodiments, the antibody The epitope is the region SKRNIQFSCKNIYR (sequence number 1) of human CD38. Number 2) at least three amino acids and region EKVQTLEAWVIHGG (distributed It contains at least three amino acids in column number 3).

[0156] In some embodiments, the antibody that specifically binds CD38 is, respectively, SEQ ID NO: 6. It contains the amino acid sequences of HCDR1, HCDR2, and HCDR3 of 7 and 8.

[0157] In some embodiments, the antibody that specifically binds CD38 is, respectively, SEQ ID NO: 9. It contains the amino acid sequences of LCDR1, LCDR2, and LCDR3 of 10 and 11.

[0158] In some embodiments, the antibody that specifically binds CD38 is, respectively, SEQ ID NO: 6. 7, 8, 9, 10 and 11 HCDR1, HCDR2, HCDR3, LCDR1, LCD Includes the amino acid sequences of R2 and LCDR3.

[0159] In some embodiments, the antibody that specifically binds CD38 is SEQ ID NO: 4 and 95%, VH that are 96%, 97%, 98%, 99%, or 100% identical, and sequence numbers 5 and 95. Includes VLs that are 96%, 97%, 98%, 99%, or 100% identical.

[0160] In some embodiments, the antibody that specifically binds CD38 is VH of SEQ ID NO: 4 and Includes VL of sequence number 5.

[0161] In some embodiments, the antibody that specifically binds CD38 is the heavy chain of SEQ ID NO: 12 It includes the light chain of sequence number 13.

[0162] Other exemplary anti-CD38 antibodies that can be used in any embodiment of the present invention are as follows: .

[0163] VH as described in U.S. Patent No. 7,829,693, Sequence IDs 14 and 15, respectively. mAb003 containing the sequence and VL sequence. The VH and VL of mAb003 are IgG1 / κ and It can be expressed as follows.

[0164] Sequence ID 14 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAFSWVRQ APGQGLEWMGRVIPFLGIANSAQKFQGRVTITADKSTSTA YMDLSSLRSEDTAVYYCARDDIAALGPFDYWGQGTLVTVS SAS

[0165] Sequence ID 15 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQK PEKAPKSLIYAASSLQSGVPSRFSGSGGSGTDFTLTISSLQ PEDFATYYCQQYNSYPRTFGQGTKVEIK

[0166] VH as described in U.S. Patent No. 7,829,693, Sequence IDs 16 and 17, respectively. mAb024 containing the sequence and VL sequence. The VH and VL of mAb024 are IgG1 / κ and It can be expressed as follows.

[0167] Sequence ID 16 EVQLVQSGAEVKKPGESLKISCKGSGYSFSNYWIGWVRQ MPGKGLEWMGIIYPHSDARYSPSFQGQVTFSADKSISTA YLQWSSLKASDTAMYYCARHVGWGSRYWYFDLWGRGTLVT VSS

[0168] Sequence ID 17 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQK PGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLE P EDFAVYYCQQRSNWPPTFGQGTKVEIK;

[0169] VH as described in U.S. Patent No. 8,088,896, Sequence ID Nos. 18 and 19, respectively. MOR-202 (MOR-03087) including sequence and VL sequence. VH of MOR-202 And VL can be expressed as IgG1 / κ.

[0170] Sequence ID 18 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQ APGKGLEWVSGISGDPSNTYYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCARDLPLVYTGFAYWGQGTLVTVS S

[0171] Sequence ID 19 DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYWYQQKP GQAPVLVIYGDSKRPSGIPERFSGSNSGNTATLTISGTQA EDEADYYCQTYTGGASLVFGGGGTKLTVLGQ

[0172] VH as described in U.S. Patent No. 8,153,765, Sequence IDs 20 and 21, respectively. Isatuximab containing the sequence and VL sequence. The VH and VL of isatuximab are IgG1 / It can be expressed as κ.

[0173] Sequence ID 20: QVQLVQSGAEVAKPGTSVKLSCKASGYTFTDYWMQWVKQ RPGQGLEWIGTIYPGDGDTGYAQKFQGKATLTADKSSKTV YMHLSSLASEDSAVYYCARGDYYGSNSLDYWGQGTSVTVS S

[0174] Sequence ID 21 DIVMTQSHLSMSSTSLGDPVSITCKASQDVSTVVAWYQQK PGQSPRRLIYSASYRYIGVPDRFTGSGAGTDFTFTISSVQ AEDLAVYYCQQHYSPPYTFGGGTKLEIK

[0175] Other exemplary anti-CD38 antibodies that can be used in the method of the present invention include: International Publication Nos. 05 / 103083, 06 / 125640, and 07 / 042309 The items listed in issue 08 / 047242, or issue 14 / 178820 It can be listed.

[0176] The present invention also relates to a CD containing therapeutically effective amounts of SEQ ID NO: VH and SEQ ID NO: VL. An antibody that specifically binds to 38 is provided to patients who require it for a sufficient period of time to treat solid tumors. The invention also provides methods for treating patients with solid tumors, including administering medication.

[0177] The present invention also comprises therapeutically effective amounts of SEQ ID NO: 14 VH and SEQ ID NO: 15 VL An antibody that specifically binds to CD38, for a sufficient period of time to treat solid tumors, is needed for patients. The invention also provides a method for treating patients with solid tumors, including administering the drug to the patient.

[0178] The present invention also comprises therapeutically effective amounts of SEQ ID NO: 16 VH and SEQ ID NO: 17 VL An antibody that specifically binds to CD38, for a sufficient period of time to treat solid tumors, is needed for patients. The invention also provides a method for treating patients with solid tumors, including administering the drug to the patient.

[0179] The present invention also comprises therapeutically effective amounts of SEQ ID NO: 18 VH and SEQ ID NO: 19 VL. An antibody that specifically binds to CD38, for a sufficient period of time to treat solid tumors, is needed for patients. The invention also provides a method for treating patients with solid tumors, including administering the drug to the patient.

[0180] The present invention also comprises therapeutically effective amounts of SEQ ID NO: 20 VH and SEQ ID NO: 21 VL An antibody that specifically binds to CD38, for a sufficient period of time to treat solid tumors, is needed for patients. The invention also provides a method for treating patients with solid tumors, including administering the drug to the patient.

[0181] In some embodiments, the solid tumor is a melanoma.

[0182] In some embodiments, the solid tumor is lung cancer.

[0183] In some embodiments, the solid tumor is non-small cell lung cancer (NSCLC).

[0184] In some embodiments, the solid tumor is non-squamous NSCLC.

[0185] In some embodiments, the solid tumor is lung adenocarcinoma.

[0186] In some embodiments, the solid tumor is renal cell carcinoma (RCC) (e.g., clear cell carcinoma or It is renal papillary cell carcinoma, or a metastatic lesion thereof.

[0187] In some embodiments, the solid tumor is a mesothelioma.

[0188] In some embodiments, the solid tumor is nasopharyngeal carcinoma (NPC).

[0189] In some embodiments, the solid tumor is colorectal cancer.

[0190] In some embodiments, the solid tumor is prostate cancer or castration-resistant prostate cancer.

[0191] In some embodiments, the solid tumor is stomach cancer.

[0192] In some embodiments, the solid tumor is ovarian cancer.

[0193] In some embodiments, the solid tumor is gastric cancer.

[0194] In some embodiments, the solid tumor is liver cancer.

[0195] In some embodiments, the solid tumor is pancreatic cancer.

[0196] In some embodiments, the solid tumor is thyroid cancer.

[0197] In some embodiments, the solid tumor is a squamous cell carcinoma of the head and neck.

[0198] In some embodiments, the solid tumor is a carcinoma of the esophagus or gastrointestinal tract.

[0199] In some embodiments, the solid tumor is breast cancer.

[0200] In some embodiments, the solid tumor is fallopian tube cancer.

[0201] In some embodiments, the solid tumor is brain cancer.

[0202] In some embodiments, the solid tumor is urethral cancer.

[0203] In some embodiments, the solid tumor is a genitourinary cancer.

[0204] In some embodiments, the solid tumor is endometriosis.

[0205] In some embodiments, the solid tumor is cervical cancer.

[0206] In some embodiments, solid tumors are metastatic sites of cancer.

[0207] In some embodiments, solid tumors lack detectable CD38 expression.

[0208] Using well-known methods, compare with a control, for example, an expression counter-iso detected by an anti-CD38 antibody. The expression detected by the type of control antibody is compared to that in solid tumor tissue or isolated from solid tumors. When CD38 expression on the cells is not statistically significant, solid tumors are considered to have detectable CD3 It lacks expression of gene 8.

[0209] The anti-CD38 antibody used in the method of the present invention is, for example, derived from a novel phage presentation library. It may also be selected, and this phage is human immunoglobulin or a part thereof (e.g., F ab, single-chain antibody (scFv), or unpaired or paired antibody variable region) They have been genetically engineered to exhibit this trait (Knappik et al., (2000)J Mol Biol 296:57~86;Krebs et al.,(2001)J Immunol Meth 254:67~84;Vaughan et al.,(1 996)Nature Biotechnology 14:309~314;Shee ts et al.,(1998) PITAS(USA)95:6157~6162;H oogenboom and Winter,(1991)J Mol Biol 22 7:381;Marks et al.,(1991)J Mol Biol 222: 581). CD38-binding variable domains are, for example, Shi et al., (2010) This information is described in J Mol Biol 397:385~96 and International Publication No. 09 / 085462. The antibody weight is described as a fusion protein with the bacteriophage pIX coated protein. It can be isolated from phage-presenting libraries that express chain and light chain variable regions. The cells were screened for binding to the extracellular domain of human CD38, and the resulting positive results were obtained. Further characterization of the clone led to the isolation of Fab from the clonal lysate, followed by full-length antibody It is cloned as a whole body. Such phage presentation methods for isolating human antibodies are the technique. It is established in the field of technology. For example, U.S. Patent No. 5,223,409 and No. 5,403 , No. 484, No. 5,571,698, No. 5,427,908, No. 5,580, No. 717, No. 5,969,108, No. 6,172,197, No. 5,885,7 No. 93, No. 6,521,404, No. 6,544,731, No. 6,555,31 See issues 3, 6,582,915, and 6,593,081.

[0210] In some embodiments, the anti-CD38 antibody is IgG1, IgG2, IgG3, or I It is the gG4 isotype.

[0211] The Fc portion of antibodies is responsible for antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell phagocytosis. The effector function of antibodies such as ADCP or complement-dependent cell-mediated cytotoxicity (CDC) This can be done through the phagocytic activity of the FC effector domain(s). By binding to Fc receptors on immune cells that have sexual or lytic activity, or by Fc effect This can be mediated by the binding of the ter domain (or multiple ter domains) to the components of the complement system. Typically, Fc binding occurs. Actions mediated by syncytial cells or complement components are mediated by target cells, such as CD38 cells. This leads to inhibition and / or depletion of the current cells. Human IgG isotypes include IgG1 and I. gG2, IgG3, and IgG4 exhibit specific capabilities in terms of effector functions. ADCC is mediated by IgG1 and IgG3, while ADCP is mediated by IgG1 and IgG2 , mediated by IgG3 and IgG4, and CDC by IgG1 and IgG3 It can be mediated.

[0212] Antibodies that are substantially identical to antibodies containing VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 are, It may be used in the Ming method. When used herein, the term “substantially identical” means The amino acid sequences of the two antibodies VH or VL being compared are identical or "very slight phases" It means having a "difference." A very slight difference is one that does not adversely affect the properties of the antibody. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 1 in the antibody heavy chain or light chain This involves substitutions of 3, 14, or 15 amino acids. The identity percentage is, for example, Vect or A of NTI v.9.0.0 (Invitrogen, Carlsbad, CA) Determined by pairwise alignment using the default settings of the lignX module. This can be done. Using the protein sequence of the present invention as a query sequence, public or patent data A search may be performed against the database to identify, for example, related sequences. The example program used to execute this is XBLAST, which uses the default settings. Alternatively, the BLASTP program (http_ / / www_ncbi_nlm / nih_ (gov), or GenomeQuest (trademark) (GenomeQuest, Westb This is a suite of tests performed on antibodies that specifically bind CD38. The exemplary substitutions obtained are, for example, by using amino acids having similar charge, hydrophobicity, and stereochemical properties. These are conservative substitutions. Conservative substitutions also affect the properties of antibodies, such as stability or affinity. This may also be done to improve or to improve the function of antibody effectors. 1. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids Acid substitution can be performed, for example, on the heavy or light chain of an anti-CD38 antibody. Furthermore, alanine • As previously mentioned regarding scanning mutation introduction methods (MacLenna n et al.,Acta Physiol.Scand.Suppl.643:55 ~67,1998;Sasaki et al.,Adv.Biophys.35:1~ (24, 1998), any native residue in VH or VL can also be substituted with alanine. The desired amino acid substitution can be determined by a person skilled in the art at the time such substitution is desired. Acid substitution can be performed, for example, by PCR mutagenesis (U.S. Patent No. 4,683,195). It is possible to do so. The mutant library can be created using a well-known method, for example, random codon (NNK) or non-random codon, for example, 11 amino acids (Ala, Cys, Asp, DV encoding Glu, Gly, Lys, Asn, Arg, Ser, Tyr, Trp) Using the K codon, and then screening a library to find mutants with the desired characteristics It may be generated by [doing something]. The generated mutant is [something] to CD38 in vitro. Binding of these, inducing ADCC, ADCP, or apoptosis, or CD38 enzyme activity They can be tested using the methods described herein with respect to their ability to modulate. Yes.

[0213] In some embodiments, an antibody that specifically binds CD38 can bind human CD38 with a wide range of affinities (K D ). In one embodiment according to the invention, and in some of any of the numbered embodiments listed below, an antibody that specifically binds CD38, as determined by surface plasmon resonance or Kinexa methods performed by those skilled in the art, has a high affinity, for example, K is about 10 M or less, for example, but not limited to these 1 to 9.9 (i.e., any value within or in the range such as 1, 2, 3, 4, 5, 6, 7, 8, or 9) × 10 D M, 10 -7 M, 10 M, 10 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -1 1 M, 10 -12 M, 10 -13 M, 10 -14 M, 10 -15 M, or any range or value within that range binds to CD38. One example of an affinity is 1 × 10 M or less. Another example of an affinity is 1 × 10 -8 M or less. There is. Another example of an affinity is 1 × 10 -9 M or less.

[0214] In some embodiments, an antibody that specifically binds CD38 is a bispecific antibody. The VL and / or VH regions of existing anti-CD38 antibodies, or VL and VH regions newly identified as described herein, may be genetically engineered to be bispecific full-length antibodies. Such bispecific antibodies are described in U.S. Patent No. 7,695,936, International Publication No. No. Patent Application No. 04 / 111233, U.S. Patent Publication No. 2010 / 0015133, U.S. Patent Application Publication No. 2007 / 0287170, International Publication No. 2008 / 119353, U.S. Patent Patent Application Publication No. 2009 / 0182127, U.S. Patent Application Publication No. 2010 / 0286374 U.S. Patent Application Publication No. 2011 / 0123532, International Publication No. 2011 / 13174 Patent No. 6, International Publication No. 2011 / 143545, or U.S. Patent Application Publication No. 2012 / 01 Using techniques such as those described in No. 49876, a monospecific antibody is formed to create a bispecific antibody. The antibodies of the present invention can be produced by regulating the CH3 interaction between isomer antibody heavy chains. An additional bispecific structure in which the VL and / or VH regions may be incorporated is, for example, a bivariate structure. It is either a domain immunoglobulin (International Publication No. 2009 / 134776) or leucine. Two antibody arms with specific properties, such as a zipper or collagen dimerization domain A structure containing various dimerization domains for binding (International Publication No. 2012 / 022811) (U.S. Patent Nos. 5,932,448 and 6,833,441).

[0215] For example, bispecific antibodies are produced according to the method described in International Publication No. 2011 / 131746. In vitro in a cell-free environment, the C of two monospecific homodimer antibodies An asymmetric mutation is introduced into the H3 region, and under reducing conditions that isomerize the disulfide bond... Therefore, two parent monospecific homodimer antibodies are used to form a bispecific heterodimer antibody. It may be generated from a first monospecific bivalent antibody (e.g., anti-CD). 38 antibody) and the second monospecific bivalent antibody promote the stability of the heterodimer CH3 dormancy These antibodies are genetically engineered to have specific substitutions in the ring, but these antibodies are not affected by the hinge region. Under reducing conditions sufficient to cause disulfide bond isomerization of cysteine ​​in the region They are incubated together, which generates bispecific antibodies via Fab arm exchange. The incubation conditions may be returned to non-reducing conditions, if optimal. Examples of reducing agents include 2-mercaptoethylamine (2-MEA) and dithiothreitol. (DTT), dithioerythritol (DTE), glutathione, tris(2-carboxy) Ethyl)phosphine (TCEP), L-cysteine, and beta-mercaptoethanol Preferably, 2-mercaptoethylamine, dithiothreitol, and tris(2-) A reducing agent selected from the group consisting of (ruboxyethyl)phosphine. For example, at least Also at a temperature of 20°C, in the presence of at least 25 mM 2-MEA or at least 0. In the presence of 5 mM dithiothreitol, pH 5-8, for example, pH 7.0 or pH 7. In step 4, incubation for at least 90 minutes may be used.

[0216] Exemplary CH3 mutations that can be used in the first and second heavy chains of bispecific antibodies are: This is K409R and / or F405L.

[0217] The method of the present invention can be used to treat animal subjects belonging to any classification. Examples of such animals include mammals such as humans, rodents, dogs, cats, and domesticated animals. It can be done.

[0218] Administration / Pharmaceutical Composition In the method of the present invention, the antibody that specifically binds CD38 specifically binds CD38 The antibody may be provided in a suitable pharmaceutical composition comprising a pharmaceutically acceptable carrier. The carrier is a diluent, adjuvant, or excipient administered together with an antibody that specifically binds CD38. , or may be a vehicle. Such a vehicle may be peanut oil, soybean oil, mineral oil, sesame oil Liquids such as water and oil, including those of petroleum, animal, plant, or synthetic origin. You may use these solutions. For example, 0.4% physiological saline and 0.3% glycine may be used. The liquid is sterilized and generally does not contain particulate matter. These are standard, well-known sterilization techniques (for example) It can be sterilized by filtration. This composition is designed to approximate physiological conditions. Pharmaceutically acceptable auxiliary substances required, such as pH adjusters and buffers, stabilizers, It may contain thickeners, lubricants, and colorants. CD3 in such formulation The concentration of the antibody that specifically binds to 8 may vary widely, i.e., approximately 0.5% by weight. From less than 1% by weight, usually at least about 1% by weight, up to 15 or 20% by weight, 25% by weight, It may be 30% by weight, 35% by weight, 40% by weight, 45% by weight, or up to 50% by weight. Furthermore, depending on the specific administration method selected, the required dose, fluid volume, viscosity, etc. will be determined accordingly. Selected based on the following criteria: Suitable vehicles and formulations (other human proteins, e.g., human serum). (including albumin) is, for example, Remington: The Science and Public of Pharmacy, 21 st Edition, Troy, DBed., Lipincott Williams and Wilkins, P. hiladelphia,PA 2006,Part 5,Pharmaceutica l Manufacturing is described on pages 691-1092, and especially on page 95. Please refer to 8-989.

[0219] The method for administering an antibody that specifically binds to CD38 in the present invention is relevant to the art. As is well known, parenteral administration is also possible, for example, intradermal, intramuscular, intraperitoneal, intravenous, or subcutaneous. , intrapulmonary, transmucosal (oral, intranasal, vaginal, rectal), or other means as understood by those skilled in the art. This could be any preferred route. Antibodies that specifically bind CD38 can be obtained using known methods. Therefore, it may be administered intratumorally to the lymph node drain site for local delivery within the tumor.

[0220] Antibodies that specifically bind CD38 can be administered, for example, by intravenous (iv) injection or bolus injection. The drug is administered to the patient via injection, parenterally, through any preferred route such as intramuscular, subcutaneous, or intraperitoneal. It can be administered intravenously in doses of, for example, 15, 30, 60, 90, 120, or 18. 0, or over 240 minutes, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 It may be carried out over a period of 1 or 12 hours.

[0221] The dose administered to the patient shall alleviate or at least partially cessate the disease being treated. This is sufficient to be effective ("therapeutably effective dose"), and sometimes ranges from 0.005 mg to approximately 100 mg / kg, 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, For example, the amount may be approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / kg. However, even higher amounts, for example, about 15, 16, 17, 18, 19, 20, 21, 22, 23 , 24, 25, 30, 40, 50, 60, 70, 80, 90 or 100 mg / kg It's okay to have it.

[0222] For example, a fixed unit dose of 50, 100, 200, 500, or 1000 mg is given. Or, based on the patient's surface area, for example, 500, 400, 300, 250, 200, Alternatively, 100 mg / m² 2 It may be given in doses of 1 to 8 (for example, 1 , 2, 3, 4, 5, 6, 7, or 8) may be administered, but 9, 10, 11, 12, 13, Administering doses of 14, 15, 16, 17, 18, 19, 20, or higher is recommended. It is possible.

[0223] In the method of the present invention, the administration of the antibody that specifically binds CD38 is performed on days 1, 2, and 3. 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 2 months The treatment can be repeated after 3 months, 4 months, 5 months, 6 months or more. This is also possible, and long-term administration is also possible. Repeated administration is possible with the same dose. There may be one or different doses. For example, CD38 in the method of the present invention may be specifically The antibody that binds to the antibody is administered intravenously at a dose of 8 mg / kg or 16 mg / kg every week. It is administered for 8 weeks, and then 8 mg / kg or 16 mg / kg every 2 weeks for another 16 weeks. The administration of the drug continues, followed by administration of 8 mg / kg or 16 mg / kg every four weeks. It is possible to do so.

[0224] In the method of the present invention, the antibody that specifically binds CD38 is administered, for example, once a week for 6 months. The above may be used as maintenance therapy.

[0225] For example, the antibodies that specifically bind CD38 in the method of the present invention are 24, 12, 8, Using single doses or divided doses every 6, 4, or 2 hours, or a combination thereof. As a daily dose of approximately 0.1 to 100 mg / kg, for example, 0.5, 0. 9, 1.0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 1 3, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg / kg, after the start of treatment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or This occurs on at least one day out of 40, or on days 1, 2, 3, 4, 5, 6, 7, 8, and 9. , during weeks 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 They may be offered in at least one week, or in a combination of these.

[0226] The antibody that specifically binds CD38 in the method of the present invention also reduces the risk of cancer progression. This delays the onset of events in cancer progression and / or when cancer goes into remission. It may be administered prophylactically to reduce the risk of recurrence. This is due to other biological factors. Therefore, in patients where it is difficult to pinpoint the location of a known tumor This could be particularly useful.

[0227] The antibody that specifically binds CD38 in the method of the present invention is freeze-dried for storage and used. It can be redissolved in a suitable carrier beforehand. This technique relates to ordinary protein preparations. It has been shown to be effective, and well-known freeze-drying and reconstitution techniques can be used. ru.

[0228] The antibody that specifically binds CD38 in the method of the present invention is administered in combination with the second therapeutic agent. It is permissible.

[0229] In the method of the present invention, the antibody that specifically binds CD38 is a chemotherapeutic agent known to those skilled in the art. Alternatively, it may be administered in combination with any one or more other anti-cancer therapies. Chemotherapy drugs are used in cancer Compounds useful in the treatment of [condition], including proliferation inhibitors or other cytotoxic agents, alkylating agents, etc. Antineolytic agents, antimicrotubule inhibitors, topoisomerase inhibitors, receptor tyrosine kinase inhibitors Examples include angiogenesis inhibitors. Examples of chemotherapy drugs include thiotepa and cyclophosph Alkylating agents such as cyclosphosphamide (CYTOXAN®); Alkyl sulfonates such as sulfan, improsulfan, and biposulfan; benzo Benzodopa, carbocon, meturedopa, and uredopa Aziridines such as altoretamine, triethylenemelamine, and triethylenephosphoramide (trietylenephosphoramide), triethylenethiophosphoramide (triethylenethiophos Ethylene imitation containing phaoramide and trimethylolomelamine Methylamelamines; chlorambucil, chlornafadin, Chlorophosphamide, estramustine, ifosfamide, meclo Retamin, mechloretamine oxide hydrochloride, melphalan, nobuenvicin, feneste Nitrogens such as phosphorus, prednimustine, trophosphamide, and uracil mustard. Mustard; carmustine, chlorozotosine, fotemustine, lomustine, nimustine, Nitrosoureas such as ranimustine; aclasinomycin, actino Mycin, anthramycin, azacerin, bleomycin, cactino Mycin, caritiamycin, carbicin, carminomycin, cardino Phylin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-di Azo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, Idarubicin, marcelomycin, mitomycin, mycophenolic acid, nogaramycin , olibomycin, peplomycin, porphyromycin, puromycin Icin, Queramycin, Rhodolubicin, Streptonigrin, Streptozocin, Tuberculin Antibiotics such as Lucidin, Ubenimex, Zinostatin, and Zolubicin; Methotrexate and antimetabolites such as 5-FU; denopterin, methotrexate, pteropterin, Folic acid analogs such as rimetrexate; fludarabine, 6-mercaptopurine, thiamide Phosphorus, thioguanine and other purine analogs; ancitabine, azacitidine, 6-azauri Zin, carmofur, cytarabine, dideoxyuridine, doxifluridine, fennel Pyrimidine analogs such as phloxuridine; carsterone, dromos propionate androgens such as tanolone, epithiostanol, mepitiostane, and testactone; Anti-adrenal agents such as aminoglutethimide, mitotane, and trilostane; folinic acid (frolinic acid) Folic acid supplements such as cid; acegraton; aldofsphamide glycoside; aminolevriel Amsacrin; Bestlovesil; Bisantrene; Edatraxate ); defofamine; demecoltin; diaziquan; eflornithine (el fornithine; eriptinium acetate; etoglucide; gallium nitrate; hydroxyurea; le Ntinan; Ronidamin; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine Pentostatin; Fenamet; Pirarubicin; Podophyllic acid; 2-Ethylhydrazine Do; Procarbazine; PSK(registered trademark); Lazoxane; Schizophyllan; Spirogermani Um; Tenuazonic acid; Triadicone; 2,2',2”-Trichlorotriethylamine; U Retan; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolacto Lu; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Shik Lophosphamide; Thiotepa; Paclitaxel (TAXOL®), Docetaxel (TAXOTERE® registered trademark) and their analogues, such as taxoids or taxanes. Family products; chlorambucil; gemcitabine; 6-thioguanine; mercaptopri Methotrexate; platinum analogs such as cisplatin and carboplatin; vinbrain Styn; Platinum; Etoposide (VP-16); Ifosfamide; Mitomycin C; Mitox Santrone; vincristine; vinorelbine; navelbine; novanthrone; teniposide; Daunomycin; Aminopterin; Xeloda; Ibandronate; CPT-11; Topoiso Melase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoid Sorafenib; Esperamicin; Capecitabine; NEXAVAR (registered trademark) (Sorafenib) SUTENT (registered trademark) (sunitinib), VOTRIENT (trademark) (pazopanib), PALLADIA (trademark) (toceranib), ZACTIMA (trademark) (vandetanib), RECENTIN (registered trademark) (cedilanib), regorafenib (BAY 73-450 6) Axitinib (AG013736), Restaurtinib (CEP-701), TA RCEVA (registered trademark) (erlotinib), IRESSA (trademark) (gefitinib), G ilotrif® (afatinib), TYKERB® (lapatinib) ), including receptor tyrosine kinases and / or angiogenesis inhibitors, as well as Examples include pharmaceutically acceptable salts, acids, or derivatives of any of the above. The term also includes anti-inhibitory agents that work to regulate or inhibit the action of hormones in tumors. Hormone drugs, for example, tamoxifen, raloxifen, aromatase inhibitors 4(5 )-imidazole, 4-hydroxytamoxifen, trioxyfen, keoxyfen LY 117018, Onapriston, and FARESTON (registered trademark) (TremiF Anti-estrogen drugs such as benzodiazepines; as well as flutamide, nitramide, bicalutamide, and lycopherol. - Antiandrogenic drugs such as prolides and goserelin; and pharmaceutically acceptable salts, It is an acid, or a derivative of any of the above. (Wiemann et al., 198) 5,Medical Oncology(Calabresi et aL, eds.) Chapter 10, as disclosed in McMillan Publishing. Any other conventional cytotoxic compound can be applied to the method of the present invention.

[0230] A representative antibody that can be used in combination with an antibody that specifically binds CD38 in the method of the present invention. As pharmaceuticals, tyrosine kinase inhibitors, as well as IRESSA® (gefitinib) and This includes cancer-targeted therapies such as Tarceva® (erlotinib), as well as other HER-mediated therapies. 2. Antagonists of HER3, HER4, or VEGF are examples. A typical example is HER2. As an antagonist, CP-724-714, HERCEPTIN (trademark) (trust Zumab), OMNITARG (trademark) (pertuzumab), TAK-165, TYKERB (Registered Trademark) (Lapatinib) (EGFR and HER2 inhibitor), and GW-28297 Four examples include anti-Her3 antibodies (for example, US). (See National Patent Application Publication No. 2004 / 0197332) is one example. A typical example is HER4. As an antagonist, anti-HER4 siRNA (e.g., Maatta et al., (See Mol Biol Cell 17:67~79, 2006) is one example. The VEGF antagonist is Avastin (trademark) (bevacizumab).

[0231] A representative antibody that can be used in combination with an antibody that specifically binds CD38 in the method of the present invention. Examples of medications include standard treatments for solid tumors or immune checkpoint inhibitors.

[0232] The second therapeutic agent in the method of the present invention may be an immune checkpoint inhibitor.

[0233] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody, anti-PD- L1 antibody, anti-PD-L2 antibody, anti-LAG3 antibody, anti-TIM3 antibody, or anti-CTLA-4 antibody It is the body.

[0234] In some embodiments, immune checkpoint inhibitors are antagonist anti-PD-1 Antibodies, antagonist anti-PD-L1 antibodies, antagonist anti-PD-L2 antibodies, antagonist This is either a striker anti-LAG3 antibody or an antagonist anti-TIM3 antibody.

[0235] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0236] In some embodiments, the immune checkpoint inhibitor is an anti-PD-L1 antibody.

[0237] In some embodiments, the immune checkpoint inhibitor is an anti-PD-L2 antibody.

[0238] In some embodiments, the immune checkpoint inhibitor is an anti-LAG3 antibody.

[0239] In some embodiments, the immune checkpoint inhibitor is an anti-TIM3 antibody.

[0240] In some embodiments, the immune checkpoint inhibitor is an anti-CTLA-4 antibody.

[0241] Any antagonist anti-PD-1 antibody may be used in the method of the present invention. Typical anti-PD-1 antibodies include OPVIDO® (nivolumab) and KEYTRUD A (Registered Trademark) (Pembrolizumab). OPVIDO (Registered Trademark) (Nivolumab) For example, it is described in U.S. Patent No. 8,008,449 (Antibody 5C4), and the sequence number is Includes VH 24 and VL 25. KEYTRUDA® (Pembroli) Zumab is described, for example, in U.S. Patent No. 8,354,509, and Sequence ID No. 22. Includes VH and VL of SEQ ID NO: 23. Also includes the amino acid sequences of nivolumab and pembrolizumab. It is available through CAS registration. Additional PD-1 antibodies that can be used are listed in the U.S. 7 Patent No. 332,582, U.S. Patent Application Publication No. 2014 / 0044738, International Publication No. 20 As described in Patent No. 14 / 17966 and U.S. Patent Application Publication No. 2014 / 0356363 ru.

[0242] An "antagonist," when it binds to a cellular protein, becomes the natural ligand for that protein. Refers to a molecule that inhibits at least one reaction or activity induced by [the substance]. A small number of reactions or activities are suppressed in the absence of an antagonist (e.g., negative control). At least 30%, 40%, 45%, 50% more than one reaction or activity. , 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or When it is 100% inhibited, or when its inhibition is compared to inhibition in the absence of an antagonist, When the result is statistically significant, the molecule is an antagonist. Antagonists are antibodies, etc. It may be a soluble ligand, a small molecule, DNA, or RNA such as siRNA. For example, PD The typical response or activity induced by -1 is its receptor, PD-L1 or PD -By binding to L2, antigen-specific CD4 + Alternatively, CD8 + Cell proliferation may decrease, This means that interferon-γ (IFN-γ) production by T cells may be reduced, for example. For example, it leads to the suppression of the immune response against tumors. Typical reactions induced by TIM-3 The response or activity is due to the binding of the receptor, for example, galectin-9, to antigen-specific CD4 + Alternatively, CD8 + Cell proliferation may decrease, IFN-γ production by T cells may decrease, and This is the surface expression of CD137 (CD4 + Alternatively, CD8 + This means that the (on cells) may decrease. This leads to, for example, the suppression of the immune response against tumors. Therefore, it specifically binds to PD-1. Specifically targeting antagonist PD-1 antibody, antagonist PD-L2, and TIM-3. The binding antagonist antibody induces an immune response by inhibiting the inhibitory pathway.

[0243] Sequence ID 22 QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQ APGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTA YMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVS S

[0244] Sequence ID 23 EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHW YQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTI SSLEPEDFAVYYCQHSRDLPLTFGGGGTKVEIK

[0245] Sequence ID 24 QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQ APGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTL FLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSS

[0246] Sequence ID 25 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQK PGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLE PEDFAVYYCQQSSNWPRTFGQGTKVEIK

[0247] Anti-PD-L1 antibodies that enhance the immune response may be used in the method of the present invention (for example, an anti-PD-L1 antibody). (Tagonist anti-PD-L1 antibody). A representative anti-PD-L1 antibody that can be used is Durvalum. B, atezolizumab and avelumab, and, for example, U.S. Patent Application Publication No. 2009 / 0 U.S. Patent No. 055944, U.S. Patent No. 8,552,154, U.S. Patent No. 8,217,149, and the same This is described in item No. 8,779,108.

[0248] Durvalumab includes VH (SEQ ID NO: 26) and VL (SEQ ID NO: 27).

[0249] Atezolizumab includes VH (SEQ ID NO: 28) and VL (SEQ ID NO: 29).

[0250] Avelumab includes VH (SEQ ID NO: 30) and VL (SEQ ID NO: 31).

[0251] Sequence ID 26 EVQLVESGGG LVQPGGSLRLSCAASGFTFSRYWMSWVR QAPGKGLEWVAN IKQDGSEKYYVDSVKGRFTISRDNAKN SLYLQMNSLRAEDTAVYYCAREG GWFGELAFDYWGQGTL VTVSS

[0252] Sequence ID 27 EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQ K PGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISR LEPEDFAVYYCQQYGSLPWTFGQGTKVEIK

[0253] Sequence ID 28 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQ APGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS

[0254] Sequence ID 29 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQK PGKAPKLLIYSASFLYSGVPSRFSGSGSGTFTLTISSLQ PEDFATYYCQQYLYHPATFGQGTKVEIK

[0255] Sequence ID 30 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQ APGKGLEWVSSIYPSGGITFYADTVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVS S

[0256] Sequence ID 31 QSALTQPASVGSGSPGQSITISCTGTSSDVGGYNYVSWYQ QHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISG LQAEDEADYYCSSYTSSSTRRVFGTGTKVTVL

[0257] The present invention also relates to a CD containing therapeutically effective amounts of SEQ ID NO: VH and SEQ ID NO: VL. Antibodies that specifically bind 38 include anti-P, such as VH of SEQ ID NO: 24 and VL of SEQ ID NO: 25. It is administered in combination with D-1 antibody to patients who require it for a sufficient period of time to treat solid tumors. The invention also provides methods for treating patients with solid tumors, including the following.

[0258] The present invention also relates to a CD containing therapeutically effective amounts of SEQ ID NO: VH and SEQ ID NO: VL. Antibodies that specifically bind 38 include anti-P, such as VH of SEQ ID NO: 22 and VL of SEQ ID NO: 23. It is administered in combination with D-1 antibody to patients who require it for a sufficient period of time to treat solid tumors. The invention also provides methods for treating patients with solid tumors, including the treatment of solid tumors.

[0259] The present invention also relates to a CD containing therapeutically effective amounts of SEQ ID NO: VH and SEQ ID NO: VL. Antibodies that specifically bind 38 include anti-P antibodies such as VH of SEQ ID NO: 26 and VL of SEQ ID NO: 27. It is administered in combination with D-L1 antibody to patients who require it for a sufficient period of time to treat solid tumors. The invention also provides methods for treating patients with solid tumors, including [specific methods].

[0260] The present invention also relates to a CD containing therapeutically effective amounts of SEQ ID NO: VH and SEQ ID NO: VL. Antibodies that specifically bind 38 include anti-P, such as VH of SEQ ID NO: 28 and VL of SEQ ID NO: 29. It is administered in combination with D-L1 antibody to patients who require it for a sufficient period of time to treat solid tumors. The invention also provides methods for treating patients with solid tumors, including [specific methods].

[0261] The present invention also relates to a CD containing therapeutically effective amounts of SEQ ID NO: VH and SEQ ID NO: VL. Antibodies that specifically bind 38 include anti-P, such as VH of SEQ ID NO: 30 and VL of SEQ ID NO: 31. It is administered in combination with D-L1 antibody to patients who require it for a sufficient period of time to treat solid tumors. The invention also provides methods for treating patients with solid tumors, including [specific methods].

[0262] The present invention also relates to a CD containing therapeutically effective amounts of SEQ ID NO: VH and SEQ ID NO: VL. Antibodies that specifically bind 38 include anti-P, such as VH of SEQ ID NO: 24 and VL of SEQ ID NO: 25. It is administered in combination with D-1 antibodies to patients who require an enhancement of the immune response for a sufficient period of time. It also provides methods to enhance the patient's immune response, including [specific example].

[0263] The present invention also relates to a CD containing therapeutically effective amounts of SEQ ID NO: VH and SEQ ID NO: VL. Antibodies that specifically bind 38 include anti-P, such as VH of SEQ ID NO: 22 and VL of SEQ ID NO: 23. It is administered in combination with D-1 antibodies to patients who require an enhancement of the immune response for a sufficient period of time. It also provides methods to enhance the patient's immune response, including [specific example].

[0264] The present invention also relates to a CD containing therapeutically effective amounts of SEQ ID NO: VH and SEQ ID NO: VL. Antibodies that specifically bind 38 include anti-P antibodies such as VH of SEQ ID NO: 26 and VL of SEQ ID NO: 27. It is administered in combination with D-L1 antibody for a sufficient period to enhance the immune response in patients who require it. It also provides methods to enhance the patient's immune response, including [specific example].

[0265] The present invention also relates to a CD containing therapeutically effective amounts of SEQ ID NO: VH and SEQ ID NO: VL. Antibodies that specifically bind 38 include anti-P, such as VH of SEQ ID NO: 28 and VL of SEQ ID NO: 29. It is administered in combination with D-L1 antibody for a sufficient period to enhance the immune response in patients who require it. It also provides methods to enhance the patient's immune response, including [specific example].

[0266] The present invention also relates to a CD containing therapeutically effective amounts of SEQ ID NO: VH and SEQ ID NO: VL. Antibodies that specifically bind 38 include anti-P, such as VH of SEQ ID NO: 30 and VL of SEQ ID NO: 31. It is administered in combination with D-L1 antibody for a sufficient period to enhance the immune response in patients who require it. It also provides methods to enhance the patient's immune response, including [specific example].

[0267] The present invention also provides an antibody that specifically binds a therapeutically effective amount of CD38 to an antagonist. In combination with an anti-PD-1 antibody, it is used in patients who require it for a sufficient period of time to treat colorectal cancer. The invention also provides methods for treating patients with colorectal cancer, including administration of medication.

[0268] The present invention also provides an antibody that specifically binds a therapeutically effective amount of CD38 to an antagonist. In combination with an anti-PD-L1 antibody, for a sufficient duration to treat colorectal cancer in patients who require it. The invention also provides a method for treating patients with colorectal cancer, which includes administering a drug to them.

[0269] The present invention also provides an antibody that specifically binds a therapeutically effective amount of CD38 to an antagonist. In combination with an anti-PD-L2 antibody, for a sufficient period of time in patients who require it for the treatment of colorectal cancer. The invention also provides a method for treating patients with colorectal cancer, which includes administering a drug to them.

[0270] The present invention also provides an antibody that specifically binds a therapeutically effective amount of CD38 to an antagonist. It is administered in combination with an anti-PD-1 antibody to patients who require it for a sufficient period of time for the treatment of lung cancer. It also provides methods for treating patients with lung cancer, including [specific treatment methods].

[0271] The present invention also provides an antibody that specifically binds a therapeutically effective amount of CD38 to an antagonist. It is administered in combination with an anti-PD-L1 antibody to patients who require it for a sufficient period of time for the treatment of lung cancer. It also provides methods for treating patients with lung cancer, including [specific treatments].

[0272] The present invention also provides an antibody that specifically binds a therapeutically effective amount of CD38 to an antagonist. It is administered in combination with an anti-PD-L2 antibody to patients who require it for a sufficient period of time for the treatment of lung cancer. It also provides methods for treating patients with lung cancer, including [specific treatments].

[0273] The present invention also provides an antibody that specifically binds a therapeutically effective amount of CD38 to an antagonist. In combination with an anti-PD-1 antibody, it is administered to patients who require it for a sufficient period of time to treat prostate cancer. The invention also provides methods for treating patients with prostate cancer, including providing a solution.

[0274] The present invention also provides an antibody that specifically binds a therapeutically effective amount of CD38 to an antagonist. In combination with an anti-PD-L1 antibody, it is used in patients who require it for a sufficient period of time for the treatment of prostate cancer. The invention also provides methods for treating patients with prostate cancer, including administration of drugs.

[0275] The present invention also provides an antibody that specifically binds a therapeutically effective amount of CD38 to an antagonist. In combination with an anti-PD-L2 antibody, it is used in patients who require it for a sufficient period of time for the treatment of prostate cancer. The invention also provides methods for treating patients with prostate cancer, including administration of drugs.

[0276] Anti-LAG-3 antibodies that enhance the immune response may be used in the method of the present invention. Typical anti-LAG-3 antibodies are described, for example, in International Publication No. 2010 / 019570. It is.

[0277] Anti-CTLA-4 antibodies that enhance the immune response may be used in the method of the present invention. A representative anti-CTLA-4 antibody is ipilimumab.

[0278] Anti-PD-1, anti-PD-L1, anti-PD-L2, anti-LAG3, anti- TIM3 and anti-CTLA-4 antibodies are newly generated using the method described herein. That's fine.

[0279] In some embodiments, anti-PD1 includes VH of SEQ ID NO: 32 and VL of SEQ ID NO: 33. Antibodies may be used.

[0280] In some embodiments, anti-PD1 includes VH of SEQ ID NO: 34 and VL of SEQ ID NO: 35. Antibodies may be used.

[0281] In some embodiments, anti-TIM includes VH of SEQ ID NO: 36 and VL of SEQ ID NO: 37. -3 antibody may be used.

[0282] In some embodiments, anti-TIM includes VH of SEQ ID NO: 38 and VL of SEQ ID NO: 39. -3 antibody may be used.

[0283] Sequence ID 32 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQ APGQGLEWMGGIIPIFDTANYAQKFQGRVTITADESTSTA YMELSSLRSEDTAVYYCARPGLAAAYDTGSLDYWGQGTLV TVSS

[0284] Sequence ID 33 EIVLTQSPATLSLSPGERATLSCRASQSVRSYLAWYQQK PGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLE PEDFAVYYCQQRNYWPLTFGQGTKVEIK

[0285] Sequence ID 34 EVQLVESGGGLVQPGGSLRLSCAASGFAFSRYDMSWVRQ APGKGLESVAYISGGGANTYYLDNVKGRFTISRDNAKNSL YLQMNSLRAEDTAVYYCASPYLSYFDVWGQGTLVTVSS

[0286] Sequence ID 35 EIVMTQSPATLSVSPGERATLSCRASQSLSDYLHWYQQK PGQAPRLLIKSASQSISGIPARFSGSGSGTEFTLTISSLQ SEDFAVYYCQNGHSFPYTFGQGTKLEIK

[0287] Sequence ID 36 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQ APGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCAKSPYAPLDYWGQGTLVTVSS

[0288] Sequence ID 37 EIVLTQSPATLSLSPGERATLSCRASQSVNDYLAWYQQK PGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLE PEDFAVYYCQQGGHAPITFGQGTKVEIK

[0289] Sequence ID 38 EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWMQWVRQ MPGKGLEWMGAIYPGDGDIRYTQNFKGQVTISADKSISTA YLQWSSLKASDTAMYYCARWEKSTTVVQRNYFDYWGQGTT VTVSS

[0290] Sequence ID 39 DIQMTQSPSSLSASVGDRVTITCKASENVGTFVSWYQQK PGKAPKLLIYGASNRYTGVPSRFSGSGSGTFTLTISSLQ PEDFATYYCGQSYSYPTFGQGTKLEIK

[0291] The present invention also relates to a CD containing therapeutically effective amounts of SEQ ID NO: VH and SEQ ID NO: VL. Antibodies that specifically bind 38 include anti-P, such as VH of SEQ ID NO: 32 and VL of SEQ ID NO: 33. It is administered in combination with D-1 antibody to patients who require it for a sufficient period of time to treat solid tumors. The invention also provides methods for treating patients with solid tumors, including the treatment of solid tumors.

[0292] The present invention also relates to a CD containing therapeutically effective amounts of SEQ ID NO: VH and SEQ ID NO: VL. Antibodies that specifically bind 38 include anti-P, such as VH of SEQ ID NO: 34 and VL of SEQ ID NO: 35. It is administered in combination with D-1 antibody to patients who require it for a sufficient period of time to treat solid tumors. The invention also provides methods for treating patients with solid tumors, including the treatment of solid tumors.

[0293] The present invention also relates to a CD containing therapeutically effective amounts of SEQ ID NO: VH and SEQ ID NO: VL. Antibodies that specifically bind 38 include anti-T antibodies such as VH of SEQ ID NO: 36 and VL of SEQ ID NO: 37. It is administered in combination with the IM-31 antibody to patients who require it for a sufficient period of time to treat solid tumors. The report also provides methods for treating patients with solid tumors, including [specific methods].

[0294] The present invention also relates to a CD containing therapeutically effective amounts of SEQ ID NO: VH and SEQ ID NO: VL. Antibodies that specifically bind 38 include anti-T antibodies such as VH of SEQ ID NO: 38 and VL of SEQ ID NO: 39. It is administered in combination with the IM-31 antibody to patients who require it for a sufficient period of time to treat solid tumors. The report also provides methods for treating patients with solid tumors, including [specific methods].

[0295] In the method of the present invention, the combined use of an antibody that specifically binds CD38 and a second therapeutic agent is optional. It may be administered within a convenient time frame. For example, an antibody that specifically binds CD38 and The second drug may be administered to the patient again on the same day via the same intravenous infusion. However, CD38 The antibody that specifically binds to the second therapeutic agent is also administered every other day, every other week, or every other month. In some embodiments, an antibody that specifically binds CD38 and a second therapeutic agent are used. This means that they are simultaneously present in the treated patient at detectable concentrations (for example, in the serum). It may be administered in close proximity within a certain time frame. In some methods, a large number of doses are administered over a period of time. The entire series of therapies using antibodies that specifically bind CD38, consisting of a number of administrations, is a large number of administrations. A series of treatments with a second drug, consisting of multiple doses, follows or precedes this. The recovery period of one, two, several days, or several weeks is required for CD38 to specifically bind. It may be used between the administration of the antibody and the administration of the second therapeutic agent.

[0296] An antibody that specifically binds to CD38 or an antibody that specifically binds to CD38 and a second therapeutic agent In combination with any form of radiotherapy (external beam radiation therapy, intensity-modulated radiation therapy (IMRT)) , focused radiotherapy, etc., and any form of radiation surgery (gamma knife, cyberknife, Linac, and intra-tissue radiation (e.g., implantation of radioactive seeds, Glia Si) It may be administered in conjunction with procedures such as TE balloons and / or surgical procedures.

[0297] Possible focused radiotherapy methods include stereotactic radiosurgery, fractionated stereotactic radiosurgery, and intensity Modulated radiation therapy (IMRT) is one example. Stereotactic radiosurgery is used, for example, for brain tumors. In this case, radiation is precisely delivered to the tumorous tissue while avoiding surrounding healthy tissue without tumors. It is clear that this is involved. The dose of radiation applied by stereotactic radiosurgery varies. However, the amount obtained is typically between 1 Gy and about 30 Gy, for example, 1 to 5, 10, 15, 20, 2 5. May include an intermediate range in dose, including up to 30 Gy. Non-invasive fixed device Thanks to this, stereotactic radiotherapy does not need to be delivered in a single treatment. The treatment plan is adjusted daily. It can be reliably replicated, thereby enabling the delivery of divided radiation doses for multiple uses. If radiation surgery is used to treat a tumor over time, such radiation The treatment method is called "fractionated stereotactic radiosurgery" or FSR. In contrast to stereotactic radiosurgery and This refers to the procedure performed in a single session. Fractionated stereotactic radiosurgery has a high success rate, i.e., This results in killing tumor cells at a high rate and having low impact on normal tissue. Obtain. Tumors and normal tissues are affected by a single high dose of radiation, and by multiple low doses. Each irradiation dose elicits a different response. When a high dose of radiation is irradiated at once... This could potentially kill more healthy tissue than multiple low-dose radiation exposures. Therefore, by irradiating with low doses multiple times, it is possible to preserve normal tissue while increasing the amount of radiation. It can kill many tumor cells. The radiation applied by fractionated stereotactic radiosurgery The amount can vary in the range of 1 Gy to approximately 50 Gy, for example, 1 to 5, 10, 15, 20, 25 This may include intermediate ranges in fractional doses, including 30, 40, and up to 50 Gy. Intensity-modulated radiation therapy (IMRT) may also be used. IMRT is a high-precision three-dimensional conformal radiation therapy. This is an advanced mode of 3DCRT, using a computer-controlled linear accelerator. , it delivers a precise dose of radiation to a malignant tumor or a specific area within the tumor. 3D In a CRT, the profile of each radiation beam is determined by a multi-leaf collimator. Using (MLC), the beam direction image (BEV) is fitted to the target profile. It is shaped in such a way that it generates many beams. IMRT controls the intensity of the radiation beam. By modulating the radiation dose into multiple small amounts, the radiation dose can be precisely controlled based on the three-dimensional (3D) shape of the tumor. It enables a close alignment. Therefore, IMRT can connect to the surrounding normal and important structures. This makes it possible to minimize the dose while concentrating a higher dose of radiation on a specific area within the tumor. IMRT is used, for example, when a tumor is located in a vulnerable structure such as the spinal cord, major organs, or blood vessels. When the treatment encloses the body, it improves the ability to adjust the treatment volume to conform to the recessed shape of the tumor.

[0298] Subcutaneous administration of a pharmaceutical composition containing an antibody that specifically binds CD38 and hyaluronidase. Antibodies that specifically bind CD38, and hyaluronic acid It can be administered subcutaneously as a pharmaceutical composition containing dase.

[0299] The concentration of the antibody that specifically binds to CD38 in the subcutaneously administered pharmaceutical composition is approximately 20 mg. It may be / mL.

[0300] The subcutaneously administered pharmaceutical composition contains approximately 1,200 mg to 1,800 mg of CD38 specifically It may contain an antibody that binds to it.

[0301] The subcutaneously administered pharmaceutical composition contains approximately 1,200 mg of an antibody that specifically binds to CD38. It may be included.

[0302] The subcutaneously administered pharmaceutical composition contains approximately 1,600 mg of an antibody that specifically binds to CD38. It may be included.

[0303] The subcutaneously administered pharmaceutical composition contains approximately 1,800 mg of an antibody that specifically binds to CD38. It may be included.

[0304] The pharmaceutical composition administered subcutaneously contains approximately 30,000 to 45,000 units of hyaluronider. It may contain "ze".

[0305] The subcutaneously administered pharmaceutical composition contains approximately 1,200 mg of an antibody that specifically binds CD38. It may contain approximately 30,000 U of hyaluronidase.

[0306] The subcutaneously administered pharmaceutical composition contains approximately 1,800 mg of an antibody that specifically binds CD38. It may contain approximately 45,000 U of hyaluronidase.

[0307] The subcutaneously administered pharmaceutical composition contains approximately 1,600 mg of an antibody that specifically binds CD38. It may contain approximately 30,000 U of hyaluronidase.

[0308] The subcutaneously administered pharmaceutical composition contains approximately 1,600 mg of an antibody that specifically binds CD38. It may contain approximately 45,000 U of hyaluronidase.

[0309] The pharmaceutical composition administered subcutaneously is a hyaluronider having the amino acid sequence of SEQ ID NO: 40. It may contain zeroHuPH20.

[0310] rHuPH20 is recombinant hyaluronidase (HYLENEX® recombinant) Yes, it is described in International Patent Publication No. 2004 / 078140.

[0311] Hyaluronidase breaks down hyaluronic acid (EC 3.2.1.35) and the extracellular matrix. It reduces the viscosity of hyaluronan within the substance, thereby increasing tissue permeability.

[0312] Sequence ID 40 MGVLKFKHIFFRSFVKSSGVSQIVFTFLLIPCCLTLNFR APPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSP RINATGQGVTIFYVDRLGYYPYIDSITGVTVNGGIPQKIS LQDHLDKAKKDITFYMPVDNLGMAVIDWEEWRPTWARNWK PKDVYKNRSIELVQQQNVQLSLTEATEKAKQEFEKAGKDF LVETIKLGKLLRPNHLWGYYLFPDCYNHHYKKPGYNGSCF NVEIKRNDDLSWLWNESTALYPSIYLNTQQSPVAATLYVR NRVREAIRVSKIPDAKSPLPVFAYTRIVFTDQVLKFLSQD ELVYTFGETVALGASGIVIWGTLSIMRSMKSCLLLDNYME TILNPYIINVTLAAKMCSQVLCQEQGVCIRKNWNSSDYLH LNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSEKFYCSCYS TLSCKEKADVKDTDAVDVCIADGVCIDAFLKPPMETEEPQ IFYNASPSTLSATMFIVSILFLIISSVASL

[0313] The administration of a pharmaceutical composition containing an antibody that specifically binds CD38 and hyaluronidase is 1 Day 1, 2nd, 3rd, 4th, 5th, 6th, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks It can be repeated after 7 weeks, 2 months, 3 months, 4 months, 5 months, 6 months or more. The treatment process can be repeated, and long-term administration is also possible. The dose may be the same or different. For example, a dose that specifically binds CD38 A pharmaceutical composition containing the matching antibody and hyaluronidase is administered once a week for 8 weeks, followed by 2 weeks. The drug may be administered once every four weeks for 16 weeks. The administered pharmaceutical composition is approximately 1,2 An antibody that specifically binds 00 mg of CD38 and approximately 30,000 U of hyaluronidase It may contain, and the concentration of the antibody that specifically binds CD38 in the pharmaceutical composition is approximately 20 mg The concentration is / mL. The administered pharmaceutical composition specifically binds approximately 1,800 mg of CD38. The drug composition may include an antibody and approximately 45,000 U of hyaluronidase. The product consists of approximately 1,600 mg of an antibody that specifically binds CD38 and approximately 30,000 U of hya. The pharmaceutical composition to be administered may contain luronidase and CD38. It may contain an antibody that specifically binds to and approximately 45,000 U of hyaluronidase.

[0314] A pharmaceutical composition containing an antibody that specifically binds CD38 and hyaluronidase is applied to the abdomen. It may be administered via pedicine.

[0315] A pharmaceutical composition containing an antibody that specifically binds CD38 and hyaluronidase, in total quantity approximately It may be administered in doses of 80 mL, 90 mL, 100 mL, 110 mL, or 120 mL.

[0316] Prior to administering the mixture to the subject, 25 mM sodium acetate and 60 mM chloride were added. Sodium, 140 mM D-mannitol, 0.04% polysorbate 20, pH 5. In component 5, an antibody that specifically binds CD38 at a concentration of 20 mg / mL is used in 10 mM L-histidine. , 130 mM NaCl, 10 mM L-methionine, 0.02% polysorbate 80, Mix with 1.0 mg / mL (75-150 kU / mL) of rHuPH20 in pH 6.5. That's fine.

[0317] Although the present invention has been described in general terms, embodiments of the present invention are described within the scope of the claims. Further disclosures in the following embodiments should not be interpreted as limiting.

[0318] Further embodiments of the present invention Further embodiments of the present invention, as disclosed elsewhere in this specification, are listed below. The features of the embodiments of the present invention described above as relating to the present invention as disclosed in the details are This also relates to each of these numbered further embodiments. 1. An antibody that specifically conjugates CD38 for use in the treatment of patients with solid tumors. 2. CD38 for use in the treatment of patients with regulatory T cell (Treg)-mediated diseases An antibody that specifically binds to [a specific substance]. 3. This includes administering a therapeutically effective amount of an antibody that specifically binds CD38 to the target. For use in the treatment of patients with myeloid-derived suppressor cell (MDSC)-mediated diseases. An antibody that specifically binds to CD38. 4. Contact regulatory T cells (Tregs) with an antibody that specifically binds to CD38. An antibody that specifically binds CD38, including [specific component], for use in suppressing the activity of regulatory T cells. 5. Bone marrow-derived suppressor cells (MDSCs) are contacted with an antibody that specifically binds CD38. CD38 is specifically bound to this substance for use in inhibiting MDSC activity, including contact with it. antibody. 6. By administering an antibody that specifically binds CD38 to the patient, the control of the patient CD for use in the treatment of patients with solid tumors, including reducing the number of genital T cells. An antibody that specifically binds to 38. 7. By administering an antibody that specifically binds CD38 to the patient, bone in the patient Patients with solid tumors, including those with reduced medullary cell-derived suppressor cells (MDSCs). An antibody that specifically binds CD38 for use in the treatment of [unclear]. 8. The antibody is used according to any of Embodiments 1 to 7 to induce an immune response in the patient. An antibody that specifically binds CD38 for this purpose. 9. Any of Embodiments 1 to 8 in which the immune response is an effector T cell (Teff) response. An antibody that specifically binds CD38 for use according to [the specified method]. 10. Teff response is CD4 + T cells or CD8 + mediated by T cells, implementation An antibody that specifically binds CD38 for use according to one of the states 1-9. 11. Teff response is CD8 + mediated by T cells, according to Embodiment 9 or 10 An antibody that specifically binds CD38 for use in [specific application / use]. 12. Teff response, CD8 + Increased T cell count, CD8 + Increased T cell proliferation, T cells Increased clonal proliferation, CD8+ Increased memory cell formation, increased antigen-dependent antibody production, and Embodiment 1 is an increase in cytokine, chemokine, or interleukin production. An antibody that specifically binds CD38 for use according to any of the following 11 instructions. 13. The antibody inhibits the function of immune suppressor cells, in any of embodiments 1 to 13. Therefore, an antibody that specifically binds CD38 for use. 14. Immune suppressor cells are regulatory T cells (Treg) or bone marrow-derived suppressors. CD38 cells (MDSCs) for use according to any of Embodiments 1-14 An antibody that specifically binds to [a specific substance]. 15. Treg, CD3 + CD4 + CD25 + CD127 dim T cells, An antibody that specifically binds CD38 for use according to Form 15. 16. Treg expressing CD38, for use according to Embodiment 14 or 15 An antibody that specifically binds to CD38. 17. The function of Treg is inhibited by killing Treg, in embodiments 13-16. An antibody that specifically binds CD38 for use according to a specific method. 18. Treg killing is induced by antibodies that specifically bind CD38, anti body-dependent cell cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), cell-dependent cell Used according to Embodiment 17, mediated by injury (CDC) or apoptosis. An antibody that specifically binds to CD38. 19. The killing of Tregs is mediated by ADCC, according to Embodiment 17 or 18 An antibody that specifically binds CD38 for use. 20. Approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, or 60% of Tregs kill or injure. The method according to claims 17 to 19. 21. MDSC is CD11b + HLA-DR - CD14 - CD33 + CD15 + cell An antibody that specifically binds to CD38 for use according to Embodiment 14. 22. CD11b + HLA-DR - CD14 - CD33 + CD15 + Cells An antibody that expresses and specifically binds CD38 for use according to Embodiment 21. 23. In Embodiment 21 or 22, the function of the MDSC is inhibited by the killing of the MDSC. Therefore, an antibody that specifically binds CD38 for use. 24. Killing of MDSCs is induced by antibodies that specifically bind to CD38. body-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cells Used according to Embodiment 23, mediated by injury (CDC) or apoptosis. An antibody that specifically binds to CD38. 25. The killing of MDSC is mediated by ADCC, according to Embodiment 23 or 24 An antibody that specifically binds CD38 for use. 26. Approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, or 60% of MDSCs are lethal. CD38 is specifically bound for use according to any of embodiments 23 to 25. Antibodies that produce antibodies. 27. Embodiment 1, in which Teff or immune suppressor cells are present in the bone marrow or peripheral blood. An antibody that specifically binds CD38 for use according to one of the following 4-26. 28. Solid tumors include melanoma, lung cancer, squamous non-small cell lung cancer (NSCLC), and non-squamous cell lung cancer. NSCLC, colorectal cancer, prostate cancer, castration-resistant prostate cancer, stomach cancer, egg Focal cancer, gastric cancer, liver cancer, pancreatic cancer, thyroid cancer, squamous cell carcinoma of the head and neck, esophagus or This includes gastrointestinal cancers, breast cancer, fallopian tube cancer, brain cancer, urethral cancer, urogenital cancer, endometriosis, cervical cancer, and CD38 for use according to any of embodiments 14-27, which is a metastatic lesion of cancer. Antibodies that bind specifically. 29. If the solid tumor lacks CD38 expression, use according to any of Embodiments 1 to 28. An antibody that specifically binds CD38 for use. 30. The antibody has the heavy chain variable region (VH) of SEQ ID NO: 4 and the light chain variable region (VH) of SEQ ID NO: 5. An antibody containing L) competes with any of Embodiments 1 to 29 for binding to CD38. Therefore, an antibody that specifically binds CD38 for use. 31. The antibody contains at least the human CD38 (SEQ ID NO: 1) region SKRNIQFSCK Binds to NIYR (SEQ ID NO: 2) and region EKVQTLEAWVIHGG (SEQ ID NO: 3). an antibody that specifically binds CD38 for use according to any of embodiments 1 to 30. body. 32. The antibodies correspond to the heavy chain complementarity determination region (HCDR) 1 of SEQ ID NOs. 6, 7, and 8, respectively. Embodiments 1 to 31 include (HCDR1), 2(HCDR2), and 3(HCDR3) sequences. An antibody that specifically binds CD38 for use according to one of the following methods. 33. The antibodies are located in the light chain complementarity determination regions (LCDRs) of SEQ ID NOs: 9, 10, and 11, respectively. Embodiments 1 to 3 include arrays 1 (LCDR1), 2 (LCDR2), and 3 (LCDR3). An antibody that specifically binds CD38 for use according to either of the following two conditions. 34. The antibodies are HCDR1 and HCD, respectively, with sequence numbers 6, 7, 8, 9, 10, and 11. Embodiments 1 to 2000 include R2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences. An antibody that specifically conjugates CD38 for use according to one of the 33 methods. 35. The antibody is identical to SEQ ID NO: 4 at 95%, 96%, 97%, 98%, 99%, or 100%. VH is one, and sequence number 5 is 95%, 96%, 97%, 98%, 99%, or 100%. CD38 for use according to any of Embodiments 1 to 34, including VL which is % identical An antibody that specifically binds to [a specific substance]. 36. The antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5, according to Embodiments 1 to 31. An antibody that specifically binds CD38 for use according to a specific method. 37. Antibodies, a. VH of sequence number 14 and VL of sequence number 15, b. VH of sequence number 16 and VL of sequence number 17, c. VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or d. HCDR1, HCDR2, HC of sequence number 20 (VH) and sequence number 21 (VL) Any of Embodiments 1 to 29, including DR3, LCDR1, LCDR2, and LCDR3 Therefore, an antibody that specifically binds CD38 for use. 38. Anti-CD38 antibody, a. VH of sequence number 14 and VL of sequence number 15, b. VH of sequence number 16 and VL of sequence number 17, c. VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or d. Using according to Embodiment 37, including VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21 An antibody that specifically binds CD38 for this purpose. 39. The antibody is administered in combination with the second therapeutic agent, according to any of Embodiments 1 to 38. An antibody that specifically binds to CD38 for use in that purpose. 40. The second type of treatment is chemotherapy drugs, targeted anti-cancer therapy, Embodiment 39 is a standard therapeutic agent for the treatment of solid tumors, or an immune checkpoint inhibitor. An antibody that specifically binds CD38 for use according to [the specified method]. 41. Immune checkpoint inhibitors include anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-PD- Embodiments include L2 antibody, anti-LAG3 antibody, anti-TIM3 antibody, or anti-CTLA-4 antibody. An antibody that specifically binds CD38 for use according to 40. 42. The second therapeutic agent is administered simultaneously, sequentially, or separately, according to Embodiment 39. An antibody that specifically binds CD38 for use. 43. The patient is treated by radiotherapy according to any of embodiments 39 to 42. An antibody that specifically binds CD38 for use. 44. Sequence ID No. 4 VH and Sequence ID No. 5 for use in the treatment of patients with solid tumors. An antibody that specifically binds CD38, including VL. 45. The antibody, combined with anti-PD-1 antibodies including VH of SEQ ID NO: 22 and VL of SEQ ID NO: 23, The VH of SEQ ID NO: 4 and the VH of SEQ ID NO: 4 are administered for use in the treatment of patients with solid tumors. An antibody that specifically binds CD38 containing VL of SEQ ID NO: 5. 46. ​​The antibody, combined with anti-PD-1 antibodies including VH of SEQ ID NO: 24 and VL of SEQ ID NO: 25 The VH of SEQ ID NO: 4 and the VH of SEQ ID NO: 4 are administered for use in the treatment of patients with solid tumors. An antibody that specifically binds CD38 containing VL of SEQ ID NO: 5. 47. Sequence ID No. 4 VH and Sequence ID No. 5 VL for use in enhancing the patient's immune response. An antibody that specifically binds CD38, which contains [specific component]. 48. The antibody, combined with anti-PD-1 antibodies including VH of SEQ ID NO: 22 and VL of SEQ ID NO: 23, The VH and sequence numbers of Sequence ID No. 4 are administered for use in enhancing the patient's immune response. An antibody that specifically binds CD38, including VL of type 5. 49. The antibody, combined with anti-PD-1 antibodies including VH of SEQ ID NO: 24 and VL of SEQ ID NO: 25 The VH and sequence numbers of Sequence ID No. 4 are administered for use in enhancing the patient's immune response. An antibody that specifically binds CD38, including VL of type 5. 50. The antibody is an anti-PD-L1 antibody containing VH of SEQ ID NO: 26 and VL of SEQ ID NO: 27. The VH of SEQ ID NO: 4, which is administered in combination with the treatment of patients with solid tumors, An antibody that specifically binds CD38, including VL of sequence number 5. 51. The antibody is an anti-PD-L1 antibody containing VH of SEQ ID NO: 28 and VL of SEQ ID NO: 29. The VH of SEQ ID NO: 4, which is administered in combination with the treatment of patients with solid tumors, An antibody that specifically binds CD38, including VL of sequence number 5. 52. The antibody is an anti-PD-L1 antibody containing VH of SEQ ID NO: 30 and VL of SEQ ID NO: 31. The VH of SEQ ID NO: 4, which is administered in combination with the treatment of patients with solid tumors, An antibody that specifically binds CD38, including VL of sequence number 5. 53. The antibody is an anti-PD-L1 antibody containing VH of SEQ ID NO: 26 and VL of SEQ ID NO: 27. The VH and sequence of SEQ ID NO: 4, which are administered in combination, are intended for use in enhancing the patient's immune response. An antibody that specifically binds CD38 containing VL (number 5). 54. The antibody is an anti-PD-L1 antibody containing VH of SEQ ID NO: 28 and VL of SEQ ID NO: 29. The VH and sequence of SEQ ID NO: 4, which are administered in combination, are intended for use in enhancing the patient's immune response. An antibody that specifically binds CD38 containing VL (number 5). 55. The antibody is an anti-PD-L1 antibody containing VH of SEQ ID NO: 30 and VL of SEQ ID NO: 31. The VH and sequence of SEQ ID NO: 4, which are administered in combination, are intended for use in enhancing the patient's immune response. An antibody that specifically binds CD38 containing VL (number 5). [Examples]

[0319] Example 1. General materials and methods Sample collection and processing Peripheral blood and bone marrow aspirate were measured at baseline values ​​immediately before the initial infusion, and at specific points during treatment. The sample was collected in a heparinized tube. Upon arrival at the central laboratory 24-48 hours after collection, the sample was processed. Most of the data was evaluated using real-time flow cytometry. Peripheral blood mononuclear cells (PBMs) C) was obtained from whole blood, isolated by density gradient centrifugation, and frozen for storage until analysis. Cell activation, clonality, and CD38 + Treg suppression assays use frozen PBMCs Using a pull method, pre- and post-treatment samples were analyzed simultaneously.

[0320] NK, T, B, myeloma cells (CD138 + ) and evaluation of CD38 expression, Using proven immunophenotypic assays, BARC global central Flow cytometry analysis of the sample was performed in the boratory. In short, blood Liquid samples and bone marrow samples were subjected to the following multifluorescent dye antibody panel, i.e., the cell line panel: P erCPCy5.5α-CD19(cloneHIB19;Becton Dickin son[BD]), APCα-CD24(SN3;eBioscience), PC7α -CD3(UCHT-1;Beckman Coulter), V500α-CD16( 3G8; BD), and PEα-CD56 (MY; BD); regulatory T cells (T reg ) Panel Le: APCα-CD25 (2A3; BD), PEα-CD127 (HIL-7R-M21 ;BD), APC-H7α-HLA-DR(G46-6;BD), and PerCPα-C D4(L200;BD); Naive / Memory T cell panel: APC-H7α-CD4( RPA-T4;BD), PerCP-Cy5.5α-CD8(RPA-T4BD), PE α-CD62L(SK11;BD), and APCα-CD45RA(HI100;BD) Staining was performed. CD38 expression has the VH and VL sequences of SEQ ID NO: 14 and SEQ ID NO: 15. The Alexa 647-labeled antibody mAb 00 described in U.S. Patent No. 7,829,693 Evaluation was performed using method 3. Blood samples were prepared using various lyse-wash methods. For bone marrow aspirate samples, membrane or intracellular staining is performed using various antibodies. For lysing red blood cells in peripheral blood samples, Becton Dickinson FACS was used. Lysing solution was used, and Invitrogen was used for intracellular staining of bone marrow aspirate samples. Using Fix and Perm Cell Permeabilization Reagent Samples stained with a FACS Canto II flow cytometer were obtained, and Fac The data was analyzed using sDiva software. The logarithmic scale and the percentage of lymphocytes in the bone marrow sample were determined at all points in time during the examination.

[0321] T cell receptor (TCR) sequencing T cell diversity is analyzed by deep sequencing of TCR rearrangement, and PBM Using genomic DNA derived from C samples, CD8 + The clonal nature of T cells was evaluated. TCR sequencing is commercially available from Adaptive Biotechnologies. The analysis was performed using the Immunoseq (trademark) assay, and pre-approved multipliers were used. Rex polymerase chain reaction (PCR) assay (TR2015CRO-V-019) (Variable (V) gene (forward primer) and binding (J) gene (reverse primer) (Consists of forward and reverse primers that directly target the family of -) The procedure was carried out using the following: Each V and J gene primer increased the somatically recombinant TCR. Acting as priming pairs to broaden the range, each primer targets a specific universal DNA sequence. It contained [the following]. After the initial PCR amplification, each amplification product was subjected to DNA testing using Illumina. Forward and reverse ply, including universal sequences and adapter sequences necessary for sequencing. A second amplification was performed using Mar.

[0322] T cell response to viral antigens and alloantigens Patient PBMCs were seeded into a 96-well plate (2 × 10 5 Cells / wells), human cells Megalovirus (CMV), Epstein-Barr virus (EBV), and influenza 23 major histocompatibility complex (MHC) class I genes derived from the zvirus Viral peptide cocktail (2 μg / mL; CEF peptide pool; PANATecs) (Registered trademark), or 5 allogeneic PBMCs derived from healthy donors irradiated with the same number of 25 Gy doses. Stimulated for several days. Unstimulated PBMC and beads coated with anti-CD3 / CD28. PBMCs stimulated with [method] were used as negative and positive controls, respectively. On day 5, cells containing [method] were used. Interferon-gamma (IFN-γ) in the supernatant was analyzed using a sandwich enzyme-linked immunosorbent assay. (ELISA; Human IFNγELISA Ready-SET-Go; eBioscie It was measured by nce) and used as a surrogate marker for T cell activation.

[0323] Suppression of regulatory T cells (Treg) in effector cell function: Carboxyfluorescein Ccinimidil (CFSE) Dilution Assay PBMCs derived from healthy donors are used in PerCP-Cy5.5α-CD3(SK7;BD) , KOα-CD45 (J33; Beckman Coulter), V450α-CD4 (SK3; BD), PEα-CD25 (M-A251, BD), PECy7α-CD12 Labeled with 7(HIL-7R-M21;BD) and APCα-CD38(HB-7;BD). Then, I sorted them using FACS Aria (BD). The sorted effect pedals are detailed... Carboxyfluorothane succinimidyl ester (CFSE; eBioscienc e) Labeled with RPMI+10% fetal bovine serum, CD38 + Treg or CD38 - T In the presence or absence of reg (Treg vs. effector cell ratio 1:1), anti-CD3 / C Stimulation was performed using beads coated with D28. After 72 hours, flow cytometry was performed. This procedure was performed, and the dilution ratio of CFSE was used as a substitute for T cell proliferation.

[0324] Phenotyping of bone marrow-derived suppressor cells (MDSCs) and DARZALEX (trademark) Daratumumab-mediated ADCC PBMCs derived from three normal, healthy donors were selected from myeloma tumor cell lines (RPMI8226, U266, H929) for 6 days, and granulocytic MDSC (G-MDSC) (CD11 b + CD14 - HLA - DR - CD15 + CD33 + The production of (Gor (Gun et al., Blood 121:2975~87, 2013). G- MDSCs were not present in normal, healthy PBMCs, but were present in all three types of myeloma cell lines. After co-culturing, G-MDSCs were present as 5-25% of the total PBMC population (data shown). (zu). The gating strategy for evaluating G-MDSC by flow cytometry is, Gate 1 is CD11b + This includes, followed by CD14 - and HLA -DR - Goethe Afterwards, CD15 + and CD33 + The gating continued. GM DSC is related to CD38 expression levels and DARZALEX (daratumumab)-mediated AD. Cells were sorted and evaluated for their sensitivity to CC. MDSC A To evaluate the effects of DARZALEX (daratumumab) on DCC / CDC Therefore, serum containing complement or isotype control was added to the ADCC assay.

[0325] Naive and memory T cell analysis Before each infusion of DARZALEX (trademark) (daratumumab), a heparinized peripheral blood sample is administered. Peripheral blood mononuclear cells (PBMCs) were obtained from patients using a Ficol-Hypak density gradient centrifugation. Isolation was performed by separation, and the cells were stored in a cryopreservation medium (10% human serum and 10% dimethyl) in liquid nitrogen. The PBMCs were stored in RPMI (Rapid-Retaining Microwave Oxide) with added sulfoxide. For FACS analysis, the PBMCs were thawed and... , 2×10 6 Cells / panels are subjected to phosphate buffering containing 0.05% azide and 0.1% HAS. The solution was resuspended in saline solution (PBS).

[0326] Data Analysis All data analysis and creation of related graphs were performed using R software (R: A Language). e and Environment for Statistical Computing ing,R Development Core Team,R Foundation for Statistical Computing,Vienna,Austri a,2011,ISBN 3-900051-07-0 http_ / / _www_R- It was executed using project_org / exclusively. All of the responses that have an evaluable value. The treated subjects were included in the data analysis. Consistently, the responders were the most... A good response is defined as a subject with sCR, VGPR, or PR, and non-responders are, Subjects are defined as those whose best response to IRC is MR, SD, or PD.

[0327] As various statistical comparisons, (i) the baseline level between responders and non-responders. (ii) For responders and non-responders, reference values ​​versus during treatment, (iii) (iv) Percentage change between responders and non-responders, including the percentage change between baseline and during treatment. For comparison, first, we used the Shapiro-Wilk test (Royston (199)). 5)Remark AS R94:A remark on Algorithm AS 181:The W test for normality.Applied St Normality tests using atistics (44, 547-551) were mentioned. Almost exceptional. It was found that the data did not follow a normal distribution. As a test of the level of difference, non Parametric Wilcoxon rank-sum test (Hollander and Wolf) e(1973), Nonparametric Statistical Method s.New York:John Wiley & Sons.Pages 27~33 (one-sample), 68-75 (two-sample), and Box-Cox variant Substitution t-test (Weisberg, S. (2014) Applied Linear R) egression,Fourth Edition,Wiley Wiley,Cha It was suggested that both of the following be performed (pter 7). In the Box-Cox transform, equal to zero. A decimal (1e-07) was added to the original value. In all cases, the two tests agreed. Unless otherwise stated, the p-values ​​for the Wilcoxon rank-sum test are shown in tables throughout the specification. The results will be shown. For responders and non-responders, the difference between the reference value and the value during treatment will be examined. When determining the case, a paired test is performed on the subjects, and in all other cases, a paired test is performed on the subjects. An independent examination was conducted.

[0328] Samples for analyzing various lymphocyte populations were used due to different dosing schedules. Since data was not collected at a single point in time, group modeling was performed. Regarding the ranking of hospital visits, the modeling A fitting was performed. For population modeling of total and activated NK cells, a broken rod model was used. This includes the application to Lutz et al., "Statistical mod el to estimate a threshold dose and its confidence limits for the analysis of su blinear dose-response relationships, exem plified for mutagenicity data.”Mutation Research / Genetic Toxicology and Environm Ental Mutagenesis 678.2 (2009):118~122). A linear mixed-effects model using volume sections and slopes was applied to B cells, T cell subpopulations, and leukocytes. This was applied to patient population data for monocytes, neutrophils, and lymphocytes (Bates et al.). al.,(2014). “lme4:Linear mixed-effects mo dels using Eigen and S4.”ArXiv e-print;J Posted to ournal of Statistical Software, http:_ ( / / _arxiv_org / abs / _1406.5823). Relative days after the start of treatment (A Linear mixed modeling was performed in DY. For the logarithmically transformed response variable, A mixed-type model was fitted. If the response variable value is equal to zero, the model is on a logarithmic scale. To enable ringing, 0.1 was added to all response variable values.

[0329] Example 2. Design of Test 54767414MMY2002 (SIRIUS) The target population in trial 54767414MMY2002 (SIRIUS) was proteasophyll. The patient has a history of at least three types of treatment, including immunosuppressants (PIs) and immunomodulatory drugs (IMiDs). or patients with advanced multiple myeloma who are dually resistant to PI and IMiD. The primary endpoint / final analysis of treatment efficacy was based on the 2011 IMWG guidelines. This is based on evaluation by an independent review committee (IRC) and computerized algorithms. (Clinical trial summary report: At least three prior treatments (including proteasome inhibitors and IMiD) Multiple cases of (mu) or dual resistance to proteasome inhibitors and IMiD. The efficacy of DARZALEX (trademark) (daratumumab) in patients with myeloma. An open-label, multicenter Phase 2 trial to investigate safety (EDMS-ERI-92399922;de Weers et al.,(2011)J Immunol 186(3):184 (0-1848).

[0330] These evaluations include the overall response rate (ORR), duration of response, time to response and best effect, and clinical Treatment efficacy, time to progression (TTP), progression-free survival (PFS), and overall survival (OS). ) included.

[0331] In this trial, a total of 124 subjects were treated with DARZALEX (daratumumab). Treated (de Weers et al., (2011) J Immunol 186) (3):1840~1848). 18 subjects were treated with 8 mg / kg, and 106 subjects The patient was treated with 16 mg / kg. The administration schedule was as follows:

[0332] Group A: DARZALEX (trademark) (daratumumab) 16 mg / kg: 1 and 2 cycles Day 1, 8, 15, and 22 (weekly), cycles 3-6, and days 1 and 15 (every other week) From the 7th cycle onward, day 1 (every 4 weeks). Each cycle was 4 weeks long.

[0333] Group B: DARZALEX (trademark) (daratumumab) 8 mg / kg: from the first cycle onward, Day 1 (every 4 weeks).

[0334] The primary objective of this trial is to study patients who have a history of at least three types of treatment, including PI and IMiD, or The disease is multiple myeloma that is resistant to both PI and IMiD. In the subject, when measuring with ORR (CR+PR) DARZALEX (trademark) The objective was to determine the effectiveness of two treatment regimens using tumumab (Clinical Trial Summary Report: You have a history of at least three different treatments (including proteasome inhibitors and IMiD), or you have a history of pur Patients with multiple myeloma who are double-resistant to roteasome inhibitors and IMiD A study investigating the efficacy and safety of DARZALEX (daratumumab) in elephants. A blinded, multicenter phase 2 trial. (EDMS-ERI-92399922).

[0335] The secondary objectives of this study are to assess the safety and tolerability of DARZALEX® (daratumumab). Additional efficacy evaluations (e.g., clinical) involving assessment of tolerability, pharmacokinetics, immunogenicity, and pharmacodynamics. Demonstration of floor efficacy, TTP, PFS, and OS, and DARZALEX(trademark) One of the goals was to explore biomarkers that predict the response to daratumumab. Further information related to the trial can be found in the clinical trial protocol (clinical trial summary report: at least three types of treatments). A history of (including proteasome inhibitors and IMiD), or proteasome inhibitors and In patients with multiple myeloma who are resistant to IMiD, DARZA An open-label, multicenter Phase 2 trial to investigate the efficacy and safety of LEX (daratumumab). This can be confirmed from EDMS-ERI-92399922.

[0336] In Part 1, Stage 1, one subject (6%) responded in the 8 mg / kg group, and the 16 mg group... In the 16 mg / kg group, 5 subjects (31%) responded. Therefore, only the 16 mg / kg group was selected. It progressed to Stage 2 of Part 1, and then to Part 2.

[0337] In the 16 mg / kg group, 31 subjects achieved a response of PR or better based on IRC evaluation. The ORR was 29% (95% CI: 21%, 39%). Three subjects (3%) achieved sCR. This was achieved, with 13 subjects (12%) achieving VGPR or better.

[0338] Example 3. Patients enrolled in the 54767414MMY2002 study (SIRIUS) DARZALEX (trademark) (daratumumab) for T cell proliferation and activity in patients The effect CD38 is expressed in various immune cells and hematopoietic cells. Flow cytometry reveals... This involves performing broad immunoprofiling and targeting DARZALEX to a subset of immune cells. The relationship between the effects of (trademark) (daratumumab) and the clinical response of these cells to normal levels. This was investigated. T cells (CD3 + CD4 + CD8 + and regulatory T cells (Treg), B cells (CD19 + ), NK cells, monocytes (CD14 + ), white blood cells, and various neutrophils Cell populations were compared to reference values ​​and peripheral values ​​after DARZALEX (trademark) (daratumumab) treatment. Blood and bone marrow aspirate are evaluated by flow cytometry to determine responders and non-responders. We monitored the changes in these cell populations in the cell block.

[0339] Lymphocytes, white blood cells, monocytes, and neutrophils White blood cell, lymphocyte, monocyte, and neutrophil counts were measured in the peripheral regions of responders and non-responders. The test was performed in the blood. In responders, both 8 mg / kg and 16 mg / kg doses showed D It has been found that total lymphocyte counts increased with ARZALEX (trademark) (daratumumab) treatment. (Figure 1). Linear mixed-effects modeling showed that 0.0% of the data per 100 days was obtained on a logarithmic scale. 8×10 6 An increase in cells / μL was observed (CI=0.06, 0.11). Monocytes and For white blood cells, the logarithmic scale showed 0.03 × 10⁻¹⁰ days for each 100-day period. 6 cells / μ L(CI=0.01, 0.04), and 0.03×10 6 cells / μL (CI=0.01 A slight increase was observed, with a significant increase of 0.05. The median neutrophil count was based on The values ​​were consistent with baseline levels and did not fluctuate significantly, but neutropenia was observed in some patients. .

[0340] The reference levels for each of these cell populations were compared among the response groups. Wilcoxon Using the signed-rank test, no differences in any cell type were observed between response groups at the reference level. It was not possible (Table 1).

[0341] [Table 1]

[0342] NK cells Total NK cells (CD16 + CD56 + ) and activated NK cells (CD16 + CD56 dim ) decreased over time with DARZALEX (trademark) (daratumumab) treatment (data (Not shown).

[0343] B cells B cells (CD45) in peripheral blood or bone marrow aspirate + CD3 - CD19 + The absolute number of ) is the response In responders and non-responders, DARZALEX (trademark) (daratumumab) treatment Measurements were taken over time during treatment. B cells were slightly increased in whole blood and maintained in bone marrow aspirate. Linear mixed modeling of peripheral blood B cells was performed on a logarithmic scale for each 100-day period. The minimum increase is 0.1 × 10 6 An increase in cells / μL was observed [CI=0.0 4, 0.16] (during DARZALEX (trademark) (daratumumab) treatment). Responder In either the daratumumab treatment or non-responder group, B cells (CD4) in bone marrow aspirate are present during daratumumab treatment. 5+ CD3 - CD19 + The proportion of lymphocytes did not change (p=0.1 and p=0.1 respectively). (0.4). Furthermore, there was a difference in the number of B cells relative to the reference value between responders and non-responders. It was not observed (p=0.5).

[0344] T cells Although B cells showed only a minimal increase (see above), DARZALEX (commercial An increase in lymphocytes was observed with daratumumab treatment (Figure 1). Further investigation is needed. Therefore, various T cell populations were examined in both peripheral blood and bone marrow (CD3 + CD4 + CD8 + T cells, regulatory T cells).

[0345] CD3 + CD4 + and CD8 + T cells are DARZALEX (trademark) (daratumumab After treatment, peripheral blood (both absolute number / μL and lymphocyte percentage) increased. Figure 2 shows Peripheral blood CD3 in all patients + T cells (CD45 + CD3 + The absolute number of the base This shows the percentage change over time from the baseline value. The black line in the figure represents the absolute number × 10 for all patients. 6 cell The median value of / μL is shown. Only outpatient visits with three or more observation results are included in the figure. Figure 3 shows all Peripheral blood CD4 in the patient + T cells (CD45 + CD3 + CD4 + The absolute number of ) The graph shows the percentage change over time from the reference value. The black line in the graph represents the median value for all patients. 3 Only outpatients with observation results of one or more times are included in the figure. Figure 4 shows peripheral blood in all patients. Medium CD8 + T cells (CD45 + CD3 + CD8 + The change over time from the reference value of the absolute number of ) The percentage is shown. The black line in the figure represents the median for all patients. This applies to patients with three or more observation results. Only outpatient visits were included in the figure. Linear mixed modeling was performed on the absolute number of peripheral blood cells to determine the mean total T cells. cells (CD45 + CD3 + For each 100-day period, 0.13 × 10⁻¹⁰ on a logarithmic scale. 6 An increase in cells / μL (CI=0.1, 0.15) was observed (DARZALEX (commercial (After daratumumab treatment). CD8 + T cells, on a logarithmic scale, per 100 days 0.16 × 10 6 A significant increase in cells / μL was observed (CI=0.13, 0.19). ). CD4 + The cells grew 0.11 × 10⁶ times per 100 days on a logarithmic scale. 6 cells / μ A moderate increase in L was observed (CI = 0.09, 0.13).

[0346] For each T cell subpopulation, responders have higher baseline values ​​than non-responders. This shows the maximum rate of change in absolute numbers relative to (CD3 + p=3.2993e-05;CD4 + p=3.486e-05;CD8 + p=2.7172e-05; regulatory T cells p=0.0 02). Table 2 shows the percentage change in absolute number relative to the reference value for responders and non-responders. Results of Wilcoxon signed-rank test for comparison of peripheral blood T cell subpopulations between the two groups. show.

[0347] [Table 2]

[0348] Similarly, in the bone marrow, total T cells (CD45 + CD3 + (as a percentage of lymphocytes) and CD 8 + T cells (CD45 + CD3 + CD8 + (As a percentage of lymphocytes) Responders and In both non-responders and those undergoing treatment with DARZALEX (daratumumab), It was found that there was a significant increase (CD3 + Responder p = 3.8147e-06, No Responder p=9.8225e-05;CD8 + Responder p = 3.8147e- 06. Non-responders (p=0.0003). In all clinical response groups in the bone marrow, CD 4 + The median T cell count remained unchanged. Table 3 shows various T cell counts as % lymphocytes in the bone marrow. The results of Wilcoxon's signed-rank test for DARZALEX are shown. Figure 5 shows the results of DARZALEX (quotient). CD45 over time during daratumumab treatment + CD3 + This shows the percentage of cells (%). (Both responders and non-responders are included in the graph.) Figure 6 shows DARZALEX (Trademark) (Daratumumab) Time-course CD45 during treatment + CD3 + CD8 + Shows the percentage of cells (Both responders and non-responders are included in the graph.)

[0349] [Table 3]

[0350] Both the responder and non-responder groups showed an increase in T cells in peripheral blood and bone marrow. However, the responders showed the largest percentage change from the baseline. Responders or non-responders In the responder, CD3 + CD4 + and CD8 + Identify differences at the T cell level. Therefore, prior to DARZALEX (trademark) (daratumumab) treatment, the peripheral blood of each subgroup was measured. We compared it with the reference measurement values.

[0351] Absolute T cell count in peripheral blood (Table 4) or percentage of T cells from total lymphocytes in bone marrow (Table 5) showed no statistically significant difference between responders and non-responders. (Wilcoxon signed-rank test).

[0352] [Table 4]

[0353] [Table 5]

[0354] T regulatory cells Treg cells are CD3 in the sample + CD4 + CD25 + CD127 dim cell population It was identified as CD8. + The ratio of T cells to Tregs is DARZALEX (trademark) The ratio was evaluated in peripheral blood and bone marrow of patients treated with daratumumab over time. Increased levels were observed in both peripheral and bone marrow. Figure 7A shows the peripheral blood levels of all patients at that time. CD8 + / Treg and CD8+ / CD4 + The median cell ratio is shown. Figure 7B shows the bone marrow. CD8 of all patients at that time + / Treg and CD8 + / CD4 + Median T cell ratio This indicates CD8 + Treg and CD8 + / CD4 + The change in the absolute ratio of is observed over time during treatment. Significant differences were observed in peripheral blood (Table 6) and bone marrow (Table 7) (Wilcoxon signed-rank test). ).

[0355] In the comprehensive data analysis of the SIRIUS and GEN501 trials (Example 6), peripheral blood showed that, CD8 + / CD4 + and CD8 + The median ratio of Treg cells was at week 8 (p=5.1). ×10 -5 (CD8 + / CD4 + ) and p = 1.8 × 10 -7 (CD8 + / Treg), Furthermore, week 16 (p=0.00017(CD8) + / CD4 + ) and p = 4.1 × 10 - 7 (CD8 + It increased in / Treg). Similarly, in the bone marrow, CD8 + / CD4 + and CD8 + The median ratio of Treg cells was compared to the normal range during treatment (12 weeks ± 1 week). (p=0.00016(CD8)) increased + / CD4 + and p = 2.8 × 10 - 7 (CD8 + / Treg)). A significant difference was observed between responders and non-responders. It wasn't there.

[0356] [Table 6]

[0357] [Table 7]

[0358] Example 4. Test Design (GEN501) The GEN501 trial (NCT00572488) was conducted in patients with double-treatment-resistant MM. DARZALEX (daratumumab) was evaluated as monotherapy. Sample isolation, The processing and statistical analysis were as described in Examples 1 and 2. This test was conducted at Lo khorst et al.,N Eng J Med 373:1207~19,20 It is described in 05.

[0359] In short, the GEN501 test involved DARZALEX in subjects with MM. This was the first-in-human clinical trial of (trademark) (daratumumab). This is a Phase 1 / 2 dose-escalation safety study divided into two parts. Part 1 is an open-label dose-escalation trial. This is an experiment, and Part 2 will use the dose levels established in Part 1 as a baseline for multiple cohorts. This is an open-label, single-arm trial.

[0360] In Part 1, we have 0.005, 0.05, 0.10, 0.50, 1, 2, 4, 8, 16, And evaluation of DARZALEX (trademark) (daratumumab) in 10 dose levels of 24 mg / kg It was worthwhile. The two lowest dose cohorts were each assigned 1 (+3) subjects, and standard The allocation of the three (+3) subjects was applied to the remaining eight dose cohorts. Part 2 is This was an open-label single study involving two dose levels, 8 mg / kg and 16 mg / kg. Part 1 included 32 subjects, and Part 2 included 72 subjects.

[0361] Example 5. DARZALEX (trademark) (daratumumab) treatment showed that T cells in patients Loan-like In the MY2002 trial, CD8 was found in both peripheral and bone marrow. + T cell proliferation was confirmed. Considering this, the Immunoseq® assay was used to analyze T cell receptors (TCRs). High-throughput next-generation sequence determination was performed, CD8 + An increase in T cells indicates an adaptive immune response. In effect, it was determined whether or not the cells were clonal. The subjects included in the GEN501 trial... A total of 17 patient samples were evaluated (n=6 were responders, i.e., ≥PR; n=11 represents non-responders (i.e., MR, SD, PD).

[0362] TCR sequencing has shown that treatment with DARZALEX (daratumumab) can help patients It was found that it significantly increased clonality throughout the entire population. Figure 8A shows DA This shows the correlation between T cell clonality before and after RZALEX (trademark) (daratumumab) treatment. (p=0.0056). Figure 8B shows the clonal scaling change in individual patients. Responders are marked with a star. This data is from DARZALEX (trademark) (Daratum). This suggests that the T-cell proliferation observed with mab therapy may be virtually clonal. Yes, they are.

[0363] Compared to non-responders, responders show changes in TCR repertoire (abundance). The total proliferation (measured as CIA) was large. Figure 8C shows the CIA% for individual patients. Group A: Responders, Group B: Non-responders. A statistically significant difference was observed between them (p=0.037). Figure 8D shows the proliferated T cells of each group. Regarding clones, the absolute change in abundance between responders and non-responders (CIA) The sum of the values ​​is shown. Figure 8E shows the maximum CIA% for individual patients. Group A: Responders, Group B Group: Non-responders. A statistically significant difference was observed between responders and non-responders. (p=0.048). Figure 8F shows the responders (Group A) and non-responders (Group B). This shows the maximum CIA of a single T cell clone.

[0364] Fisher's exact test (DeWitt et al. J. Virol. 2015) Using ), the absolute values ​​of the changes in abundance for each multiplied clone are summed up, and the two CIA was obtained by identifying significant differences in clonal abundance between samples.

[0365] Example 6. DARZALEX® in patients enrolled in the GEN501 study Immunomodulatory effects of (daratumumab) In the responders and non-responders incorporated into GEN501, various T The B cell population was also evaluated.

[0366] lymphocytes Similar to the SIRIUS (MMY2002) trial, lymphocytes were tested using DARZALEX (trademark). During treatment with daratumumab, levels increased in both peripheral blood and bone marrow. This increase was attributed to CD 4 + and CD8 + This was due to an increase in the number of both cells.

[0367] CD8 + Central memory cells In a subset of 17 patients enrolled in the GEN501 trial, CD8 + T cells The phenotype was examined over time in patients treated with DARZALEX (daratumumab). We used standard methods to analyze patient-derived CD8 + Cells, naive (CD45RO- / C D62L + )(T N ) or central memory (T CM )(CD45RO + / CD62L +high They were identified as ) cells.

[0368] Figure 9A shows CD8 + Naive cells % (CD8 + Figure 9B shows the percentage of cells, and CD8 + Se This shows the percentage of central memory cells treated with DARZALEX (trademark) (daratumumab). Naive CD8 + The amount of T cells was significantly reduced (p=1.82×10). -4 (As of week 8) CD8 + The amount of memory T cells increased significantly (p=4.88×10⁻⁶). -2 As of week 8 This is a note that naive cytotoxic T cells can be activated in response to specific antigens. This suggests conversion to Lee T cells. White squares indicate at least minimal response (≧MR) achieved. The chart shows patients who had a stable or progressive condition, with black squares indicating patients whose condition was stable or progressive. CD8 + Naive T-shirt (thin) A significantly greater reduction in cell count was evident in patients who responded to treatment (data not shown). Figure 9C shows that treatment with DARZALEX (trademark) (daratumumab) can lead to virus-specific... The proportion of HLA class I-bound T cells partially promotes the alloreactive T cell response. This indicates an increase. Figure 9D shows the effector memo expressing low levels of CD38. This indicates that Lee T cells are proliferating. These T cells are reacting to viral peptides and allogeneic antibodies. It is important to note that the original substance exhibits normal and even increased functional activity (Examples) (See 8). Based on these functional outcomes, during treatment with DARZALEX® (daratumumab) This includes an increase in or enhancement of the activity of T cells that have experienced the antigen against the virus and its alloantigen. This was the conclusion. Unlike the regulatory cell subset, these data showed that effector T cells This suggests that the cells do not require CD38 expression to function properly and proliferate. .

[0369] CD38 positive regulatory T cells Recent literature shows that some immunosuppressive cell subsets express CD38. In addition, stable proliferation and enhanced activity of cytotoxic T cells were observed, indicating control Regulatory T cells (Treg), a population of sex cells, and myeloid-derived suppressor cells (MDSCs) The effect of DARZALEX (daratumumab) on regulatory B cells (Bregs) This prompted further consideration.

[0370] Regulatory T cells (Treg) (CD3 + CD4 + CD25 + CD127 dim ) to standard Treg cells were isolated using a specific method. The frequency of Treg cells was analyzed using flow cytometry.

[0371] A subpopulation of peripheral Tregs (10% ± 10%) exhibits high levels of CD3 prior to Treg activation. It expressed 8. The upper panel of Figure 10A shows CD3 at the reference value. + CD4 + cell collection This shows the frequency of Treg cells in a group (P4 cell population). The lower panel of Figure 10A shows high CD38 levels. This shows a subset of expressed Treg cells (P5 cell population). These CD38 + Tre g showed a high response to DARZALEX (trademark) (daratumumab) treatment, and DARZ ALEX (trademark) (daratumumab) showed a significant and nearly rapid decrease after the initial dose. n=17 patients; P=8.88 × 10 -16 (at week 1 relative to the baseline). DARZ The frequency of Tregs after ALEX(trademark) (daratumumab) treatment is shown in the upper panel of Figure 10B. (P4 cell population). The lower panel of Figure 10B shows CD38 high Treg(P5 thin The most significantly depleted cells were those that were depleted after the initial DARZALEX (daratumumab) injection. This indicates that it was a Treg population. + Treg is DARZALEX( (Trademark) (Daratumumab) remained depleted during treatment (p=8.88×10 -16 , 1. 11×10 -15 , and 1.50 × 10 -11 1, 4, and 8 relative to the reference value, respectively. (At week 1). Figure 10C shows normal values, week 1, week 4, week 8, relapse, and end of treatment (EO). T) CD38 in the 6th month following high Treg%(Total CD3) + (From cells) CD38 high Treg had recovered to normal levels by that point. CD38 + T Changes in reg were similar between patients who responded to treatment and those who did not, D8 +The T cell:Treg ratio is related to the response to DARZALEX (daratumumab). In patients who showed this symptom, the level was significantly higher at 8 weeks (P=0.00955; Figure 10D).

[0372] CD38 + The concept of Treg depletion and DARZALEX (daratumumab) treatment. To evaluate the biological relevance, CD38 + TReg vs. CD38 - Treg, house CD3 + The inhibitory capacity on T cells was evaluated using samples from multiple healthy donors. In a series of experiments conducted, CD38 + Treg is CD38 - Treg (Observed details) T cell proliferation was stronger in 53.2% of cells or in negative controls (74.9% of observed cell proliferation). Cellular proliferation was suppressed (9.9% of observed cell proliferation) (Figure 10E).

[0373] MDSC was not readily detectable in frozen PBMC samples, therefore CD38 + Granulocytic MDSC (CD11b + CD14 - HLA-DR - CD15 + CD33 + )of, Patients with normal values, and patients who have received one injection of DARZALEX (trademark) (daratumumab). It was produced in vitro from PBMCs isolated from [unspecified source]. Figure 11 shows the identified MD. The flow cytometry histogram of SC is shown (Figure 11, the histogram above, enclosed in a rectangle). (A population of cells). Approximately half of the MDSCs expressed CD38 (Figure 11, center graph; (P7 cell population enclosed in a circle). CD38 high MDSC is a trademark of DARZALEX. In patients treated with daratumumab, it was almost completely depleted (Figure 11, graph below; circled P). (7-cell population).

[0374] CD38 high Systemic nonspecific MDSCs are non-responders and are less responsive to treatment. In both patients who achieved minimal repose, DARZALEX® (Daratumumab) treatment led to depletion over time. Figure 12 shows CD38 high MDSC The percentage of patients decreased to almost 0% in patients at week 1, week 4, or week 8 of treatment. Show. CD38 high Systemic nonspecific MDSCs recovered to normal levels after the completion of treatment.

[0375] CD38 is the most common in nonspecific MDSCs. + Patients with a population are DARZALEX ( It showed the best and most sustained response to (daratumumab) treatment. Figure 13 shows , the highest CD38 high It has a proportion of MDSC (shown in Figure 11), and PR or M Patients 2, 4, 15, 16, and 17, who were classified as R patients, were progression-free for at least 8 months. This indicates that the patient had a progression-free survival (PFS).

[0376] Also, CD38 high Nonspecific MDSCs are DARZALEX (trademark) (Daratum Mab-induced ADCC was also observed in vitro in the ADCC assay. It is a CD38 derived from two donors. high MDSCs and Dau as control target cells The di cell assay was performed using an effector:target cell ratio of 50:1. Figure 14 shows the results for one individual. The experimental results for the donor are shown. DARZALEX (trademark) (daratumumab) is used with MDSC cells. This induced dissolution.

[0377] CD38 + Breg patients treated with DARZALEX (trademark) (daratumumab) When measured in n=16, CD38 + Similar to Treg, DARZALEX ( Depletion occurred after the first dose of (trademark) (daratumumab) (p=0.0018, compared to the reference value) Week 1; paired Wilcoxon rank test), the patient remained low while being treated. It was found (Figure 15A). Breg cells sorted by FACS, when stimulated, produced IL-10 It produced (Figure 15B).

[0378] Overall, these observations suggest immunosuppressive CD38 + MDSC, Breg, and Tre The depletion of g is due to DARZALEX(trademark) in T cell populations and clonality. (b) This suggests that it is a mechanism that significantly induces induced changes.

[0379] Example 7. CD38 + MDSC cells are present in cancer patients. MDSC(Lin - CD14 - HLADR low / - ) and the proportion of those CD38 Currently, peripheral blood from NSCLC or prostate cancer patients is being examined using flow cytometry. I defeated him.

[0380] The proportion of MDSCs was P in the analysis samples of NSCLC and prostate cancer patients, respectively. CD38 expression was observed in approximately 10% to 37% and 10% to 27% of BMCs. Lin derived from the PBMC of the person - CD14 + HLADR - / low MDSC 80-100 It was identified in % and 70-100% of MDSCs derived from PBMCs in prostate cancer patients.

[0381] Example 8. DARZALEX (trademark) (daratumumab) enhances the antiviral T cell response. strengthen The effects of DARZALEX (trademark) (daratumumab) on T cell activation and functionality To further evaluate IFN-γ production from peripheral T cells in response to viruses and alloantigens, Patients treated with DARZALEX (daratumumab), which has a variety of clinical outcomes. Measurements were taken at (n=7). Patients with a PR or better rating were measured using DARZALEX(trademark) (Daratum). After treatment with Mab, compared to the normal range, the viral and at least one time point during treatment were elevated. It showed a significant increase in IFN-γ secretion in response to the same antigen, and T cell function was low in CD38 This suggests that it was not damaged by the present (see Example 6, Figure 9C). TCR Chromium Similar to the performance data, this increase is in response to DARZALEX® (daratumumab). The effect was more pronounced in patients who responded than in those who did not. Figure 16A shows one representative patient. Figure 16B shows the antiviral response of a typical VGPR patient. Figure 16C shows the antiviral response of a representative PD patient. D shows the antiviral response of one representative MR patient. In the figure, there are two error bars. The standard error of the mean values ​​of repeated cultures is shown. An asterisk indicates a statistically significant difference between the comparisons shown. This signifies a significant change. It demonstrates the best effect as determined by an independent review committee. These results are consistent with the results of the study. In patients with VGPR (Figure 16E) or CR (Figure 16F), virus-reactive T cells are DARZALEX (trademark) (daratumumab) treatment showed increased proliferative capacity.

[0382] Example 9. DARZALEX™ (Daratum) CD38-expressing immune cell subtype Sensitivity mechanism to (B) Based on data from both the GEN501 and SIRIUS trials, DARZALEX (trademark) Tummumab therapy depletes some immune cells that express CD38 (NK cells, regulatory cells). T cells (Treg), regulatory B cells (Breg), and myeloid-derived suppressor cells (MD) SC)), on the other hand, the number of other cells expressing CD38 increases (cytotoxic and helper This has been shown to be related to T cells.

[0383] To address the susceptibility mechanism, healthy donors and GEN501 or SIRIUS trials are being conducted. In multiple myeloma patients enrolled in the study, the expression of CD38 in various immune cell subpopulations was observed. The levels were evaluated. Figure 17A shows the CD38 expression levels in immune cells derived from healthy donors. The histogram is shown, and Figure 17B shows the CD38 levels in immune cells derived from multiple myeloma patients. The expression histogram is shown. In healthy donors, CD38 expression is highest in NK cells, followed by... These were monocytes, B cells, and T cells. In patients with multiple myeloma, CD38 expression was most prevalent in plasma cells. This was followed by B cells, NK cells, monocytes, and subsets of B cells and T cells (Figure 1). 7C consists of NK cells, Treg, Breg, B, and T derived from patients with relapsed and refractory myeloma. This shows a comparison of the mean fluorescence intensity (MFI) of CD38 in cells, with plasma cells showing the highest intensity in NK cells. They also express CD38 at a high level, followed by regulatory T cells (Treg) and regulatory B cells ( This indicates that it was Breg.

[0384] In addition to CD38 expression, complement inhibitory proteins (CIP; CD46, CD55, CD59) Other cell surface proteins such as ) are affected by DARZALEX (trademark) (daratumumab) This may contribute to susceptibility or resistance. CIP in a subpopulation of immune cells iTrial evaluation revealed that NK cells express very low levels of CD59 and CD55. On the other hand, other T and B cell populations were found to be expressed at much higher levels. This also relates to the diverse DARZALEX (trademark) (daratumumab) for immune cell subtypes. It may contribute to sensitivity (data not shown).

[0385] Consideration This trial involved DARZALEX (trademark) (daratumumab), which was previously unknown. ) of, CD38 + A decrease in the immunosuppressive cell population and a response to the associated viral peptides. Helper and cytotoxic T cell proliferation, induction of IFN-γ production, and improved adaptation This explains the immunomodulatory effect due to the clonal increase in TCRs that indicate an immune response.

[0386] This study showed that MDSC and Breg express CD38, and DARZALEX (trademark) These cells showed sensitivity to daratumumab treatment. It exists at the border and contributes to tumor growth, immune evasion, angiogenesis, metastasis, and the production of inhibitory cytokines. These CD38 are known to be involved. + In addition to the inhibitory cell subset, This novel subpopulation also expressed high levels of CD38 and exhibited excellent autologous T cell suppression ability. Regulatory T cells (CD4 + CD25 + CD127 dim ) were identified. These details The cells are also sensitive to DARZALEX (trademark) (daratumumab), and in patients who have received treatment... These CD38 + DARZALEX (trademark) immunoregulatory cells Mumab-mediated immunosuppression reduces local immunosuppression within the myeloma microenvironment and positive immunoeffects This can enable the proliferation of Kutar cells and their contribution to the antitumor response.

[0387] In reality, CD4 is found in both peripheral blood and bone marrow (i.e., tumors). + and CD8 + A significant increase in a broad T cell population, including both specific CD8, was observed. + The subgroup is D ARZALEX™ (daratumumab) therapy alters these cells, including naive T cells. A significant decrease in and the associated effector memory CD8 + Includes a significant increase in T cells These are rare, and they exhibit a phenotype that has experienced the antigen (retaining immunological memory and being able to react to tumor antigens). This shows the migration of effector T cells to CD8. + :CD4 + and CD8 + :Tre The ratio of g also increased significantly with treatment, indicating a shift from negative immunomodulatory factors to positive ones. It is.

[0388] Proliferated CD4 + and CD8 + Evaluate whether the T cells were effectively clonal. Therefore, the T cell repertoire was examined in a patient subset. T cell clonality was best. Even in patients whose condition is stable (SD) or whose disease has progressed, DARZALEX (trademark) (daratumumab) The number of T cells increased significantly with treatment. Therefore, the increase in T cell clonality was not simply due to a decrease in tumor volume. This cannot be the cause. However, T-cell clonal distortion is significant in patients with a good clinical response. CD8 +DARZALEX (trademark) was observed to correlate with an increase in T cells. This suggests that the T-cell proliferation induced by (daratumumab) treatment was due to the antigen. This is particularly evident in patient groups that have received a large amount of preliminary treatment (median treatment history, 5 sessions). Therefore, it cannot be expected that a strong anti-tumor immune response will be initiated. In addition to the increase in TCR clonality. Patients who responded to DARZALEX (trademark) (daratumumab) were found to be in pre-existing conditions. The increased T-cell response to Rus and alloantigens suggests that the immune system is in an immunosuppressed state. This suggested that he had recovered.

[0389] Treatment with DARZALEX (trademark) (daratumumab) is used for immunosuppressive MDSCs, and This led to a decrease in regulatory T and B cells. These decreases were linked to CD4 + T-Helper Thin Cells and CD8 + This was accompanied by proliferation of cytotoxic T cells. T cells were measured by IFN-γ production. Cellular clonal and functional antiviral responses are also supported by DARZALEX (trademark) (daratumumab). ) increased with treatment. These observations suggest that T cells, despite low CD38 expression, increased. This indicates that it continued to function correctly, and the increase in T cell response may be due to the depletion of regulatory cells. This suggests that... Furthermore, these changes in T cell proliferation, activity, and clonality are related to DA Patients who responded to RZALEX (daratumumab) compared to patients who did not respond. This was more pronounced in the case of relapse after DARZALEX (daratumumab) therapy. This was associated with the recovery of many of these changes. This is related to the clinical response and its effectiveness. Further development of DARZALEX (daratumumab) through immunomodulation, which may contribute to this This suggests a mechanism of action whose characteristics have not been previously understood.

[0390] Recently, the effectiveness of antibodies that promote anti-tumor immune responses has been varied, rather than directly targeting cancer. This has been revealed in various fields. Antibodies that inhibit CTLA-4 and PD-1 promote T cell proliferation. By promoting and enhancing T cell activation, it is effective in treating advanced solid tumors and Hodgkin lymphoma. In patients with any hematological malignancy, it leads to extended survival and delayed disease recurrence. By enhancing immunity, these immunomodulatory antibodies can induce clinical responses. Moreover, it can also prevent disease recurrence.

[0391] Example 10.54767414MMY2002 (SIRIUS) Part 2 Clinical Trial And, received monotherapy with DARZALEX (trademark) (daratumumab). Serum proteomics analysis of multiple myeloma Biomarker sample collection and processing Collect a peripheral blood sample in a standard serum separation tube (2.5 mL to 5 mL), and then extract a portion of the serum. SomaLog, frozen for multiplex analytes serum protein profiling. I sent it to ic, Inc (Boulder, CO).

[0392] Serum protein profiling utilizes affinity-based molecules called SOMAmers. The SOMAscan assembly, which measures 1129 types of protein analytes, has been pre-validated. The procedure was performed using SomaLogic with method (I). The SOMAmer reagent is a single-stranded DNA system. This is a protein affinity reagent. This assay uses a small injection sample (150 μL of plasma). Using this method, protein signals are quantified by a custom DNA microarray. Convert to SOMAmer signal.

[0393] Each SOMAmer contains the following four functional components: 1. Unique protein recognition sequence 2. Biotin for capture 3. Light-cutting linker 4. Fluorescent molecules for detection

[0394] The unique protein recognition sequence uses DNA and chemically modified DNA that mimics amino acid side chains. By incorporating creotides, the diversity of standard aptamers is expanded, and protein-nucleic acid interactions are improved. It enhances the specificity and affinity of its action (Gold et al., PLoS One 5 (e15004,2010). The aptamer is selected by SELEX. SOMA Mer reagents are selected using proteins in their natural higher-order structure state. Thus, SO MAmer reagents require undenatured protein tertiary structures for binding. Proteins that are denatured or possibly inactive are not detected by the SOMAmer reagent. stomach.

[0395] The master mixture of SOMAmer reagents is grouped by sample type and dilution. Prior to the incubation of the sample, the reagent is prepared in streptavidin beads. They bind together. During equilibration, the proteins in the sample are bound to the same type of SOMAmer. Wash, incubate with NHS-biotin, wash again, and then expose the beads to UV light. The linker, which can be cut by light, is then cleaved. The eluate contains biotin-labeled proteins. Contains SOMAmer reagent. Streptoavidin capture and subsequent washing remove unbound cells. Remove the SOMAmer reagent. In the final eluate, alloproteins are denatured under denaturation conditions. SOMAmer molecules are released from this. The final eluate is processed using a custom Agilent DN A microarray and fluorophores (relative fluorescence units (RFU)) derived from SOMAmer molecules Hybridize the sample (quantified using ). RFU is proportional to the amount of protein in the sample. .

[0396] Samples for the MMY2002 trial were tested in two main batches. Batch 1 The 180 samples included the corresponding first day of the first cycle (C1D1, reference value) and C This included serum samples from 90 subjects on 3D1 (3rd cycle, day 1). The samples were analyzed together on three separate SomaScan plates. The second batch The sample includes 50 C1D1 samples, including 35 duplicate samples from Batch 1. Born.

[0397] Data Analysis Input dataset and definition Treated subjects with an evaluable response were included in the data analysis. Consistency throughout this report. The responder then determined that the overall best effect (according to IRC for MMY2002) was sCR, VGP. Subjects with R, PR, stable (SD), minimal response (MR), or SD were defined as follows: It is understood that non-responders are progressing with the best overall effect (according to IRC of MMY2002) (P It is defined as an object that is D).

[0398] Somalogicdata preprocessing Batch sorting Batch 1 and 2 of the MMY2002 sample were scanned using two different versions of SOMAscan. I checked on the platform. The differences between the two versions are slight, and between versions It contained three modified SOMAmer sequences (CTSE:3594-6_1 →3594-6_5, FCN1:3613-62_1→3613-62_5, BMPER (3654-27_1→3654-27_4). These were excluded from the analysis.

[0399] Measurement of three Batch 1 plates follows SomaLogic's standard inter-plate calibration. Following the procedure, the measurement of the master mixture-specific comprehensive reference value using seven in-plate control standards was performed. By calculating the ratio of the value to the median, the total plate calibration multiplier for each SOMAmer is calculated. The plates were aligned by determining the ratio. The plate-specific magnification of each SOMAmer reagent was determined by the plate. The same method was applied to each sample on the sheet.

[0400] Considering the different SOMAscan platform versions of batches 1 and 2, By utilizing repeated measurements of 35 samples between intervals, SomaLogic A modified version of the standard inter-plate calibration procedure was performed to systematically correct for inter-batch variability. For each SOMAmer, the ratio of the measured value after calibration in batch 1 to the measured value before calibration in batch 2. This was calculated for each of the 35 repeated samples (ri,j). The ratio of these 35 was The median value was used to determine the modified SOMAmer-specific calibration factor for the batch 2 samples. Ta

[0401]

number

[0402]

number

[0403] After calculating the modified calibration magnification, the distribution of all magnifications for each analysis batch was plotted, and the outliers were identified. The presence or absence of a value was evaluated. 9 samples were found with extremely large or small standard substances (>0.25 and <3). One SOMAmer was excluded from the analysis due to poor reproducibility.

[0404] After batch sorting and SOMAmer selection are completed for MMY2002, MMY200 Applying log2 transformation to all protein concentration values ​​in step 2 makes the data more closely match a normal distribution. This improved the implementation of parametric statistical tests.

[0405] Confounding variable correction This can be explained by metavariables (such as demographic factors, response classes, and sampling time points). Predicting the variable portion of the dataset and identifying possible confounding factors involves centering and This was performed using principal component analysis on a scaled dataset. A simple linear model was used. Then, we identified the highest-ranking PC that was significantly associated with each of the target variables. The significance of these associations is determined using Wald's test and explained by this model. The rate of PC variability was estimated using the R² value of the fitted model. In the MMY2002 data, the facility It was found that the ID correlated with PC1, explaining the largest portion of the dataset's variability (≧7). 0.37%, p-value = 3.71 × 10⁻⁹). Within the data, the sampled facility-related effects... To mitigate the impact, ComBat28 was used to correct the facility ID effect.

[0406] Integration of repeated samples Data from 35 samples repeated between batches 1 and 2 of MMY2002, each tan The data was integrated by calculating the average protein content.

[0407] Protein concentration difference analysis Responder vs. Non-responder DARZALEX (trademark) (daratumumab) responder vs. non-responder Statistical comparison of protein concentration distributions can be performed using the following two supplementary methods: (i) individual SOMA Wilcoxon rank-sum test for mer (Hollander and Wolfe ,Ninparametirc Statistical Methods.New Y ork:John Wiley & Sons.1973.27~33(one-sam (i) 68-75 (two-sample), and (ii) all SOMAmer Limma analysis for (Ritchie, ME, et al., Nucleic Using Acids Res. 2015;20:43(7):e47) simultaneously, reference values The tests were performed both before and during treatment. All p-values ​​are based on Benjamin's assessment of multiple hypothesis adjustments. Corrected using the mini-Hochberg (BH) method (Benjamini and Hochberg, (1995) JRStatist.Soc.B.57:289 ~300;R:A Language and Environment for St aistical Computing,R Development Core T eam,R Foundation for Statistical Computing ng,Vienna,Austria.2011;ISBN 3-900051-07- 0). The null hypothesis that there is no differential expression was rejected when the corrected p-value was <0.05.

[0408] During treatment vs. normal values The normal range versus the protein concentration during treatment can be measured using three different statistical methods: (i) two-way reconciliation. Re-measures ANOVA6, (ii) Wilcoxon signed-rank test, and (iii) Friedma Biostatistics 8 Comparison was made using (1):118~127). All p-values ​​are B for multiple hypothesis adjustments. The FDR was corrected to the control using the H method (Benjamini and Hochber). g, JR Statist. Soc. B. 57:289~300, 1995). Treatment In addition to significance, two-way repeated measures ANOVA (Chambers et al., Anal ysis of variance;designed experiments:Ch apter 5.Statistical Models in S,Editors JM Chambers and TJ Hastie.Wadsworth & Brookes / Cole (1992) states that significant time points: the interrelationship between response classes is such that each SO It was also applied to determine whether or not MAmer occurred. Responder and non To specifically determine whether responders showed different therapeutic effects, all subjects The difference between protein concentration values ​​during treatment and the reference range was calculated, and the Wilcoxon rank-sum test was performed. A modified Wilcoxon rank-sum test was applied as a post-hoc test. Significance: The values ​​were corrected using the BH method, and the null hypothesis was rejected when the corrected p-value was <0.05.

[0409] classifier training We created a classifier to predict responses using reference protein concentration data from MMY2002. I raised it. There are four types of machine learning machines: Support Vector Machines (SVM), Random Forecaster. Nested loop layering using STR (RF), Naive Bayes (NB), and j48 decision trees. The 10-fold cross-validation method was repeated 30 times. In each learning model, the training procedure was balanced to 10. We started by creating well-partitioned datasets (outer loop). One group is kept as the test cohort, while the remaining nine are used as the training cohort in the inner loop. The training was then performed. Within the inner loop, the training cohort was again divided into 10 balanced segments, and the inner training and An internal test set was created. The learner was trained on each of these internal training sets. This process was repeated 30 times for each cohort in the outer loop. Using the accuracy of each inner loop learner in the prediction of the net, features are selected and model parameters are adjusted. The process was optimized. After 30 inner loops were completed for each training cohort, each corresponding For the test cohort, the performance of the outer loop (using optimization parameters and features) was evaluated. It was worthwhile. Next, the entire outer looping was repeated 30 times to examine all samples in the dataset. This generated 30 different response predictions. The AUC obtained using this looping method The statistics for sensitivity and specificity are obtained from the final model trained on the complete original dataset. However, it approximated how well it would perform for new trial cases.

[0410] Results from the MMY2002 trial Various comparisons were conducted, including treatment-induced response-dependent changes in protein expression. One of the proteins that showed a decrease in expression over time in this study was PD-L1, while PD -L1 protein expression increased over time in non-responders. Binding to T cells leads to decreased T cell function and increased Treg development. Figure 18 This applies to responders, non-responders, and stable patients, in the first cycle and The protein expression profile of PD-L1 in the third cycle is shown.

[0411] The binding of PD-L1 to its receptor PD-1 suppresses the antitumor response, leading to T cell anergy and depletion. While not bound by any particular theory, downregulation of PD-L1 by CD38 therapy may also result in an improved enhancement of the antitumor immune response in solid tumors. The present invention may encompass the following embodiments. [1] A method for treating a patient having a solid tumor, comprising administering to the patient, for a period sufficient to treat the solid tumor, an antibody that specifically binds to CD38 in a therapeutically effective amount. [2] The method according to [1], wherein the antibody that specifically binds to the CD38 induces an immune response in the patient. [3] The method according to [2] above, wherein the immune response is an effector T cell (Teff) response. [4] The method according to [3] above, wherein the Teff response is mediated by CD4+ T cells or CD8+ T cells. [5] The method according to [4] above, wherein the Teff response is mediated by the CD8+ T cells. [6] The method according to [3] above, wherein the Teff response is an increase in the number of CD8+ T cells, an increase in CD8+ T cell proliferation, an increase in T cell clonal proliferation, an increase in CD8+ memory cell formation, an increase in antigen-dependent antibody production, an increase in cytokine production, an increase in chemokine production, or an increase in interleukin production (by cell). [7] The method according to [1] above, wherein the antibody that specifically binds to the aforementioned CD38 inhibits the function of immune suppressor cells. [8] The method according to [7] above, wherein the immune suppressor cells are regulatory T cells (Treg). [9] The method according to [8] above, wherein the Treg is a CD3+CD4+CD25+CD127dim T cell.

[10] The method according to [9] above, wherein the Treg expresses CD38.

[11] The method according to

[10] above, wherein the function of the Treg is inhibited by killing the Treg.

[12] The method according to

[11] above, wherein the killing of the Treg is mediated by antibody-dependent cell-mediated cytotoxicity (ADCC).

[13] The method according to [7] above, wherein the immune suppressor cells are myeloid-derived suppressor cells (MDSCs).

[14] The method according to

[13] , wherein the MDSC is a CD11b+HLADR-CD14-CD33+CD15+ cell.

[15] The method according to

[14] , wherein the CD11b+HLADR-CD14-CD33+CD15+ cells express CD38.

[16] The method according to

[15] above, wherein the function of the MDSC is inhibited by killing the MDSC.

[17] The method described above

[16] , wherein the killing of MDSCs is mediated by ADCCs.

[18] The method according to [7] above, wherein the immune suppressor cells are regulatory B cells (Bregs).

[19] The method according to

[18] above, wherein the Breg is a CD19+CD24+CD38+ cell.

[20] The method according to

[19] above, wherein the function of the Breg is inhibited by killing the Breg. [twenty one] The method according to

[20] above, wherein killing the Breg is mediated by ADCC. [twenty two] The method according to [7] above, wherein the immune suppressor cells are present in the bone marrow or peripheral blood. [twenty three] The method according to any one of the above [1] to

[22] , wherein the solid tumor is melanoma, lung cancer, squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC, colorectal cancer, prostate cancer, castration-resistant prostate cancer, stomach cancer, ovarian cancer, gastric cancer, liver cancer, pancreatic cancer, thyroid cancer, squamous cell carcinoma of the head and neck, carcinoma of the esophagus or gastrointestinal tract, breast cancer, fallopian tube cancer, brain cancer, urethral cancer, genitourinary cancer, endometriosis, cervical cancer, or a metastatic lesion of the said cancer. [twenty four] The method according to any one of the above [1] to

[23] , wherein the solid tumor lacks detectable CD38 expression. [twenty five] The method according to any one of the above [1] to

[24] , wherein the antibody that specifically binds to the aforementioned CD38 is a non-agonist antibody.

[26] The method according to

[25] , wherein the non-agonist antibody induces proliferation of a peripheral blood mononuclear cell sample in vitro in a manner that is not statistically significant.

[27] The method according to any one of the above [1] to

[26] , wherein the antibody that specifically binds to CD38 competes with the antibody comprising the heavy chain variable region (VH) of SEQ ID NO: 4 and the light chain variable region (VL) of SEQ ID NO: 5 for binding to CD38.

[28] The method according to

[27] , wherein the antibody that specifically binds to the aforementioned CD38 binds to at least the region SKRNIQFSCKNIYR (SEQ ID NO: 2) and the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1).

[29] The method according to any one of the above [1] to

[28] , wherein the antibody that specifically binds to the CD38 contains the amino acid sequences of heavy chain complementarity determining region (HCDR) 1, HCDR2, HCDR3, light chain complementarity determining region (LCDR) 1, LCDR2, and LCDR3 of SEQ ID NOs. 6, 7, 8, 9, 10, and 11, respectively.

[30] The method according to any one of the above [1] to

[29] , wherein the antibody that specifically binds to the aforementioned CD38 includes VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[31] The antibody that specifically binds to the aforementioned CD38, a) VH of sequence number 14 and VL of sequence number 15, b) VH of sequence number 16 and VL of sequence number 17, c) VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or d) The method according to any one of the above [1] to

[26] , comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

[32] The antibody that specifically binds to the aforementioned CD38, a) VH of sequence number 14 and VL of sequence number 15, b) VH of sequence number 16 and VL of sequence number 17, c) VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or d) The method according to

[31] above, comprising VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

[33] The method according to any one of the above [1] to

[32] , wherein the antibody that specifically binds to the aforementioned CD38 is administered in combination with a second therapeutic agent.

[34] The method according to

[33] above, wherein the second therapeutic agent is a chemotherapy agent, a cancer-targeted therapy, a standard therapeutic agent for the treatment of solid tumors, or an immune checkpoint inhibitor.

[35] The method according to

[34] above, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an anti-LAG3 antibody, an anti-TIM3 antibody, or an anti-CTLA-4 antibody.

[36] The method according to

[35] above, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

[37] The aforementioned anti-PD-1 antibody, a) VH of sequence number 22 and VL of sequence number 23, b) VH of sequence number 24 and VL of sequence number 25, c) VH of SEQ ID NO: 32 and VL of SEQ ID NO: 33, or d) The method described in

[36] above, comprising VH of SEQ ID NO: 34 and VL of SEQ ID NO: 35.

[38] The method according to

[35] above, wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody.

[39] The aforementioned anti-PD-L1 antibody, a) VH of sequence number 26 and VL of sequence number 27, b) VH of SEQ ID NO: 28 and VL of SEQ ID NO: 29, or c) The method described in

[38] above, comprising VH of SEQ ID NO: 30 and VL of SEQ ID NO: 31.

[40] The method according to

[35] above, wherein the immune checkpoint inhibitor is an anti-PD-L2 antibody.

[41] The method according to

[35] above, wherein the immune checkpoint inhibitor is an anti-LAG3 antibody.

[42] The method according to

[35] above, wherein the immune checkpoint inhibitor is an anti-TIM-3 antibody.

[43] The aforementioned anti-TIM-3 antibody a) VH of SEQ ID NO: 36 and VL of SEQ ID NO: 37, or b) The method described in

[42] above, comprising VH of SEQ ID NO: 38 and VL of SEQ ID NO: 39.

[44] The method according to any of the above

[33] to

[43] , wherein the second therapeutic agent is administered simultaneously, sequentially, or separately.

[45] The method according to any one of the above [1] to

[44] , wherein an antibody that specifically binds to the aforementioned CD38 is administered intravenously.

[46] The method according to any one of the above [1] to

[44] , wherein the antibody that specifically binds to CD38 is administered subcutaneously in a pharmaceutical composition comprising the antibody that specifically binds to CD38 and hyaluronidase.

[47] The method according to

[46] , wherein the hyaluronidase is rHuPH20 of Sequence ID No. 40.

[48] The method according to any of the above [1] to

[47] , wherein the patient is being treated with or has already been treated with radiotherapy.

[49] The method described in any of the above [1] to

[47] , which the patient has undergone or will undergo thereafter.

[50] A method for suppressing the activity of immunosuppressor cells, comprising contacting the immunosuppressor cells with an antibody that specifically binds to CD38.

[51] The method according to

[50] above, wherein the immunosuppressor cell is Treg.

[52] The method according to

[51] above, wherein the Treg is a CD3+CD4+CD25+CD127dim T cell.

[53] The method according to

[50] above, wherein the immune suppressor cells are MDSCs.

[54] The method according to

[53] , wherein the MDSC is a CD11b+HLADR-CD14-CD33+CD15+ cell.

[55] The method according to

[50] above, wherein the immunosuppressor cell is Breg.

[56] The method according to

[55] above, wherein the Breg is a CD19+CD24+CD38+ cell.

[57] The method according to any one of the above

[50] to

[56] , wherein the antibody that specifically binds to the CD38 is a non-agonist antibody.

[58] The method according to

[57] , wherein the non-agonist antibody induces proliferation of a peripheral blood mononuclear cell sample in vitro in a manner that is not statistically significant.

[59] The method according to any one of the above

[50] to

[58] , wherein the antibody that specifically binds to CD38 competes with the antibody comprising SEQ ID NO: VH of SEQ ID NO: 4 and SEQ ID NO: VL for binding to CD38.

[60] The method according to

[59] , wherein the antibody that specifically binds to the CD38 binds to at least the region SKRNIQFSCKNIYR (SEQ ID NO: 2) and the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1).

[61] The method according to any one of the above

[50] to

[60] , wherein the antibody that specifically binds to the CD38 contains the amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs. 6, 7, 8, 9, 10, and 11, respectively.

[62] The method according to

[61] , wherein the antibody that specifically binds to the CD38 includes VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[63] The antibody that specifically binds to the aforementioned CD38, a) VH of sequence number 14 and VL of sequence number 15, b) VH of sequence number 16 and VL of sequence number 17, c) VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or d) The method according to any one of the above

[50] to

[58] , comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

[64] The antibody that specifically binds to the aforementioned CD38, a) VH of sequence number 14 and VL of sequence number 15, b) VH of sequence number 16 and VL of sequence number 17, c) VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or d) The method described in

[63] above, comprising VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

[65] A method for enhancing the immune response in a patient, comprising administering to the patient an antibody that specifically binds to CD38.

[66] The method according to

[65] above, wherein the patient has cancer or a viral infection.

[67] The method according to

[65] or

[66] , wherein the antibody that specifically binds to CD38 is a non-agonist antibody.

[68] The method according to

[67] , wherein the non-agonist antibody induces proliferation of a peripheral blood mononuclear cell sample in vitro in a manner that is not statistically significant.

[69] The method according to any one of the above

[65] to

[68] , wherein the antibody that specifically binds to CD38 competes with the antibody comprising SEQ ID NO: VH of SEQ ID NO: SEQ ID NO: VL for binding to CD38.

[70] The method according to any one of the above

[65] to

[69] , wherein the antibody that specifically binds to the CD38 binds to at least the region SKRNIQFSCIYR (SEQ ID NO: 2) and the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1).

[71] The method according to any one of the above

[65] to

[70] , wherein the antibody that specifically binds to the CD38 contains the amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs. 6, 7, 8, 9, 10, and 11, respectively.

[72] The method according to any one of the above

[65] to

[70] , wherein the antibody that specifically binds to the aforementioned CD38 includes VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[73] The antibody that specifically binds to the aforementioned CD38, a) VH of sequence number 14 and VL of sequence number 15, b) VH of sequence number 16 and VL of sequence number 17, c) VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or d) The method according to any one of the above

[65] to

[68] , comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

[74] The antibody that specifically binds to the aforementioned CD38, a) VH of sequence number 14 and VL of sequence number 15, b) VH of sequence number 16 and VL of sequence number 17, c) VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or d) The method described in

[73] above, comprising VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

[75] A method for treating a patient having a viral infection, comprising administering to the patient an antibody that specifically binds to CD38 for a period sufficient to treat the viral infection.

[76] The method according to

[75] , wherein the antibody that specifically binds to CD38 is a non-agonist antibody.

[77] The method according to

[75] or

[76] above, wherein the non-agonist antibody induces proliferation of a peripheral blood mononuclear cell sample in vitro in a manner that is not statistically significant.

[78] The method according to any one of the above

[75] to

[77] , wherein the antibody that specifically binds to CD38 competes with the antibody comprising SEQ ID NO: VH of SEQ ID NO: 4 and SEQ ID NO: VL for binding to CD38.

[79] The method according to any one of the above

[75] to

[78] , wherein the antibody that specifically binds to the CD38 binds to at least the region SKRNIQFSCIYR (SEQ ID NO: 2) and the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1).

[80] The method according to any one of the above

[75] to

[79] , wherein the antibody that specifically binds to the CD38 contains the amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs. 6, 7, 8, 9, 10, and 11, respectively.

[81] The method according to any one of the above

[75] to

[80] , wherein the antibody that specifically binds to the CD38 includes VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[82] The antibody that specifically binds to the aforementioned CD38, a) VH of sequence number 14 and VL of sequence number 15, b) VH of sequence number 16 and VL of sequence number 17, c) VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or d) The method according to any one of the above

[75] to

[77] , comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

[83] The antibody that specifically binds to the aforementioned CD38, a) VH of sequence number 14 and VL of sequence number 15, b) VH of sequence number 16 and VL of sequence number 17, c) VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or d) The method described in

[82] above, comprising VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

Claims

1. A pharmaceutical composition for use in suppressing the activity of immune suppressor cells in patients with cancer, The pharmaceutical composition comprises an antibody that specifically binds to CD38. The aforementioned antibody is of the IgG1 isotype. The aforementioned antibody is a) The heavy chain variable region (VH) amino acid sequence of Sequence ID No. 4, and b) Light chain variable region (VL) amino acid sequence of SEQ ID NO: 5 A pharmaceutical composition containing the above.

2. The pharmaceutical composition according to claim 1, wherein the cancer is multiple myeloma.

3. The pharmaceutical composition according to claim 1 or 2, wherein the immune suppressor cells include regulatory T cells (Treg).

4. a) The Treg is CD3 ＋ CD4 ＋ CD25 ＋ CD127 ｄｉｍ Including T cells, b) The Treg expresses CD38, c) The function of the Treg is inhibited by killing the Treg, The pharmaceutical composition according to claim 3, or any combination thereof.

5. The pharmaceutical composition according to claim 4, wherein the function of the Treg is inhibited by killing the Treg, and the killing of the Treg is mediated by antibody-dependent cell-mediated cytotoxicity (ADCC).

6. The pharmaceutical composition according to claim 1 or 2, wherein the immune suppressor cells include bone marrow-derived suppressor cells (MDSCs).

7. a) the MDSC includes CD11b ＋ HLADR － CD14 － CD33 ＋ CD15 ＋ cells b) The MDSC expresses CD38, c) The function of the MDSC is inhibited by killing the MDSC, The pharmaceutical composition according to claim 6, or any combination thereof.

8. The pharmaceutical composition according to claim 7, wherein the function of the MDSC is inhibited by killing the MDSC, and the killing of the MDSC is mediated by ADCC.

9. The pharmaceutical composition according to claim 1 or 2, wherein the immune suppressor cells include regulatory B cells (Breg).

10. a) The Breg is CD19 ＋ CD24 ＋ CD38 ＋ Including cells, b) The function of the Breg is inhibited by killing the Breg, The pharmaceutical composition according to claim 9, which is either a) and b).

11. The pharmaceutical composition according to claim 10, wherein the function of the Breg is inhibited by killing the Breg, and the killing of the Breg is mediated by ADCC.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the immune suppressor cells are present in the bone marrow or peripheral blood.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the pharmaceutical composition is formulated for intravenous administration.

14. The pharmaceutical composition according to any one of claims 1 to 12, wherein the pharmaceutical composition further comprises hyaluronidase and is formulated for subcutaneous administration.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the patient is treated with an immune checkpoint inhibitor.

16. The pharmaceutical composition according to claim 15, wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an anti-LAG3 antibody, an anti-TIM3 antibody, or an anti-CTLA-4 antibody.

17. The pharmaceutical composition according to claim 16, wherein the immune checkpoint inhibitor comprises an anti-PD-1 antibody.

18. The aforementioned anti-PD-1 antibody, a) VH of sequence number 22 and VL of sequence number 23, b) VH of sequence number 24 and VL of sequence number 25, c) VH of SEQ ID NO: 32 and VL of SEQ ID NO: 33, or d) The pharmaceutical composition according to claim 17, comprising VH of SEQ ID NO: 34 and VL of SEQ ID NO:

35.

19. The pharmaceutical composition according to claim 16, wherein the immune checkpoint inhibitor comprises an anti-PD-L1 antibody.

20. The aforementioned anti-PD-L1 antibody, a) VH of sequence number 26 and VL of sequence number 27, b) VH of SEQ ID NO: 28 and VL of SEQ ID NO: 29, or c) The pharmaceutical composition according to claim 19, comprising VH of SEQ ID NO: 30 and VL of SEQ ID NO:

31.

21. The pharmaceutical composition according to claim 16, wherein the immune checkpoint inhibitor comprises an anti-PD-L2 antibody.

22. The pharmaceutical composition according to claim 16, wherein the immune checkpoint inhibitor comprises an anti-LAG3 antibody.

23. The pharmaceutical composition according to claim 16, wherein the immune checkpoint inhibitor comprises an anti-TIM-3 antibody.

24. The aforementioned anti-TIM-3 antibody, a) VH of SEQ ID NO: 36 and VL of SEQ ID NO: 37, or The pharmaceutical composition according to claim 23, comprising VH of SEQ ID NO: 38 and VL of SEQ ID NO:

39.

25. The pharmaceutical composition according to any one of claims 1 to 24, wherein the antibody that specifically binds to the CD38 comprises the heavy chain of SEQ ID NO: 12 and the light chain of SEQ ID NO:

13.

26. The pharmaceutical composition according to any one of claims 1 to 24, wherein the antibody that specifically binds to CD38 is daratumumab.

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