Dosing regimen and combination therapies for multispecific antibodies targeting b-cell maturation antigen

Abstract

To provide a method for treating a subject suffering from multiple myeloma.SOLUTION: The present invention provides a method comprising administering a bispecific antibody having binding specificity for B cell maturation antigen (BCMA) and CD3.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] 1. Sequence Listing This application contains a Sequence Listing which has been submitted electronically in ASCII format, the entirety of which is as follows: This ASCII copy was created on May 14, 2020. It is created and named NOV-011USP4_SL.txt, and is 15,390 bytes in size. It is.

[0002] 2. Incorporation by Reference All publications, patents, patent applications, and other references cited in this application are the property of their respective owners. Each publication, patent, patent application or other document is incorporated by reference for all purposes. and incorporated by reference in its entirety for all purposes to the same extent as if individually indicated. Incorporated herein by reference. Between one or more of the references incorporated herein and the teachings of this disclosure In case of conflict, the teachings of the present specification are intended. [Background technology]

[0003] BCMA is a tumor necrosis family receptor (TNF) receptor expressed on cells of the B cell lineage. BCMA expression is associated with plasma cells, plasmablasts, and activated B cells and memory - in terminally differentiated B cells that assume a long-lived plasma cell fate, including a subpopulation of B cells BCMA mediates plasma cell survival to maintain long-term humoral immunity. BCMA expression has been linked to many cancers, autoimmune diseases, and infectious diseases. Cancers with increased expression of BCMA include several hematological cancers, such as multiple myeloma, These include lymphoma, Hodgkin's and non-Hodgkin's lymphoma, various leukemias, and glioblastoma. do.

[0004] BCMA antibody-drug conjugates, such as GSK2857916 (GlaxoSmi thkline) and a bispecific BCMA-binding molecule targeting BCMA and CD3, For example, PF06863135 (Pfizer), EM 901 (EngMab), JNJ -Various models including 64007957 (Janssen) and AMG 420 (Amgen) BCMA-binding molecules are in clinical development. Cho et al., 2018, Front Immunol.9:1821; International Publication No. 2016 / 0166629 Brochure Please refer to.

[0005] One of the major safety concerns for any antibody-based drug, including CD3 bispecific molecules, is its potential to induce life-threatening side effects such as cytokine release syndrome ("CRS"); Shimabukuro-Vornhagen et al., 2018, J. See Immunother Cancer. 6:56. Summary of the Invention

[0006] Therefore, it binds to BCMA and has an improved safety profile while retaining high efficacy. polypeptides, e.g., antibodies, that have a function (e.g., that reduce cytokine release) And there is an unmet medical need for multispecific binding molecules.

[0007] Additionally, BCM is being used to reduce the likelihood of unwanted side effects, including CRS. An unmet medical need for appropriate administration of antibodies and multispecific binding molecules that bind to A There is a need.

[0008] In particular, B-cell maturation antigen (BCMA) binding molecules (e.g., immunoglobulins described herein) Multispecific antibodies, which may be phospho-based multispecific binding molecules (MBMs), more specifically In addition, the ability to target BCMA-expressing cells and further engage T cells (e.g., CD4+). and methods of use, including BCMA binding molecules having 3 binding arms. Methods, formulations, combinations, and compositions are disclosed herein. The compositions are exemplified by a BCMA-binding molecule referred to herein as BSBM3. Thus, reference to a "BCMA binding molecule" also applies to BSBM3.

[0009] Methods for treating or preventing cancer (e.g., preventing or preventing recurrence of cancer) Prevents the onset of flu-like symptoms) and is administered at a dose of about 0.25 μg / kg to about 1200 μg / kg ( For example, a BCMA-binding molecule is administered to a subject at a dose of 1 μg / kg to about 1000 μg / kg. Disclosed herein are methods that include administering

[0010] The BCMA binding molecule may be administered in a variety of doses. For example, in one embodiment, BCMA The MA-binding molecule is administered to a subject at a dose of about 0.5 μg / kg to about 20 μg / kg. In embodiments, the BCMA binding molecule is administered at a dose of about 0.5 μg / kg to 10 μg / kg. In one embodiment, the BCMA binding molecule is administered to a subject at a dose of about 1 μg / kg to 10 μg / kg. In one embodiment, the BCMA binding molecule is administered to a subject at a dose of about 5 μg / kg. In one embodiment, the antibody is administered to a subject at a dose of 10 μg / kg to 10 μg / kg. The binding molecule is administered to the subject at a dose of about 1 μg / kg. The combined molecule is administered to the subject at a dose of about 3 μg / kg. The combined molecule is administered to the subject at a dose of about 6 μg / kg. The combined molecule is administered to a subject at a dose of about 10 μg / kg. The binding molecule is administered to the subject at a dose of about 10 μg / kg to 20 μg / kg. wherein the BCMA-binding molecule is administered to the subject at a dose of about 10 μg / kg to 15 μg / kg. In one embodiment, the BCMA binding molecule is administered to a subject at a dose of about 12 μg / kg. In one embodiment, the BCMA binding molecule is administered at a dose of about 20 μg / kg to about 40 μg / kg. In one embodiment, the BCMA binding molecule is administered to a subject at a dose of about 20 μg In one embodiment, the BCMA antibody is administered to a subject at a dose of about 30 μg / kg to about 30 μg / kg. The combined molecule is administered to a subject at a dose of about 24 μg / kg. The binding molecule is administered to the subject at a dose of about 30 μg / kg. The A-binding molecule is administered to a subject at a dose of about 40 μg / kg to about 80 μg / kg. In one embodiment, the BCMA binding molecule is administered to a subject at a dose of about 40 μg / kg to about 60 μg / kg. In one embodiment, the BCMA binding molecule is administered at a dose of about 48 μg / kg. In one embodiment, the BCMA binding molecule is administered to an elephant at a dose of about 80 μg / kg to about 12 In one embodiment, the BCMA binding molecule is administered to a subject at a dose of about 0 μg / kg. The subject is administered a dose of 80 μg / kg to about 100 μg / kg. The BCMA binding molecule is administered to the subject at a dose of about 96 μg / kg. In one embodiment, the BCMA binding molecule is administered to the subject at a dose of about 100 μg / kg. In this case, the BCMA binding molecule is administered to the subject at a dose of about 100 μg / kg to about 200 μg / kg. In one embodiment, the BCMA binding molecule is administered at a dose of about 150 μg / kg to about 200 μg / kg. In one embodiment, the BCMA binding molecule is administered to a subject at a dose of about 19 g / kg. In one embodiment, the BCMA binding molecule is administered to a subject at a dose of about 2 μg / kg. In one embodiment, the subject is administered a dose of 150 μg / kg to about 250 μg / kg. In one embodiment, the BCMA binding molecule is administered to the subject at a dose of about 200 μg / kg. In this case, the BCMA-binding molecule is administered to the subject at a dose of about 300 μg / kg to about 500 μg / kg. In one embodiment, the BCMA binding molecule is administered to the subject at a dose of about 384 μg / kg. In one embodiment, the BCMA binding molecule is administered at a dose of about 400 μg / kg. In one embodiment, the BCMA binding molecule is administered to a subject at a dose of about 500 μg / kg to about In one embodiment, the BCMA binding molecule is administered to a subject at a dose of 700 μg / kg. , is administered to the subject at a dose of about 600 μg / kg.

[0011] The BCMA binding molecule may be administered to a subject by any effective method. Thus, the BCMA binding molecule is administered intravenously to the subject.

[0012] Where the BCMA binding molecule may be administered intravenously to a subject, the BCMA binding molecule may be administered intravenously at a specific time point. For example, in one embodiment, the BCMA binding molecule is administered over a period of 2 hours. It may be administered over a period of time.

[0013] The BCMA binding molecule may also be administered to a subject one or more times over time. In embodiments, the BCMA binding molecule may be administered to a subject once a week for four weeks. .

[0014] The BCMA binding molecule may also be administered as a priming dose. The amount can be administered prior to the initiation of treatment with a therapeutic dose (e.g., a therapeutically effective therapeutic dose). The priming dose may be equal to or less than the subsequent therapeutic dose. In one embodiment, the BCMA binding molecule is administered at a dose that is less than the first therapeutic dose. The priming dose may be administered as a single dose or as two or more doses. In one embodiment, the priming dose may be divided into two consecutive doses. In one embodiment, the priming agent is divided into two doses given on successive days. One-third of the priming dose is administered to the subject on one day, and two-thirds of the priming dose is administered to the subject on the next day. It is administered to elephants.

[0015] The BCMA binding molecules may also be administered with side effect reducing agents (e.g., acetaminophen and / or difluprevir). In one embodiment, the side effect reducing agent may be administered with BCM. In one embodiment, the side effect reducing agent may be administered simultaneously with the BCMA-binding molecule. In one embodiment, the side effect reducing agent may be administered after the BCMA binding molecule. can be given to

[0016] Side effect reducing agents may, in some cases, reduce the onset or severity of cytokine release syndrome (CRS). In one embodiment, the side effect reducing agent is a glucocorticoid. In one embodiment, the glucocorticoid is methylprednisolone. In this method, methylprednisolone is given to the subject at a dose of at least 2 mg / kg. In one embodiment, the side effect reducer is paracetamol, acetaminophen, an antihistamine, The other treatments are anti-inflammatory drugs, ... In embodiments, the side effect reducing agent is tocilizumab, canakinumab, or any of these. It is a combination anti-T cell directed therapy.

[0017] Subjects who have been or will be administered a BCMA binding molecule may also be administered a second therapeutic agent. In certain embodiments, the subject may be administered one or more second therapeutic agents. In one embodiment, the BCMA binding molecule and the second therapeutic agent are administered simultaneously, separately, or in combination. It is administered over a period of time.

[0018] In one embodiment, the second therapeutic agent is a gamma secretase inhibitor (GSI). In an embodiment, the GSI is LY-450139, PF-5212362, BMS-70 8163, MK-0752, ELN-318463, BMS-299897, LY-41 1575, DAPT, AL-101(BMS-906024), AL-102(BMS- 986115), PF-3084014, RO4929097, or LY3039478 In one embodiment, the GSI is administered orally. is administered prior to administration of the BCMA binding molecule.

[0019] In one embodiment, the second therapeutic agent is an immunomodulatory agent. In one embodiment, the second therapeutic agent is an immune checkpoint inhibitor. In one embodiment, the TIM-3 inhibitor is MBG453. In one embodiment, the second therapeutic agent is a LAG-3 inhibitor. wherein the LAG-3 inhibitor is LAG525. In one embodiment, the second therapeutic agent is , a PD-1 inhibitor. In one embodiment, the PD-1 inhibitor is PDR001, nibo lumab, pembrolizumab, pidilizumab, MEDI0680, REGN2810, T SR-042, PF-06801591, BGB-A317, BGB-108, INCS In one embodiment, the PD-1 inhibitor is P In one embodiment, the PD-1 inhibitor is administered at a dose of about 100 mg once every four weeks. or about 200 mg once every 4 weeks, or about 300 mg once every 4 weeks, or about 400 mg once every four weeks or about 500 mg once every four weeks. In this study, the PD-1 inhibitor is administered at a dose of approximately 400 mg once every four weeks.

[0020] The second therapeutic agent can be administered by any effective method. For example, the second therapeutic agent can be administered orally. In another embodiment, the second therapeutic agent may be administered intravenously.

[0021] The BCMA binding molecule and / or one or more second therapeutic agents may prevent or treat cancer. In an embodiment, the cancer is a hematological cancer. In one embodiment, the hematological cancer is multiple myeloma. is.

[0022] In certain embodiments, the subject has previously been treated for cancer. In one embodiment, the subject has relapsed and / or refractory multiple myeloma. Previously treated with at least two previous treatment regimens. In one embodiment, the previous treatment regimen did not include a multispecific antibody. immunomodulatory drug (IMiD), proteasome inhibitor, anti-CD38 inhibitor, or any of these In one embodiment, the prior treatment regimen included lenalidomide, pomalidomide, or a combination thereof. In one embodiment, the prior treatment included an IMiD that was a combination of lidomide, lidomide, or both. The plan is to use proteasome inhibitors, bortezomib, carfilzomib, or both. In one embodiment, the previous treatment regimen included an anti-CD38 antibody, anti-CD38 In one embodiment, the anti-CD38 antibody was daratumab. In embodiments, the previous treatment regimen may include autologous bone marrow transplant, BCMA CAR-T, BCMA antibody-drug conjugate, or any combination thereof.

[0023] Subjects treated with BCMA binding molecules have (a) serum M protein of 1.0 g / dL or greater (b) urinary M protein of 200 mg / 24 hours or more; (c) associated FLC of 100 mg / or (d) any combination thereof. .

[0024] In one embodiment, a subject treated with a BCMA binding molecule may provide a clinical benefit. are ineligible for treatment with other anti-cancer regimens known to cause

[0025] The subject to be treated with the BCMA binding molecule is a subject who has (a) severe hypersensitivity to the BCMA binding molecule. (b) no history of reaction; (b) no history of toxicity to previous BCMA-targeted agents (c) not having any other malignant disease other than the cancer being treated and / or prevented; (d (e) no active, known or suspected autoimmune disease; Concomitant medications that cannot be discontinued for at least 1 week before starting treatment with A-binding molecules (f) not currently receiving treatment for human immunodeficiency virus (HIV), active hepatitis B virus (g) Not infected with hepatitis B virus (HBV) or hepatitis C virus (HCV); No cardiac dysfunction or clinically significant cardiac disease, including any of the following: (i) no need for treatment Congestive heart failure (NYHA grade ≥ 2), uncontrolled hypertension or clinically significant clinically significant and / or uncontrolled cardiac disease, such as arrhythmia; (ii) QTcF>47 0 msec screening ECG or congenital long QT syndrome; or (iii) BCM Acute myocardial infarction or unstable angina within 3 months prior to initiation of treatment with an A-binding molecule; (h) lysis With the exception of localized radiation therapy for chronic bone lesions or plasmacytomas, the first administration of a BCMA-binding molecule (i) before the first dose of the BCMA-binding molecule; (j) no major surgery within 2 weeks; (j) chronic systemic steroid therapy (≥ 10 mg / kg / day) prednisone or equivalent) or any combination thereof within 7 days of the first administration of the BCMA binding molecule (k) not receiving any immunosuppressive therapy; (k) receiving any systemic treatment with immunosuppressants (l) Grade ≥2 neuropathy or Grade ≤1 or greater than baseline (m) No residual toxic effects from previous treatment that have not been resolved; (m) No other disease than multiple myeloma No plasma cell leukemia or other plasmacytoid disorders; (n) Have none of the following laboratory test results: (i) Have had a proliferative disorder within 7 days prior to the start of treatment (ii) absolute neutrophil count (ANC) <1,000 / mm3 without supportive medication; (iii) platelet count <75,000 mm3 without transfusion support within 7 days; (iv) upper limit of normal range ( (iv) bilirubin greater than 1.5 times the ULN; (iv) aspartate aminotransferase greater than 3 times the ULN transferase (AST) or alanine aminotransferase (ALT); or ( v) Creatinine clearance calculated according to the Cockcroft-Gault formula of less than 30 ml / min (o) activity requiring systemic treatment within 2 weeks prior to the first dose of a BCMA-binding molecule No sexually transmitted diseases or other severe infections; (p) POEMS syndrome (polyneuropathy) -, organomegaly, endocrine disorders, monoclonal proteins, plasma cell dysplasia with skin changes (q) no prior allogeneic SCT at any time (r) an infectious disease (e.g., influenza, (s) BCMA-binding proteins; If cytotoxicity or minor adverse events occur within 14 days or 5 half-lives before the first dose of the child, whichever is shorter, Not treated with targeted anti-tumor drugs or any experimental therapy; (t) initiation of treatment Hematopoietic colony-stimulating growth factors (e.g., G-CSF, M-CSF), thrombin time (T2) and thrombin time (T3) were administered within the previous 2 weeks. (u) had not started an erythropoietin mimetic or erythropoiesis-stimulating agent; (u) had not started an erythropoietin mimetic or erythropoiesis-stimulating agent within the last 28 days immediately prior to treatment; (v) had not received intravenous IG infusion for infection prophylaxis within days prior to the start of treatment; Symptomatic CNS metastases or local CNS-directed therapy (radiation therapy or surgery) within 2 weeks Active central nervous system (CNS) involvement due to the grade or presence of CNS metastases requiring or increased doses of corticosteroids; (w) any potential risk factors for treatment (x) not have a serious medical or psychiatric illness that is highly likely to cause death; (x) are pregnant or breastfeeding (nu (y) BCMA-binding molecule at least one BCMA-binding molecule-associated cytotoxicity syndrome (PCS) during treatment with BCMA-binding molecule and for 6 months after the last dose of BCMA-binding molecule risk of pregnancy unless effective methods of birth control (e.g., two), including highly effective methods, are used rather than potential women (defined as women who are physiologically capable of becoming pregnant). Highly effective methods of contraception include, but are not limited to, i) total abstinence; ii) ) female sterilization, iii) male sterilization, and (iv) oral, injectable, or implantable Use of hormonal contraception alone or an intrauterine device (IUD) or intrauterine system (IUS) ) or other forms of hormonal contraception with equivalent effectiveness (failure rate <1%), e.g. hormonal vaginal ring or transdermal hormonal contraception; other effective methods of contraception include euthanasia. Co-administered with a sperm foaming agent (e.g., foam, gel, film, cream, or vaginal suppository) Contraceptive methods such as condoms or occlusive caps (diaphragms or cervical / fornix caps) or (z) any combination thereof.

[0026] In one embodiment, administration of the BCMA binding molecule is ineffective if the subject develops toxicity and is not treated with IMWG. Treatment should continue until there is clinical evidence of disease progression and / or at the discretion of the treating physician. It is interrupted.

[0027] Further disclosed herein are combination therapies comprising a BCMA binding molecule and a second therapeutic agent. In certain embodiments, the combination therapy may include two or more second therapeutic agents.

[0028] In some embodiments, the second therapeutic agent is a gamma secretase inhibitor (GSI). In terms of form, GSI is LY-450139, PF-5212362, BMS-708 163, MK-0752, ELN-318463, BMS-299897, LY-411 575, DAPT, AL-101 (BMS-906024), AL-102 (BMS-9 86115), PF-3084014, RO4929097, or LY3039478 be.

[0029] In certain embodiments, the second therapeutic agent is an immunomodulatory agent. The second therapeutic agent is an immune checkpoint inhibitor. In one embodiment, the therapeutic agent is a TIM-3 inhibitor. 453. In certain embodiments, the second therapeutic agent is a LAG-3 inhibitor. In an embodiment, the LAG-3 inhibitor is LAG525. The second therapeutic agent is a PD-1 inhibitor. In one embodiment, the PD-1 inhibitor is DR001, nivolumab, pembrolizumab, pidilizumab, MEDI0680, RE GN2810, TSR-042, PF-06801591, BGB-A317, BGB- 108, INCSHR1210, or AMP-224.

[0030] In certain embodiments, the combination is about 100 mg, or about 200 mg, or about 30 In certain embodiments, the second therapeutic agent comprises about 0 mg, about 400 mg, or about 500 mg. In this case, the combination is about 2 mg, or about 10 mg, or about 20 mg, or about 40 mg, or about 80 mg, or about 160 mg, or about 320 mg of the compound; and about 100 mg, or about 200 mg, or about 300 mg, or about 400 mg, or about 500 mg of a second therapeutic agent Includes:

[0031] Also described herein are the disclosed combination therapies for use in treating cancer. In some embodiments, the combination therapy is for use in the prevention of cancer.

[0032] In some embodiments, the method comprises administering to a subject a compound as described above for the manufacture of a medicament for treating or preventing cancer. Uses of combination therapy are disclosed herein. In certain embodiments, the use is in the treatment of cancer. In one embodiment, the use is for the prevention of cancer. .

[0033] In some embodiments, the cancer is a hematological cancer. In some embodiments, the hematological cancer is a multifocal cancer. It is myeloma.

[0034] (a) BCMA-binding molecule; (b) histidine; (c) sucrose; and (d) PS20 Further described herein is a pharmaceutical composition comprising:

[0035] In certain embodiments, the composition is a liquid. In one embodiment, the sucrose concentration is 240 mM. In one embodiment, the PS20 concentration is 0.04%. H is approximately 5.5±0.3.

[0036] (a) 10 mg / mL BCMA-binding molecule; (b) 20 mM histidine; (c) 24 (d) 0.04% PS20; and (e) a pH of about 5.5±0.3. Also described herein is a vial containing [Brief explanation of the drawings]

[0037] [Figure 1] A form of BCMA-binding molecule designated as BSBM3. [Figure 2-1] Figure 2: Figure 2 shows BSBM3-mediated T cell proliferation, cytokine production, and specific lysis of KMS11 myeloma cells by RTCC. Healthy donor T cells were co-cultured with KMS11 cells overexpressing luciferase at a 1:1 ratio in the presence of BSBM3 or a non-targeting (NT) control antibody at the indicated concentrations. Figure 2A shows IFNγ and TNFα levels as measured by the MSD assay using cell culture supernatants collected at 24 h. Figure 2B shows T cell numbers determined by CD3+ event counts using flow cytometry and normalized to counting bead controls after 4 days in co-culture. Figure 2C shows %RTCC (% lysis of KMS11 cells) as determined by the reduction in luciferase activity compared to KMS11 cells alone at 72 h. Shown are mean values ​​+ / - SEM from T cells of three individual healthy donors, each with three independent experiments (total of nine biological replicates). [Figure 2-2] (As mentioned above.) [Figure 2-3] (As mentioned above.) [Figure 3] This shows that the RTCC assay is the most sensitive in vitro functional assay. The EC30 values ​​of BSBM3 were plotted for three different types of in vitro functional assays: RTCC, T cell proliferation, and cytokine production (as shown in Figure 2). Each data point represents one of nine biological replicates (T cells from three healthy donors were tested individually in three independent experiments). [Figure 4]Figure 1 shows that soluble BCMA reduces the activity of BSBM3 in an RTCC assay. Shown are the EC30 values ​​for BSBM3 in an RTCC assay with soluble BCMA added as indicated. Each data point represents one of nine biological replicates (T cells from three healthy donors were tested individually in three independent experiments). [Figure 5] Figure 1 shows the antitumor activity of BSBM3 in KMS11 xenografts in a human PBMC adoptive transfer mouse model. NSG mice were inoculated with KMS11 cells by tail vein injection on day 0 (D0), adoptively transferred with PBMCs on D7, and treated with BSBM3 at the following doses on D15: 0.03 mg / kg (triangles), 0.3 mg / kg (circles), or 3.0 mg / kg (diamonds). Controls included tumor-bearing mice without human PBMCs (increasing circles), and tumor-bearing mice with human PBMCs but without Ab treatment (squares). Results from one representative experiment are shown from three biological replicates. *p<0.05, Dunnett's multiple comparison test. Data are expressed as geometric mean + / - SEM from five mice per group. [Figure 6] 1 shows the trial scheme of the clinical trial for BSBM3. [Figure 7] BSBM3 International Classification System for Clinical Trials. [Figure 8] Figure 1 shows the effect of AL-102 on BCMA shedding and membrane BCMA expression levels in KMS11 cells. Soluble BCMA levels (ng / mL) from culture supernatants of KMS11 cells treated with serial dilutions of AL-102 for 20 hours are shown on the left Y-axis. The antibody binding ability (ABC) of an anti-BCMA antibody (clone 19F2) on the surface of these AL-102-treated KMS11 cells is shown on the right Y-axis. [Figure 9] Shown is BSBM3 EC50 (mean + / - SEM) using increasing concentrations of AL-102: 5-fold serial dilutions of 1000 nM over 8 points. T cell donors n=3. AL-102 improved the RTCC efficacy of BSBM3 in a dose-dependent manner. DETAILED DESCRIPTION OF THE INVENTION

[0038] Although certain embodiments are shown and described throughout, such embodiments are not intended to be limiting. Numerous variations, changes, and substitutions may be made without departing from the invention. Various alternatives to the embodiments of the invention described herein will occur to those skilled in the art. It should be understood that the present invention may be practiced using the same techniques.

[0039] The present disclosure provides methods for treating and / or preventing diseases (e.g., cancer) in a subject in need thereof. The subject is a patient with a BCMA-binding molecule, particularly a BCMA-binding molecule designated as BSBM3. In some embodiments, the method comprises administering a composition comprising one or more The present disclosure further includes administering a therapeutic agent, such as one or more anti-tumor agents, to the patient. administration, dosing regimens and schedules, biomarkers, drug combinations, and other relevant Further clinical features are provided.

[0040] According to the present disclosure, BCMA binding molecules, such as BSBM3, including but not limited to inhibitory molecules, Inhibitors (e.g., checkpoint inhibitors), activators of costimulatory molecules, chemotherapeutic agents, targets anti-cancer therapy, oncolytic drug, cytotoxic drug, or any of the therapeutic agents disclosed herein In certain embodiments, one or more additional therapeutic agents may be used in combination with The present invention relates to a method for treating and / or preventing cancer in patients / subjects, comprising administering to the patient a PD-1 inhibitor, LAG- 3 inhibitor, cytokine, A2A antagonist, GITR agonist, TIM-3 inhibitor The agonist may be a vasopressin-releasing agent, a STING agonist, or a TLR7 agonist.

[0041] Details of the present disclosure are set forth in the accompanying description below. Although any equivalent methods and materials can be used in the practice or testing of the present disclosure, exemplary methods are described herein. Methods and materials are described. Other features, objects, and advantages of the present disclosure are set forth in the specification and claims. It will be clear from the scope of the present specification and the appended claims that the context makes it particularly clear. Unless otherwise stated, the singular forms include the plural. All technical and scientific terms used herein are understood to be within the meaning of the present invention and are understood to be within the meaning of the present invention. It has the same meaning as understood.

[0042] 6.1.Definition As used herein, the following terms are intended to have the following meanings: .

[0043] ADCC: As used herein, "ADCC" or "antibody-dependent cell-mediated cell proliferation" refers to "Cytotoxicity" refers to the ability of nonspecific cytotoxic cells expressing FcγRs to bind to bound antigens on target cells. ADCC refers to a cell-mediated response that recognizes antibodies and subsequently causes lysis of the target cells. , correlated with binding to FcγRIIIa; increased binding to FcγRIIIa correlated with A This results in increased DCC activity.

[0044] ADCP: "ADCP" or antibody-dependent cell-mediated phagocytosis as used herein The use of FcγRs is a process in which nonspecific phagocytes expressing FcγRs recognize and ingest the bound antibody on target cells. It refers to a cell-mediated reaction that subsequently leads to phagocytosis of the target cell.

[0045] Additional Agents: Conveniently, agents used in combination with the antigen-binding molecules of the present disclosure may be any of the agents described herein. These are referred to as "additional" agents in the specification.

[0046] Antibody: The term "antibody" as used herein refers to a non-covalently, reversibly A polypeptide of the immunoglobulin family capable of efficiently and specifically binding to an antigen. For example, naturally occurring "antibodies" of the IgG type are composed of disulfide bonds. It contains at least two heavy (H) chains and two light (L) chains interconnected by bond bonds. Each heavy chain is a tetramer. The heavy chain constant region is composed of three domains: CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as VL) and a light The light chain constant region is composed of one domain (referred to herein as CL). The VH and VL regions are called framework regions (FR). They contain hypervariable regions called complementarity-determining regions (CDRs), interspersed with more conserved regions. Each VH and VL can be further subdivided into regions in the following order: FR1, CDR1, FR2 , CDR2, FR3, CDR3, FR4 arranged from the amino terminus to the carboxy terminus It consists of three CDRs and four FRs. The variable regions of the heavy and light chains interact with antigens. The constant region of an antibody contains a binding domain that binds to various cells of the immune system (e.g., immune cells). to host tissues or factors, including the first component of the classical complement system (Clq) and the first component of the classical complement system (C1q). The term "antibody" includes, but is not limited to, monoclonal antibodies capable of mediating the binding of immunoglobulins. Clonal antibodies, human antibodies, humanized antibodies, camelized antibodies, chimeric antibodies, bispecific or polyclonal antibodies Polyspecific and anti-idiotypic (anti-Id) antibodies (e.g., anti-Id antibodies to the antibodies of the present disclosure) Antibodies include antibodies of any isotype / class (e.g., IgG, IgE , IgM, IgD, IgA and IgY) or subclass (e.g., IgG1, IgG2, The antibodies may be of the following types: IgG3, IgG4, IgA1 and IgA2.

[0047] Both the light and heavy chains are divided into regions of structural and functional homology. The term "variable" is used functionally. In this context, light (VL) and heavy (VH) It will be appreciated that the variable domains of both chains determine antigen recognition and specificity. Conversely, the constant domains of the light chain (CL) and heavy chain (CH1, CH2, or CH3) are involved in secretion, They confer important biological properties such as transplacental mobility, Fc receptor binding, and complement fixation. Therefore, the numbering of the constant region domains is more distal from the antigen binding site or amino terminus of the antibody. In wild-type antibodies, the N-terminal region is the variable region, and the C-terminal region is the The CH3 and CL domains are actually the constant regions of the heavy and light chains, respectively. Contains an oxy terminus.

[0048] Antibody fragment: As used herein, an "antibody fragment" of an antibody The term "antibody" refers to one or more portions of an antibody. In certain embodiments, these portions are part of an antibody. In certain other embodiments, these portions are part of the contact domains of the In the context of the present invention, the term "antigen-binding fragment," "antigen-binding fragment thereof," "antigen-binding portion," etc. The ability to bind antigen non-covalently, reversibly, and specifically, sometimes referred to as Examples of binding fragments include, but are not limited to, However, single chain Fv (scFv), Fab fragments, VL, VH, CL and CH1 domains monovalent fragments consisting of F(ab)2 fragments, disulfides in the hinge region; A bivalent fragment containing two Fab fragments linked by a peptide bridge; an Fd fragment consisting of the CH1 domain and the VL and VH domains of a single arm of an antibody; Fv fragments consisting of the VH domain; dAb fragments (Ward et al. al., (1989) Nature 341:544-546); and isolated complement The term "antibody fragment" therefore includes the CDRs. Proteolytic fragments of antibodies (e.g., Fab and F(ab)2 fragments) and and modified proteins comprising one or more portions of an antibody (e.g., scFv).

[0049] Antibody fragments include single domain antibodies, maxibodies, minibodies, intrabodies, bibodies, Also in bispecific antibodies, trispecific antibodies, tetraspecific antibodies, v-NAR and bis-scFv (e.g., Hollinger and Hudson, 2005, Na (See Nature Biotechnology 23:1126-1136). Antibody fragments are based on polypeptides such as fibronectin type III (Fn3). and can be grafted into a scaffold (US Pat. No. 6,233,199 describes a fibronectin polypeptide monobody). See Patent No. 6,703,199).

[0050] An antibody fragment comprises a complementary light chain polypeptide (e.g., VL-VC-VL-VC). A pair of tandem Fv segments (e.g., VH) that together form a pair of antigen-binding regions -CH1-VH-CH1) (Zapata et al. al., 1995, Protein Eng. 8:1057-1062; and U.S. Pat. 5,641,870).

[0051] Antibody numbering system: As used herein, numbered amino acid residues in an antibody domain References to EU numbering systems are based on the EU numbering system unless otherwise specified. delman et al.,1969,Proc.Nat'l Acad.Sci.U SA 63:78-85, originally devised by Kabat et al., 1991 ,in Sequences of Proteins of Immunologic al Interest, US Department of Health and This is described in detail in Human Services, NIH, USA.

[0052] Antigen-binding domain: The term "antigen-binding domain" or "ABD" refers to a non-covalently binding It refers to the portion of an antigen-binding molecule that has the ability to reversibly and specifically bind to an antigen. A suitable ABD retains the ability to non-covalently, reversibly, and specifically bind antigen. of antigen-binding fragments and both immunoglobulin and non-immunoglobulin based scaffolds As used herein, the term "antigen-binding domain" includes a non-covalent portion. antibody fragments that retain the ability to bind covalently, reversibly, and specifically to antigens. Includes.

[0053] Antigen-binding domain chain or ABD chain: Each ABD is a single (e.g., in the case of an scFv) It may be present as a polypeptide chain or as two or more polypeptide chains (e.g., Fab). As used herein, the term "ABD chain" refers to a chain of amino acids that can be formed by the association of two or more amino acids. The term "ABD chain" refers to all or part of the ABD present on a single polypeptide chain. The use of the term "" is intended for convenience and descriptive purposes only and does not imply a specific form. or does not suggest a method of manufacture.

[0054] Antigen-binding fragment: The term "antigen-binding fragment" of an antibody refers to a non-covalently bound "Antibody" refers to the portion of an antibody that retains the ability to reversibly and specifically bind to an antigen.

[0055] Antigen-binding molecule: The term "antigen-binding molecule" refers to a molecule that contains one or more antigen-binding domains. An antigen-binding molecule refers to a molecule, such as an antibody. An antigen-binding molecule is a molecule that consists of one or more polypeptide chains, such as one or two The polypeptides in the antigen-binding molecule may comprise three, four or more polypeptide chains. The polypeptide chains can be directly or indirectly associated with each other (e.g., a first polypeptide chain can be associated with a second polypeptide chain). The first and second polypeptide chains can be associated with each other, which in turn can be associated with a third polypeptide chain to form the first and The second polypeptide chains may form an antigen-binding molecule in which they are directly associated with each other, or the second and The first and third polypeptide chains are directly associated with each other, and the second polypeptide chains are directly associated with each other. (They are indirectly associated with each other via peptide chains).

[0056] Associated: The term "associated" in reference to a domain or region within an antigen-binding molecule. The term refers to a region between two or more polypeptide chains and / or two or more positions on a single polypeptide chain. In particular, the term "associated" refers to a functional relationship between two or more polypeptides (or multiple portions of a single polypeptide) to generate a functional antigen-binding domain, e.g. non-covalently and / or by molecular interactions, e.g., one or more sulfide bridges or This means that the antigen-binding molecules are covalently linked to each other by chemical bridges. Examples of possible associations include (but are not limited to) associations between Fc regions in an Fc domain; The association between the VH and VL regions in ab or Fv and the association between CH1 and CL in Fab Examples include:

[0057] B Cells: As used herein, the term "B cells" refers to a lymphocyte subtype These cells are of the B-cell lineage, a type of white blood cell found in the blood. Examples of B cells are plasmablasts, plasmacytoids, and thyroid Plasma cells, lymphoplasmacytoid cells, memory B cells, follicular B cells, marginal zone B cells, B-1 cells These include B cells, B-2 cells, and regulatory B cells.

[0058] B cell malignancies: As used herein, B cell malignancies are characterized by dysregulation of B cells. Examples of B-cell malignancies include non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HHL), and For example, but not limited to, B-cell malignancies include lymphoma, leukemia, and myeloma. However, multiple myeloma, chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), Follicular lymphoma, mantle cell lymphoma (MCL), diffuse large B-cell lymphoma ( DLBCL), marginal zone lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (Warblende lymphoma) Denström's macroglobulinemia), hairy cell leukemia, primary central nervous system (CNS) ) Lymphoma, primary mediastinal large B-cell lymphoma, mediastinal gray zone lymphoma (MGZL), splenic Extranodal marginal zone B-cell lymphoma, MALT-type extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma lymphoma, and primary effusion lymphoma, and plasmacytoid dendritic cell neoplasm.

[0059] BCMA: As used herein, the term "BCMA" refers to a B cell maturation antigen. BCMA (also known as TNFRSF17, BCM, or CD269) is a member of the tumor necrosis receptor (TNFR) family and is expressed primarily in terminally differentiated B cells , expressed on memory B cells and plasma cells. Its ligands are involved in B cell activation. The protein BCMA contains BCMA-related cytokines, including BCMA-related cytokines, BCMA-related cytokines, and BCMA-related cytokines. , encoded by the gene TNFRSF17. An exemplary BCMA sequence is identified under accession number Q 02223 and is available in the Uniprot database.

[0060] BCMA-binding molecule: The term "BCMA-binding molecule" refers to a molecule that binds to BCMA, particularly human BCMA. A BCMA-binding molecule is a molecule that specifically binds to BCMA. Multispecific binding molecules comprising at least one ABD, e.g., multispecific antibodies, bispecific Specific BCMA binding molecules of the present disclosure include: Herein referred to as BSBM3.

[0061] Bispecific Binding Molecule: The term "bispecific binding molecule" or "BBM" refers to a molecule that binds two antibodies. A BBM of the present disclosure refers to a molecule that specifically binds to BCMA and contains two or more ABDs. at least one antigen-binding domain specific for a different antigen and a small number of domains specific for a different antigen It contains at least one antigen-binding domain, e.g., a component of the TCR complex. BBMs are shown in Figures 1B-1AG. BBMs can be one, two, three, four or even more. The polypeptide chain may include a polypeptide chain that can

[0062] Bivalent: The term "bivalent" as used herein in reference to an antigen-binding molecule , refers to an antigen-binding molecule having two ABDs. The domains can be the same or different. Thus, a bivalent antigen-binding molecule can be monospecific or bispecific. The antibody comprises an ABD that specifically binds to BCMA and another ABD that binds to another antigen, e.g., TC Contains components of the R complex.

[0063] BSBM3: BSMB3 is a nucleotide sequence of a nucleotide sequence selected from the group consisting of (a) a nucleotide sequence of a nucleotide sequence selected from the group consisting of (b) a nucleotide sequence of ... (b) a second polypeptide whose amino acid sequence comprises the amino acid sequence of SEQ ID NO:2; and (c) a third polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO:3. When co-expressed, the first, second and third polypeptides combine to form a binding molecule having the configuration shown in FIG.

[0064] Cancer: The term "cancer" refers to the uncontrolled (often rapid) growth of abnormal cells. Cancer cells spread to the rest of the body either locally or through the bloodstream and lymphatic system. It may spread to other sites. Examples of various cancers are described herein, including but not limited to leukemia. , multiple myeloma, asymptomatic myeloma, Hodgkin's lymphoma and non-Hodgkin's lymphoma, e.g. The term "cancerous B cell" includes any BCMA-positive cancer of any of the types described above. refers to B cells that are undergoing or have undergone uncontrolled proliferation.

[0065] CD3: The term "CD3" or "cluster of differentiation 3" refers to the cluster of differentiation triad of T cell receptors. CD3 is a group of receptors that bind to cytotoxic T cells (e.g., CD8+ naive T cells) and promotes the activation of both CD4+ and T helper cells (e.g., naive CD4+ T cells) and Different chains: one CD3 gamma chain (e.g., Genbank accession numbers NM_000073 and MP_000064 (human)), one CD3 delta chain (e.g., Genbank accession number N M_000732, NM_001040651, NP_00732 and NP_00103 5741 (human)) and two CD3ε chains (e.g., Genbank accession number NM_00 CD3 chains are composed of a single extracellular Highly related cells of the immunoglobulin superfamily that contain immunoglobulin domains CD3 molecules are surface proteins that associate with the T cell receptor (TCR) and the ζ-chain. The T cell receptor (TCR) complex functions in generating activation signals in T lymphocytes Unless expressly indicated, references to CD3 in this application refer to CD3 co-receptors. The term "CD3 receptor" may refer to a receptor, a CD3 co-receptor complex, or any polypeptide chain of a CD3 co-receptor complex. do.

[0066] Chimeric antibody: The term "chimeric antibody" (or antigen-binding fragment thereof) refers to (a) The constant region or a part thereof is a class of antigen-binding site (variable region) that is different or modified. the effector functions and / or species constant regions or those that confer new properties to the chimeric antibody. They can be linked to completely different molecules, such as enzymes, toxins, hormones, growth factors, drugs, etc. or (b) the variable region or portion thereof is different or modified; antibody molecule (or its antigen) modified, substituted or replaced with a variable region having a specific antigen specificity For example, mouse antibodies have their constant regions replaced by human immunoglobulins. The antibody can be modified by substituting the constant region from a human antibody. While chimeric antibodies have reduced antigenicity in humans compared to the original mouse antibodies, , allowing the antibody to retain its specificity in recognizing the antigen.

[0067] Complementarity Determining Region: "Complementarity Determining Region" or "CDR" as used herein The term refers to the sequence of amino acids within an antibody variable region that confers antigen specificity and binding affinity. For example, typically, three CDRs (e.g., CDR-H1, CDR-H2, CDR-H3, CDR-H4, CDR-H5, CDR-H6, ​​CDR-H7, CDR-H8, CDR-H9, CDR-H10, CDR-H11, CDR-H12, CDR-H13, CDR-H14, CDR-H15, CDR-H16, CDR-H17, CDR and CDR-H2 and CDR-H3) and three CDRs in each light chain variable region (CDR-L1, The exact amino acid sequence boundaries of a given CDR are abat et al. (1991), “Sequences of Proteins of Immunological Interest”,5th Ed.Publi c Health Service,National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme), Al-L azikani et al.,(1997)JMB 273,927-948(``Ch othia" numbering scheme) or a combination thereof and ImMunoGenTics ( IMGT) numbering (Lefranc, 1999, The Immunologist, 7:132-136;Lefranc et al.2003,Dev.Comp.Im munol.27,55-77 ("IMGT" numbering scheme) It can be determined using any one of several well-known schemes, including: R region (e.g., HC CDR1, HC CDR2, HC CDR3, LC CDR1, Combined Kabat and Choth for LC CDR2 or LC CDR3 In the ia numbering scheme, in certain embodiments, the CDRs are Chothia CDRs together with the amino acid residues defined as part of the Kabat CDRs. As used herein, "Chothia" numbers correspond to amino acid residues in the The CDRs defined according to this naming scheme are sometimes referred to as "hypervariable loops."

[0068] For example, Kabat reports that the CDR amino acid residues in the heavy chain variable domain (VH) are 3 1–35 (CDR-H1) (e.g., insertion after position 35), 50–65 (CDR-H2) and 95 to 102 (CDR-H3); CDRs in the light chain variable domain (VL) R amino acid residues are 24-34 (CDR-L1) (e.g., insertion after position 27), 50- They are numbered 56 (CDR-L2) and 89-97 (CDR-L3). According to Chothia, the CDR amino acids in VH are 26 to 32 (CDR-H1) (e.g., For example, insertion after position 31), 52-56 (CDR-H2) and 95-102 (CDR-H 3); amino acid residues in VL are numbered 26 to 32 (CDR-L1) (e.g., Insertion after position 30), 50-52 (CDR-L2) and 91-96 (CDR-L3) Combining both Kabat and Chothia CDR definitions Thus, the CDRs may be, for example, amino acid residues 26 to 35 (CDR-H1) in human VH, 0-65 (CDR-H2) and 95-102 (CDR-H3) and amino acids in human VL Acid residues 24–34 (CDR-L1), 50–56 (CDR-L2), and 89–97 (CDR-L3) According to IMGT, the CDR amino acid residues in VH are Approximately 26-35 (CDR1), 51-57 (CDR2), and 93-102 (CDR3) The CDR amino acid residues in the VL are numbered as follows: approximately 27-32 (CDR1), 50-5 2 (CDR2) and 89-97 (CDR3) (numbered according to "Kabat" numbering) By IMGT, the CDR regions of the antibody are generated by the program IMGT / Domain Gap Generally, unless otherwise indicated, antibody molecules may contain one or more It may contain any combination of the above Kabat and / or Chothia CDRs.

[0069] Concurrently: The term "concurrently" refers to the administration of therapeutic agents (e.g., prophylactic or therapeutic agents) at the exact same time. ), and a pharmaceutical composition comprising an antigen-binding molecule may act together with an additional therapeutic agent. and in a sequence that may provide increased benefit over when they are administered in other ways. It means that the administration is to a subject within a time interval.

[0070] Conservative sequence modifications: The term "conservative sequence modifications" refers to modifications of a BCMA binding molecule or its constituent elements. The binding properties of the protein (e.g., ABD or Fc region) are not substantially affected or altered. Such conservative modifications include amino acid substitutions, additions, and deletions. Modifications can be made using standard techniques such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are those in which the amino acid residues have similar side chains. A family of amino acid residues with similar side chains. These families include those with basic side chains. amino acids with acidic side chains (e.g., lysine, arginine, histidine); (e.g., aspartic acid, glutamic acid), amino acids with uncharged polar side chains (e.g., , glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), amino acids with nonpolar side chains (e.g., alanine, valine, leucine , isoleucine, proline, phenylalanine, methionine), and amino acids with β-branched side chains amino acids (e.g., threonine, valine, isoleucine) and amino acids with aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Therefore, one or more amino acid residues in the BBM may be linked to other amino acids from the same side chain family. The modified BBM can be, for example, substituted with an aryl group or a carboxylic acid residue, and the ... The proteins can be tested for their heterodimerization and / or effector function.

[0071] Epitope: An epitope or antigenic determinant is a molecule that binds to an antibody or other antigen described herein. An epitope is the portion of an antigen that is recognized by a binding moiety. An epitope can be linear or conformational. do.

[0072] Effector function: The term "effector function" usually refers to the binding of an effector molecule. by binding through a domain of the antibody other than the antigen-binding domain, which is mediated by binding Effector functions refer to the activities of antibody molecules mediated by the antibody. Complement activation involves the activation of complement-mediated effector functions mediated by the binding of complement factors. It is important in the opsonization and lysis of vacuolar pathogens. Complement activation also stimulates the inflammatory response. Effector functions are mediated by Fc receptors (FcRs) and may also be involved in autoimmune hypersensitivity. Effector functions also include binding of the constant domain of an antibody to an Fc receptor (FcR) Binding of antibodies to Fc receptors on the cell surface can sometimes result in the formation of antibodies that are coated on the cell surface. Phagocytosis and destruction of infected particles, clearance of immune complexes, ADCC, ADCP, inflammatory mediators It is involved in many important and diverse biological processes, including the regulation of ATP release, placental transit, and immunoglobulin production. The effector functions of antibodies are directed against enzymes such as Fc receptors or complement components. by modifying, e.g., increasing or decreasing, the affinity of the antibody for the effector molecule. Binding affinity can generally be altered by modifying the effector molecule binding site. In this case, the region of interest is located and at least a portion of this region is visualized in a suitable manner. It is appropriate to modify the antibody by the method described above. Although the overall binding affinity need not be substantially altered, the effector mechanism may be disrupted in a non-productive manner. It is also conceivable that the geometry of the interaction could be altered to nullify it in the case Effector functions are not directly involved in effector molecule binding, but rather in the function of the effector molecule itself. It is further contemplated that the activity may be altered by modifying sites otherwise involved in the performance of the activity. can be obtained.

[0073] Fab: As used herein, "Fab" or "Fab region" refers to a region of a VH, It refers to the polypeptide region comprising the CH1, VL and CL immunoglobulin domains. These terms can refer to this region alone or to this region in the context of an antigen-binding molecule.

[0074] The Fab domain is bound to the VH domain, with the CL domain bound to the VL domain The VH domain is formed by pairing with the VL domain. The CH1 domain is paired with the CL domain to form the Fv region, and the CH1 domain is paired with the CL domain to form the binding module. The disulfide bond between the two constant domains further stabilizes the Fab domain. It can be further stabilized.

[0075] The Fab region is the region where the protein of the immunoglobulin molecule is purified (e.g., using an enzyme such as papain). It can be produced by proteolytic cleavage or recombinant expression. Fab is a protein that binds to two different polypeptide chains (e.g., VH-CH1 on one chain). The Fab region is typically formed by two VL-CL domains (one VL domain and one VL domain on the other chain). It is typically expressed recombinantly on one polypeptide chain, but single-chain Fabs are also available. Contemplated herein.

[0076] Fc region: As used herein, the term "Fc region" or "Fc chain" refers to , a polypeptide comprising the CH2-CH3 domains of an IgG molecule and, in some cases, the hinge. In the EU numbering for human IgG1, the CH2-CH3 domains are , which contains amino acids 231 to 447, and the hinge is from 216 to 230. The definition of the "region" is amino acids 231 to 447 (CH2-CH3) or 216 to 447 ( The term "Fc fragment" in this context refers to a fragment of a human Fc-like protein (e.g., a ribonucleotide sequence ... "Fragment" contains fewer amino acids from either or both the N-terminus and C-terminus Although it is possible to do so, it is generally done using standard size-based methods (e.g., non-denaturing chromatography, The dimerization with another Fc region can be detected using size exclusion chromatography (HPLC). The human IgG Fc region is particularly referred to in this disclosure as Useful may be an Fc region from human IgG1, IgG2 or IgG4.

[0077] Fc domain: The term "Fc domain" refers to a pair of related Fc regions. Fc regions dimerize to form an Fc domain. Two Fc regions within an Fc domain , identical to each other (such as Fc domains referred to herein as "Fc homodimers") or can be different (such as an Fc domain referred to herein as an "Fc heterodimer").

[0078] Fv: The term "Fv", "Fv fragment" or "Fv region" refers to a tightly coupled, non-covalently coupled The region containing the VL and VH domains of the linked antibody fragments (VH-VL dimer) In this configuration, the three CDRs of each variable domain interact to form a target binding site. In most cases, the six CDRs confer target binding specificity to an antigen-binding molecule. However, in some cases, only a single variable domain (or three CDs) specific for a target may be used. Even the half of the Fv containing R may have the ability to recognize and bind to the target. In a globulin molecule, the VH and VL of the Fv are on separate polypeptide chains, but The term may be used to refer to a single chain Fv (scFv) that is engineered to contain disulfides for added stability. Also included are Fvs engineered by the introduction of peptide bonds.

[0079] Reference herein to a VH-VL dimer is not intended to denote any particular form. For example, in scFv, VH is not N-terminal or C-terminal to VL. (wherein the VH and VL are typically linked by a linker as described herein) in).

[0080] Half antibody: The term "half antibody" refers to an antibody that contains at least one ABD or ABD chain, e.g., For example, disulfide bridges or molecular interactions (e.g., knob-in-hole interactions between Fc heterodimers) It refers to a molecule that can associate with another molecule containing an ABD or an ABD chain through a molecular interaction (antibody interaction). The antibody may comprise one polypeptide chain or two or more polypeptide chains (e.g., the two polypeptide chains of a Fab). In one embodiment, the half antibody comprises an Fc region.

[0081] An example of a half antibody is a molecule that contains the heavy and light chains of an antibody (e.g., an IgG antibody). Another example is a first polypeptide comprising a VL domain and a CL domain, and a VH domain a second polypeptide comprising a CH1 domain, a hinge region, a CH2 domain, and a CH3 domain; and a peptide, where the VL and VH domains form an ABD. Yet another example of a polypeptide comprising an scFv domain, a CH2 domain, and a CH3 domain. It is a peptide.

[0082] A half antibody can contain two or more ABDs, for example, a half antibody can contain (in order from N-terminus to C-terminus) 2) scFv domain, CH2 domain, CH3 domain and another scFv domain nothing.

[0083] A half antibody is an ABD that forms a complete ABD when associated with another ABD chain in another half antibody. It may also contain a BD strand.

[0084] Thus, a BBM may comprise one, more typically two or even three or more half antibodies. , a half antibody may comprise one or more ABDs or ABD chains.

[0085] In some BBMs, the first half antibody associates with the second half antibody, e.g., In other BBMs, the first half antibody is heterodimerized, for example, by a disulfide bridge. or by chemical cross-linking. One half antibody has both covalent and non-covalent interactions, e.g., disulfide bridges and knob- It associates with the second half antibody through in-hole interactions.

[0086] The term "half antibody" is intended for descriptive purposes only and does not refer to a specific form or preparation. The "first" half antibody, the "second" half antibody, the "left" half antibody, The description of half antibodies as "right" half antibodies is for convenience and illustrative purposes only.

[0087] Hole: As used in knob-into-hole, the "hole" is the area from the first Fc chain boundary to the recessed, thus stabilizing the Fc heterodimer, thereby e.g. The adjacent interface of the second Fc chain is preferably 100 to 1500, so as to favor Fc heterodimer formation over Fc heterodimer formation. refers to at least one amino acid side chain that can be positioned on a complementary "knob" in the .

[0088] Host cell or recombinant host cell: The term "host cell" or "recombinant host cell" refers to a refers to cells that have been genetically modified, for example, by the introduction of heterologous nucleic acid. It is understood that the term "cell" is intended to refer not only to the particular subject cell but also to the progeny of such a cell. It should be understood that certain modifications may occur in subsequent generations, either due to mutation or environmental influences. Such progeny may not, in fact, be identical to the parent cell, since they may exist in different However, these are still included within the scope of the term "host cell" as used herein. The host cell may be, for example, transiently expressing an extrachromosomal heterologous expression vector or, for example, The heterologous nucleic acid can be stably carried by integrating it into the genome. For this purpose, the host cells are monkey kidney cells (COS, e.g., COS-1, COS-7). ), HEK293, Baby Hamster Kidney (BHK, e.g., BHK21), Chinese Hamster ovary (CHO), NSO, PerC6, BSC-1, human hepatocellular carcinoma cells (e.g. For example, Hep G2, SP2 / 0, HeLa, Madin-Darby bovine kidney (MDB K), myeloma and lymphoma cells or their derivatives and / or engineered variants, The cell line may be of mammalian origin or have mammalian-like characteristics. CAM profile modified and / or site-specific integrated site derivatives.

[0089] Humanized: The term "humanized" forms of non-human (e.g., murine) antibodies refers to the use of non-human immunoglobulins. A humanized antibody is a chimeric antibody that contains minimal sequence derived from a human globulin. Residues from the recipient hypervariable region are selected to provide a polypeptide with the desired specificity, affinity, and potency. derived from the hypervariable regions of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate In some cases, the target antibody is a human immunoglobulin (recipient antibody) in which the target amino acid residues have been replaced by the target amino acid residues. , in which framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues Furthermore, humanized antibodies may contain residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. Generally, humanization An antibody comprises substantially all of at least one, and typically two, variable domains, wherein: All or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin, and the FR All or substantially all of the antibody is human immunoglobulin lo sequence. Optionally, at least a portion of an immunoglobulin constant region (Fc), typically a human immunoglobulin Humanized antibodies typically have a greater immunogenicity to humans than non-humanized antibodies. Humanized antibodies are less infectious and therefore offer therapeutic benefits in certain situations. These can be generated using known methods, e.g., Hwang et al., 2005, Met hods 36:35;Queen et al.,1989,Proc.Natl.A cad.Sci.USA86:10029-10033;Jones et al .,1986,Nature 321:522-25,1986;Riechmann et al.,1988,Nature 332:323-27; et al.,1988,Science 239:1534-36; et al.,1989,Proc.Natl.Acad.Sci.USA86: 3833-3837; U.S. Patent Nos. 5,225,539; 5,530,101 Specification No. 5,585,089; Specification No. 5,693,761; No. 5 ,693,762; and 6,180,370; and WO 90 Please refer to the following review articles and references cited therein: Presentation:Presta,1992,Curr.Op.Struct.Biol.2:593- 596;Vaswani and Hamilton,1998,Ann.Allerg y,Asthma&Immunol.1:105-115;Harris,1995,B iochem.Soc.Transactions 23:1035-1038;Hur le and Gross,1994,Curr.Op.Biotech.5:428- See also 433.

[0090] Human antibody: The term "human antibody" as used herein refers to a human antibody in the framework Also included are antibodies having variable regions in which both the CDR and CDR regions are derived from sequences of human origin. Additionally, if the antibody contains a constant region, the constant region may be derived from such human sequences, e.g., human germline sequences. Human germline sequences or mutants of the human germline sequence or, for example, Knappik et al. As described in J Mol Biol 296, 57-86, 2000, The antibody-containing consensus framework sequence derived from framework sequence analysis also The structure and location of immunoglobulin variable domains, e.g., CDRs, are determined according to well-known numbering schemes. numbering scheme, e.g., Kabat numbering scheme, Chothia numbering scheme, or Kab It can be defined using any combination of at and Chothia (e.g., Lazikan i et al.,1997,J.Mol.Bio.273:927 948;Kaba et al., 1991, Sequences of Proteins of I mmunological Interest,5th edit.,NIH Publ ication no.91-3242 USDepartment of Hea lth and Human Services;Chothia et al.,19 87,J.Mol.Biol.196:901-917;Chothia et al. , 1989, Nature 342:877-883).

[0091] Human antibodies may contain amino acid residues that are not encoded by human sequences (e.g., amino acids derived from in vitro Introduced by random or site-specific mutation or in vivo somatic mutation However, the present invention may contain mutations that enhance the stability or production of the polypeptides. However, the term "human antibody" as used herein refers to antibodies derived from other mammals, such as mice. CDR sequences derived from the germline of a mammalian species are grafted onto human framework sequences. The term "antibodies" is not intended to include antibodies.

[0092] In combination: As used herein, administered in combination means two The delivery of one (or more) different therapeutic agents to a subject during the course of the subject's disease. For example, two or more therapeutic agents may be administered after a subject has been diagnosed with a disease and after the disease has been cured or eliminated. This means that the drug is delivered before the patient is taken out of the hospital or before treatment is stopped for other reasons.

[0093] Knob: As in knob-into-hole, the "knob" protrudes from the boundary of the first Fc chain. and thus stabilize the Fc heterodimer, thereby reducing the Fc homodimer formation, e.g. The complementary structure at the interface with the second Fc chain is used to favor Fc heterodimer formation. It refers to at least one amino acid side chain that is positionable in a "hole."

[0094] Knobs and holes (or knobs-into-holes): One mechanism of Fc heterodimerization In the art, this is often referred to as "knob and hole," or "knob-in-hole," or "knob- These terms are commonly referred to as "into the hole." al.,1996,Protein Engineering 9(7):617;A twell et al., 1997, J. Mol. Biol. 270:26; and the United States As described in the specification of Patent No. 8,216,805, Fc heterodimers are produced rather than Fc homodimers. Refers to amino acid mutations that create steric effects that favor dimer formation. The in-hole mutation can be combined with other methods to improve heterodimerization.

[0095] Monoclonal antibody: As used herein, the term "monoclonal antibody" refers to a The term refers to antibodies, antibody fragments, molecules (including BBMs) etc. derived from the same genetic source. It refers to a polypeptide comprising:

[0096] Monovalent: The term "monovalent" as used herein in reference to antigen-binding molecules , refers to an antigen-binding molecule that has a single antigen-binding domain.

[0097] Multispecific binding molecule: The term "multispecific binding molecule" or "MBM" refers to at least one It also refers to an antigen-binding molecule that specifically binds to two antigens and contains two or more ABDs. , each independently an antibody fragment (e.g., scFv, Fab, nanobody), antibody- or non-antibody-derived binding agents (e.g., fibronectin, Fynomer, DARPin ) can be.

[0098] Mutation or Modification: The terms "modification" and "abruption" are used in reference to the primary amino acid sequence of a polypeptide. The term "mutation" refers to an amino acid substitution in a polypeptide sequence compared to a reference polypeptide. Furthermore, the term "modification" refers to, for example, chemical conjugates, substitutions, insertions, and / or deletions. conjugation (e.g., of a drug or polyethylene glycol moiety) or post-translational modification (e.g., It further encompasses modifications to amino acid residues (e.g., glycosylation).

[0099] Nucleic Acid: The term "nucleic acid" is used interchangeably herein with the term "polynucleotide." and deoxyribonucleotides or ribonucleotides in either single-stranded or double-stranded form. The term refers to nucleotides and their polymers, including synthetic, natural, and non-natural nucleotides. A known nucleotide that has similar binding properties to the reference nucleic acid and is metabolized similarly to the reference nucleotide. These include nucleic acids containing nucleotide analogs or modified backbone residues or linkages. Examples of thiol groups include, but are not limited to, phosphorothioates, phosphoramidates, methylphosphatides, and the like. Sulfonates, chiral-methylphosphonates, 2-O-methylribonucleotides and peptides Examples include polynucleotides such as polynucleotides (PNAs).

[0100] Unless otherwise indicated, a particular nucleic acid sequence refers to the nucleic acid sequence, not just the sequence explicitly indicated. Conservatively modified variants of a sequence (e.g., degenerate codon substitutions) and complementary sequences are also implicitly encompassed. Specifically, as detailed below, degenerate codon substitutions are made by using one or more selected ( or all) codons with a substitution of mixed base and / or deoxyinosine residues at the third position. This can be achieved by generating sequences (Batzer et al., (1991) Nucleic Acid Res.19:5081;Ohtsuka et al., (1985) J. Biol. Chem. 260:2605-2608; and Rossol ini et al.,(1994)Mol.Cell.Probes 8:91-98 ).

[0101] Operably linked: The term "operably linked" refers to two or more peptides or refers to the functional relationship between polypeptide domains or nucleic acid (e.g., DNA) segments The term "operably linked" in reference to a fusion protein or other polypeptide The term refers to two or more amino acid segments linked to form a functional polypeptide. For example, in the context of an antigen-binding molecule, a separate ABM (or chain of ABM) The polypeptide chains of the antigen-binding molecule may be operably linked via a peptide linker sequence. In the context of a nucleic acid encoding a fusion protein, such as The amino acid sequences encoded by the two nucleic acids remain in frame. In the context of transcriptional regulation, the term refers to the binding of a gene to a transcribed sequence. Refers to the functional relationship of transcriptional regulatory sequences. For example, a promoter or enhancer sequence A codon is a polypeptide that stimulates or modulates the transcription of a coding sequence in an appropriate host cell or other expression system. The gene is operably linked to a code sequence.

[0102] Polypeptides and proteins: The terms "polypeptide" and "protein" refer to The term is used interchangeably herein to refer to a polymer of amino acid residues. Amino acids in which one or more amino acid residues are artificial chemical mimics of the corresponding natural amino acids These include acid polymers as well as natural and non-natural amino acid polymers. The term also refers to compounds that have been modified, for example, by one or more side chain or terminal synthetic derivatizations, glycosylation, P EG, circular permutation, cyclization, and conversion to other molecules Linkers, fusions to proteins or protein domains and peptide tags or targets The term "amino acid polymer" includes amino acid polymers that are derivatized by the addition of amino acids.

[0103] Recognize: The term "recognize" as used herein refers to the ability of an individual to recognize an epitope. ABD refers to an ABD that finds a target and interacts with it (e.g., binds to it).

[0104] Single-chain Fab or scFab: The terms "single-chain Fab" and "scFab" refer to V The antibody heavy chain variable domain (VH), antibody constant domain 1 (CH1), antibody light chain variable domain (VL), In some embodiments, the polypeptide comprises a light chain constant domain (CL) and a linker. wherein the antibody domains and linker are arranged in one of the following orders from N- to C-terminus: a) VH-CH1-linker-VL-CL, b) VL-CL-linker-VH-CH1, c) VH-CL-linker-VL-CH1 or d) VL-CH1-linker-VH-CL The linker has at least 30 amino acids, for example, 32 to 50 amino acids. The single chain Fab can be a polypeptide having a natural structure between the CL domain and the CH1 domain. It is stabilized by disulfide bonds.

[0105] Simultaneous or Concurrent Delivery: Some Implementations In some embodiments, there is overlap in administration so that delivery of one therapeutic agent may be delayed by delivery of a second therapeutic agent. This is referred to herein as "simultaneous" or "simultaneous." is sometimes referred to as "concurrent delivery." In either case, in some embodiments, the therapeutic The drugs are more effective due to the combination. For example, the second therapeutic agent is more effective, e.g., If an equivalent effect is seen with a lesser amount of the second therapeutic agent, or if the second therapeutic agent is more effective than the second therapeutic agent, The drug reduces symptoms to a greater extent than would be seen if the drug were administered without the first therapeutic agent, or A similar situation occurs with the first therapeutic agent. In certain embodiments, delivery is accompanied by symptomatic relief or Other disease-related parameters are observed with one therapeutic agent delivered without the other. The effects of the two therapeutic agents are partially additive. The effects may be fully additive, fully additive, or more than additive. The effect of one therapeutic agent is such that it is still detectable when the second therapeutic agent is delivered. could be.

[0106] Single-chain Fv or scFv: As used herein, "single-chain Fv" or "scFv" refers to a single-chain Fv. covalently linked to the variable light chain domain using an ABD linker, generally as described herein, It means an scFv or a variable heavy chain domain that forms an scFv domain. The VH-linker-VL or VL-linker-VH orientation is N-terminal to C-terminal. For a summary of scFvs, see Plueckthun in the Pharmacology of Monoclonal Antibodies,v ol.113,Rosenburg and Moore eds.,(1994)Sp See Ringer-Verlag, New York, pp. 269-315 .

[0107] Specific (or selective) binding: "specifically (or selectively)" binding to an antigen or epitope The term "bind" refers to the binding of a homologous antigen or enzyme to a heterogeneous population of proteins and other biological substances. The antigen-binding molecule or ABD of the present disclosure is typically , 5 x 10 -2 Under M, 10 -2 Less than M, 5 x 10 -3 Under M, 10 -3 Less than M, 5x 10 -4 Under M, 10 -4 Less than M, 5 x 10 -5 Under M, 10 -5 Less than M, 5 x 10 -6 Under M, 10 -6 Less than M, 5 x 10 -7 Under M, 10 -7 Less than M, 5 x 10 -8 Less than M, 10 -8 Less than M, 5 x 10 -9 Less than M or 10 -9 Dissociation rate constant (KD) less than M (ko ff / kon) and its affinity for binding to non-specific antigens (e.g., HSA) At least 2-fold higher (more typically, at least 20-fold, at least 50-fold or less) The binding affinity is measured by Biacore, SPR, or can be measured using a BLI assay.

[0108] The term "specifically binds" does not exclude cross-species reactivity. antigen-binding modules (e.g., antigen-binding fragments of antibodies) that "specifically bind" to their antigens An antigen may also "specifically bind" to the corresponding antigen in one or more other species. Therefore, such cross-species cross-reactivity itself does not allow the antigen-binding module to be a "specific" binding agent. In certain embodiments, the antigen-binding domain specifically binds to a human antigen. The main focus is on one or more non-human mammalian species, such as primate species (e.g., cynomolgus monkeys (Macaca fascicularis)). fascicularis), rhesus monkeys (Macaca mulatta) and pigs including, but not limited to, one or more of the following: or interspecific hybrids with rodent species, e.g., house mice (Mus musculus). In other embodiments, the antigen-binding domain does not have cross-species reactivity.

[0109] Subject: The term "subject" includes humans and non-human animals. Non-human animals include all vertebrates. Animals, e.g., mammals such as non-human primates, sheep, dogs, cows, chickens, amphibians, and reptiles Unless otherwise specified, the term "patient" or "subject" refers to a mammal or non-mammal. Used interchangeably herein.

[0110] Tandem of VH domains: As used herein, a "VH domain (or VH The term "tandem of VH domains" refers to a series of VH domains consisting of multiple identical VH domains of an antibody. Each VH domain, except for the last one at the end of the tandem, is connected to the linker - has its C-terminus linked to the N-terminus of another VH domain. has at least two VH domains, and in some embodiments of the BBM has 3, 4, 5, 6, 7, 8, 9 or 10 VH domains. Recombinant methods with or without linkers that allow the polypeptides to be produced as chains The VH domains can be generated by combining the encoding nucleic acids for each VH domain in the desired order using the The N-terminus of the first VH domain of the tandem is defined as the N-terminus of the tandem. , the C-terminus of the last VH domain of the tandem is defined as the C-terminus of the tandem.

[0111] Tandem of VL domains: As used herein, a "VL domain (or VL The term "tandem of VL domains" refers to a series of VL domains consisting of multiple identical VL domains of an antibody. Each VL domain, except for the last one at the end of the tandem, is connected to the linker The VL has its C-terminus linked to the N-terminus of another VL, with or without a VL. and in certain embodiments of the BBM, has at least two VL domains, and in certain embodiments has 3, 4, 5, 6, 7, The VL domains are tandem, meaning that they form a single polypeptide. using recombinant methods with or without linkers that allow the The VL domains can be generated by combining the encoding nucleic acids for each VL domain in the desired order. The N-terminus of the first VL domain of a tandem is defined as the N-terminus of the tandem, while the N-terminus of the tandem The C-terminus of the last VL domain of the tandem is defined as the C-terminus of the tandem.

[0112] Target antigen: As used herein, a "target antigen" refers to an antigen that is targeted by an antigen-binding domain. By "antibody" is meant a molecule that is non-covalently, reversibly and specifically bound by an ion exchange bond.

[0113] Therapeutically effective amount: A "therapeutically effective amount" is a dose, at a dosage and for a duration necessary to achieve a desired therapeutic result. refers to an effective amount in

[0114] Treat, Treatment, Treating: As used herein, "treat," "cure," The terms "therapy" and "treating" refer to a therapeutic agent resulting from the administration of one or more antigen-binding molecules. Reduction or amelioration of the progression, severity and / or duration of a proliferative disorder or It refers to the improvement of one or more symptoms (e.g., one or more identifiable symptoms). In this context, the terms "treat," "treatment," and "treating" are not necessarily used by patients. at least one measurable physical parameter of a proliferative disorder, such as tumor growth, that is not identified by a In other embodiments, "treat," "treatment," and "treating" refer to the improvement of the meter. The term "and" refers to a condition that can be physically resolved, for example by the stabilization of discernible symptoms, e.g., physical pain. Inhibition of the progression of proliferative diseases either physiologically or both by stabilization of the parameters In another embodiment, the terms "treat," "treatment," and "treating" are used interchangeably. The term refers to a reduction or stabilization of tumor size or cancerous cell number.

[0115] Tumor: The term "tumor" is used interchangeably herein with the term "cancer." For example, both terms encompass solid and liquid, e.g., diffuse or circulating tumors. As used herein, the term "cancer" or "tumor" refers to pre-malignant as well as malignant cancers and This includes tumors.

[0116] Variable region: As used herein, a "variable region" or "variable domain" refers to a Vκ, Vλ and / or VH genes that constitute the κ, λ and heavy chain immunoglobulin loci, respectively and one or more Ig domains substantially encoded by any one of the genes, "Variable heavy domain" refers to the region of an immunoglobulin containing the CDRs that confer specificity. " can pair with a "variable light chain domain" to form an antigen-binding domain ("ABD"). Furthermore, each variable domain is arranged in the following order: FR1-CDR1-FR2-CDR2-FR Three hypervariable regions arranged from amino to carboxy termini in 3-CDR3-FR4 regions ("complementarity determining regions", "CDRs") (CDR-H1, CDR-H2 for the variable heavy chain domain, CDR-H2, CDR-H3, and CDR-L1, CDR-L2 for the variable light chain domain , CDR-L3) and four framework (FR) regions.

[0117] Vector: The term "vector" refers to a vector that transports another polynucleotide to which it is linked. A vector is intended to refer to a polynucleotide molecule capable of carrying out the steps of: is a "plasmid," which is a vector into which additional DNA segments can be ligated. Another type of vector is a viral vector. wherein additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial bacterial vectors with an origin of replication and episomal mammalian vectors). Other vectors (e.g. (e.g., non-episomal mammalian vectors) are vectors that, upon introduction into a host cell, are integrated into the genome of the host cell. In addition, certain vectors can be integrated into the host genome, thereby replicating along with the host genome. They are capable of inducing the expression of genes to which they are operably linked. These vectors are referred to herein as "recombinant expression vectors" (or simply "expression vectors"). Generally, expression vectors useful in recombinant DNA techniques are in the form of plasmids. Since plasmids are the most commonly used form of vector, In the specification, the terms "plasmid" and "vector" may be used interchangeably. However, the present disclosure also provides viral vectors (e.g., replication-deficient retroviruses) that perform equivalent functions. such other forms of expression vectors (e.g., HIV, adenoviruses and adeno-associated viruses) is intended to include.

[0118] VH: The term "VH" refers to an antibody containing the heavy chain of an Fv, scFv, dsFv, or Fab. It refers to the variable region of the immunoglobulin heavy chain of the body.

[0119] VL: The term "VL" refers to the light chain of an immunoglobulin, including the light chain of an Fv, scFv, dsFv, or Fab. Refers to the variable region of the immunoglobulin light chain.

[0120] VH-VL or VH-VL pair: refers to a VH-VL pair, either on the same polypeptide chain or on different polypeptide chains. Regardless of which polypeptide chains are involved, the terms "VH-VL" and "VH-VL pair" refer to are used for convenience and are not intended to indicate any particular orientation unless the context requires otherwise. Therefore, scFs containing "VH-VL" or "VH-VL pairs" are not intended to be synonymous with "VH-VL" or "VH-VL pairs." v can be VH and VL in any orientation, e.g., VH N-terminus to VL or VL N-terminus to VH. and a VL domain.

[0121] 6.2.BCMA binding molecules The present disclosure provides therapeutic regimens and formulations of BCMA binding molecules. The subject also includes multispecific binding molecules, e.g., multispecific antibodies, that bind to BCMA and CD3. More particularly, bispecific binding molecules, such as bispecific antibodies.

[0122] In a particularly preferred embodiment, the BCMA binding molecule is referred to herein as BSBM3. BSBM3 is a molecule that contains the Fab domain that targets BCMA and CD3. BSBM3 has a single-chain Fv (scFv) domain that targets three polypeptides. It consists of two halves, which, when expressed in the same cell, form the two halves shown in Figure 1. The antibody is formed by combining a light chain polypeptide having the amino acid sequence of SEQ ID NO: 2 with the sequence The first half antibody is composed of a heavy chain polypeptide having the amino acid sequence of SEQ ID NO: 1. 19. The heavy chain polynucleotide has the amino acid sequence of SEQ ID NO: 3. The second half antibody, composed of a peptide, contains an scFv domain that binds to CD3. The Fc domain of BSBM3 mediates non-selective T cell proliferation via FcR (Fc receptor)-mediated cross-linking. This includes eliminating binding to human Fcγ receptors to reduce the risk of activation. Without being bound by theory, it is believed that the Fc domain is a non-modified FcRn (neonatal Fc receptor This is thought to provide IgG-like in vivo persistence due to its affinity to the receptor. Without being limited to this, the expression of BCMA in multiple myeloma (MM) cells and T cells Multiple BSBM3 subunits interact with the CD3 subunit of the T cell receptor (TCR) complex in the Molecular binding leads to TCR cross-linking and the formation of a cytolytic immune synapse, resulting in T cell activation. It is also thought that this results in the activation and specific lysis of MM cells.

[0123] Pharmaceutical Compositions The BCMA binding molecules of the disclosure may be administered in, for example, one or more pharmaceutically acceptable excipients or carriers. The BCM of the present disclosure may be formulated as a pharmaceutical composition comprising a BCMA-binding molecule containing To prepare a pharmaceutical or sterile composition containing a BCMA-binding molecule, the BCMA-binding molecule formulation may be prepared in one It may be combined with the above pharmaceutically acceptable excipients or carriers.

[0124] For example, a formulation of a BCMA binding molecule may comprise incorporating the BCMA binding molecule in a physiologically acceptable carrier, and excipients or stabilizers, e.g., lyophilized powders, slurries, aqueous solutions, lotions, or suspensions. can be prepared by mixing in the form (e.g., Hardman et al., 2 001,Goodman and Gilman's The Pharmacolog ical Basis of Therapeutics,McGraw-Hill,N ew York, NY; Gennaro, 2000, Remington: The Science and Practice of Pharmacy,Lippinc ott,Williams,and Wilkins,New York,NY;A vis et al.(eds.),1993,Pharmaceutical Dos age Forms:General Medications,Marcel Dek ker, NY; Lieberman et al. (eds.), 1990, Pharm. aceutical Dosage Forms:Tablets,Marcel De kker, NY; Lieberman et al. (eds.), 1990, Phar Maceutical Dosage Forms: Disperse Systems ,Marcel Dekker,NY;Weiner and Kotkoskie,2 000,Excipient Toxicity and Safety,Marcel See Dekker, Inc., New York, NY).

[0125] For intravenous formulations, the BCMA binding molecule may be formulated with one or more excipients. In one embodiment, the BCMA binding molecule is formulated with an amino acid. In one embodiment, the BCMA binding molecule is formulated with a sugar. The binding molecule is formulated with a surfactant. In one embodiment, the BCMA binding molecule is In one embodiment, the BCMA binding molecule is formulated with an amino acid, a sugar, or may be formulated with one or more of a surfactant.

[0126] In some embodiments, the amino acid may be histidine. The sugar can be sucrose. In one embodiment, the surfactant is Tween 20 Polysorbates such as polysorbate 20 ("PS20"), also known as obtain.

[0127] Accordingly, the present disclosure provides a method for producing a BCMA-binding molecule comprising: (a) an amino acid, such as histidine; (c) a surfactant such as PS20; or (d) any of the above. The present invention provides pharmaceutical compositions containing any two or all of the above in combination. In the given case, the pharmaceutical composition may be a liquid pharmaceutical composition.

[0128] A suitable concentration of histidine is in the range of 10 mM to 50 mM. The concentration of histidine is 20 mM.

[0129] A suitable concentration of sucrose is in the range of 150 mM to 300 mM. The concentration of sucrose is 240 mM.

[0130] A suitable concentration of PS20 is in the range of 0.02% to 0.06%. , the concentration of PS20 is 0.04%.

[0131] The pharmaceutical composition may contain, for example, histidine, sucrose, and PS20 in the concentrations described above. To obtain a solution for administration containing one or more of the above, the solution is lyophilized and a suitable volume of the solution is added. It can be restored to the body.

[0132] In certain embodiments, the pH of the formulation may be acidic. For example, in one embodiment The pH of the formulation may be from about 5.0 to about 6.5. In one embodiment, the pH of the formulation is The pH of the formulation may be about 5.0 to about 6.0. In one embodiment, the pH of the formulation is about 5.5. obtain.

[0133] Suitable pH for liquid pharmaceutical compositions comprising BCMA binding molecules for parenteral, e.g., intravenous, administration The range is acidic, e.g., from about 5.0 to about 6.5. In certain embodiments, the pH is about 5. The pH ranges from about 0.0 to about 6.0, and in one embodiment, the pH is about 5.5.

[0134] A suitable concentration range for the BCMA binding molecule is 5 mg / mL to 20 mg / mL. In the form of 10 mg / mL.

[0135] Thus, in certain embodiments, the present disclosure provides a method for treating a BSBM3 deficiency, comprising: (a) administering to a subject a BSBM3 deficiency virus containing 10 mg / mL of BSBM3; (b) 20 mM histidine; (c) 240 mM sucrose; (d) 0.04% P S20; and (e) a vial containing a pH of about 5.5±0.3.

[0136] 7. Administration 7.1. Amount of BCMA-binding molecules BCMA binding molecules may be used in the prevention and / or treatment of cancer.

[0137] In one embodiment, the subject is administered from about 0.5 μg / kg of a BCMA binding molecule. In one embodiment, the subject may be administered from about 1 μg / kg of a BCMA binding molecule. In one embodiment, the subject receives from about 10 μg / kg of a BCMA binding molecule. In one embodiment, a subject may be administered a BCMA-binding protein from about 30 μg / kg. In one embodiment, subjects may receive a BCMA antibody dose of from about 50 μg / kg. In one embodiment, a subject may be administered a BCM combination of from about 75 μg / kg. In one embodiment, a subject may be administered a dose of from about 100 μg / kg to about 100 μg / kg of an A-binding molecule. In one embodiment, the subject may be administered about 200 μg / kg of a BCMA binding molecule. In one embodiment, a subject may receive about 300 μg of a BCMA binding molecule. In one embodiment, a subject may be administered from about 40 / kg of a BCMA binding molecule. In one embodiment, the subject may be administered a BCMA binding molecule from 0 μg / kg. From about 500 μg / kg of the BCMA binding molecule may be administered. Elephants may be administered from about 600 μg / kg of a BCMA binding molecule. Thus, a subject may be administered from about 700 μg / kg of a BCMA binding molecule. In one embodiment, a subject may receive from about 800 μg / kg of a BCMA binding molecule. In embodiments, subjects may be administered from about 900 μg / kg of a BCMA binding molecule. In one embodiment, the subject is administered from about 1000 μg / kg of a BCMA binding molecule. It is possible.

[0138] For example, in one embodiment, a subject is administered a dose of about 1 μg / kg to about 20 μg / kg. In one embodiment, the subject may receive a BCMA binding molecule at a dose of about 20 μg / kg to The BCMA binding molecule may be given at a dose of about 40 μg / kg. Elephants may receive the BCMA binding molecule at a dose of about 80 μg / kg to about 120 μg / kg. In one embodiment, the subject receives B at a dose of about 150 μg / kg to about 250 μg / kg. In one embodiment, a subject may receive a CMA-binding molecule at a dose of about 300 μg / kg to The BCMA binding molecule may be given at a dose of about 500 μg / kg. The subject receives the BCMA binding molecule at a dose of about 500 μg / kg to about 700 μg / kg. In one embodiment, the subject receives a dose of about 600 μg / kg to about 900 μg / kg. The BCMA binding molecule can be administered in a

[0139] In one embodiment, the subject receives between about 1 μg / kg and about 1000 μg / kg of BCMA binding. In one embodiment, a subject may be administered a dose of about 10 μg / kg to about 900 μg / kg. In one embodiment, the subject may receive the BCMA binding molecule at a dose of about 100 mg / kg. The BCMA binding molecule may be given at a dose of 20 μg / kg to about 800 μg / kg. In some embodiments, the subject receives a BCMA-binding antibody at a dose of about 30 μg / kg to about 700 μg / kg. In one embodiment, a subject can receive from about 50 μg / kg to about 600 μg In one embodiment, the subject may receive the BCMA binding molecule at a dose of about 7 / kg. The BCMA binding molecule may be given at a dose of 5 μg / kg to about 500 μg / kg. In one embodiment, the subject is administered a BCMA-binding antibody at a dose of about 100 μg / kg to about 400 μg / kg. In one embodiment, a subject can receive a dose of from about 150 μg / kg to about 300 μg / kg. In one embodiment, the subject may receive the BCMA binding molecule at a dose of about 100 mg / kg. The BCMA binding molecule may be given at a dose of 200 μg / kg to about 250 μg / kg.

[0140] Additionally, any of the dosages disclosed throughout this disclosure may be administered, for example, as a first or subsequent treatment. It can be used to administer a BCMA binding molecule at a therapeutic dose.

[0141] In one embodiment, the therapeutic dose is from about 1 μg / kg to about 1200 μg / kg or about 50 In another embodiment, the therapeutic dose may be from about 3 μg / kg to about 96 mg. In another embodiment, the treatment may be 600 μg / kg or about 150 μg to about 48 mg. The therapeutic dose may be from about 5 μg / kg to about 100 μg / kg or from about 150 μg to about 8 mg. In another embodiment, the therapeutic dose is from about 10 μg / kg to about 200 μg / kg or about 5 In another embodiment, the therapeutic dose may be about 50 μg / kg. In another embodiment, the dose may be from about 2.5 mg to about 32 mg. The therapeutic dose is about 100 μg / kg to about 600 μg / kg or about 5 mg to about 96 mg. In another embodiment, the therapeutic dose is about 1 μg / kg or about 50 μg to about 80 μg. In another embodiment, the therapeutic dose may be about 3 μg / kg. In embodiments, the therapeutic dose may be from about 150 μg to about 240 μg. In this case, the therapeutic dose may be about 6 μg / kg or about 300 μg to about 480 μg. In this embodiment, the therapeutic dose is about 12 μg / kg or about 600 μg to about 960 μg. In another embodiment, the therapeutic dose is about 24 μg / kg or about 1.2 mg to about In another embodiment, the therapeutic dose may be about 48 μg / kg or about In another embodiment, the therapeutic dose is about 96 mg. g / kg or about 4.8 mg to about 7.68 mg. The amount can be about 192 μg / kg or about 9.6 mg to about 15.36 mg. In this embodiment, the therapeutic dose is about 384 μg / kg or about 19.2 mg to about 30.72 mg. In another embodiment, the therapeutic dose is about 600 μg / kg or about 30 mg to about It can be 48 mg.

[0142] In some cases, a priming dose is required or used. The amount can be any of the doses described herein, and in certain embodiments, the first treatment For example, if the first therapeutic dose of a BCMA binding molecule is 30 μg / kg, If present, the priming dose may be given at any dose less than 30 μg / kg. In certain cases, the priming dose is less than 30 μg / kg, for example 29 μg / kg It may be given in smaller doses, for example, 10 μg / kg or 1 μg / kg. In some embodiments, the priming dose is equal to the first therapeutic dose. The compound may be administered in a single dose, or alternatively, in multiple doses (e.g., two doses). In some embodiments, one-third of the priming dose is administered on day 1, and Two-thirds of the dose is administered on day 2, eg, the day after day 1.

[0143] In one embodiment, the priming dose is from about 0.5 μg / kg to about 6 μg / kg, or In another embodiment, the priming dose ranges from about 25 μg to about 480 μg. In another embodiment, the amount is about 1 μg / kg or about 50 μg to about 80 μg. The administration dose is about 2 μg / kg or about 100 μg to about 160 μg. Therefore, the priming dose is about 3 μg / kg or about 150 μg to about 240 μg. In embodiments, the priming dose is about 4 μg / kg or about 200 μg to about 320 μg. In another embodiment, the priming dose is about 5 μg / kg or about 250 μg. In another embodiment, the priming dose is about 6 μg / kg to about 400 μg. Or about 300 μg to about 480 μg.

[0144] 7.2. Administration time Administration can occur over several hours. For example, if administration of the BCMA binding molecule is intravenous, When used, it can be done by infusion. Infusion can be administered over a period of about 30 minutes to about 6 hours. In certain embodiments, the infusion is carried out over a period of about 30 minutes. In some embodiments, the infusion may be carried out over a period of about 1 hour. In some embodiments, the infusion may occur over a period of about 1.5 hours. In some embodiments, the infusion may be carried out over a period of about 2 hours. In one embodiment, the infusion is carried out over a period of about 3 hours. In one embodiment, the infusion is carried out over a period of about 3.5 hours. In certain embodiments, the infusion may be carried out over a period of about 4 hours. In some embodiments, the infusion may occur over a period of about 4.5 hours. In some embodiments, the infusion may be carried out over a period of about 5 hours. The infusion may be carried out over a period of about 5.5 hours. In certain embodiments, the infusion is carried out over a period of about This may be done over a 6 hour period.

[0145] In certain embodiments, the infusion may occur over a period of about 30 minutes to about 1 hour. In some embodiments, the infusion may occur over a period of about 1 hour to about 2 hours. In embodiments, the infusion may occur over a period of about 2 hours to about 3 hours. In some embodiments, the infusion may be carried out over a period of about 3 to about 4 hours. In one embodiment, the infusion may be carried out over a period of about 4 to about 5 hours. In this case, the infusion may be carried out over a period of about 5 to about 6 hours.

[0146] In certain embodiments, the infusion may occur over a period of about 30 minutes to about 6 hours. In certain embodiments, the infusion may be carried out over a period of about 1 hour to about 5 hours. In embodiments, the infusion may be carried out over a period of about 1.5 hours to about 4 hours. In embodiments, the infusion may occur over a period of about 2 to about 3 hours.

[0147] Additionally, any of the administration times disclosed throughout may be used in combination with a BCMA binding molecule and / or It may be used to administer any of the other therapeutic agents disclosed throughout.

[0148] 7.3. Administration Schedule In certain embodiments, the BCMA binding molecule may be administered once a week. In one embodiment, the BCMA binding molecule may be administered twice a week. The binding molecule may be administered once every two weeks.

[0149] In certain embodiments, the BCMA binding molecule may be administered in a single dose. Thus, the BCMA molecule may be administered twice. In one embodiment, the BCMA binding molecule is In one embodiment, the BCMA binding molecule may be administered four times.

[0150] In one embodiment, the BCMA binding molecule may be administered for one week. In some embodiments, the BCMA binding molecule may be administered over a two week period. In one embodiment, the BCMA binding molecule may be administered for three weeks. The BCMA binding molecule may be administered for four weeks.

[0151] In one embodiment, the BCMA binding molecule is administered to a patient (in relation to cancer) until remission, e.g., In one embodiment, the BCMA binding molecule is administered in a portion It may be administered until remission, e.g., until a partial response is observed. The BCMA binding molecule may be administered until complete remission, e.g., until a complete response is observed. .

[0152] In relation to any priming dose given, the priming dose is It may be given at any time prior to the first therapeutic dose, e.g., for priming. The dose may be given once a week before the first therapeutic dose is given. The timing dose may be given twice within one week before the first therapeutic dose is given.

[0153] In one embodiment, one-third of the priming dose is administered to the subject on day 1 of the treatment course. In one embodiment, the first priming dose is administered on day 1 of treatment, and the remainder of the priming dose is administered on day 2 of treatment. , the first treatment dose is then administered on one of days 5-11 of treatment (e.g., days 6-10) one of days 7-9, or day 8), and a second therapeutic dose However, thereafter, on one of the 12th to 18th days of treatment (e.g., on one of the 13th to 17th days) , one of days 14-16, or day 15) and administered to the subject at one-third of the therapeutic dose. However, thereafter, on one of the 19th to 25th days of treatment (e.g., on one of the 20th to 24th days) , one of days 21-23, or day 22).

[0154] 7.4. Side effect reducers With respect to side effect reducing agents, the agents and dosages described throughout this disclosure are Furthermore, these side effect-reducing agents are safe and effective. It can be used when it is known that

[0155] 8. Combinations The BCMA binding molecules of the present disclosure may be used in combination with other known drugs and therapies For example, BCMA-binding molecules can be used to treat various diseases, including surgery, chemotherapy, antibodies, radiation, and peptide vaccines. , steroids, cytotoxins, proteasome inhibitors, immunomodulatory drugs (e.g., IMiDs), B Treatment in combination with H3 mimetics, cytokine therapy, stem cell transplantation, or any combination thereof can be used in treatment planning.

[0156] For convenience, agents used in combination with BCMA binding molecules are referred to herein as "additional These drugs are called "anti-inflammatory" drugs.

[0157] As used herein, administration "in combination" refers to the administration of two (or more) different The therapeutic agent may be delivered to a subject during the course of the subject's disease, e.g., two or more therapeutic agents. The above therapeutic agents are administered after a subject has been diagnosed with a disease and before or after the disease has been cured or eliminated. This means that the administration of the drug is completed before the drug is stopped for other reasons. delivery of one therapeutic agent may be initiated when delivery of a second therapeutic agent begins, so that there is an overlap. This is referred to herein as "concurrent" or "concurrent delivery." The term "concurrently" refers to the exact same therapeutic agent (e.g., BCM) and pharmaceutical compositions comprising BCMA-binding molecules, but not limited to administration of BCMA-binding molecules and additional agents. However, BCMA-binding molecules may also act together with additional therapeutic agents to treat patients who are not otherwise administered. be administered to a subject in a sequence and within time intervals that may provide increased benefit than if the For example, each therapeutic agent may be administered to a subject simultaneously or at different times, sequentially, in any order. If not administered simultaneously, they may be administered in a manner that provides the desired therapeutic effect. They should be administered close enough in time.

[0158] The BCMA binding molecule and one or more additional agents may be administered simultaneously in the same or separate compositions. In the case of sequential administration, the BCMA binding molecule may be administered first, followed by The additional agent may be administered second, or the order of administration may be reversed.

[0159] The BCMA binding molecule and additional agent may be administered in any suitable form and by any suitable route. In some embodiments, the routes of administration are the same. In some embodiments, the route of administration may vary.

[0160] In other embodiments, the delivery of one therapeutic agent ends before the delivery of another therapeutic agent begins. do.

[0161] In either embodiment, the therapeutic agents are more effective when administered in combination. For example, a second therapeutic agent may be more effective than, for example, a second therapeutic agent that is equally effective but less effective. or when the second therapeutic agent is administered without the first therapeutic agent. relieves symptoms to a greater extent than seen with the first therapeutic agent, or a similar condition is observed with the first therapeutic agent. In some embodiments, delivery is achieved by reducing symptoms or other parameters associated with the disease. greater than that observed with one therapeutic agent delivered without the other. The effects of the two therapeutic agents may be partially additive, fully additive, or Delivery can be more than additive. The effect of a first therapeutic agent being delivered can be greater than the effect of a second therapeutic agent being delivered. The target may be such that it is still detectable when the target is removed.

[0162] The BCMA binding molecule and / or additional agent may be administered during active disease or in remission or activity. The BCMA binding molecule may be administered during a period of disease when the disease is less aggressive. Administered concurrently with additional drug therapy, after additional drug therapy, or during disease remission. can be given.

[0163] When administered in combination, the BCMA binding molecule and / or the additional agent may be administered in combination, e.g., Amounts or doses greater than, less than, or equal to the amounts or doses of each drug used individually as monotherapy It can be administered in doses.

[0164] The additional agents of the combination therapies of the present disclosure may be administered to a subject simultaneously. The term "administration of therapeutic agents" is not limited to the administration of simultaneous therapeutic agents (e.g., prophylactic or therapeutic agents), but includes B Pharmaceutical compositions comprising CMA-binding molecules are disclosed in which the molecules of the disclosure act in conjunction with an additional therapeutic agent to: The sequence and timing of administration may provide increased benefit over other methods of administration. This means that the therapeutic agents are administered to a subject at intervals, e.g., at the same time or at different times. They may be administered to a subject sequentially in any order; however, if not administered simultaneously, they may be administered as desired. Each treatment should be administered sufficiently closely in time to provide a therapeutic or prophylactic effect. The agents may be administered separately to a subject in any appropriate form and by any suitable route.

[0165] The BCMA binding molecule and the additional agent may be administered to the subject by the same or different routes of administration. It is possible.

[0166] The BCMA binding molecule and the additional agent may be administered in cycles. administration of a first therapeutic agent (e.g., a first prophylactic or therapeutic agent) over a period of time, followed by administration of a second therapeutic agent (e.g., a first prophylactic or therapeutic agent) over a period of time. administration of a second therapeutic agent (e.g., a second prophylactic or therapeutic agent), optionally followed by a period of and administering a third therapeutic agent (e.g., a prophylactic or therapeutic agent) over a period of time, and repeating this sequential administration. and reducing the development of resistance to one of the therapeutic agents and to avoid or reduce side effects and / or improve the effectiveness of therapeutic agents .

[0167] Optionally, the one or more additional agents are other anti-cancer agents, anti-allergic agents, anti-emetic agents (or antiemetics), analgesics, cytoprotective agents and combinations thereof.

[0168] The BCMA binding molecules may be used in combination with gamma secretase inhibitors ("GSIs"). do.

[0169] Thus, in one aspect, the present disclosure provides a method for treating a patient suffering from a disease associated with BCMA expression. 1. A method for treating an elephant comprising administering to an elephant an effective amount of: (i) a BCMA-binding molecule; and (ii) gamma The method includes administering a secretase inhibitor (GSI) to a subject.

[0170] In another embodiment, the present disclosure provides a method for treating a disease associated with BCMA expression. 1. A method for treating a subject with BCMA comprising administering to a subject an effective amount of: (i) a BCMA-binding molecule, and (ii) ) GSI to a subject.

[0171] In one embodiment, the BCMA binding molecule and the GSI are administered simultaneously or sequentially. In one embodiment, the BCMA binding molecule is administered prior to administration of the GSI. In one embodiment, the GSI is administered prior to administration of the BCMA binding molecule. The BCMA binding molecule and the GSI are administered simultaneously.

[0172] In one embodiment, the GSI is administered prior to administration of the BCMA binding molecule (e.g., G SI is administered 1, 2, 3, 4, or 5 days prior to administration of the BCMA binding molecule), optionally Specifically, after administration of the GSI and before administration of the BCMA binding molecule, the subject is monitored for cell surface BCMA expression. Increased levels and / or decreased levels of soluble BCMA are shown.

[0173] In one embodiment, the GSI reduces the expression and / or function of gamma secretase A small molecule, such as a small molecule GSI disclosed herein. In one embodiment, the GSI LY-450139, PF-5212362, BMS-708163, MK-075 2, ELN-318463, BMS-299897, LY-411575, DAPT, A L-101 (also known as BMS-906024), AL-102 (BMS-9 86115), PF-3084014, RO4929097 and L Y3039478. In one embodiment, the GSI is selected from PF-521236 2, ELN-318463, BMS-906024 and LY3039478 An exemplary GSI is described by Takebe et al., Pharmacol Ther. 2014 Feb;141(2):140-9; and Ran et al., EMBO Mol Med. 2017 Jul;9(7):950-966. In an embodiment, the GSI is AL-101. The structure of AL-102 is shown below. [ka]

[0174] In one embodiment, MK-0752 is administered in combination with docetaxel. In one embodiment, MK-0752 is administered in combination with gemcitabine. In some embodiments, BMS-906024 is administered in combination with chemotherapy.

[0175] In a further embodiment, the GSI is a compound as described in U.S. Pat. No. 7,468,365. In one embodiment, the GSI is LY-450139, i.e., a compound Magacestat, (S)-2-hydroxy-3-methyl-N-((S)-1-(((S) -3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepi (1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)butanamide or its pharmaceutical In one embodiment, the GSI is an acceptable salt thereof. [ka] or a pharmaceutically acceptable salt thereof.

[0176] In a further embodiment, the GSI is a compound as described in U.S. Pat. No. 7,687,666. In one embodiment, the GSI is PF-5212362, i.e. Vegacestat, GSI-953 or (R)-5-chloro-N-(4,4,4-trifluoromethyl) Oro-1-hydroxy-3-(trifluoromethyl)butan-2-yl)thiophene-2 -sulfonamide, or a pharmaceutically acceptable salt thereof. In one embodiment, the GSI is [ka] or a pharmaceutically acceptable salt thereof.

[0177] In a further embodiment, the GSI is a compound as described in U.S. Pat. No. 8,084,477. In one embodiment, the GSI is BMS-708163, i.e. Avagacestat or (R)-2-((4-chloro-N-(2-fluoro-4-(1,2 ,4-Oxadiazol-3-yl)benzyl)phenyl)sulfonamido)-5,5, 5-trifluoropentanamide or a pharmaceutically acceptable salt thereof. GSI is [ka] or a pharmaceutically acceptable salt thereof.

[0178] In one embodiment, the GSI is a compound described in U.S. Pat. No. 7,160,875. In one embodiment, the GSI is RO4929097, i.e., (S) -2,2-dimethyl-N1-(6-oxo-6,7-dihydro-5H-dibenzo[b,d ]azepin-7-yl)-N3-(2,2,3,3,3-pentafluoropropyl)malon In one embodiment, the GSI is [ka] or a pharmaceutically acceptable salt thereof.

[0179] In one embodiment, the GSI is [ka] or a pharmaceutically acceptable salt thereof.

[0180] In one embodiment, the GSI is a compound described in U.S. Pat. No. 6,984,663. In one embodiment, the GSI is MK-0752, i.e., 3-((1 S,4R)-4-((4-chlorophenyl)sulfonyl)-4-(2,5-difluorophenyl) The compound is a phenyl)cyclohexyl)propanoic acid or a pharmaceutically acceptable salt thereof. In this situation, GSI [ka] or a pharmaceutically acceptable salt thereof.

[0181] In one embodiment, the GSI is a compound described in U.S. Pat. No. 7,795,447. In one embodiment, the GSI is PF-3084014, i.e., nitrite. Rogacestat or (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrafluoroethane N-(1-(2-methyl-1-(trihydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentyl) (ethylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide or is a pharmaceutically acceptable salt thereof.

[0182] In one embodiment, the GSI is [ka] or a pharmaceutically acceptable salt thereof.

[0183] In one embodiment, the GSI is a compound described in U.S. Pat. No. 7,939,657. In one embodiment, the GSI is ELN-318463, i.e., HY -50882 or (R)-N-(4-bromobenzyl)-4-chloro-N-(2-oxo azepan-3-yl)benzenesulfonamide or a pharmaceutically acceptable salt thereof. In some embodiments, the GSI is [ka] or a pharmaceutically acceptable salt thereof.

[0184] In one embodiment, the GSI is a compound described in U.S. Pat. No. 8,629,136. In one embodiment, the GSI is BMS-906024, i.e., (2 R,3S)-N-[(3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydriodide 1H-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoromethyl)- In one embodiment, the compound is (fluoropropyl)succinamide or a pharmaceutically acceptable salt thereof. GSI is [ka] or a pharmaceutically acceptable salt thereof.

[0185] In one embodiment, the GSI is a compound described in U.S. Pat. No. 8,629,136. In one embodiment, the GSI is LY3039478, i.e., clonidine. Gacestat or 4,4,4-trifluoro-N-((R)-1-(((S)-5-(2 -hydroxyethyl)-6-oxo-6,7-dihydro-5H-benzo[d]pyrido[2 ,3-b]azepin-7-yl)amino)-1-oxopropan-2-yl)butanamine or a pharmaceutically acceptable salt thereof. In one embodiment, the GSI is [ka] or a pharmaceutically acceptable salt thereof.

[0186] In one embodiment, the GSI is BMS-299897, i.e., 2-[(1R)- 1-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)amino] Ethyl-5-fluorobenzenebutanoate or a pharmaceutically acceptable salt thereof. In form, GSI is [ka] or a pharmaceutically acceptable salt thereof.

[0187] In one embodiment, the GSI is LY-411575, i.e., LSN-41157 5. (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetone (S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzamide 2,3-dimethyl-2,4-diazepine-7-yl)propanamide or a pharmaceutically acceptable salt thereof. In one embodiment, the GSI is [ka] or a pharmaceutically acceptable salt thereof.

[0188] In one embodiment, the GSI is DAPT, i.e., N-[(3,5-difluoromethyl)-2-(2-methyl-2-propanol]-3,5-difluoro ... [phenyl)acetyl]-L-alanyl-2-phenyl]glycine-1,1-dimethylethyl ester or a pharmaceutically acceptable salt thereof. [ka] or a pharmaceutically acceptable salt thereof.

[0189] In one embodiment, the GSI is a compound as described in U.S. Patent Application Publication No. 2015-307533. In one embodiment, the compound is a compound described in the document (e.g., in the table on pages 13 to 16). GSI is [ka] or a pharmaceutically acceptable salt thereof.

[0190] In one embodiment, the GSI is a compound of U.S. Pat. No. 8,188,069. In one embodiment, the GSI is [ka] or a pharmaceutically acceptable salt thereof.

[0191] In one embodiment, the GSI is a compound as described in U.S. Pat. No. 9,096,582 (e.g., In one embodiment, the GSI is a compound described in the table on pages 13-17. [ka] or a pharmaceutically acceptable salt thereof.

[0192] In one embodiment, the GSI is a compound disclosed in U.S. Patent Application Publication No. 2011-0257163. In one embodiment, the compound is one described in the detailed description (e.g., paragraphs

[0506] to

[0553] ). In form, GSI is [ka] and pharmaceutically acceptable salts thereof.

[0193] In one embodiment, the GSI is [ka] and pharmaceutically acceptable salts thereof.

[0194] In one embodiment, the GSI is [ka] and pharmaceutically acceptable salts thereof.

[0195] In one embodiment, the GSI reduces the expression and / or function of gamma secretase In one embodiment, the GSI targets a subunit of gamma secretase. In one embodiment, the GSI is an anti-presenilin antibody molecule, an anti-nicastrin antibody molecule, an anti-APH-1 antibody molecule, or an anti-PEN-2 antibody molecule; do.

[0196] Exemplary antibody molecules that target subunits of gamma secretase (e.g., presecretase Nilin, Nicastrin, APH-1 or PEN-2) are disclosed in U.S. Patent No. 8,394,376 No. 8,637,274 and U.S. Pat. No. 5,942,400 It is stated in the specification.

[0197] In one aspect, the disclosure provides a method for treating a subject having a B-cell condition or disorder. and (ii) a gamma-secretase modulator (e.g., a BCMA-binding molecule) in an amount sufficient to induce BCMA-specific cell death. The present invention provides methods for treating BCMA-associated leukemia (e.g., leukemia-associated leukemia (GIL)) and γ-cell lymphoma (e.g., leukemia-associated leukemia (GIL)). Exemplary B-cell conditions or disorders that can be treated with a combination of cretase modulators include multiple myeloma, Myeloma, Waldenstrom's macroglobulinemia, chronic lymphocytic leukemia, B-cell Non-Hodgkin's lymphoma, plasmacytoma, Hodgkin's lymphoma, follicular lymphoma, small non-cleaved lymphoma Nuclear cell lymphoma, endemic Burkitt lymphoma, sporadic Burkitt lymphoma, marginal zone lymphoma lymphoma, extranodal mucosa-associated lymphoid tissue lymphoma, nodal monocytic B-cell lymphoma, splenic lymphoma, Mantle cell lymphoma, large cell lymphoma, diffuse mixed cell lymphoma, immunoblastic lymphoma lymphoma, primary mediastinal B-cell lymphoma, pulmonary B-cell angiocentric lymphoma, small lymphocytic lymphoma tumor, B-cell proliferation of undetermined grade, lymphomatoid granulomatosis, post-transplant lymphoproliferative disorder, immunomodulatory disability, rheumatoid arthritis, myasthenia gravis, idiopathic thrombocytopenic purpura, antiphospholipid syndrome , Chagas disease, Graves' disease, Wegener's granulomatosis, Polyarteritis nodosa, Sjogren's disease syndrome, pemphigus vulgaris, scleroderma, multiple sclerosis, antiphospholipid syndrome, ANCA-associated pulmonary vasculitis, Goodpasture's syndrome, Kawasaki disease, autoimmune hemolytic anemia, rapidly progressive glomerulonephritis , heavy chain disease, primary or immune cell-associated amyloidosis, and monoclonal gamma of unknown significance Examples include globulinemia.

[0198] In one embodiment, the gamma secretase modulator is In one embodiment, the gamma-secretase modulator is a gamma-secretase modulator described in the pamphlet. Secretase modulators include gamma-secretase inhibitor I (GSI I) Z-Leu-Leu- γ-Secretase Inhibitor II (GSI II); γ-Secretase Inhibitor I II (GSI III), N-benzyloxycarbonyl-Leu-leucinal, N- (2-Naphthoyl)-Val-phenylalaninal; γ-secretase inhibitor IV (G SI IV); γ-secretase inhibitor V (GSI V), N-benzyloxycarbonyl Leu-phenylalaninal; γ-secretase inhibitor VI (GSI VI), 1 -(S)-endo-N-(1,3,3)-trimethylbicyclo[2.2.1]hepta- 2-yl)-4-fluorophenylsulfonamide; γ-secretase inhibitor VII(G SI VII), Menthyloxycarbonyl-LL-CHO; γ-secretase inhibitor I X(GSI IX), (DAPT), N-[N-(3,5-difluorophenacetyl-L -alanyl)]-S-phenylglycine t-butyl ester; γ-secretase inhibitor X (GSI X), {1S-benzyl-4R-[1-(1S-carbamoyl-2-phenethyl] [1S-3-methylbutylcarbamoyl]-2R-hydroxy-5-(4-methyl-2 ... {phenylpentyl}carbamic acid tert-butyl ester; γ-secretase inhibitor XI (GSI XI), 7-amino-4-chloro-3-methoxyisocoumarin; γ-secreta γ-Secretase inhibitor XII (GSI XII), Z-Ile-Leu-CHO; γ-secretase Inhibitor XIII (GSI XIII), Z-Tyr-Ile-Leu-CHO; γ-Sec Glycine Glutamate Inhibitor XIV (GSI XIV), Z-Cys(t-Bu)-Ile-Leu- CHO; γ-secretase inhibitor XVI (GSI XVI), N-[N-3,5-difluoromethyl [Orophenacetyl]-L-alanyl-S-phenylglycine M ethyl ester;γ-sec γ-Secretase inhibitor XVII (GSI XVII); γ-Secretase inhibitor XIX (GSI XIX), benzo[e][l,4]diazepin-3-yl)-butyramide; γ-sec Glycerinase inhibitor XX (GSI XX), (S,S)-2-[2-(3,5-difluoromethyl)propanol] phenyl)acetylamino]-N-(5-methyl-6-oxo-6,7-dihydro-5H- Dibenzo[b,d]azepin-7-yl)propionamide; γ-secretase inhibitor X XI (GSI XXI), (S,S)-2-[2-(3,5-difluorophenyl)-a cetylamino]-N-(l-methyl-2-oxo-5-phenyl-2-,3-dihydro- lH-Benzo[e][l,4]diazepin-3-yl)-propionamide;γ40 sec Leucinease inhibitor I, N-trans-3,5-dimethoxycinnamoyl-Ile-leucine γ40 secretase inhibitor II, N-tert-butyloxycarbonyl-Gly -Val-Valinal; Isovaleryl-V V-Sta-A-Sta -OCH3;MK-0752(Merck);MRK-003(Merck);Semagase Stat / LY450139 (Eli Lilly); RO4929097; PF-03 084014; BMS-708163; MPC-7869 (γ-secretase modulator), YO-01027 (dibenzazepine); LY411575 (Eli Lilly and Co.);L-685458(Sigma-Aldrich);BMS-289948 (4-chloro-N-(2,5-difluorophenyl)-N-((lR)-{4-fluoro -2-[3-(lH-imidazol-l-yl)propyl]phenyl}ethyl)benzene sulfonamide hydrochloride); or BMS-299897 (4-[2-((lR)-l-{[ (4-chlorophenyl)sulfonyl]-2,5-difluoroanilino}ethyl)-5- Fluorophenylbutanoic acid (Bristol Myers Squibb).

[0199] 9. Therapeutic indications The BCMA binding molecules of the present disclosure can be used to treat any disease associated with BCMA expression. In one aspect, the disclosure provides a method of treating cancer in a subject, the method comprising: and administering a BCMA-binding molecule to the subject such that cancer is treated in the subject. An example of a cancer treatable by CMA-targeted drugs is multiple myeloma (also known as MM). These cancers are associated with BCMA expression, such as leukemia (Claudio et al., 2017). 02, Blood.100(6):2175-86; and Novak et al.,2 004, Blood. 103(2):689-94). Multiple myeloma, also known as Myeloma, is a condition caused by abnormal or malignant plasma B cells in the bone marrow. Cancer is characterized by the accumulation of bone marrow cells. Cancer cells invade adjacent bones, destroying the skeletal structure. Most cases of myeloma are caused by a cluster of malignant plasma cells. Paraprotein (M-protein), an abnormal immunoglobulin, is overproduced due to the proliferation of It is also characterized by the production of 30g / L of erythrocyte proliferation inhibitor (also known as myeloma protein or myeloma protein). Serum paraprotein levels exceeding 100% are reported by The International Myel The diagnostic criteria of the International Mammography Working Group (IMWG) (Kyle et al. , 2009, Leukemia.23:3-9) for the diagnosis of multiple myeloma. Other symptoms or signs of multiple myeloma include decreased kidney function or kidney failure, These include bone lesions, anemia, hypercalcemia, and neurological symptoms.

[0200] 10. Patient population The BCMA binding molecules can be used to treat a subject in need thereof. In some embodiments, the subject may be diagnosed with a hematological cancer, such as multiple myeloma. They may have been previously treated with one or more therapeutic agents. In certain embodiments, the treatment includes: There is a possibility that it failed.

[0201] In one embodiment, the subject has previously undergone one or more prior treatments for their disease. In one embodiment, the subject has previously undergone one prior treatment for their disease. In certain embodiments, the subject has previously undergone one prior treatment for their disease. In certain embodiments, the subject has previously undergone one prior treatment for their disease. In some embodiments, the subject has previously undergone one prior treatment for their disease.

[0202] In one embodiment, the subject is receiving treatment with an IMiD, a proteasome inhibitor, an anti-CD38 antibody, or any combination thereof. In one embodiment, the subject has previously been administered I In one embodiment, the subject has previously received a proteasome inhibitor. In certain embodiments, the subject has previously been administered an anti-CD38 antibody.

[0203] 10.1. Eligibility Criteria Subjects who may be treated with a BCMA binding molecule may be administered an Infolab or Infolab prior to treatment with the BCMA binding molecule. This may include subjects who signed a informed consent form.

[0204] Subjects who can be treated with the BCMA binding molecules include male or female subjects aged 18 years or older. It may include.

[0205] Subjects who may be treated with a BCMA-binding molecule include those who have two (2) or fewer Eastern Cooper Patients with Eastern Cooperative Oncology Group (ECOG) performance status ECOG performance status may be measured by a BCMA-binding molecule-treated subject. The determination may be made at any time before the

[0206] Subjects who may be treated with a BCMA binding molecule may include subjects who have received a confirmed diagnosis of cancer. For example, subjects who may be treated with a BCMA-binding molecule are those with a confirmed diagnosis of multiple myeloma. Subjects may also have received two or more standard of care (SoC) regimens. SoC regimens include IMiDs (e.g., lenalidomide or pomalidomide), proteasome inhibitors, and inhibitors (e.g., bortezomib, carfilzomib), and / or anti-CD38 agents (e.g., dapagliflozin ... Subjects may also be relapsed and / or refractory to each regimen, or incompetent. Subjects may also experience disease progression (IMWG criteria) even after previous treatment. Subjects may also have documented evidence of a previous autologous bone marrow transplant, BCMA CAR-T or B It is possible that CMA-ADC has been previously administered.

[0207] Subjects who can be treated with BCMA binding molecules have serum M protein levels of 1.0 g / dL or greater. The present invention may include subjects with measurable disease as defined by the BCMA binding molecule. Eligible subjects are defined by a urinary M protein level of 200 mg / 24 hours or greater. Subjects who may be treated with BCMA binding molecules may include subjects with measurable disease. Measurable disease defined by serum free light chain (sFLC) levels greater than 100 mg / L The subject may include a subject with a disease.

[0208] Subjects who may be treated with BCMA binding molecules are willing to undergo serial bone marrow aspirations and / or biopsies. Serial bone marrow aspirations and / or biopsies may be performed prior to treatment with a BCMA binding molecule. Serial bone marrow aspirations and / or biopsies may be performed at any time during treatment with BCMA-binding molecules. Serial bone marrow aspirations and / or biopsies may be performed at any time thereafter. may be performed for assessment of pharmacodynamics.

[0209] 10.2. Exclusion criteria In certain embodiments, subjects who may be treated with a BCMA binding molecule are those described in this Section 10 must not have or have had one or more of the following exclusion criteria disclosed in .2: For example, in one embodiment, the subject may Subjects are excluded if they have or have had any one of the following exclusion criteria disclosed in .2: As another example, patients with BCMA-binding molecules should not be treated with BCMA-binding molecules. Potential subjects must meet two or more of the following exclusion criteria disclosed in this Section 10.2: As another example, a person must not have or have ever had a BCMA. Subjects who may be treated with the binding molecules must meet the following exclusion criteria disclosed in this Section 10.2: You must not have or have had more than three of these. Thus, subjects who may be treated with BCMA binding molecules include those disclosed in this Section 10.2. Patients must not have or have had four or more of the following exclusion criteria: As another example, subjects who may be treated with a BCMA binding molecule are those described in this Section 10.2 must not have or have had five or more of the following exclusion criteria disclosed in This should not happen.

[0210] Subjects who may be treated with BCMA binding molecules may be those who have not received prior radiation therapy. In other embodiments, the subject may have received prior radiation therapy. In one embodiment, radiation therapy was not administered within one month of the start of treatment. In some embodiments, radiation therapy was not administered within three weeks of the start of treatment. In an embodiment, radiation therapy was not administered within two weeks of the start of treatment. In the present study, radiation therapy was not administered within one week of the start of treatment.

[0211] There may be some exceptions to previous radiation therapy, for example if the radiation therapy was local. For example, localized radiation therapy may be administered to bone lesions, such as lytic bone lesions. Alternatively, in some cases, localized radiation therapy may be administered to the plasmacytoma. Under these circumstances, the subject may be eligible for treatment with a BCMA binding molecule.

[0212] Subjects who may be treated with BCMA binding molecules are those who will not have undergone recent major surgery. In one embodiment, recent major surgery must have occurred within six months of initiating treatment. In one embodiment, recent major surgery was not performed within 5 months of initiation of treatment. In one embodiment, recent major surgery was not performed within four months of initiation of treatment. In one embodiment, recent major surgery was not performed within 3 months of initiation of treatment. In one embodiment, no recent major surgery was performed within two months of initiation of treatment. In one embodiment, recent major surgery was not performed within one month of initiating treatment. In some embodiments, recent major surgery was not performed within three weeks of initiating treatment. In embodiments, recent major surgery was not performed within two weeks of initiation of treatment. In embodiments, no recent major surgery was performed within one week of initiating treatment.

[0213] Subjects who may be treated with BCMA binding molecules may be those who would not be using steroid treatment. In certain embodiments, the steroid may include prednisone, dexamethasone, Cortisol, their equivalents, or any other corticosteroid for human use In certain embodiments, the steroid treatment should be a long-term steroid treatment. For example, daily use of 10 mg or more of prednisone or equivalent is not recommended for long-term steroid use. It can be considered a therapeutic approach.

[0214] There may be some exceptions when the steroid is topical, inhaled, intranasal, or intraocular. Under these circumstances, the subject may be eligible for treatment with a BCMA binding molecule.

[0215] Subjects who can be treated with BCMA binding molecules are not using any immunosuppressive therapy / drugs. In one embodiment, the immunosuppressive therapy / drug is a BCMA-binding molecule. In one embodiment, immunosuppressive therapy should not be given within one month of treatment with a child. The therapy / drug should not be given within 4 weeks of treatment with a BCMA binding molecule. In this form, immunosuppressive therapy / drugs were given within 3 weeks of treatment with BCMA-binding molecules. In one embodiment, the immunosuppressive therapy / drug is a BCMA-binding molecule-mediated In one embodiment, immunosuppressive therapy / drugs should not be given within two weeks of treatment. In certain embodiments, the BCMA-binding molecule may not be administered within one week of treatment with the BCMA-binding molecule. Immunosuppressants are not a systemic treatment.

[0216] In conjunction with steroid and / or immunosuppressive therapy, these considerations may contribute to the development of BCMA-associated Immunotherapy to prevent / ameliorate any side effects (e.g., CRS) associated with treatment with the synthetic molecule Regardless of potential prior, concurrent, or subsequent treatment with immunosuppressants. , before, during, or after immunosuppressive therapy as part of a treatment regimen that includes a BCMA-binding molecule may still be eligible for treatment with BCMA-binding molecules.

[0217] Subjects who may be treated with the BCMA binding molecules must have previously received any BCMAxCD3 bispecific This may include subjects who have never used antibody therapy.

[0218] Subjects who may be treated with a BCMA binding molecule include those who have received any of the following: Must not have or have had a history of hypersensitivity reactions to For example, the subject may have a hypersensitivity reaction to any of the excipients in the formulation. In some embodiments, the subject may not have or have had , must not have or have had hypersensitivity reactions to other monoclonal antibodies In certain embodiments, the hypersensitivity reaction is a severe hypersensitivity reaction.

[0219] Subjects who can be treated with a BCMA binding molecule may have been previously treated with any BCMA-targeted drug. This may include subjects who would not be subject to toxicity from the agent.

[0220] Subjects who may be treated with a BCMA binding molecule include those with a disease that is being treated with a BCMA binding molecule, such as In other words, a subject may have two or more The subjects may include subjects without malignant disease, one of which is treated with a BCMA binding molecule. It has not been done.

[0221] With some exceptions, if the malignancy has been previously treated and a complete response / remission of the malignancy has been observed In other words, previous treatment of the malignant tumor may have been curative. In some embodiments, the malignant tumor has not recurred within the past five years. The malignancy has not recurred within the past four years. In one embodiment, the malignant tumor has not recurred within the past two years. In one embodiment, the malignant tumor has not recurred within the past year. In one embodiment, the malignant tumor has not recurred within the past six months. This includes subjects who have had basal cell and squamous cell skin cancers removed. This may include any type of in situ completely resected carcinoma. can be treated with a BCMA binding molecule.

[0222] Subjects that can be treated with a BCMA binding molecule can include subjects who do not have an active autoimmune disease. Subjects who may be treated with BCMA binding molecules are not known to have an autoimmune disease. Subjects who may be treated with a BCMA binding molecule may include those who have an autoimmune disease. may include subjects who are not suspected of

[0223] Some exceptions to autoimmune diseases include subjects with vitiligo, hypothyroidism, or psoriasis. If the subject has hypothyroidism, the subject may be given a steroid drug to treat residual hypothyroidism. In one embodiment, if the subject has residual hypothyroidism, BCM Subjects who can be treated with the A-binding molecules require only hormone replacement. In some embodiments, the subject may be treated with a BCMA binding molecule without requiring systemic treatment. In this condition, if the subject has psoriasis, the condition is not expected to recur. In this situation, the subject can be treated with a BCMA binding molecule.

[0224] Subjects who may be treated with a BCMA binding molecule may include subjects who are not being treated with prohibited concomitant medications. In certain embodiments, the subject is allowed to discontinue treatment for at least three months prior to initiation of treatment. In one embodiment, the subject is not being treated with a prohibited concomitant drug. For at least 2 months, patients have not been taking any prohibited concomitant medications that cannot be discontinued. In this embodiment, the subject is taking a combination drug that cannot be discontinued for at least one month before the start of treatment. In some embodiments, the subject is not being treated with a prohibited drug. In one embodiment, the patient has not been treated with any prohibited concomitant medications that cannot be discontinued for 4 weeks. Subjects were taking prohibited concomitant medications that could not be discontinued for at least 3 weeks prior to the start of treatment. In one embodiment, the subject has not discontinued the treatment for at least two weeks prior to initiation of the treatment. In some embodiments, the subject is not being treated with a prohibited concomitant drug that cannot be used to treat the disease. Not being treated with any prohibited concomitant medications that cannot be discontinued for at least 1 week prior to the start of treatment In one embodiment, the subject can discontinue treatment for at least 6 days prior to initiation of treatment. In some embodiments, the subject is not being treated with any concomitant medications. In some embodiments, the patient has not been taking any prohibited concomitant medications that cannot be discontinued for at least 5 days. In this study, subjects were required to be on prohibited concomitant medications that could not be discontinued for at least 4 days before the start of treatment. In one embodiment, the subject has not been treated for at least 3 days prior to the start of treatment. In one embodiment, the subject is not being treated with a prohibited concomitant medication that cannot be discontinued. Not being treated with any prohibited concomitant medications that cannot be discontinued for at least 2 days prior to the start of treatment In certain embodiments, the subject may discontinue treatment for at least one day prior to initiation of treatment. Not being treated with any prohibited concomitant medications.

[0225] Subjects who may be treated with a BCMA-binding molecule are those who do not have grade 2 or higher neuropathy. It may include.

[0226] Subjects who may be treated with BCMA binding molecules are those who have Grade 1 or higher BCMA from any prior therapy. This may include subjects with no residual toxic effects.

[0227] Subjects that may be treated with BCMA-binding molecules include those with plasma cell leukemia and other diseases other than multiple myeloma. The subject may include a subject who does not have a plasmacytoid cell disorder.

[0228] Subjects who can be treated with BCMA-binding molecules have a tumor size of >1,000 / mm3 without growth factor support. This may include subjects who do not have a laboratory test result of an absolute neutrophil count (ANC) of The ANC number may be measured one month prior to the start of treatment. In one embodiment, the ANC count can be measured 3 weeks before the start of treatment. In one embodiment, the ANC count is measured two weeks before the start of treatment. In some embodiments, the ANC number may be measured one week before the start of treatment. In an embodiment, the ANC count may be measured 6 days before the start of treatment. In some embodiments, the ANC count may be measured 5 days before the start of treatment. The ANC count may be measured 4 days before the start of treatment. In one embodiment, the ANC count can be measured 2 days before the start of treatment. In certain embodiments, ANC counts may be measured one day prior to the start of treatment. do.

[0229] Subjects who can be treated with BCMA-binding molecules have a blood volume of less than 75,000 mm3 without transfusion support. Subjects without platelet count laboratory results may be included. The platelet count is measured one month after the start of treatment. In one embodiment, the platelet count is measured 4 weeks before the start of treatment. In certain embodiments, platelet counts may be measured three weeks prior to the start of treatment. In some embodiments, the platelet count may be measured two weeks prior to the start of treatment. In one embodiment, the platelet count can be measured one week before the start of treatment. The platelet count may be measured 6 days before the start of treatment. In one embodiment, the platelet count is In some embodiments, platelet counts may be measured 5 days prior to the start of treatment. In one embodiment, the platelet count is measured 3 days before the start of treatment. In certain embodiments, the platelet count may be measured two days before the start of treatment. In some embodiments, the platelet count may be measured one day before the start of treatment.

[0230] Subjects who may be treated with a BCMA binding molecule have a BCMA level greater than 1.5 times the upper limit of normal (ULN). In some embodiments, subjects may be included who do not have laboratory test results for their lirubin levels. In one embodiment, the bilirubin level may be greater than 1.1 times the ULN. In one embodiment, the bilirubin level may be greater than 1.2 times the ULN. In one embodiment, the bilirubin level is greater than 1.3 times the ULN. In one embodiment, the bilirubin level is greater than 1.6 times the ULN. In one embodiment, the bilirubin level is greater than 1.7 times the ULN. In certain embodiments, bilirubin levels may be greater than 1.8 times the ULN. In some embodiments, bilirubin levels may be greater than 1.9 times the ULN. In some cases, bilirubin levels may be greater than 2.0 times the ULN.

[0231] Subjects who may be treated with BCMA binding molecules have an aspartate receptor agonist (ASR) level greater than 3 times the upper limit of normal (ULN). This included subjects without laboratory test results for AST levels. In some embodiments, AST levels may be greater than 1.5 times the ULN. In an embodiment, the AST level may be greater than 2.0 times the ULN. In some embodiments, the AST level may be greater than 2.5 times the ULN. The level may be greater than 3.5 times the ULN. In one embodiment, the AST level is greater than 4.5 times the ULN. In one embodiment, the AST level may be greater than 5.0 times the ULN. do.

[0232] Subjects who may be treated with BCMA binding molecules have a BCMA level greater than 3 times the upper limit of normal (ULN). may include subjects who do not have laboratory test results for acetylcholinesterase (ALT) levels. In some embodiments, the ALT level may be greater than 1.5 times the ULN. In certain embodiments, the ALT level may be greater than 2.0 times the ULN. The ALT level may be greater than 2.5 times the ULN. In one embodiment, the ALT level In one embodiment, AST levels may be greater than 3.5 times the ULN. In one embodiment, the ALT level is greater than 4.5 times the ULN. In one embodiment, the ALT level may be greater than 5.0 times the ULN.

[0233] Subjects who may be treated with a BCMA binding molecule have a calculated creatinine clearing rate of less than 30 ml / min. In some embodiments, subjects without clinical test results of 10 ml / min. In one embodiment, a calculated creatinine clearance of less than 20 ml / min. Creatinine Clearance. In one embodiment, a calculated creatinine clearance of less than 40 ml / min is In one embodiment, a calculated creatinine clearance of less than 50 ml / min Calculated creatinine clearance can be measured by any known method. For example, the Cockcroft-Gault formula is used to calculate creatinine clearance. obtain.

[0234] Subjects that may be treated with a BCMA binding molecule may include subjects without cardiac dysfunction. Subjects who can be treated with MA binding molecules do not have clinically significant cardiac disease. For example, a subject , clinically significant, such as congestive heart failure (e.g., NYHA grade ≥ 2) requiring treatment have severe and / or uncontrolled heart disease, uncontrolled hypertension, or clinically significant arrhythmias In one embodiment, the subject has a QTcF > 470 msec at screening. In one embodiment, the subject does not have ECG or congenital long QT syndrome. No acute myocardial infarction or unstable angina for less than 3 months.

[0235] Subjects who may be treated with a BCMA binding molecule may include subjects who do not have an active infection. In some embodiments, the subject does not have an active infection requiring systemic treatment. In some embodiments, the subject does not have any serious infection within one month prior to treatment. In some embodiments, the subject does not have any serious infection within four weeks prior to treatment. In an embodiment, the subject does not have any serious infection within three weeks prior to treatment. In some embodiments, the subject does not have any serious infection within two weeks prior to treatment. In one embodiment, the subject does not have any serious infections within one week prior to treatment. .

[0236] Subjects who may be treated with the BCMA binding molecules include those with POEMS syndrome (polyneuropathy, vascular Plasma cell dyscrasia with organ hyperplasia, endocrine disorders, monoclonal proteins, and skin changes) The subject may include a subject who does not have

[0237] Subjects who may be treated with BCMA binding molecules include those who have not had any prior allogeneic SCT. It may include.

[0238] Subjects who may be treated with the BCMA binding molecules include those with human immunodeficiency virus (HIV infection). It may include subjects that are not

[0239] Subjects who may be treated with the BCMA binding molecules include those with active hepatitis B (HBV) or hepatitis C (HCV). HBV infection may be present in subjects who are not infected with HBV. If the disease is controlled under antiviral therapy, There may be some exceptions to the V / HCV requirement. In some cases, e.g., HBV or HCV HBV if clinically indicated or if the patient has a history of HBV or HCV infection V / HCV will be tested.

[0240] Subjects who can be treated with BCMA binding molecules must be at least 18 years of age or older and must be at least 18 years of age or older. In one embodiment, the subject is a patient who has not used steroids for at least two weeks prior to initiating treatment. In one embodiment, subjects are not administered any live vaccines within 3 weeks of starting treatment. In one embodiment, the subject has not used any live vaccines within a short time of starting treatment. No live vaccines have been used within the last four weeks. In one embodiment, the subject has not used any live vaccines within the first month of treatment. In one embodiment, the subject has not received any live vaccines within two months of starting treatment. Do not use any live vaccines within 3 months of starting treatment.

[0241] Subjects who can be treated with BCMA-binding molecules may receive cytotoxic or small molecule targeted anti-tumor agents prior to treatment. In some embodiments, the present invention may include subjects who have not been treated with anti-cancer drugs or any experimental treatment. Subjects must have had cytotoxic or minor inflammatory bowel disease within one month prior to initiating treatment with the BCMA binding molecule. have not been treated with a molecularly targeted anti-tumor agent or any experimental treatment. Subjects must have had cytotoxic or minor cytotoxic events within 4 weeks prior to initiating treatment with the BCMA binding molecule. have not been treated with a molecularly targeted anti-tumor agent or any experimental treatment. Subjects must have had cytotoxic or minor cytotoxic events within 3 weeks prior to initiating treatment with the BCMA binding molecule. have not been treated with a molecularly targeted anti-tumor agent or any experimental treatment. Subjects must have had cytotoxic or minor cytotoxic events within 2 weeks prior to initiating treatment with the BCMA binding molecule. have not been treated with a molecularly targeted anti-tumor agent or any experimental treatment. Subjects must have had cytotoxic or minor inflammatory bowel disease within one week prior to initiating treatment with the BCMA binding molecule. have not been treated with a molecularly targeted anti-tumor agent or any experimental treatment. The subject must have had cytotoxic or non-cytotoxic BCMA-binding activity within 10 half-lives prior to initiating treatment with the BCMA-binding molecule. The patient has not been treated with a small molecule targeted anti-tumor drug or any experimental treatment. In this case, the subject must have had cytotoxic or cytotoxic T cells within 7 half-lives of the BCMA-binding molecule prior to initiating treatment. or have not been treated with a small molecule targeted anti-tumor drug or any experimental treatment. In the method, the subject is required to undergo cytotoxic or or have not been treated with a small molecule targeted anti-tumor drug or any experimental treatment. In the method, the subject has cytotoxicity within four half-lives prior to initiating treatment with the BCMA binding molecule. or have not been treated with a small molecule targeted anti-tumor drug or any experimental treatment. In this embodiment, the subject receives a cytotoxic agent within 3 half-lives prior to initiating treatment with the BCMA binding molecule. have not been treated with anti-cancer or small molecule targeted anti-tumor drugs or any experimental treatment. In one embodiment, the subject receives a BCMA-binding molecule within two half-lives of the cell line prior to initiating treatment with the BCMA-binding molecule. Not treated with toxic or small molecule targeted anti-tumor drugs or any experimental treatments.

[0242] Subjects who can be treated with BCMA binding molecules must undergo hematopoietic colony stimulation for no more than two weeks prior to the start of treatment. Growth factors (e.g., G-CSF, M-CSF), thrombopoietin mimetics or erythropoiesis This may include subjects who did not have a stimulant initiation. In some cases, initiation occurred before the start of treatment. In some cases, onset occurred less than 4 weeks before the start of treatment. In some cases, onset did not occur less than 3 weeks before the start of treatment. In some cases, onset occurred less than one week before the start of treatment.

[0243] the subject received a thrombopoietin mimetic for more than 2 weeks prior to treatment with the BCMA binding molecule; If the subject continues to receive treatment, the subject may be administered a BCMA binding molecule.

[0244] Subjects that can be treated with a BCMA binding molecule can include subjects who have not received GM-CSF. do.

[0245] Subjects who may be treated with BCMA binding molecules are those receiving intravenous IG injections given to prevent infection. In one embodiment, the IG infusion may include a subject who has not received an IG infusion. In one embodiment, the I G infusions should be terminated 2 months prior to the initiation of treatment with BCMA-binding molecules. In one embodiment, IG infusions are terminated one month prior to the initiation of treatment with the BCMA binding molecule. In one embodiment, IG infusion is administered to a subject receiving a BCMA-binding molecule. It should be terminated 4 weeks before the start of treatment. In one embodiment, IG infusion should be completed 3 weeks before initiation of treatment with a BCMA-binding molecule. In this study, IG infusion was terminated 4 weeks before the start of treatment with the BCMA-binding molecule. In one embodiment, IG infusion is used to initiate treatment with BCMA binding molecules. This should be completed one week before the start of the program.

[0246] Subjects who may be treated with a BCMA binding molecule have had symptomatic CNS tumors within two weeks prior to the start of treatment. Metastases, or CNS metastases requiring local CNS-directed therapy (such as radiation therapy or surgery) Active central nervous system (CNS) involvement due to the grade or presence of In some embodiments, the CNS problem is a symptom of a condition that is associated with the onset of treatment. In one embodiment, the CNS problem should not have occurred within 3 months of starting treatment. In one embodiment, the CNS problem should not have occurred more than two months prior to the start of In one embodiment, CNS problems should not have occurred within one month of the start of treatment. should not have occurred within 4 weeks prior to the start of treatment. The problem should not have occurred 3 weeks prior to the start of treatment. NS problems should not have occurred within one week prior to the start of treatment.

[0247] Subjects who may be treated with a BCMA binding molecule may be at risk for precluding treatment with the BCMA binding molecule. The subject may include subjects with any serious medical or psychiatric illness in which the risk of developing a high risk of developing a heart attack or stroke is high.

[0248] Subjects who may be treated with BCMA binding molecules include those who are pregnant or nursing (breastfeeding) Pregnancy may be confirmed by a positive hCG laboratory test. Pregnancy may be defined as the state of a woman from conception to the end of pregnancy, ascertained by a gestational age.

[0249] Subjects who may be treated with BCMA binding molecules, in one embodiment, have one highly effective Use effective contraceptive methods (e.g., two), including a method that is effective during and after study drug administration. Not a woman of childbearing potential unless she has not taken the drug for 6 months after administration. A woman with a fertility disorder can be defined as any woman who is physiologically capable of becoming pregnant. , had 12 months of spontaneous amenorrhea with an appropriate clinical profile ( i.e., age-appropriate, history of vasomotor symptoms), or bilateral oophorectomy at least 6 weeks prior ( If you have had a hysterectomy (with or without hysterectomy), a total hysterectomy, or a tubal ligation, or are postmenopausal Ovariectomy alone does not alter a woman's reproductive status by changing hormone levels. Women are considered non-fertile only if confirmed by follow-up evaluation.

[0250] Highly effective methods of contraception include, but are not limited to, total abstinence and female sterilization. , male sterilization, and the use of oral, injectable, or implantable hormonal contraception or Placement of an intrauterine device (IUD) or intrauterine system (IUS) and its equivalent efficacy (failure) Other forms of hormonal contraception with a rate of <1% (e.g., hormonal vaginal ring or transdermal hormone) Other effective methods of contraception include spermicides (e.g., foams, gels, etc.). condoms or occlusive caps (diaphragms) along with barrier methods of contraception such as uterine prostatectomy (IVF) or cervical / fornix cap.

[0251] Related to abstinence, periodic abstinence (e.g., calendar method, ovulation method, symptom-temperature method, post-ovulation method) Intravaginal ejaculation (IVF) and withdrawal are not acceptable methods of contraception.

[0252] In relation to female sterilisation, examples include, but are not limited to, the following: Bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or If oophorectomy is performed alone, the woman's reproductive status may be assessed by hormone level monitoring. Only if confirmed by the price.

[0253] Regarding male sterilization, this must have occurred at least 6 months prior to screening. For female subjects, the vasectomized male partner must It should be your only partner.

[0254] In the case of oral contraception use, in one embodiment, the female is treated with a BCMA binding molecule. You must have been taking the same pill continuously for at least three months before starting treatment. [Example]

[0255] 11. Working Example 11.1. Example 1: Identification of BSBM3 BCMA is expressed in plasma cells as well as other B-cell malignancies, particularly multiple myeloma. For effective drug development, nonclinical pharmacokinetic and toxicity studies are required. To achieve this, human antigens as well as corresponding antigens in model non-human primate species (e.g., cynomolgus monkeys) are It is highly desirable to have antibodies that are cross-reactive with both antigens.

[0256] To identify antibodies that are cross-reactive with both human and cynomolgus BCMA, human A naive phage library containing antibody fragments was then cloned into recombinant human and cynomolgus monkeys. Approximately 400 single phage colonies were subjected to four rounds of panning against the BCMA antigen. Nine unique clones were taken from the fourth panning and used as phage clones for phage ELISA. Clones were selected for amplification and rescue as a hybridization vector. Their affinity for BCMA was analyzed.

[0257] One of the clones was subjected to affinity maturation in the form of an enzyme surface scFv. After screening, the affinity-matured anti-BCMA pool is purified to a heterodimeric bispecific antibody format (Figure 1). The gene was cloned into HEK 293 cells and expressed in Jurkat NFAT cells. on tumor cells in a target-dependent manner using the JNL reporter assay The ability to bind to BCMA and activate T cells was tested.

[0258] From these assays, a bispecific binding molecule, designated herein as BSBM3, was identified. The sequence of BSBM3 is shown in Table 1 below.

[0259] [Table 1]

[0260] [Table 2]

[0261] [Table 3]

[0262] [Table 4]

[0263] The activity of BSBM3 was compared with that of a BCMA-CD3 bispecific antibody being developed for the treatment of multiple myeloma. The activity of the antibody was compared with that of the antibody ch2B4_C29 (International Publication No. WO 2016 / 016662 (See Brochure No. 9.) Bivalent BS from KMS11 and PBMC / T cell co-culture studies. Preliminary data for BM3 and h2B4_C29 show that bivalent BSBM3 is 29 (data not shown), which mediates cytokine induction at lower levels. showed that patients treated with BSBM3 had a significantly increased risk of cytotoxicity compared with patients treated with h2B4_C29. Preliminary data suggest that K may have a reduced risk of steroid release syndrome. T cells activated by h2B4_C29 in the presence of MS11 cells expressed bivalent BSBM We also demonstrated that 3 mediates TCR downregulation in more T cells activated by 3 (data not shown). (not shown), which suggests that BSBM3 may exhibit more sustained anti-cancer activity than h2B4_C29. Furthermore, some preliminary results were obtained in the KMS11 xenograft model. Data show that BSBM3 (as well as h2B4_C29) is The results suggest that the compound has greater antitumor activity than the BCMA-CD3 bispecific molecule manufactured by NIH. is doing.

[0264] 11.2. Example 2: Characteristics of BSBM3 BSBM3 was produced in Chinese hamster ovary (CHO) cells and expressed as an IgG1 antibody. As shown in Figure 1, BSBM3 targets BCMA. It has a Fab domain that targets CD3, a single-chain Fv (scFv) domain that targets F The c domain provides IgG-like in vivo retention with unmodified FcRn (neonatal Fc receptor) affinity. The Fc domain of BSBM3 abolishes binding to human Fcγ receptors and inhibits Fc It contains substitutions that reduce the risk of non-selective T cell activation by Fc receptor (Fc receptor)-mediated cross-linking. The affinity of BCMA and its affinity for CD3 are summarized in Table 2. BCMA in MM cells and CD3 in the T cell receptor (TCR) complex in T cells Binding of multiple molecules of BSBM3 simultaneously to the subunits mediates TCR cross-linking and cytolytic immunity. It results in the formation of synapses, activation of T cells and specific lysis of MM cells.

[0265] [Table 5]

[0266] 11.3. Example 3: Non-clinical Pharmacology (In Vitro) The activity of BSBM3 was assessed using the BCMA+ myeloma cell line KMS11 and healthy donor T cells. BSBM3 was characterized in an in vitro co-culture system at concentrations of ≥1 nM. Consistently, BSBM3 induced T cell proliferation and cytokine secretion in a concentration-dependent manner (Fig. 2). potent redirected T cell cytotoxicity (RTCC) in KMS11 in a sustainable manner. In contrast, the non-targeting control antibody NT-CD3 (same anti-CD3 scFv BCMA Fab but with a non-targeting Fab instead of the anti-BCMA Fab) inhibits T cell proliferation or did not induce significant death of KMS11 cells, suggesting that BCMA-specific These data indicate that specific binding is required for T cell activation and cytotoxicity. BSBM3 can potently and specifically activate T cells in the presence of BCMA+ cells, targeting This suggests that it results in specific cell death.

[0267] To identify an in vitro assay with the most sensitive readout of BSBM3 activity, To do this, EC30 values ​​were calculated from the various assays, each with nine biological replicates. (T cells from three healthy donors were used in three independent experiments. Redirected T cells were used to detect specific lysis of MM cells (Figure 3). The RTCC assay provides the most sensitive and reproducible EC30 values. Therefore, the minimum predicted biological effect level (MABE) was used to inform the starting dose. L) was calculated based on the EC30 values ​​from the RTCC assay.

[0268] BCMA undergoes protease cleavage within its transmembrane domain by γ-secretase. It has been shown that β-lactamase acts as a decoy to neutralize its ligand, APRIL. Shedding of its extracellular domain as a soluble factor (henceforth referred to as soluble BCMA) (Laurent 2015). The mean blood concentration of soluble BCMA is 39 ng / mL in subjects with smoldering myeloma, 89 ng / mL in subjects with smoldering myeloma, and It has been reported to be 506 ng / mL in diagnosed MM subjects (Gherm ezi et al.,2017,Haematologica.102(4):785 Soluble BCMA in the blood and bone marrow of a subject binds to BSBM3 and binds to BSBM As expected, the activity of 30, 100, or 300 ng / mL In the presence of soluble BCMA, the EC30 for BSBM3 was 6, 15, and 16, respectively. 41-fold increase (Figure 4). 93% of subjects with active and untreated MM had their serum Because they have shed BCMA greater than 107.6 ng / mL (Ghermezi et al. al., 2017, Haematologica 102(4):785-795), RTCC assays containing 100ng / mL soluble BCMA were used to assess the BSBM3 Therefore, 0.753 ng / mL (100 ng / mL) is likely to be a better representation of the activity of Calculate the starting dose using the MABEL method to determine the EC30 of soluble BCMA (mL). This was taken into consideration when developing CD3-directed bispecific antibodies. al.,2017,Regul Toxicol Pharmacol;90:144 This is consistent with the approach described by W.-152.

[0269] 11.4. Example 4: Non-clinical Pharmacology (In Vivo) The in vivo activity of BSBM3 was determined by adoptive transfer in human PBMCs from healthy donors. This was evaluated using a KMS11 xenograft model in immunodeficient NSG mice (Figure 5). KMS11 cells were engineered to overexpress luciferase, which then Allows tumor burden measurement by bioluminescence intensity (BLI). Doses ≥ 0.3 mg / kg Mice treated with BSBM3 were cultured separately with PBMCs from two different healthy donors. Three independent experiments using this demonstrated robust tumor rejection (data).

[0270] Adoptive transfer model using KMS11 xenografts supports the mechanism of action of BSBM3 However, the activation markers were significantly higher compared to T cells in donor PBMCs at the time of isolation. Adoptively transferred human T cells are highly active as shown by dramatically elevated expression of Car Therefore, it is likely to overpredict anti-MM activity (data shown; Ali et al. al., 2012, PLoS ONE;7(8):e44219). Therefore, this Administration of BSBM3 demonstrated anti-MM activity in models is not directly translatable to subjects .

[0271] 11.5. Example 5: Nonclinical Pharmacokinetics and Metabolism To investigate the pharmacokinetics (PK) of BSBM3 in unbound mice, an NSG mouse PK assay was performed. Experiments were performed with and without human peripheral blood mononuclear cells (PBMC). The antibody showed a biphasic pattern of blood concentrations as expected for a monoclonal antibody in a non-binding species. In NSG mice humanized with human PBMCs, AUCla Exposure, as measured by st, was lower than in PBMC-naive mice. Non-linear elimination was evident, indicating the expected target-mediated drug disposition (TMDD).

[0272] BSBM3 binds to both targets (BCMA and CD3) in cynomolgus monkeys. Therefore, the toxicokinetic profile of BSBM3 was evaluated in a single-dose non-GLP toxicology study (data The toxicity was investigated in a 4-week GLP toxicology study (data not shown) and a 4-week GLP toxicology study (data not shown). A single-dose study showed that exposure to BSBM3, as measured by AUClast, was 0.3, A dose-proportional increase was observed across the doses tested of 1 and 3 mg / kg. Of the five animals administered, one animal (at a dose of 0.3 mg / kg) developed anti-drug antibodies (ADA). ) was confirmed.

[0273] In a 4-week cynomolgus monkey GLP toxicology study, animals were dosed at 1, 3, and 10 mg / kg The mice were given five weekly intravenous (iv) infusions of 1000 mg of BSBM3. ) After injection, the maximum exposure to BSBM3 was 0.667 p.i., the first time point after administration. The observed Cmax was ~4.17 hours, as measured by Cmax and AUC0-τ (τ = 7 days). Exposure to BSBM3 during treatment was approximately dose-proportional over the dose range of 1 to 10 mg / kg. Accumulation was increased and similar in both sexes. After 4 weeks of administration, the AUC0-τ was approximately 1.5 to 1.9 times higher (based on AUC0-τ). ADA was detected on day 28 in the main part of the study (1 out of 24 animals). 1 treated animal, 1 mg / kg dose). During the 6-week recovery portion of the study, ADA was detected in 57 Day 71 (1 of 6 treated animals, 3 mg / kg dose) and Day 72 (2 of 6 treated animals, The data suggest that there may be no significant effect of ADA on TK. ADA was not detected in control animals.

[0274] 11.6. Example 6: Nonclinical Toxicology The safety of BSBM3 was investigated in in vitro and in vivo studies. , performed in cynomolgus monkeys, which were identified as a pharmacologically relevant species for BSBM3. It was.

[0275] The results of safety pharmacology studies have demonstrated that the central nervous system (CNS), respiratory, and cardiovascular functions In general, findings from in vivo studies suggest a low risk of BSBM3. BSBM3-associated predicted pharmacology, B cell and plasma cell depletion and selection in peripheral blood, bone marrow and tissues Rapid increase and more sustained blood and tissue T cell proliferation after administration of selected serum cytokines The results were consistent with activation of the gastrointestinal-associated lymphoid tissue (GALT), lymph nodes, and spleen (B cells). Lymphocyte depletion in the basal cell region (alveolar region) was observed at all BSBM3 dose levels in GLP studies. During the recovery phase, lymphoid hyperplasia in these organs was consistent with the regenerative process. Furthermore, mixed cell immunoinflammatory lesions were observed in various organs (i.e., gastrointestinal tract (GIT), liver, , spleen, heart, kidneys, and lungs) and in some cases were associated with infectious agents.

[0276] The highest non-serious toxicity dose (HNSTD) in GLP studies is 1 mg / kg It was identified as g.

[0277] 11.7. Example 7: Clinical Trial Clinical trials following the scheme shown in Figure 6 are being conducted with IMiDs (e.g., lenalidomide or pomarin). domide), proteasome inhibitors (e.g., bortezomib, carfilzomib), and anti-C Received two or more standard of care (SoC) lines of therapy containing a D38 agent (e.g., daratumab) Multiple myeloma that has relapsed and / or is refractory to, or intolerant to, each regimen The study was conducted to determine the safety and efficacy of BSBM3 in subjects with

[0278] The study consists of a dose escalation part followed by an expansion part.

[0279] This includes IMiDs (e.g., lenalidomide or pomalidomide), proteasome inhibitors ( bortezomib, carfilzomib), and anti-CD38 agents (e.g., daratumab). have received two or more standard of care (SoC) lines of therapy, including steroid therapy, and have had relapsed or failed treatment with each regimen and / or refractory or intolerant, and International Myeloma Clinically relevant, with documented evidence of disease progression according to the Interventional Medicine Working Group (IMWG) criteria. Multiple myeloma who are ineligible for treatment with other regimens known to provide efficacy BSBM3 (specifically BCMA and CD3, as described throughout this disclosure) in subjects with FIH, Phase 1 study to determine the safety and efficacy of a novel antibody (a heterogeneous binding bispecific antibody) This is a large-scale, multicenter, open-label study.

[0280] Eligibility Criteria Subjects included in the study had a confirmed diagnosis of multiple myeloma and, when available, IMiD ( lenalidomide or pomalidomide), proteasome inhibitors (e.g., bortezomib, Two or more standard therapies, including anti-CD38 agents (e.g., daratumab), and anti-CD38 agents (e.g., carfilzomib). Relapsed and / or refractory to each regimen, or incurable Resistant and with documented evidence of disease progression (IMWG criteria), as determined by the investigator Patients who are eligible for treatment with other regimens known to provide clinical benefit when (received prior autologous bone marrow transplant, BCMA CAR-T, or BCMA-ADC therapy) Subjects who have received the study or meet the eligibility criteria are eligible for this study; Eastern Cooperative Oncology Group (ECOG) Have a performance status ≤ 2; defined by at least one of the following three measures: have measurable disease as defined by: (i) serum M protein ≥ 1.0 g / dL; (ii) urine M protein ≥ 200 mg / 24 hours; or (iii) serum free light chain (sFLC) > 10 Associated FLC of 0 mg / L.

[0281] 11.7.2. Exclusion criteria Subjects meeting any of the following criteria are ineligible for entry into this study: lytic bone disease Within 14 days before the first dose of study drug, except for localized radiation therapy for tumors or plasmacytoma radiation therapy; major surgery within 2 weeks before the first dose of study drug; systemic chronic steroid therapy (≥10 mg / day prednisone or equivalent), or study treatment (topical, inhaled, intranasal or intraocular steroids are tolerated) use; previous use of BCMAxCD3 bispecific therapy; any immunosuppressive medication (as described above) Subjects receiving systemic treatment with any of the study drugs and other mAbs History of severe hypersensitivity reactions to ingredients and / or their excipients; previous BCMA targeting Subjects with toxicity to the drug; malignant disease other than that being treated in this study. (Exceptions to this exclusion include: therapeutically treated patients who have relapsed within 2 years prior to study treatment completely excised basal cell and squamous cell skin cancers, and any type completely excised carcinoma in situ); vitiligo, residual carcinoma requiring only hormone replacement hypogonadism, psoriasis not requiring systemic treatment, or conditions not expected to recur Active, known or suspected autoimmune disease other than that of the intended target; Subjects currently receiving treatment with prohibited concomitant medications that cannot be discontinued for at least 1 week; Subjects with neuropathy of grade ≥ 2 and residual toxic effects from prior treatment of grade ≤ 1 or recovered to baseline; non-MM, plasma cell leukemia Subjects with pulmonary embolism and other plasmacytoid cell disorders; any of the following clinical test results: (i) Treatment Absolute neutrophil count (ANC) <1,000 / m without growth factor support within 7 days prior to initiation of treatment m3; (ii) platelet count <75,000 mm3 without transfusion support within 7 days prior to initiation of treatment (iii) bilirubin greater than 1.5 times the upper limit of normal (ULN); (iv) greater than 2 times the ULN 0.5-fold higher aspartate aminotransferase (AST) or alanine aminotransferase (v) less than 30 ml / min according to the Cockcroft-Gault formula (vi) cardiac dysfunction or clinically significant cardiac disease; Active infection requiring systemic treatment or other severe infection within 2 weeks prior to the first dose of study drug Infection; POEMS syndrome (polyneuropathy, organomegaly, endocrine disorders, monoclonal plasma cell dyscrasia with leukemia, skin changes); informed consent for the study Previous allogeneic SCT at any time before signing the contract; human immunodeficiency virus (H IV infection); active hepatitis B (HBV) or hepatitis C (HCV) infection; Any infection (e.g., influenza, chickenpox, pneumococcus) within the first 4 weeks Use of vaccine; within 14 days or 5 half-lives, whichever is shorter, before the first dose of study treatment Treatment with a cytotoxic or small molecule targeted anti-tumor drug, or any experimental treatment; Hematopoietic colony-stimulating growth factors (e.g., G-CSF, M-CSF) within 2 weeks of initiating treatment Initiation of thrombopoietin mimetics or erythropoiesis-stimulating agents; IVs given to prevent infection Intravenous IG infusion must be discontinued at least 28 days before the start of study treatment; Symptomatic CNS metastases within 2 weeks prior to the start of treatment, or local CNS-directed therapy (radiation therapy or Active central nervous system (CN) disease due to the severity or presence of CNS metastases requiring treatment (e.g., surgery) S) Involvement of any of the following: Serious medical or psychiatric illnesses that are highly susceptible to lactating women (where pregnancy is confirmed by a positive hCG laboratory test) defined as the state of a woman after conception until the end of pregnancy; and Women of childbearing potential (WHO) are defined as all women who are physiologically capable of having a child. At the time of informed consent, during study drug administration, and for 6 months after the last dose of study drug and are not using two effective methods of contraception, including at least one highly effective method. (Unless otherwise stated).

[0282] 11.7.3. Drug products The drug product is formulated as a liquid in a vial (LIVI) and contains 10 mg / m L BSBM3, 20 mM histidine, 240 mM sucrose, PS20 0.04 %, pH 5.5±0.3.

[0283] All doses prescribed and administered to subjects and all dose changes during the study will be recorded in the Dosage Recorded on the Administration Record eCRF.

[0284] [Table 6]

[0285] Investigation of alternative doses and / or dosing regimens of BSBM3 will be conducted after the initiation of the expansion part of the RD. Even if the subjects are enrolled simultaneously, they may be examined in increments. Cohort allocation will stagger across all study sites.

[0286] 11.7.4. Treatment process BSBM3 will initially be administered once weekly (Q1W). Study drug treatment will be administered according to the IMWG. Therefore, treatment will continue until the subject develops unacceptable toxicity, progressive disease, or the study is discontinued. The study design is summarized in Figure 6. Preliminary results from this ongoing study suggest that a dosing schedule (e.g., Q2W, Q3W, TIW) may be beneficial. Implemented in trials if supported by new data including K, PD, and efficacy findings Clinically significant cytokine release syndrome (CRS) or related symptoms may occur during dose escalation. If observed during the administration schedule, the option of a priming dose may be introduced. The rule can be adjusted.

[0287] The design of this phase I, open-label study included patients who had been treated with at least two prior regimens. and receive IMiDs, proteasome inhibitors, and anti-CD38 antibodies (if available). Safety and efficacy of BSBM3 in subjects with relapsed and / or refractory multiple myeloma To characterize the efficacy and tolerability of the drug and to determine recommended doses and regimens for future studies. If necessary, dose escalation will be performed to allow the MTD of BSBM3 to be established. It is based on a Bayesian hierarchical logistic regression model (BLRM).

[0288] BLRM is a well-established method for estimating MTD in cancer subjects. Reactive BLRM is designed to control the risk of DLT in future subjects being studied. Guided by titration using dose control (EWOC) principles. For small data sets The use of Bayesian response adaptation models is recognised by the EMEA ("Guideline e on clinical trials in small population s”, February 1, 2007), and many publications (Babb et al., 1 998,Stat Med;17(10):1103-20);(Neuenschwa nder et al.,2008,Stat Med;27(13):2420-39 );(Neuenschwander et al.,2010,Clin Trial s;7(1):5-18);(Neuenschwander et al.,2014 ,in A Bayesian Industry Approach to Phas e I Combination Trials in Oncology.In St aistical Methods in Drug Combination St udies.Zhao W and Yang H(eds),Chapman&Hal FDA approved the use of steroids in the treatment of steroids (Illegible / Cold Ribs, 2014), and its development and appropriate use are being monitored by the FDA. FDA's Critical Path Initiative This is one aspect of the 'titiative'.

[0289] The decision regarding the new dose level will be based on PK, PD, and preliminary activity data available at the time of the decision. information, along with subject tolerability and safety information (including BLRM-derived estimates of DLT risk) This will be done at the dose escalation meeting based on the review of the

[0290] Dose Escalation During dose escalation, subjects with relapsed and / or refractory MM will continue treatment until the MTD / RD is reached. An estimated 21 subjects will be treated with BSB3 at dose ≥ 100 mg / kg to define the MTD / RD. This is required during escalation.

[0291] The safety (including dose-DLT relationships) and tolerability of the study treatment will be evaluated, and the regimen and Doses will be identified for use in the expansion part based on a review of these data. RD is also guided by available information on PK, PD, and preliminary antitumor activity. Dose escalation was performed according to the Excessive Weighted Overdose Control (EWOC) principle using an adaptive Bayesian hierarchical method. It is derived by a logistic regression model (BLRM).

[0292] Once the MTD / RD is determined in the titration part, the PK, PD, and safety of the study drug will be assessed. To further characterize the profile and evaluate the preliminary anti-tumor activity of BSBM3 In order to do so, more subjects will be enrolled in the expanded part. More than one dose level may be investigated as an RD for expansion. The schedule may be examined in the escalation phase. A new schedule RD may be assigned. do.

[0293] In the expansion part, subjects with relapsed and / or refractory MM are treated with BSBM3. The expansion part will enroll approximately 20 subjects. Enrollment will be based on data from the expansion cohort. may be terminated earlier based on ongoing review of the

[0294] 11.7.5.1. Interim Administration The dose of BSBM3 was determined based on predicted pharmacokinetics, mechanism of action, and in vitro efficacy (MABEL dose). Circulating BCMA in cynomolgus monkey GLP toxicology studies (to inform clinical trials) The results are based on an integrated evaluation of the effects and in vivo safety of BSBM3 for subjects. The starting dose is 3 mcg / kg administered as a 2-hour intravenous infusion.

[0295] The BSBM3 starting doses and dose levels that may be evaluated during this study are listed in Table 4. This starting dose is based on the RTCC, which is considered the most clinically relevant measure of pharmacological activity. The EC50 value from the assay (in which recombinant soluble BCMA was not added) was approximately 0.07 μg / mL) and is the most sensitive and reproducible in vitro study for BSBM3 This is a reliable assay readout (data not shown).

[0296] Actual dose levels will be determined based on available toxicity, pharmacokinetic, and pharmacodynamic data. Dose escalation will be guided by the BLRM. Dose escalation will continue until one or more MTDs or RDs are determined. Continue.

[0297] [Table 7]

[0298] Optionally, during dose escalation, two patients experienced a grade ≥3 infusion-related reaction (IRR). Events or cytokine release that does not return to grade ≤1 or baseline within 48 hours If CRS occurs, a priming dose is used.

[0299] The priming dose is selected at a dose level determined to be safe (the dose is At least less than the maximum volume tested in the previous cohort and meeting the EWOC criteria Additionally, as an added safety measure, the priming dose One-third of the dose is given on day 1 and two-thirds of the dose is given on day 2. Once the target dose level is determined, the dose levels that may be evaluated in subsequent cohorts will be determined based on the target dose level. The priming dose is defined as 100 mg / kg of 1000 mg ... 00 mcg / kg (i.e., dose level X in Table 5), on Day 1 The dose on day 1 was 33.33 mcg / kg, and the dose on day 2 was 66.66 mcg / kg. The third and subsequent injections (days 8, 15, and 22) were administered at 200 mcg / kg (i.e., Dose level X+1, where X+1 is the next interim dose level after X listed in Table 3 The actual dose level will be determined based on the available toxicity, pharmacokinetic, and pharmacodynamic data. A separate BHLRM will be constructed to guide dose escalation using EWOC criteria. Dose escalation will continue until one or more MTDs or RDs are determined.

[0300] [Table 8]

[0301] Priming dose levels will be adjusted, if necessary, according to developmental study safety and tolerability findings. It can be responded to.

[0302] Guidelines for Dose Escalation and Determination of MTD / RD Dose escalation will be performed to establish the dose of BSBM3 to be used in the expansion part. Specifically, it considers safety, tolerability, and PK, taking into account the maximum tolerated dose (MTD). The most relevant benefit as assessed by any available efficacy and PD considerations. To-one or more doses considered to be at risk.

[0303] The MTD was met by dose-limiting toxicity (DLT) during the DLT evaluation period in more than 33% of treated subjects. The highest dose estimated to have less than a 25% risk of causing vasoconstriction (T). The dose selected for administration can be any dose up to the MTD, and can be used without specifying the MTD. It can be shown.

[0304] Each dose escalation cohort will start with 1 to 6 newly treated subjects. Must have sufficient exposure and follow-up to be considered evaluable for escalation decisions. stomach.

[0305] If a subject experiences a DLT during the DLT evaluation period, the minimum cohort size will be increased to 3. can be.

[0306] If one or more subjects discontinue or fail to meet the evaluation criteria, a replacement procedure will be implemented. Further subjects will be enrolled in the same cohort to support the benefit-risk assessment. It can be used to

[0307] The treatment period begins on Day 1 of Cycle 1. For scheduling and evaluation purposes, A treatment cycle consists of 28 days. The dose levels on Day 1 of Cycle 1 were determined based on those previously tested and For each cohort higher than any dose shown to be safe, A time-staggered procedure for two subjects is used. After the first subject's dose, the next subject receives the same dose as the previous one. The first two subjects will be dosed a minimum of 72 hours after the first two subjects have been dosed. After completion, subsequent subjects will be treated without a staggered time period, provided that no more than one patient in the cohort , with the first infusion on any given day. Dose escalation determinations are made until all subjects in a cohort receive D The decision is made when the LT evaluation period is completed or discontinued. The decision is based on safety information, available All data being evaluated in ongoing studies, including clear PK, available PD and preliminary efficacy The study will be based on a synthesis of all relevant data available from the dose levels.

[0308] All dose escalation decisions were made using a Bayesian hierarchical logistic regression model (BLRM). Do not exceed a dose level that satisfies the EWOC principle. For any dose level, the following escalation Doses for cohorts will not exceed a 100% increase from the previously tested safe dose. A smaller increase in dose may be recommended by the investigator and the clinical trial after review of all available clinical data. May be recommended by the client.

[0309] The safety, tolerability, PK, PD or other endpoints of BSBM3 will be evaluated before or during further escalation. To better understand the antitumor activity, additional cohorts of 1 to 6 subjects were compared with previously tested A drug may be enrolled at any dose level up to the highest dose tested and shown to be safe.

[0310] To reduce the risk of exposing subjects to excessively toxic doses, two subjects were randomly assigned to receive the new cohort. If a DLT occurs in a cohort, the BLRM will The database is updated with the latest information from all cohorts without waiting for all subjects from each cohort. - If two DLTs occur in an escalation cohort, enrollment in that cohort will be halted. , the next cohort will be opened at a lower dose level that meets the EWOC criteria. - If two DLTs occur in additional cohorts, after re-evaluation of all relevant data Further subjects will be admitted to the open cohort only if the dose still meets the EWOC criteria. Alternatively, if recruitment to the same dose is not continued, a new cohort of subjects may be enrolled. In addition, if two or more patients If a DLT occurs in a treatment cohort, the next dose escalation level will be determined by the previous dose level. Not exceeding 50%.

[0311] CRS Management At least two doses of tocilizumab per patient were administered at the institution prior to BSBM3 infusion. Hospitals should be available in a timely manner for additional doses of tocilizumab. Supportive care, tocilizumab, and corticosteroids are used for the effective management of CRS. A rapid response to tocilizumab was seen in most subjects.

[0312] Cytokine release syndrome (CRS) is identified based on clinical findings (see Table 6) Fever, hypoxia, and other causes of hypotension are evaluated and treated, and the subject is placed in a BSBM3 Patients will be monitored for signs or symptoms of CRS for at least 4 weeks after treatment with Subjects were instructed to seek immediate medical treatment if any signs or symptoms of CRS occurred at any time. is advised.

[0313] At the first sign of CRS (see Table 6), patients are immediately evaluated for hospitalization; Supportive care, tocilizumab, and / or corticosteroids may be recommended as indicated. It will be entered.

[0314] A recommended treatment algorithm for the management of CRS is presented below in Tables 7 and 8. The CRS management algorithm is a guideline, and investigators may use discretion or Alternatively, the treatment regimen may be adjusted according to the needs of the individual subject.

[0315] [Table 9]

[0316] [Table 10]

[0317] [Table 11]

[0318] If a subject does not respond to tocilizumab, other anti-cytokine therapies are also available. If the subject has progressed despite administration of anti-cytokine directed therapy, If CRS occurs during treatment, anti-T cell therapy such as cyclophosphamide, antithymocyte globulin, Anti-inflammatory drug (ATG) or alemtuzumab may be considered. These therapies are effective in patients with appropriate CRF. will be done.

[0319] Management of CRS is based solely on the clinical parameters listed in Table 7. Ferritin, CRP and serum cytokine levels are not used in clinical management decisions. Transient left ventricular dysfunction In this case, patients had severe (grade 4) CRS as assessed by echocardiogram (ECHO). Therefore, it is important to consider the possibility of ECHO during severe CRS. Monitoring cardiac function with a cardiogram is considered, especially in cases of prolonged severe hemodynamic instability. delayed response to large amounts of vasopressors and / or severe fluid overload.

[0320] 11.7.7. Primary Endpoint The primary endpoints of the study are listed in Table 9.

[0321] [Table 12]

[0322] 11.7.8.Results BSBM3 has been found to be safe and well tolerated, yet has antitumor activity. You can see that.

[0323] 11.8. Example 8 Effective Dose Range of AL-102 for Inhibition of BCMA Efflux Overview The gamma-secretase inhibitor (GSI), AL-102, was administered to KMS11 cells in vitro. Its effect on B cell maturation antigen (BCMA) shedding was assessed.

[0324] Materials and Methods GSI treatment of KMS11 cells KMS11-Luc cells were cultured in 20% FBS (Seradigm #1500-500 ) and L-glutamine (Thermo Fisher #25030-081) 12 points of AL-102 in RPMI 1640 (Gibco #11875-085) At 1.5 x 10 cells per well in a final volume of 200 µL containing 5-fold serial dilutions , and cultured in a 96-well round-bottom plate (Corning #3799). The highest starting concentration of α-glucan was 1 μM. Cells were incubated at 37°C / 5% CO2 for 20 hours. The cells were pelleted and the supernatant was collected for measurement of shed BCMA levels. Cells were collected and cell pellets were stained for assessment of BCMA membrane expression levels.

[0325] Measurement of Shedding BCMA Levels by ELISA Soluble BCMA levels in the supernatant were measured according to the protocol provided by the supplier (R&D Sy The results were determined by ELISA according to the ELISA standard (stem #DY193). Recombinant human BCMA-Fc protein is included in the kit and used to generate standard curves. A line was generated. Collected samples were assayed and sBCMA concentrations were estimated from the standard curve. The quantified values ​​determined by the kit were divided by 5.5 to generate the standard curve. The BCMA-Fc fusion protein (32,554.6 Da) used in the study was endogenously shed. The difference in molecular weight between the mass of the BCMA extracellular domain (5,899.3 Da) and the mass of the BCMA extracellular domain (5,899.3 Da) was compensated for. The results were analyzed using Tibco Spotfire or Graphp for the concentration of GSI. The results were plotted in ad Prism. Results were analyzed using SoftMax Pro v5.4. 1 and graphed in GraphPad Prism.

[0326] Analysis of BCMA Membrane Expression by Flow Cytometry Cells were pelleted by centrifugation and the supernatant was transferred to a new plate and analyzed by ELISA. The cells were frozen at -80°C for later sBCMA analysis by The cell pellet was washed with 100 μL of BD Stain Buffer (BD #554657) and incubated at 4°C for 30 minutes with anti-BCMA-PE (B iolegend, clone 19F2 1.25ul / test) and Fixable Vi ability Dye eFluor506(Thermo Scientific, The samples were stained with a 1:800 dilution of 1:1000 rRNA. Flow cytometry was used to analyze the cells. FlowJo v10 software was used for the analysis. Anti-BCMA antibody binding capacity (ABC) in KMS11 cells was measured using the antibody provided by the supplier. Quantum Simply Cellular beads (Ba) were used according to the protocol ABC was determined using a ngs Laboratories (BioScience Laboratories). ABC is the number of receptors per cell. These results were plotted against the concentration of AL-102 using Graphpad P plotted in rism.

[0327] 11.8.3.Results AL-102 enabled BCMA efflux from KMS11 cells in a dose-dependent manner inhibited BCMA expression on the cell surface over the same effective dose range. Untreated KMS11 cells expressed a BCMA antibody binding capacity (A) of approximately 14,000. The mean ABC with 1 μM AL-102 treatment was approximately 285,000. There was a 20-fold increase in cell surface BCMA expression with AL-102 treatment.

[0328] 11.9. Example 9: Effect of AL-102 on BSBM3 Efficacy Overview To assess the ability of AL-102 to enhance BSBM3 activity, we performed a redirected T Cell cytotoxicity (RTCC) assay was performed using BSBM3 and A cells in a 10 × 8 matrix format. Human T-cell and BCMA-expressing multiple myeloma treated with dose-ranging combinations of L-102 This was carried out using cell lines.

[0329] Materials and Methods Isolation of Healthy Human T Cells Human T cells were enriched from the peripheral blood of three healthy human donors. First, peripheral blood mononuclear cells (PBMCs) were isolated. PBMCs were incubated in Leucosep tubes (Greiner #227290) with Fico ll-Paque PLUS Density Gradient (GE Healthcare #17-1440 -02) from donor blood and stored as viable frozen aliquots in liquid nitrogen. PBMCs were thawed and pan-T cells were cultured according to the manufacturer's recommended protocol (Miltenyi # T cells were isolated by negative selection according to the method described in the previous section (130-096-535). The purified unlabeled cell fraction was purified by LS column (Miltenyi #130-042-401 T cells were collected by manual magnetic separation in RPMI-1640 (Gibco #11875-085), 10% FBS (Seradigm #1500-500) , 1% Pen / Strep (Life Technologies #1507006 3), 1% L-glutamine (Thermo Scientific #25030-0 81), 1% non-essential amino acids (NEAA) (Life Technologies # 11140-050), sodium pyruvate (NaPy) (Life Technology ogies #11360-070), HEPES (Life technologie) s, Cat # 15630080), 0.1% 2-β-mercaptoethanol (2-B ME) (Life Technologies, Cat # 21985-023) The cells were prepared in T cell medium (TCM).

[0330] KMS11 Multiple Myeloma Cell Line KMS11 multiple myeloma cell line was cultured in 20% FBS (Gibco #11875-08 5, Seradigm #1500-500) were cultured in RPMI 1640 supplemented with Ta.

[0331] 11.9.2.3. Redirected T-cell cytotoxicity (RTCC) assay The target MM cell line KMS11 constitutively expresses luciferase (KMS11-Luc). KMS11-Luc was transduced to measure cell viability / survival. Cells were pelleted and immediately plated to remove basal levels of shed BCMA that may be present. 7,500 KMS11- in 10 μL of TCM were resuspended in fresh medium before Luc target cells were plated in the wells of a 384-well plate (Corning #3765). 10 μl of BSBM3 at a concentration of 10 nM was added, followed by 5-fold serial dilutions, 10 μl of AL-102 at a concentration of 5-fold serial dilutions was added to the corresponding plate of the assay. 15,000 T cells were distributed in 10 μL of T cells for a 2:1 E:T ratio. The assay was performed at 37°C / 5% CO After incubation at 2°C for 48 hours, the target cells were transfected according to the manufacturer's protocol. Luciferase activity was measured to indicate cell viability (BrightGlo, Prome Plates were read on an Envision plate reader. Target cells alone (KMS11-Luc) without T cells or antibodies served as a control. 100% luciferase activity (100% viability) is represented. Data were plotted and the Gr EC50 values ​​were calculated using a sigmoidal, 4-parameter The data were calculated using nonlinear regression curve fitting.

[0332] 11.9.3.Results RTCC assay was performed to compare the dose-response curves of BSBM3 alone or in combination with AL-102. Three individual T cell donors were used, cultured with KMS11-Luc cells in the presence of a marker. BSBM3 inhibited KMS11-Luc cell death with an EC50 value of 1 nM. The combination of AL-102 and BSBM3 inhibited BSBM3 killing. AL-102 increased the BSB inhibitory activity from 1 nM to approximately 0.02 nM (Fig. 9). M3, which resulted in an improved R of BSBM3 in the presence of AL-102. This represents a 50-fold increase in BSBM3 potency. AL-102 below this level had minimal effect on BSBM3 efficacy, with a moderate effect at 1.6 nM. The effect was moderate, with concentrations of 8 nM or higher showing the greatest improvement in BSBM3 efficacy. These results suggest that the combination of AL-102 with BSBM3 significantly inhibits the RTCC of BSBM3. A synergistic improvement in efficacy was demonstrated.

Claims

1. A method of treating a subject suffering from multiple myeloma, comprising administering to a subject a compound selected from the group consisting of human BCMA and human CD3. Combined, (a) a first polypeptide whose amino acid sequence comprises the amino acid sequence of SEQ ID NO:1; (b) a second polypeptide whose amino acid sequence comprises the amino acid sequence of SEQ ID NO:2; and (c) a third polypeptide whose amino acid sequence comprises the amino acid sequence of SEQ ID NO:

3. administering to said subject one or more therapeutic doses of a bispecific antibody comprising

2. 10. The method of claim 1, wherein the subject has measurable disease.

3. 3. The method of claim 2, wherein the subject has a serum M protein level of ≧1 g / dL. 。

4. 10. The method of claim 2, wherein the subject produces a urinary M protein level of ≥ 200 mg / 24 hours. The method according to claim 3.

5. The subject has a serum free light chain (sFLC) level of at least 100 mg / L of relevant FLC. The method according to any one of claims 2 to 4, comprising:

6. The method of any one of claims 1 to 5, wherein the multiple myeloma is relapsed.

7. The method of any one of claims 1 to 6, wherein the multiple myeloma is refractory.

8. 8. The method of claim 1, wherein the bispecific antibody is administered intravenously to the subject. The method described.

9. 9. The method of claim 8, wherein the bispecific antibody is administered to the subject as an infusion.

10. 10. The method of claim 9, wherein the infusion is over a period of 1.5 to 3 hours.

11. 10. The method of claim 9, wherein the infusion is over a period of 2 hours.

12. 12. The method according to claim 1, wherein one or more therapeutic doses are administered once a week. method.

13. 13. Any one of claims 1 to 12, wherein the subject is administered at least three therapeutic doses. The method described below.

14. 14. The method of claim 13, wherein the three therapeutic doses are administered over a period of less than one month. method.

15. 15. The method of claim 14, wherein the three therapeutic doses are administered over a period of 14 or 15 days. How to post.

16. 13. Any one of claims 1 to 12, wherein the subject is administered at least four therapeutic doses. The method described below.

17. 17. The method of claim 16, wherein the four therapeutic doses are administered over a period of less than one month. method.

18. 10. The method of claim 1, wherein the four therapeutic doses are administered over a period of 21, 22, or 23 days.

7. The method according to claim 7.

19. one or more of the or each therapeutic dose (a) from about 1 μg / kg to about 1200 μg / kg; or (b) Approximately 50 μg to approximately 96 mg The method according to any one of claims 1 to 18, wherein the range is

20. one or more of the or each therapeutic dose (a) from about 3 μg / kg to about 600 μg / kg; or (b) Approximately 150 μg to approximately 48 mg 20. The method of claim 19, wherein the range is:

21. one or more of the or each therapeutic dose (a) about 5 μg / kg to about 100 μg / kg; or (b) Approximately 150 μg to approximately 8 mg 20. The method of claim 19, wherein the range is:

22. one or more of the or each therapeutic dose (a) from about 10 μg / kg to about 200 μg / kg; or (b) Approximately 500 μg to approximately 16 mg 20. The method of claim 19, wherein the range is:

23. one or more of the or each therapeutic dose (a) from about 50 μg / kg to about 400 μg / kg; or (b) Approximately 2.5 mg to approximately 32 mg 20. The method of claim 19, wherein the range is:

24. one or more of the or each therapeutic dose (a) from about 100 μg / kg to about 600 μg / kg; or (b) Approximately 5 mg to approximately 96 mg 20. The method of claim 19, wherein the range is:

25. one or more therapeutic doses or said first therapeutic dose (a) about 1 μg / kg; or (b) Approximately 50 μg to approximately 80 μg 20. The method of claim 19, wherein:

26. one or more therapeutic doses or said first therapeutic dose (a) about 3 μg / kg; or (b) Approximately 150 μg to approximately 240 μg 20. The method of claim 19, wherein:

27. one or more therapeutic doses or said first therapeutic dose (a) about 6 μg / kg; or (b) Approximately 300 μg to approximately 480 μg 20. The method of claim 19, wherein:

28. one or more therapeutic doses or said first therapeutic dose (a) about 12 μg / kg; or (b) Approximately 600 μg to approximately 960 μg 20. The method of claim 19, wherein:

29. one or more therapeutic doses or said first therapeutic dose (a) about 24 μg / kg; or (b) Approximately 1.2 mg to approximately 1.92 mg 20. The method of claim 19, wherein:

30. one or more therapeutic doses or said first therapeutic dose (a) about 48 μg / kg; or (b) Approximately 2.4 mg to approximately 3.84 mg 20. The method of claim 19, wherein:

31. one or more therapeutic doses or said first therapeutic dose (a) about 96 μg / kg; or (b) Approximately 4.8 mg to approximately 7.68 mg 20. The method of claim 19, wherein:

32. one or more therapeutic doses or said first therapeutic dose (a) about 192 μg / kg; or (b) Approximately 9.6 mg to approximately 15.36 mg 20. The method of claim 19, wherein:

33. one or more therapeutic doses or said first therapeutic dose (a) about 384 μg / kg; or (b) Approximately 19.2 mg to approximately 30.72 mg 20. The method of claim 19, wherein:

34. one or more therapeutic doses or said first therapeutic dose (a) about 600 μg / kg; or (b) Approximately 30 mg to approximately 48 mg 20. The method of claim 19, wherein:

35. administering a therapeutic dose of the bispecific antibody; (a) administering a first therapeutic dose; and (b) titrating said therapeutic dose to a final therapeutic dose.

35. The method of any one of claims 1 to 34, comprising:

36. administering a second therapeutic dose that is the same as the first therapeutic dose before escalating the therapeutic dose; 36. The method of claim 35, comprising:

37. 35 or claim 36, wherein step (b) comprises escalating the therapeutic dose two or more times.

36. The method according to claim 36.

38. 38. Any one of claims 35 to 37, wherein each dose escalation results in no more than a doubling of the previous dose. The method described in paragraph .

39. the first therapeutic dose being: (a) about 1 μg / kg to about 6 μg / kg; or (b) Approximately 50 μg to approximately 480 μg The method according to any one of claims 35 to 38, wherein the range is

40. the first therapeutic dose being: (a) about 1 μg / kg; or (b) Approximately 50 μg to approximately 80 μg The method according to any one of claims 35 to 38, wherein

41. the first therapeutic dose being: (a) about 3 μg / kg; or (b) Approximately 150 μg to approximately 240 μg The method according to any one of claims 35 to 38, wherein

42. the first therapeutic dose being: (a) about 6 μg / kg; or (b) Approximately 300 μg to approximately 480 μg The method according to any one of claims 35 to 38, wherein

43. The final therapeutic dose is (a) from about 5 μg / kg to about 600 μg / kg; or (b) Approximately 150 μg to approximately 48 mg The method according to any one of claims 35 to 38, wherein the range is

44. The final therapeutic dose is (a) from about 10 μg / kg to about 200 μg / kg; or (b) Approximately 500 μg to approximately 16 mg The method according to any one of claims 35 to 38, wherein the range is

45. The final therapeutic dose is (a) from about 50 μg / kg to about 400 μg / kg; or (b) Approximately 2.5 mg to approximately 32 mg The method according to any one of claims 35 to 38, wherein the range is

46. The final therapeutic dose is (a) from about 100 μg / kg to about 600 μg / kg; or (b) Approximately 5 mg to approximately 96 mg The method according to any one of claims 35 to 38, wherein the range is

47. The final therapeutic dose is (a) about 6 μg / kg; or (b) Approximately 300 μg to approximately 480 μg The method according to any one of claims 35 to 38, wherein

48. The final therapeutic dose is (a) about 12 μg / kg; or (b) Approximately 600 μg to approximately 960 μg The method according to any one of claims 35 to 38, wherein

49. The final therapeutic dose is (a) about 24 μg / kg; or (b) Approximately 1.2 mg to approximately 1.92 mg The method according to any one of claims 35 to 38, wherein

50. The final therapeutic dose is (a) about 48 μg / kg; or (b) Approximately 2.4 mg to approximately 3.84 mg The method according to any one of claims 35 to 38, wherein

51. said final therapeutic dose being: (a) about 96 μg / kg; or (b) Approximately 4.8 mg to approximately 7.68 mg The method according to any one of claims 35 to 38, wherein

52. The final therapeutic dose is (a) about 192 μg / kg; or (b) Approximately 9.6 mg to approximately 15.36 mg The method according to any one of claims 35 to 38, wherein

53. The final therapeutic dose is (a) about 384 μg / kg; or (b) Approximately 19.2 mg to approximately 30.72 mg The method according to any one of claims 35 to 38, wherein

54. The final therapeutic dose is (a) about 600 μg / kg; or (b) Approximately 30 mg to approximately 48 mg The method according to any one of claims 35 to 38, wherein

55. Prior to administering the first therapeutic dose of the bispecific antibody, 55. The method of claim 1, comprising administering to the subject a timing dose How to do it.

56. 56. The method of claim 55, wherein the priming dose is less than the first therapeutic dose.

57. 56. The method of claim 55, wherein the priming dose is equal to the first therapeutic dose.

58. Administration of the priming dose begins one week before administration of the first therapeutic dose.

58. The method according to any one of claims 55 to 57.

59. 59. The method of claim 55 or claim 58, wherein the priming dose is divided.

60. 60. The method of claim 59, wherein the priming dose is administered over a two day period. Law.

61. Less than half of the priming dose is administered on day 1, and the remainder of the priming dose is is administered on the second day.

62. About one-third of the priming dose is administered on day 1, and about one-third of the priming dose is administered on day 2.

62. The method of claim 61, wherein two-thirds are administered on the second day.

63. the priming dose being (a) from about 0.5 μg / kg to about 6 μg / kg; or (b) Approximately 25 μg to approximately 480 μg The method of any one of claims 55 to 62, wherein the

64. the priming dose being (a) about 1 μg / kg; or (b) Approximately 50 μg to approximately 80 μg 64. The method of claim 63, wherein:

65. the priming dose being (a) about 2 μg / kg; or (b) Approximately 100 μg to approximately 160 μg 64. The method of claim 63, wherein:

66. the priming dose being (a) about 3 μg / kg; or (b) Approximately 150 μg to approximately 240 μg 64. The method of claim 63, wherein:

67. the priming dose being (a) about 4 μg / kg; or (b) Approximately 200 μg to approximately 320 μg 64. The method of claim 63, wherein:

68. the priming dose being (a) about 5 μg / kg; or (b) Approximately 250 μg to approximately 400 μg 64. The method of claim 63, wherein:

69. the priming dose being (a) about 6 μg / kg; or (b) Approximately 300 μg to approximately 480 μg 64. The method of claim 63, wherein:

70. (a) on day 1 of said treatment, said subject receives 3 doses of a priming dose of said bispecific antibody; administering one-third; (b) on day 2 of said treatment, said subject receiving said priming dose of said bispecific antibody administering two-thirds of the dose; (c) administering a first therapeutic dose to said subject on one of days 5-11 of said treatment. To do so; (d) administering a second therapeutic dose to the subject on one of days 12-18 of said treatment. and (e) on one of days 19-25 of said treatment, administering a third therapeutic dose to said subject. To do 35. The method of any one of claims 1 to 34, comprising:

71. (a) on day 1 of said treatment, said subject is administered said priming dose of said bispecific antibody; administering one-third of the dose; (b) on day 2 of said treatment, said subject receiving said priming dose of said bispecific antibody administering two-thirds of the dose; (c) administering a first therapeutic dose to said subject on one of days 6-10 of said treatment. To do so; (d) on one of days 13 to 17 of said treatment, administering a second therapeutic dose to said subject. and (e) on one of days 20-24 of said treatment, administering a third therapeutic dose to said subject. To do 71. The method of claim 70, comprising:

72. (a) on day 1 of said treatment, said subject is administered said priming dose of said bispecific antibody; administering one-third of the dose; (b) on day 2 of said treatment, said subject receiving said priming dose of said bispecific antibody administering two-thirds of the dose; (c) on one of days 7 to 9 of said treatment, administering to said subject a first therapeutic dose. thing; (d) on one of days 14-16 of said treatment, administering a second therapeutic dose to said subject. and (e) on one of days 21-23 of said treatment, administering a third therapeutic dose to said subject. To do 71. The method of claim 70, comprising:

73. (a) on day 1 of said treatment, said subject receives 3 doses of a priming dose of said bispecific antibody; administering one-third; (b) on day 2 of said treatment, said subject receiving said priming dose of said bispecific antibody administering two-thirds of the dose; (c) on day 8 of said treatment, administering to said subject a first therapeutic dose; (d) on day 15 of said treatment, administering a second therapeutic dose to said subject; and (e) on day 22 of said treatment, administering to said subject a third therapeutic dose.

71. The method of claim 70, comprising:

74. 74. The method of any of claims 70 to 73, wherein the priming dose is the same as the first therapeutic dose. The method according to any one of claims 1 to 5.

75. 74. The method of claim 70, wherein the first therapeutic dose is 2 to 8 times the priming dose.

10. The method according to any one of claims 1 to 9.

76. 74. The method of any one of claims 70 to 73, wherein the first therapeutic dose is twice the priming dose. The method according to any one of claims 1 to 5.

77. 74. The method of any of claims 70 to 73, wherein the first therapeutic dose is four times the priming dose. The method according to any one of claims 1 to 5.

78. 74. The method of any one of claims 70 to 73, wherein the first therapeutic dose is eight times the priming dose. The method according to any one of claims 1 to 5.

79. 79. Any one of claims 70 to 78, wherein the second therapeutic dose is equal to the first therapeutic dose. The method described in paragraph .

80. 80. The method of claim 70, wherein the third therapeutic dose is the same as the first therapeutic dose.

1. The method according to claim 1.

81. and administering to the subject one or more agents that mitigate side effects of the bispecific antibody. The method of any one of claims 1 to 80, further comprising:

82. the agent is administered prior to, simultaneously with, or after initiation of treatment with the bispecific antibody 82. The method of claim 81, administered subsequently, or in any combination of the above.

83. Claim 81 or claim 82, wherein the side effect is cytokine release syndrome (CRS). The method described below.

84. 84. The method of claim 83, wherein the one or more agents reduce the incidence or severity of CRS. Law.

85. 85. Any one of claims 81 to 84, wherein the one or more agents include a glucocorticoid. The method described below.

86. 86. The method of claim 85, wherein the glucocorticoid is methylprednisolone.

87. 9. The method of claim 8, wherein the methylprednisolone is given at a dose of at least 2 mg / kg.

6. The method according to claim 6.

88. The one or more drugs may be paracetamol, acetaminophen, antihistamines, steroids, or the like. 81-83, comprising a steroid, an anti-T cell directed therapy, or any combination thereof.

10. The method according to any one of the preceding claims.

89. The one or more drugs are tocilizumab, canakinumab, or any combination thereof.

89. The method of claim 88, comprising an anti-T cell directed therapy wherein

90. Any one of claims 1 to 89, further comprising administering a second therapeutic agent to the subject. The method described below.

91. The bispecific antibody and the second therapeutic agent may be administered simultaneously, separately, or over a period of time.

91. The method of claim 90, wherein the administration is

92. 92. The method of claim 90 or 91, wherein the second therapeutic agent is a gamma secretase inhibitor (GSI). The method described.

93. The GSI is LY-450139, PF-5212362, BMS-708163, MK-0752, ELN-318463, BMS-299897, LY-411575, DAPT, AL-101 (BMS-906024), AL-102 (BMS-98611 5), PF-3084014, RO4929097, or LY3039478, 93. The method of claim 92.

94. 94. The method of claim 93, wherein the GSI is AL-102.

95. 95. The method of any one of claims 92-94, wherein the GSI is administered orally.

96. 96. The method of any of claims 92 to 95, wherein the GSI is administered prior to administration of the bispecific antibody. The method according to any one of claims 1 to 5.

97. 92. The method of claim 90 or 91, wherein the second therapeutic agent is an immunomodulatory agent.

98. 92. The method of claim 90 or 91, wherein the second therapeutic agent is an immune checkpoint inhibitor. How to do it.

99. 92. The method of claim 90 or 91, wherein the second therapeutic agent is a TIM-3 inhibitor.

100. 100. The method of claim 99, wherein the TIM-3 inhibitor is MBG453.

101. 92. The method of claim 90 or 91, wherein the second therapeutic agent is a LAG-3 inhibitor.

102. 102. The method of claim 101, wherein the LAG-3 inhibitor is LAG525.

103. 92. The method of claim 90 or 91, wherein the second therapeutic agent is a PD-1 inhibitor.

104. The PD-1 inhibitor is PDR001, nivolumab, pembrolizumab, pidilisumab Bu, MEDI0680, REGN2810, TSR-042, PF-06801591, BGB-A317, BGB-108, INCSHR1210, or AMP-224 104. The method of claim 103.

105. The method of claim 103 or 104, wherein the PD-1 inhibitor is PDR001.

106. The PD-1 inhibitor is administered at a dose of about 100 mg once every four weeks or at a dose of about 200 mg once every four weeks. or about 300 mg once every 4 weeks, or about 400 mg once every 4 weeks, or about 500 106. The method of claim 104 or 105, wherein the dose is administered in a dose of 1 mg once every four weeks.

107. 10. The PD-1 inhibitor is administered in a dose of about 400 mg once every four weeks.

6. The method according to claim 6.

108. 108. The method of claim 90, wherein the second therapeutic agent is administered intravenously. method.

109. Claims 1-1, wherein the subject has been previously treated with at least two previous treatment regimens 08. A method according to any one of claims 08 to 08.

110. the previous treatment regimen did not include a multispecific antibody, e.g., a bispecific antibody. The method of claim 109.

111. The previous treatment regimen included immunomodulatory drugs (IMiDs), proteasome inhibitors, anti-CD38 111. The method of claim 109 or 110, comprising administering to a subject a therapeutically effective amount of a compound selected from the group consisting of a medicament for treating a pulmonary arthritis, a pulmonary arthritis, a pulmonary arthritis recurrence ... method.

112. The previous treatment regimen included an IMiD that was lenalidomide, pomalidomide, or both.

112. The method of any one of claims 109 to 111, comprising:

113. The previous treatment regimen was bortezomib, carfilzomib, or both. The method of any one of claims 109 to 112, comprising an asome inhibitor.

114. 10. The method of claim 1, wherein the previous treatment regimen included an anti-CD38 inhibitor that is an anti-CD38 antibody.

114. The method of any one of claims 109 to 113.

115. 115. The method of claim 114, wherein the anti-CD38 antibody was daratumab.

116. The previous treatment regimen included autologous bone marrow transplantation, BCMA CAR-T, and BCMA antibody-drug combination therapy. Any of claims 109 to 115, which comprised a conjugate, or any combination thereof. The method according to any one of claims 1 to 4.

117. The object is (a) no history of severe hypersensitivity reactions to BSBM3; (b) no history of toxicity to a previous BCMA-targeted agent; (c) not having any other malignant disease other than the cancer being treated and / or prevented; (d) not have any active, known or suspected autoimmune disease; (e) Concomitant use of prohibited medications that cannot be discontinued for at least one week before initiating this method currently receiving treatment for (f) Human immunodeficiency virus (HIV), active hepatitis B virus (HBV), or C Not infected with hepatitis virus (HCV); (g) No cardiac dysfunction or clinically significant cardiac disease, including any of the following: (i) Congestive heart failure requiring treatment (NYHA grade ≥ 2), uncontrolled hypertension clinically significant and / or uncontrolled cardiac disease, such as pulmonary embolism or clinically significant arrhythmias; (ii) QTcF > 470 msec on ECG at screening or congenital long QT syndrome group; or (iii) acute myocardial infarction or unstable angina within 3 months prior to study entry; (h) the first administration, except for local radiation therapy for lytic bone lesions or plasmacytomas No radiation therapy within the previous 14 days; (i) has not undergone major surgery within two weeks prior to said first administration; (j) systemic chronic steroid therapy (≥ 10 mg / day prednisone or equivalent); or not using any immunosuppressive therapy within 7 days of the first dose; (k) not receiving systemic treatment with any immunosuppressant; (l) Grade ≥ 2 neuropathy, or Grade ≤ 1 or recovered to baseline have no residual toxic effects from previous treatment; (m) no other plasmacytoid cell disorders other than plasma cell leukemia and multiple myeloma; (n) Absence of any of the following laboratory test results: (i) absolute neutrophil count (ANC) <1 without growth factor support within 7 days prior to the start of treatment; 000 / mm3; (ii) platelet count <75,000 mm3 without transfusion support within 7 days prior to initiation of treatment; (iii) bilirubin greater than 1.5 times the upper limit of normal (ULN); (iv) aspartate aminotransferase (AST) or aspartate aminotransferase (AST) greater than 3 times the ULN Lanin aminotransferase (ALT); or (v) A calculated creatinine concentration of less than 30 ml / min according to the Cockcroft-Gault formula Alanth; (o) an active infection or other serious condition requiring systemic treatment within two weeks prior to said first administration No severe infections; (p) POEMS syndrome (polyneuropathy, organomegaly, endocrine disorders, monoclonal nal protein, plasma cell dyscrasia with skin changes); (q) have never had a previous allogeneic SCT at any time; or (r) having an infectious disease (e.g., influenza, chickenpox, pneumococcus) within 4 weeks of said first administration; ) without using any live vaccine against (s) within 14 days or 5 half-lives, whichever is shorter, prior to said first administration, of a cytotoxic or have not been treated with a small molecule targeted anti-tumor drug or any experimental therapy; (t) the use of hematopoietic colony-stimulating growth factors (e.g., G-CSF, M) within 2 weeks prior to the start of treatment -CSF), thrombopoietin mimetics, or erythropoiesis-stimulating agents had not been started; (u) had not received intravenous IG infusion for infection prevention within the 28 days immediately prior to treatment; Ta; (v) Symptomatic CNS metastases or local CNS-directed treatment ( Active central nervous system disease due to the severity or presence of CNS metastases requiring treatment (e.g., radiation therapy or surgery) did not have central nervous system (CNS) involvement or increasing doses of corticosteroids; (w) No serious medical or psychiatric illnesses likely to interfere with treatment; (x) If the woman is pregnant or nursing (lactating) ) if not; (y) Females of childbearing potential (defined as females who are physiologically capable of becoming pregnant) (2) use of two effective contraceptive methods during study drug administration and for 6 months after the last dose of study drug If you are using at least one of the effective contraceptive methods, it is recommended that you use a highly effective contraceptive method. Laws (e.g., i) total abstinence, ii) female sterilization, iii) male sterilization or (iv) the use of oral, injectable, or implantable hormonal contraceptive methods or intrauterine devices. Placement of an IUD or an intrauterine system (IUS), or other form of equivalent effectiveness hormonal contraception (failure rate <1%), e.g., hormonal vaginal ring or transdermal hormonal contraception; or (z) The method according to any one of claims 1 to 116, which is any combination thereof. Law.

118. administration of the bispecific antibody results in the subject experiencing toxicity and clinical progression of disease due to IMWG. claims, and / or treatment may be discontinued at the discretion of the treating physician. Item 118. The method according to any one of Items 1 to 117.

119. the bispecific antibody (a) the bispecific antibody; (b) histidine; (c) sucrose; and (d) PS20 119. The method of any one of claims 1 to 118, wherein the compound is administered in the form of a pharmaceutical composition comprising:

120. 120. The method of claim 119, wherein the pharmaceutical composition is in liquid form.

121. 119. The method of claim 119, wherein the histidine concentration in the pharmaceutical composition is about 20 mM. Item 120. The method according to item 120.

122. Claims 119-12, wherein the sucrose concentration in the pharmaceutical composition is about 240 mM 1. The method according to any one of claims 1 to 9.

123. Claims 119-122, wherein the concentration of PS20 in the pharmaceutical composition is about 0.04% 10. The method according to any one of the preceding claims.

124. Any of claims 119 to 123, wherein the pH of the pharmaceutical composition is about 5.5±0.

3.

10. The method according to claim 1.

125. (a) binds to human BCMA and human CD3; (i) a first polypeptide whose amino acid sequence comprises the amino acid sequence of SEQ ID NO: 1; (ii) a second polypeptide whose amino acid sequence comprises the amino acid sequence of SEQ ID NO:2; and (iii) a third polypeptide whose amino acid sequence comprises the amino acid sequence of SEQ ID NO: 3; 10 mg / mL of a bispecific antibody comprising: (b) 20 mM histidine; (c) 240 mM sucrose; (d) 0.04% PS20; and (e) a pH of about 5.5±0.3 Vial containing

126. A method for treating or preventing cancer, comprising administering to a subject in need thereof at least one B-cell mature Multispecific antibodies with binding specificity for antigen (BCMA) and T cell engaging arms wherein said multiple antibody is optionally BSBM3. The specific antibody (a) about 1 μg / kg to about 1000 μg / kg; (b) about 0.25 μg / kg to about 1200 μg / kg; (c) about 0.5 μg / kg to about 900 μg / kg; or (d) Approximately 1 μg / kg to approximately 600 μg / kg wherein the compound is administered to the subject at a dose of

127. 127. The method of claim 126, wherein the T cell engaging arm binds to CD3.

128. The multispecific antibody is administered to the subject at a dose of about 0.5 μg / kg to about 900 μg / kg. The method of claim 126 or claim 127, wherein the

129. The multispecific antibody is administered to the subject at a dose of about 1 μg / kg to about 600 μg / kg. The method of claim 126 or 127,

130. 127. The multispecific antibody is administered to the subject at a dose of about 1 μg / kg. Or the method of claim 129.

131. 127. The multispecific antibody is administered to the subject at a dose of about 3 μg / kg. Or the method of claim 129.

132. 127. The multispecific antibody is administered to the subject at a dose of about 6 μg / kg. Or the method of claim 129.

133. 13. The multispecific antibody of claim 12, wherein the multispecific antibody is administered to the subject at a dose of about 10 μg / kg. 7 or the method of claim 129.

134. 13. The multispecific antibody of claim 12, wherein the multispecific antibody is administered to the subject at a dose of about 12 μg / kg. 7 or the method of claim 129.

135. The multispecific antibody is administered to the subject at a dose of about 20 μg / kg to about 40 μg / kg. The method of claim 127 or claim 129,

136. 13. The multispecific antibody of claim 12, wherein the multispecific antibody is administered to the subject at a dose of about 24 μg / kg. 7 or the method of claim 129.

137. 13. The multispecific antibody of claim 12, wherein the multispecific antibody is administered to the subject at a dose of about 30 μg / kg. 7 or the method of claim 129.

138. The multispecific antibody is administered to the subject at a dose of about 40 μg / kg to about 80 μg / kg. The method of claim 127 or claim 129,

139. 13. The multispecific antibody of claim 12, wherein the multispecific antibody is administered to the subject at a dose of about 48 μg / kg. 7 or the method of claim 129.

140. The multispecific antibody is administered to the subject at a dose of about 80 μg / kg to about 120 μg / kg.

130. The method of claim 127 or claim 129, wherein

141. 13. The multispecific antibody of claim 12, wherein the multispecific antibody is administered to the subject at a dose of about 96 μg / kg. 7 or the method of claim 129.

142. 10. The method of claim 1, wherein the multispecific antibody is administered to the subject at a dose of about 100 μg / kg. 27 or 129. The method of claim 129.

143. The multispecific antibody is administered to the subject at a dose of about 150 μg / kg to about 250 μg / kg.

130. The method of claim 127 or claim 129, wherein the

144. 10. The method of claim 1, wherein the multispecific antibody is administered to the subject at a dose of about 200 μg / kg. 27 or 129. The method of claim 129.

145. The multispecific antibody is administered to the subject at a dose of about 300 μg / kg to about 500 μg / kg.

130. The method of claim 127 or claim 129, wherein the

146. 10. The method of claim 1, wherein the multispecific antibody is administered to the subject at a dose of about 400 μg / kg. 27 or 129. The method of claim 129.

147. The multispecific antibody is administered to the subject at a dose of about 500 μg / kg to about 700 μg / kg.

130. The method of claim 127 or claim 129, wherein the

148. 10. The method of claim 1, wherein the multispecific antibody is administered to the subject at a dose of about 600 μg / kg. 27 or 129. The method of claim 129.

149. 149. Any of claims 126 to 148, wherein the multispecific antibody is administered intravenously to the subject.

1. The method according to claim 1.

150. 150. The method of claim 126, wherein the multispecific antibody is administered over a period of 2 hours.

10. The method according to any one of claims 1 to 9.

151. 10. The method of claim 1, wherein the multispecific antibody is administered to the subject once a week for four weeks. 26-150. A method according to any one of claims 26 to 150.

152. wherein the subject is administered a priming dose prior to administering the first therapeutic dose. The method of any one of claims 126 to 151.

153. 153. The method of claim 152, wherein the administration of the priming dose is divided.

154. 152. The method of claim 152, wherein the priming dose is given to the subject over two days.

153. The method according to claim 153.

155. One-third of the priming dose is given on day 1, and one-third of the priming dose is given on day 2.

155. The method of claim 154, wherein two of the doses are given on the second day.

156. 156. The method of claim 154 or claim 155, wherein the two days are consecutive.

157. Claims 152-156, wherein the priming dose is a dose less than the therapeutic dose 10. The method according to any one of the preceding claims.

158. 158. The method of any one of claims 127 to 157, wherein the subject is administered a side effect reducing agent. How to do it.

159. The side effect-reducing agent reduces the onset or severity of cytokine release syndrome (CRS). The method of claim 158.

160. The method of claim 158 or 159, wherein the side effect reducing agent is a glucocorticoid. Law.

161. 161. The method of claim 160, wherein the glucocorticoid is methylprednisolone. 。

162. 162. The method of claim 161, wherein the methylprednisolone is administered at least 2 mg / kg. How to post.

163. The side effect reducing agent is paracetamol, acetaminophen, antihistamine, steroid 158 or 159. The method of claim 158, wherein the therapeutic agent is a medicament for treating a pulmonary edema, ... an anti-T cell directed therapy, or any combination thereof.

59. The method according to claim 59.

164. The side effect reducing agent is tocilizumab, canakinumab, or any combination thereof. The method of claim 163, which is an anti-T cell directed therapy.

165. 165. The method of any one of claims 126 to 164, wherein the subject is administered a second therapeutic agent. How to do it.

166. The multispecific antibody and the second therapeutic agent may be administered simultaneously, separately, or over a period of time.

166. The method of claim 165, wherein the administration is

167. 165 or 16, wherein the second therapeutic agent is a gamma secretase inhibitor (GSI).

6. The method according to claim 6.

168. The GSI is LY-450139, PF-5212362, BMS-708163, MK-0752, ELN-318463, BMS-299897, LY-411575, DAPT, AL-101 (BMS-906024), AL-102 (BMS-98611 5), PF-3084014, RO4929097, or LY3039478, The method of claim 167.

169. 169. The method of claim 168, wherein the GSI is AL-102.

170. 170. The method of any one of claims 167-169, wherein the GSI is administered orally.

171. 171. The method of claim 167, wherein the GSI is administered prior to administration of the multispecific antibody.

10. The method according to any one of claims 1 to 9.

172. 167. The method of claim 165 or 166, wherein the second therapeutic agent is an immunomodulatory agent.

173. 167. The method of claim 165 or 166, wherein the second therapeutic agent is an immune checkpoint inhibitor. The method described.

174. 167. The method of claim 165 or 166, wherein the second therapeutic agent is a TIM-3 inhibitor. 。

175. The method of claim 174, wherein the TIM-3 inhibitor is MBG453.

176. 167. The method of claim 165 or 166, wherein the second therapeutic agent is a LAG-3 inhibitor. 。

177. 177. The method of claim 176, wherein the LAG-3 inhibitor is LAG525.

178. The method of claim 165 or 166, wherein the second therapeutic agent is a PD-1 inhibitor.

179. The PD-1 inhibitor is PDR001, nivolumab, pembrolizumab, pidilisumab Bu, MEDI0680, REGN2810, TSR-042, PF-06801591, BGB-A317, BGB-108, INCSHR1210, or AMP-224 179. The method of claim 178.

180. The method of claim 178 or 179, wherein the PD-1 inhibitor is PDR001.

181. The PD-1 inhibitor is administered at a dose of about 100 mg once every four weeks or at a dose of about 200 mg once every four weeks. or about 300 mg once every 4 weeks, or about 400 mg once every 4 weeks, or about 500 181. The method of claim 179 or 180, wherein the amount of hydroxybenzoates is administered in a dose of 0.1 mg once every four weeks.

182. 18. The PD-1 inhibitor is administered in a dose of about 400 mg once every four weeks.

1. The method according to claim 1.

183. 183. The method of any one of claims 165 to 182, wherein the second therapeutic agent is administered intravenously. How to do it.

184. 184. The method of any one of claims 126 to 183, wherein the cancer is a blood cancer.

185. 185. The method of claim 184, wherein the hematological cancer is multiple myeloma.

186. Claim 184 or 185, wherein the subject has relapsed and / or refractory multiple myeloma. The method described below.

187. 126. The subject has been previously treated with at least two previous treatment regimens.

187. The method of any one of claims 1 to 186.

188. 188. The method of claim 187, wherein the previous treatment regimen did not include a multispecific antibody.

189. The previous treatment regimen included immunomodulatory drugs (IMiDs), proteasome inhibitors, anti-CD38 189. The method of claim 187 or 188, comprising administering to a subject a therapeutically effective amount of a compound selected from the group consisting of a medicament for treating a pulmonary arthritis, a pulmonary arthritis, a pulmonary arthritis recurrence ... method.

190. The previous treatment regimen included an IMiD that was lenalidomide, pomalidomide, or both.

190. The method of any one of claims 187 to 189, comprising

191. The previous treatment regimen was bortezomib, carfilzomib, or both. The method of any one of claims 187 to 190, comprising an asome inhibitor.

192. 10. The method of claim 1, wherein the previous treatment regimen included an anti-CD38 inhibitor that is an anti-CD38 antibody. 187-191. The method of any one of claims 187-191.

193. 193. The method of claim 192, wherein the anti-CD38 antibody was daratumab.

194. The previous treatment regimen included autologous bone marrow transplantation, BCMA CAR-T, and BCMA antibody-drug combination therapy. Any of claims 187 to 193, which contained a conjugate, or any combination thereof. The method according to any one of claims 1 to 4.

195. The object is (a) serum M protein of 1.0 g / dL or greater; (b) urinary M protein ≥ 200 mg / 24 h; (c) serum free light chain (sFLC) of relevant FLC greater than 100 mg / L; or (d) any combination thereof 195. The method of any one of claims 126 to 194, comprising:

196. The object is (a) have no history of severe hypersensitivity reactions to said multispecific antibody; (b) no history of toxicity to a previous BCMA-targeted agent; (c) not having any other malignant disease other than the cancer being treated and / or prevented; (d) not have any active, known or suspected autoimmune disease; (e) Concomitant use of prohibited medications that cannot be discontinued for at least one week before initiating this method currently receiving treatment for (f) Human immunodeficiency virus (HIV), active hepatitis B virus (HBV), or C Not infected with hepatitis virus (HCV); (g) No cardiac dysfunction or clinically significant cardiac disease, including any of the following: (i) Congestive heart failure requiring treatment (NYHA grade ≥ 2), uncontrolled hypertension clinically significant and / or uncontrolled cardiac disease, such as pulmonary embolism or clinically significant arrhythmias; (ii) QTcF > 470 msec on ECG at screening or congenital long QT syndrome group; or (iii) acute myocardial infarction or unstable angina within 3 months prior to study entry; (h) the first administration, except for local radiation therapy for lytic bone lesions or plasmacytomas No radiation therapy within the previous 14 days; (i) has not undergone major surgery within two weeks prior to said first administration; (j) systemic chronic steroid therapy (≥ 10 mg / day prednisone or equivalent); or not using any immunosuppressive therapy within 7 days of the first dose; (k) not receiving systemic treatment with any immunosuppressant; (l) Grade ≥3 neuropathy or Grade ≥2 residual toxic effects from prior treatment Not having; (m) no other plasmacytoid cell disorders other than plasma cell leukemia and multiple myeloma; (n) Absence of any of the following laboratory test results: (i) absolute neutrophil count (ANC) <1 without growth factor support within 7 days prior to the start of treatment; 000 / mm3; (ii) platelet count <75,000 mm3 without transfusion support within 7 days prior to initiation of treatment; (iii) bilirubin greater than 1.5 times the upper limit of normal (ULN); (iv) aspartate aminotransferase (AST) or aspartate aminotransferase (AST) greater than 3 times the ULN Lanin aminotransferase (ALT); or (v) A calculated creatinine concentration of less than 30 ml / min according to the Cockcroft-Gault formula Alanth; (o) an active infection or other serious condition requiring systemic treatment within two weeks prior to said first administration No severe infections; (p) POEMS syndrome (polyneuropathy, organomegaly, endocrine disorders, monoclonal nal protein, plasma cell dyscrasia with skin changes); (q) have never had a previous allogeneic SCT at any time; or (r) having an infectious disease (e.g., influenza, chickenpox, pneumococcus) within 4 weeks of said first administration; ) without using any live vaccine against (s) within 14 days or 5 half-lives, whichever is shorter, prior to said first administration, of a cytotoxic or have not been treated with a small molecule targeted anti-tumor drug or any experimental therapy; (t) the use of hematopoietic colony-stimulating growth factors (e.g., G-CSF, M) within 2 weeks prior to the start of treatment -CSF), thrombopoietin mimetics, or erythropoiesis-stimulating agents had not been started; (u) had not received intravenous IG infusion for infection prevention within the 28 days immediately prior to treatment; Ta; (v) Symptomatic CNS metastases or local CNS-directed treatment ( Active central nervous system disease due to the severity or presence of CNS metastases requiring treatment (e.g., radiation therapy or surgery) did not have central nervous system (CNS) involvement or increasing doses of corticosteroids; (w) No serious medical or psychiatric illnesses likely to interfere with treatment; (x) Pregnant or nursing (lactating) women Not; (y) highly effective during administration of the study drug and for 90 days after the last dose of the study drug Women of childbearing potential (those who are physiologically capable of becoming pregnant) unless they are using a form of contraception (defined as all women who are able to conceive), where highly effective contraceptive methods are: i) universal abstinence, ii) female sterilization, iii) male sterilization, or (iv) oral, injectable or or the use of implanted hormonal contraceptive methods or intrauterine devices (IUDs) or intrauterine systems Placement of an intrauterine tube (IUS) or other form of hormone protection with equivalent efficacy (failure rate <1%) pregnancy, including hormonal vaginal rings or transdermal hormonal contraception; or (z) any combination thereof according to any one of claims 126 to 195 How to do it.

197. Any one of claims 126 to 196, wherein the multispecific antibody is a bispecific antibody. The method described below.

198. The bispecific antibody specifically binds to human BCMA and has the amino acid sequence of SEQ ID NO: 1 a first polypeptide comprising an amino acid sequence; the amino acid sequence comprising the amino acid sequence of SEQ ID NO:2; a second polypeptide comprising the amino acid sequence of SEQ ID NO:3; and a third polypeptide comprising the amino acid sequence of SEQ ID NO:

3.

198. The method of claim 197, comprising a peptide.

199. administration of the multispecific antibody results in the subject experiencing toxicity and clinical progression of disease due to IMWG. claims, and / or treatment may be discontinued at the discretion of the treating physician. Item 199. The method according to any one of items 126 to 198.

200. Binding specificity for at least B cell maturation antigen (BCMA) and T cell engaging arm and a second therapeutic agent.

201. 201. The method of claim 200, wherein the second therapeutic agent is a gamma secretase inhibitor (GSI). Combination treatment.

202. The GSI is LY-450139, PF-5212362, BMS-708163, MK-0752, ELN-318463, BMS-299897, LY-411575, DAPT, AL-101 (BMS-906024), AL-102 (BMS-98611 5), PF-3084014, RO4929097, or LY3039478, The combination treatment of claim 201.

203. The combination therapy of claim 202, wherein the GSI is AL-102.

204. 201. The combination therapy of claim 200, wherein the second therapeutic agent is an immunomodulatory agent.

205. 201. The method of claim 200, wherein the second therapeutic agent is an immune checkpoint inhibitor. Combined treatment.

206. 201. The combination therapy of claim 200, wherein the second therapeutic agent is a TIM-3 inhibitor. 。

207. The combination therapy of claim 206, wherein the TIM-3 inhibitor is MBG453. 。

208. 201. The combination therapy of claim 200, wherein the second therapeutic agent is a LAG-3 inhibitor. 。

209. The combination therapy of claim 208, wherein the LAG-3 inhibitor is LAG525. 。

210. 201. The combination therapy of claim 200, wherein the second therapeutic agent is a PD-1 inhibitor.

211. The PD-1 inhibitor is PDR001, nivolumab, pembrolizumab, pidilisumab Bu, MEDI0680, REGN2810, TSR-042, PF-06801591, BGB-A317, BGB-108, INCSHR1210, or AMP-224 , The combination therapy described in claim 210.

212. The combination is about 100 mg, or about 200 mg, or about 300 mg, or about 40 Any of claims 200-211, comprising 0 mg or about 500 mg of the second therapeutic agent. The combination treatment according to claim 1.

213. The combination is about 2 mg, or about 10 mg, or about 20 mg, or about 40 mg, or about 80 mg, or about 160 mg, or about 320 mg of the compound; and about 100 mg, or about 200 mg, or about 300 mg, or about 400 mg, or about 500 mg of said second 212. The combination therapy of any one of claims 200 to 211, comprising a therapeutic agent of

214. A combination according to any one of claims 200 to 213 for use in the treatment of cancer. Treatment.

215. A combination according to any one of claims 200 to 214 for use in the prevention of cancer. Treatment.

216. For administration according to the method of any one of claims 90 to 124 or 165 to 197 216. The combination therapy of claim 214 or claim 215.

217. A compound according to any one of claims 200 to 216 for the manufacture of a medicament for treating or preventing cancer. Use of the combination therapy described in paragraph 1.

218. Use of a combination therapy according to any one of claims 200 to 216 for the treatment of cancer. For.

219. Use of a combination therapy according to any one of claims 200 to 216 for the prevention of cancer. For.

220. The combination treatment of any one of claims 200 to 216, wherein the cancer is a blood cancer. Therapy or use according to any one of claims 217 to 219.

221. 221. The combination treatment or use of claim 220, wherein the hematological cancer is multiple myeloma.

222. (a) binding to at least B cell maturation antigen (BCMA) and T cell engaging arm multispecific antibodies with specificity; (b) histidine; (c) sucrose; and (d) PS20 A pharmaceutical composition comprising:

223. 223. The pharmaceutical composition of claim 222, wherein the composition is a liquid.

224. 224. The pharmaceutical composition of claim 222 or 223, wherein the histidine concentration is 20 mM. 。

225. 225. The method according to claim 222, wherein the sucrose concentration is 240 mM. The pharmaceutical composition described above.

226. 226. The method according to claim 222, wherein the PS20 concentration is 0.04%. A pharmaceutical composition comprising:

227. The medicament according to any one of claims 222 to 226, wherein the pH is about 5.5±0.

3. composition.

228. (a) binding to at least B cell maturation antigen (BCMA) and T cell engaging arm 10 mg / mL of a multispecific antibody having the specificity (b) 20 mM histidine; (c) 240 mM sucrose; (d) 0.04% PS20; and (e) a pH of about 5.5±0.3 Vial containing

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