[go: up one dir, main page]

WO2022097047A1 - Méthodes de traitement utilisant des conjugués anticorps-médicament anti-bcma - Google Patents

Méthodes de traitement utilisant des conjugués anticorps-médicament anti-bcma Download PDF

Info

Publication number
WO2022097047A1
WO2022097047A1 PCT/IB2021/060187 IB2021060187W WO2022097047A1 WO 2022097047 A1 WO2022097047 A1 WO 2022097047A1 IB 2021060187 W IB2021060187 W IB 2021060187W WO 2022097047 A1 WO2022097047 A1 WO 2022097047A1
Authority
WO
WIPO (PCT)
Prior art keywords
bcma
adc
seq
amino acid
acid sequence
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2021/060187
Other languages
English (en)
Inventor
Farzana WALCOTT
Nai Shun Yao
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MedImmune LLC
Original Assignee
MedImmune LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by MedImmune LLC filed Critical MedImmune LLC
Publication of WO2022097047A1 publication Critical patent/WO2022097047A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68035—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a pyrrolobenzodiazepine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/77—Internalization into the cell

Definitions

  • MM multiple myeloma
  • current treatments are highly effective in controlling the disease and producing deep remissions, including molecular remissions, the disease invariably relapses after a period of time, requiring continued therapeutic intervention to maintain disease control (Kumar et al, 2017).
  • the disease As the disease relapses, it becomes increasingly refractory to the currently available drugs resulting in ever shorter remissions, with the vast majority of patients eventually succumbing to complications of relapsed, refractory disease.
  • BCMA B-cell maturation antigen
  • TNFR tumor necrosis family receptor
  • BCMA RNA has been detected universally in multiple myeloma cells, and BCMA protein has been detected on the surface of plasma cells from multiple myeloma patients by several investigators (see, e.g., Novak et al, Blood, 103(2): 689-694 (2004); Neri et al., Clinical Cancer Research, 75(19): 5903-5909 (2007); Bellucci et al., Blood, 105( Q): 3945-3950 (2005); and Moreaux et al., Blood, 703(8): 3148-3157 (2004)). As such, BCMA has been investigated as a possible therapeutic target for multiple myeloma.
  • Treatment of multiple myeloma typically involves high-dose chemotherapy followed by hematopoietic stem cell transplantation (allogenic or autologous).
  • hematopoietic stem cell transplantation allogenic or autologous.
  • a high rate of relapse is common in multiple myeloma patients that have undergone such treatment.
  • the present disclosure provides a method of treating Multiple Myeloma (MM) in a subject, the method comprising administering to the subject about 0.0125 mg/kg to about 0.2 mg/kg of an antibody-drug conjugate (ADC), wherein the ADC is directed against B-Cell Maturation Antigen (BCMA).
  • ADC antibody-drug conjugate
  • BCMA B-Cell Maturation Antigen
  • the present disclosure also provides a method of treating Relapsed/Refractory
  • MM Multiple Myeloma
  • the method comprising administering to the subject about 0.0125 mg/kg to about 0.2 mg/kg of an antibody-drug conjugate (ADC), wherein the ADC is directed against B-Cell Maturation Antigen (BCMA).
  • ADC antibody-drug conjugate
  • BCMA B-Cell Maturation Antigen
  • the present disclosure also provides a method of killing multiple myeloma (MM) cells in a subject, the method comprising administering to the subject about 0.0125 mg/kg to about 0.2 mg/kg of an antibody-drug conjugate (ADC), wherein the ADC directed against B-Cell Maturation Antigen (BCMA).
  • ADC antibody-drug conjugate
  • BCMA B-Cell Maturation Antigen
  • the present disclosure also provides a method of increasing susceptibility Multiple Myeloma (MM) cells to Natural Killer (NK) cell-mediated killing in a subject in need thereof comprising administering to the subject about 0.0125 mg/kg to about 0.2 mg/kg of an antibody - drug conjugate (ADC) directed against B-Cell Maturation Antigen (BCMA).
  • ADC antibody - drug conjugate
  • BCMA B-Cell Maturation Antigen
  • the present disclosure also provides a method of increasing CD38 expression in Multiple Myeloma (MM) cells in a subject in need thereof comprising administering to the subject about 0.0125 mg/kg to about 0.2 mg/kg of an antibody-drug conjugate (ADC) directed against B-Cell Maturation Antigen (BCMA).
  • the ADC comprises an antibody or antigenbinding fragment thereof that specifically binds to BCMA (anti-BCMA antibody or antigenbinding fragment thereof).
  • the methods disclosed herein comprise administering to the subject about 0.0125 mg/kg , about 0.025 mg/kg , about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.10 mg/kg, about 0.11 mg/kg, about 0.12 mg/kg, about 0.13 mg/kg, about 0.14 mg/kg, about 0.15 mg/kg, about 0.16 mg/kg, about 0.17 mg/kg, about 0.18 mg/kg, about 0.19 mg/kg, or about 0.20 mg/kg.
  • the methods disclosed herein comprise administering about 0.14 mg/kg of the ADC to the subject.
  • the methods disclosed herein comprise administering about 0.20 mg/kg of the ADC to the subject.
  • one dose of ADC is administered to the subject once per treatment cycle.
  • a treatment cycle is 28 days. In some aspects, a treatment cycle is about 4 weeks.
  • the ADC is administered once every 3 weeks. In some aspects, the ADC is administered once every 6 weeks. In some aspects, the ADC is administered at a dose of about 0.14 mg/kg once every 3 weeks. In some aspects the ADC is administered at a dose of about 0.14 mg/kg once every 6 weeks.
  • the ADC comprises an anti-BCMA antibody or antigen-biding fragment thereof that binds strongly to membrane-bound BCMA.
  • the ADC comprises an anti-BCMA antibody or antigen-biding fragment thereof that binds weakly to monomeric (soluble) BCMA.
  • the ADC comprises an anti-BCMA antibody or antigen-biding fragment thereof that binds to monomeric (soluble) BCMA with a binding affinity of about 60 nM, as measured by surface plasmon resonance. In some aspects, the anti-BCMA antibody or antigen-biding fragment thereof binds to monomeric (soluble) BCMA with a binding affinity of 60.7 nM, as measured by surface plasmon resonance.
  • the ADC comprises an anti-BCMA antibody or antigen-biding fragment thereof that binds to cell-bound BCMA with a binding affinity of between about 2 nM and 4 nM, as measured by flow cytometry. In some aspects, the ADC comprises an anti-BCMA antibody or antigen-biding fragment thereof that binds to cellbound BCMA with a binding affinity of about 3 nM, as measured by flow cytometry.
  • the ADC comprises an anti-BCMA antibody or antigen-biding fragment thereof conjugated to a cytotoxin via a linker.
  • the linker is a protease-cleavable linker.
  • the cytotoxin is a pyrrolobenzodiazepine (PBD).
  • the PBD is a DNA cross-linking PBD dimer.
  • the ADC comprises an anti-BCMA antibody or antigen-biding fragment thereof, wherein the Fc effector function of the anti-BCMA antibody or antigen-biding fragment thereof is eliminated.
  • administering does not result in significant epithelial changes in the cornea.
  • the methods further comprise measuring BCMA expression in plasma cells obtained from the subject.
  • the plasma cells are obtained from a bone marrow biopsy from the subject.
  • BCMA expression is assessed by immunohistochemistry (IHC).
  • the bone marrow biopsy contains >80% CD 138+ plasma cells that are BCMA+.
  • the antibody-drug conjugate (ADC), directed against B-Cell Maturation Antigen (BCMA) is administered to a cohort of subjects.
  • the administration results in an overall response rate of at least 61%.
  • the ADC comprises an anti-BCMA antibody or antigen-biding fragment thereof comprising (a) a heavy chain variable region comprising a complementarity determining region 1 (HCDR1) amino acid sequence of SEQ ID NO: 1, an HCDR2 amino acid sequence of SEQ ID NO: 2, and an HCDR3 amino acid sequence of SEQ ID NO: 3 and (b) a light chain variable region comprising a complementarity determining region 1 (LCDR1) amino acid sequence of SEQ ID NO: 4, an LCDR2 amino acid sequence of SEQ ID NO: 5, and an LCDR3 amino acid sequence of SEQ ID NO: 6.
  • HCDR1 complementarity determining region 1
  • LCDR3 amino acid sequence of SEQ ID NO: 3 a light chain variable region comprising a complementarity determining region 1 (LCDR1) amino acid sequence of SEQ ID NO: 4
  • LCDR1 amino acid sequence of SEQ ID NO: 4 an LCDR2 amino acid sequence of SEQ ID NO: 5
  • the ADC comprises an anti-BCMA antibody or antigen-biding fragment thereof comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 7 and/or a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 8.
  • VH heavy chain variable region
  • VL light chain variable region
  • the ADC comprises an anti-BCMA antibody or antigen-biding fragment thereof comprising a full-length heavy chain (HC)comprising the amino acid sequence of SEQ ID NO: 9 and/or a full-length light chain (LC) comprising the amino acid sequence of SEQ ID NO: 10.
  • HC full-length heavy chain
  • LC full-length light chain
  • the ADC comprises a monoclonal anti-BCMA antibody or antigenbiding fragment thereof. In some aspects, the ADC comprises an anti-BCMA antibody or antigen-biding fragment thereof that is a full-length antibody. In some aspects, the ADC comprises an anti-BCMA antibody or antigen-biding fragment thereof that is an antigen binding fragment. In some aspects, the antigen binding fragment comprises a single chain Fv (scFv).
  • scFv single chain Fv
  • the subject is human.
  • the administration is intravenous.
  • the administration is intraperitoneal.
  • the administration is subcutaneous.
  • ADC antibody-drug conjugate
  • BCMA B-Cell Maturation Antigen
  • the ADC comprises: (a) an anti-BCMA antibody or antigen-biding fragment thereof comprising (a) a heavy chain variable region comprising a complementarity determining region 1 (HCDR1) amino acid sequence of SEQ ID NO: 1, an HCDR2 amino acid sequence of SEQ ID NO: 2, and an HCDR3 amino acid sequence of SEQ ID NO: 3 and (b) a light chain variable region comprising a complementarity determining region 1 (LCDR1) amino acid sequence of SEQ ID NO: 4, an LCDR2 amino acid sequence of SEQ ID NO: 5, and an LCDR3 amino acid sequence of SEQ ID NO: 6; (b) a protease-cleavable linker; and (c) a DNA cross
  • ADC antibody-drug conjugate
  • BCMA B-Cell Maturation Antigen
  • the ADC comprises: (a) an anti-BCMA antibody or antigen-biding fragment thereof comprising (a) a heavy chain variable region comprising a complementarity determining region 1 (HCDR1) amino acid sequence of SEQ ID NO: 1, an HCDR2 amino acid sequence of SEQ ID NO: 2, and an HCDR3 amino acid sequence of SEQ ID NO: 3 and (b) a light chain variable region comprising a complementarity determining region 1 (LCDR1) amino acid sequence of SEQ ID NO: 4, an LCDR2 amino acid sequence of SEQ ID NO: 5, and an LCDR3 amino acid sequence of SEQ ID NO: 6; (b) a protease-cleavable linker; and (c) a DNA cross
  • ADC antibody-drug conjugate
  • BCMA B-Cell Maturation Antigen
  • the ADC comprises: (a) an anti-BCMA antibody or antigen-biding fragment thereof comprising (a) a heavy chain variable region comprising a complementarity determining region 1 (HCDR1) amino acid sequence of SEQ ID NO: 1, an HCDR2 amino acid sequence of SEQ ID NO: 2, and an HCDR3 amino acid sequence of SEQ ID NO: 3 and (b) a light chain variable region comprising a complementarity determining region 1 (LCDR1) amino acid sequence of SEQ ID NO: 4, an LCDR2 amino acid sequence of SEQ ID NO: 5, and an LCDR3 amino acid sequence of SEQ ID NO: 6; (b) an anti-BCMA antibody or antigen-biding fragment thereof comprising (a) a heavy chain variable region comprising a complementarity determining region 1 (HCDR1) amino acid sequence of SEQ ID NO: 1, an HCDR2 amino acid sequence of SEQ ID NO: 2, and an HCDR3 amino acid sequence
  • ADC antibody-drug conjugate
  • BCMA B-Cell Maturation Antigen
  • the ADC comprises: (a) an anti-BCMA antibody or antigen-biding fragment thereof comprising (a) a heavy chain variable region comprising a complementarity determining region 1 (HCDR1) amino acid sequence of SEQ ID NO: 1, an HCDR2 amino acid sequence of SEQ ID NO: 2, and an HCDR3 amino acid sequence of SEQ ID NO: 3 and (b) a light chain variable region comprising a complementarity determining region 1 (LCDR1) amino acid sequence of SEQ ID NO: 4, an LCDR2 amino acid sequence of SEQ ID NO: 5, and an LCDR3 amino acid sequence of SEQ ID NO: 6; (b) a protease-cleavable linker; and (c
  • the subject has been pre-treated with daratumumab.
  • the administration results in a response in the subject for a duration of at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months.
  • the methods disclosed herein further comprise administration of one or more additional therapeutic agents.
  • the additional therapeutic agent is Daratumumab.
  • the additional therapeutic agents are Lenalidomide and dexamethasone.
  • the ADC and the one or more additional therapeutic agents are administered simultaneously or sequentially.
  • ADC antibody-drug conjugate
  • BCMA B-Cell Maturation Antigen
  • the ADC comprises: (a) an anti-BCMA antibody or antigen-biding fragment thereof comprising (a) a heavy chain variable region comprising a complementarity determining region 1 (HCDR1) amino acid sequence of SEQ ID NO: 1, an HCDR2 amino acid sequence of SEQ ID NO: 2, and an HCDR3 amino acid sequence of SEQ ID NO: 3 and (b) a light chain variable region comprising a complementarity determining region 1 (LCDR1) amino acid sequence of SEQ ID NO: 4, an LCDR2 amino acid sequence of SEQ ID NO: 5, and an LCDR3 amino acid sequence of SEQ ID NO: 6; (b) a protease-cleavable linker; and (c
  • FIG. 1 shows the study design for the first in human dose-escalation and expansion study described herein.
  • the Y-axis is the dosage, increasing from 0.0125 mg/kg to 0.20 mg/kg from top to bottom.
  • the X-axis is the time patients were on the treatment (in days).
  • FIG. 3 shows a concentration-time profile after the first dose of the anti-BCMA ADC. The key shows the dose tested in each cohort.
  • Each bar on the Y-axis represents one patient.
  • the X-axis is the time each patient was on the treatment.
  • ADC antibody-drug conjugate
  • BCMA B-cell maturation antigen
  • antibody includes, without limitation, a glycoprotein immunoglobulin which binds specifically to an antigen and comprises at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds.
  • Each H chain comprises a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region.
  • the heavy chain constant region comprises three constant domains, CHI, CH2 and CH3.
  • Each light chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region.
  • the light chain constant region is comprises one constant domain, CL.
  • the VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDRs complementarity determining regions
  • FR framework regions
  • Each VH and VL comprises three CDRs and four FRs, arranged from amino-terminus to carboxy -terminus in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
  • a heavy chain may have the C-terminal lysine or not.
  • the amino acids in the variable regions are numbered using the Kabat numbering system and those
  • the term “monoclonal antibodies,” as used herein, refers to antibodies that are produced by a single clone of B-cells and bind to the same epitope.
  • polyclonal antibodies refers to a population of antibodies that are produced by different B-cells and bind to different epitopes of the same antigen.
  • antibody includes, by way of example, monoclonal and polyclonal antibodies; chimeric and humanized antibodies; human or nonhuman antibodies; wholly synthetic antibodies; and single chain antibodies.
  • a nonhuman antibody may be humanized by recombinant methods to reduce its immunogenicity in man.
  • the antibody may be an antibody that has been altered (e.g., by mutation, deletion, substitution, conjugation to a non-antibody moiety).
  • an antibody may include one or more variant amino acids (compared to a naturally occurring antibody) which change a property (e.g., a functional property) of the antibody.
  • a property e.g., a functional property
  • numerous such alterations are known in the art which affect, e.g., half-life, effector function, and/or immune responses to the antibody in a patient.
  • the term antibody also includes artificial polypeptide constructs which comprise at least one antibody-derived antigen binding site.
  • antibody-drug conjugate refers to a compound comprising a monoclonal antibody (mAb) attached to a cytotoxic agent (generally a small molecule drug with a high systemic toxicity) via chemical linkers.
  • mAb monoclonal antibody
  • cytotoxic agent generally a small molecule drug with a high systemic toxicity
  • an “antigen-binding portion” of an antibody refers to one or more fragments of an antibody that retain the ability to bind specifically to the antigen bound by the whole antibody. It has been shown that the antigen- binding function of an antibody can be performed by fragments or portions of a full-length antibody.
  • binding fragments encompassed within the term “antigen-binding portion” or “antigen-binding fragment” of an antibody described herein include: (1) a Fab fragment (fragment from papain cleavage) or a similar monovalent fragment consisting of the VL, VH, LC and CHI domains; (2) a F(ab’)2 fragment (fragment from pepsin cleavage) or a similar bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (3) a Fd fragment consisting of the VH and CHI domains; (4) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (5) a single domain antibody (dAb) fragment (Ward et al., (1989) Nature 341 :544-46), which consists of a VH domain; (6) a bi-single domain antibody which consists of two VH domains linked by a hinge (dual-affinity re-target
  • the two domains of the Fv fragment, VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see, e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883).
  • single chain Fv single chain Fv
  • Such single chain antibodies are also intended to be encompassed within the term “antigen-binding portion” or “antigen-binding fragment” of an antibody.
  • Antigen-binding portions can be produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact immunoglobulins.
  • an antibody is an antigen-binding fragment.
  • the antibody-drug conjugate described herein comprises a monoclonal antibody, or an antigen-binding fragment thereof, directed against B-cell Maturation Antigen (BCMA, also known as CD269).
  • BCMA is a member of the tumor necrosis factor receptor superfamily (see, e.g., Thompson et al., J. Exp. Medicine, 192(1): 129-135 (2000), and Mackay et al., Annu. Rev. Immunol., 21: 231-264 (2003)).
  • BCMA binds B-cell activating factor (BAFF) and a proliferation inducing ligand (APRIL) (see, e.g., Mackay et al., supra, and Kalled et al, Immunological Reviews, 204'. 43-54 (2005)).
  • BAFF B-cell activating factor
  • APRIL proliferation inducing ligand
  • BCMA has been reported to be expressed mostly in plasma cells and subsets of mature B-cells (see, e.g., Laabi et al., EMBO J., 77(11): 3897-3904 (1992); Laabi et al., Nucleic Acids Res., 22(7): 1147-1154 (1994); Kalled et al., supra,' O’Connor et al., J. Exp.
  • mice deficient in BCMA are healthy and have normal numbers of B-cells, but the survival of long-lived plasma cells is impaired (see, e.g., O’Connor et al, supra,' Xu et al., Mol. Cell. Biol., 21(12): 4067-4074 (2001); and Schiemann et al., Science, 293(5537): 2111-2114 (2001)).
  • BCMA RNA has been detected universally in multiple myeloma cells, and BCMA protein has been detected on the surface of plasma cells from multiple myeloma patients by several investigators (see, e.g., Novak et al, Blood, 103(2): 689-694 (2004); Neri et al., Clinical Cancer Research, 73(19): 5903-5909 (2007); Bellucci et al., Blood, 105(10): 3945-3950 (2005); and Moreaux et al., Blood, 703(8): 3148- 3157 (2004)).
  • the monoclonal antibody, or an antigen-binding fragment thereof, directed against BCMA may comprise any suitable binding affinity to BCMA or an epitope thereof.
  • affinity refers to the equilibrium constant for the reversible binding of two agents and is expressed as the dissociation constant (KD).
  • KD dissociation constant
  • the affinity of an antibody or antigen-binding fragment thereof for an antigen or epitope of interest can be measured using any method known in the art. Such methods include, for example, fluorescence activated cell sorting (FACS), surface plasmon resonance (e.g., BiacoreTM, ProteOnTM), biolayer interferometry (BLI, e.g. Octet), kinetics exclusion assay (e.g.
  • KinExATM separable beads (e.g., magnetic beads), antigen panning, and/or ELISA (see, e.g., Janeway et al. (eds.), Immunobiology, 5th ed., Garland Publishing, New York, N.Y., 2001). It is known in the art that the binding affinity of a particular antibody will vary depending on the method that is used to analyze the binding affinity.
  • BCMA-targeted ADC refers to a BCMA-targeted ADC, active in the presence of high levels of soluble BCMA and targets multiple myeloma (MM) progenitor cells.
  • cytotoxin and “cytotoxic agent” refer to any molecule that inhibits or prevents the function of cells and/or causes destruction of cells (cell death), and/or exerts antiproliferative effects. It will be appreciated that a cytotoxin or cytotoxic agent of an ADC also is referred to in the art as the “payload” of the ADC.
  • the antibody-drug conjugate described herein, or a composition comprising the antibody-drug conjugate may be contacted with a population of multiple myeloma cells that expresses BCMA ex vivo, in vivo, or in vitro.
  • Example vivo refers to methods conducted within or on cells or tissue in an artificial environment outside an organism with minimum alteration of natural conditions.
  • in vivo refers to a method that is conducted within living organisms in their normal, intact state, while an “in vitro” method is conducted using components of an organism that have been isolated from their usual biological context.
  • the multiple myeloma cells are human multiple myeloma cells that are contacted with the ADC described herein, or a composition comprising the ADC, in vivo.
  • the terms “treatment,” “treating,” and the like refer to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect is therapeutic, i.e., the effect partially or completely cures a disease and/or adverse symptom attributable to the disease.
  • the inventive method comprises administering a “therapeutically effective amount” of the antibody or ADC or the composition comprising the antibody or ADC and a pharmaceutically acceptable carrier.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result.
  • the therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody or ADC to elicit a desired response in the individual.
  • a therapeutically effective amount of the ADC of the invention is an amount which binds to BCMA on multiple myeloma cells and destroys them.
  • the pharmacologic and/or physiologic effect may be prophylactic, i.e., the effect completely or partially prevents a disease or symptom thereof.
  • the inventive method comprises administering a “prophylactically effective amount” of the ADC or a composition comprising the ADC to a mammal that is predisposed to multiple myeloma.
  • a “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired prophylactic result (e.g., prevention of disease onset).
  • the ADC described herein, or a composition comprising the antibody ADC can be administered to a mammal (e.g., a human) using standard administration techniques, including, for example, intravenous, intraperitoneal, and subcutaneous administration. In some aspects, the ADC or composition containing the same is administered to a mammal by intravenous injection.
  • a mammal e.g., a human
  • standard administration techniques including, for example, intravenous, intraperitoneal, and subcutaneous administration.
  • the ADC or composition containing the same is administered to a mammal by intravenous injection.
  • the ADC described herein, or the composition comprising the antibody or ADC can be administered with one or more additional therapeutic agents, which can be coadministered to the mammal.
  • administering refers to administering one or more additional therapeutic agents and the ADC described herein, or the ADC-containing composition, sufficiently close in time such that the ADC can enhance the effect of one or more additional therapeutic agents, or vice versa.
  • the ADC or the composition containing the same may be administered first, and the one or more additional therapeutic agents may be administered second, or vice versa.
  • the antibody or ADC or composition containing the same may be administered in combination with other agents (e.g., as an adjuvant) for the treatment or prevention of multiple myeloma.
  • the ADC or ADC- containing composition can be used in combination with at least one other anticancer agent including, for example, any suitable chemotherapeutic agent known in the art, ionization radiation, small molecule anticancer agents, cancer vaccines, biological therapies (e.g., other monoclonal antibodies, cancer-killing viruses, gene therapy, and adoptive T-cell transfer), and/or surgery.
  • any suitable chemotherapeutic agent known in the art ionization radiation, small molecule anticancer agents, cancer vaccines, biological therapies (e.g., other monoclonal antibodies, cancer-killing viruses, gene therapy, and adoptive T-cell transfer), and/or surgery.
  • an beneficial effect refers to treatment producing a beneficial effect, e.g., amelioration of at least one symptom of a disease or disorder.
  • a beneficial effect can take the form of an improvement over baseline, i.e., an improvement over a measurement or observation made prior to initiation of therapy according to the method.
  • a beneficial effect can also take the form of a competitive overall response rate (ORR).
  • ORR overall response rate
  • a beneficial effect can also take the form of a promising clinical activity (ORR) in Relapsed/Refractory MM patients who have relapsed on current therapies.
  • an effective amount refers to an amount of an agent that provides the desired biological, therapeutic, and/or prophylactic result. That result can be reduction, amelioration, palliation, lessening, delaying, and/or alleviation of one or more of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • An effective amount can be administered in one or more administrations.
  • the effective amount of the drug or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and may stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and may stop tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer.
  • Dosing interval means the amount of time that elapses between multiple doses of a formulation disclosed herein being administered to a subject. Dosing interval can thus be indicated as ranges.
  • Dosing frequency refers to the frequency of administering doses of a formulation disclosed herein in a given time. Dosing frequency can be indicated as the number of doses per a given time, e.g., once a week or once in two weeks, etc.
  • the terms “about once a week,” “once about every week,” “once about every two weeks,” or any other similar dosing interval terms as used herein means approximate number, and “about once a week” or “once about every week” can include every seven days ⁇ two days, i.e., every five days to every nine days.
  • the dosing frequency of “once a week” thus can be every five days, every six days, every seven days, every eight days, or every nine days.
  • “Once about every four weeks” can include every 28 days ⁇ 3 days, i.e., every 25 days to every 31 days. Similar approximations apply, for example, to once about every three weeks, once about every four weeks, once about every five weeks, once about every six weeks and once about every twelve weeks.
  • a dosing interval of once about every four weeks means that the first dose can be administered any day in the first week, and then the next dose can be administered any day in fourth week.
  • a dosing interval of once about every four weeks means that the first dose is administered on a particular day of the first week (e.g., Monday) and then the next dose is administered on the same day of the fourth week (i.e., Monday), respectively.
  • a “cancer” refers a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division and growth results in the formation of malignant tumors that may metastasize to distant parts of the body through the lymphatic system or bloodstream.
  • the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).
  • the terms “about” or “comprising essentially of’ refer to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system.
  • “about” or “comprising essentially of’ can mean within 1 or more than 1 standard deviation per the practice in the art.
  • “about” or “comprising essentially of’ can mean a range of up to 10% or 20% (i.e., ⁇ 10% or ⁇ 20%).
  • about 3 mg can include any number between 2.7 mg and 3.3 mg (for 10%) or between 2.4 mg and 3.6 mg (for 20%).
  • the terms can mean up to an order of magnitude or up to 5-fold of a value.
  • the meaning of “about” or “comprising essentially of’ should be assumed to be within an acceptable error range for that particular value or composition.
  • any concentration range, percentage range, ratio range or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one-tenth and one-hundredth of an integer), unless otherwise indicated.
  • the present disclosure is directed to a method of treating Multiple Myeloma (MM) in a subject in need thereof.
  • the disclosure provides a method of treating Relapsed/Refractory MM in a subject in need thereof.
  • the disclosure provides a method of killing MM cells in a subject in need thereof.
  • the disclosure provides a method of increasing susceptibility MM cells to Natural Killer (NK) cell- mediated killing in a subject in need thereof.
  • NK Natural Killer
  • the disclosure provides a method of increasing CD38 expression in MM cells in a subject in need thereof.
  • the methods provided herein comprise administering an antibody-drug conjugate (ADC) directed against B-Cell Maturation Antigen (BCMA) (anti-BCMA ADC) to the subject.
  • a therapy comprising an anti-BCMA ADC results in better therapeutic outcomes (e.g., objective response rate and disease control rate) for afflicted subjects.
  • the methods described herein provide the antibody-drug conjugate in an amount that is effective to treat or prevent multiple myeloma.
  • the disclosure provides a method of killing multiple myeloma cells, which comprises contacting multiple myeloma cells that express BCMA with the antibody-drug conjugate described herein, or a composition comprising the ADC described herein, whereby the antibody-drug conjugate binds to BCMA on the multiple myeloma cells and kills the multiple myeloma cells.
  • the disclosure also provides use of the ADC described herein, or the composition comprising the antibody or ADC, in the manufacture of a medicament for treating multiple myeloma.
  • Multiple myeloma also known as plasma cell myeloma or Kahler’s disease, is a cancer of plasma cells, which are a type of white blood cell normally responsible for the production of antibodies (Raab et al., Lancet, 374: 324-329 (2009)). Multiple myeloma affects 1- 4 per 100,000 people per year. The disease is more common in men, and for yet unknown reasons is twice as common in African Americans as it is in Caucasian Americans. Multiple myeloma is the least common hematological malignancy (14%) and constitutes 1% of all cancers (Raab et al., supra).
  • BCMA is highly expressed by multiple myeloma cells (see, e.g., Novak et al., supra; Neri et al., supra; Bellucci et al., supra; and Moreaux et al., supra).
  • BCMA also is expressed on multiple myeloma stem cells.
  • the disclosure provides a method of killing multiple myeloma stem cells, which comprises contacting multiple myeloma stem cells that express BCMA with the antibody-drug conjugate described herein, or a composition comprising the ADC described herein, whereby the antibody-drug conjugate binds to BCMA on the multiple myeloma stem cells and kills the multiple myeloma stem cells.
  • myeloma stem cells can be identified in the bone marrow of multiple myeloma patients by their surface expression of CD 19 and lack of CD138 surface expression (see, e.g., Matsui et al., Blood, 103: 2332-6 (2004)). These cells are uniquely clonogenic and engraft immunodeficient mice, whereas the myeloma plasma cells, defined as CD 138+CD 19- do not. Multiple myeloma stem cells also are resistant to current therapies (Matsui et al., Cancer Res., 68: 190-7 (2008)).
  • the disclosure provides a method of treating Multiple Myeloma
  • the disclosure provides a method of treating Replapsed/Refractory Multiple Myeloma (MM) in a subject, the method comprising administering to the subject about 0.0125 mg/kg to about 0.2 mg/kg of an anti-BCMA ADC to the subject.
  • the disclosure provides method of killing Multiple Myeloma (MM) cells in a subject, the method comprising administering to the subject about 0.0125 mg/kg to about 0.2 mg/kg of an anti-BCMA ADC.
  • the disclosure provides a method of increasing susceptibility Multiple Myeloma (MM) cells to Natural Killer (NK) cell-mediated killing in a subject in need thereof comprising administering to the subject about 0.0125 mg/kg to about 0.2 mg/kg of an anti-BCMA ADC.
  • the disclosure provides a method of increasing CD38 expression in Multiple Myeloma (MM) cells in a subject in need thereof comprising administering to the subject about 0.0125 mg/kg to about 0.2 mg/kg of an anti- BCMA ADC.
  • the anti-BCMA ADC comprises an antibody or antigen-binding fragment thereof that specifically binds to BCMA (i.e., an anti-BCMA antibody or antigenbinding fragment thereof).
  • the methods treating Multiple Myeloma (MM) in a subject in need thereof disclosed herein comprises administering to the subject about 0.0125 mg/kg to about 0.2 mg/kg of an anti-BCMA ADC.
  • the method comprises administering about 0.0125 mg/kg , about 0.020 mg/kg, about 0.025 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.10 mg/kg, about 0.11 mg/kg, about 0.12 mg/kg, about 0.13 mg/kg, about 0.14 mg/kg, about 0.15 mg/kg, about 0.16 mg/kg, about 0.17 mg/kg, about 0.18 mg/kg, about 0.19 mg/kg, or about 0.20 mg/kg to the subject.
  • the method of treating Multiple Myeloma (MM) in a subject comprises administering about 0.07 mg/kg of the ADC to the subject. In some aspects, the method of treating Multiple Myeloma (MM) in a subject comprises administering about 0.14 mg/kg of the ADC to the subject. In some aspects, the method of treating Multiple Myeloma (MM) in a subject comprises administering about 0.20 mg/kg of the ADC to the subject.
  • the method of treating Multiple Myeloma (MM) in a subject disclosed herein comprises administering a dose of the anti-BCMA ADC to the subject once per treatment cycle.
  • one dose of ADC is administered to the subject once per treatment cycle.
  • a treatment cycle is 28 days.
  • a treatment cycle is about 4 weeks.
  • the ADC is administered once every 3 weeks.
  • the ADC is administered once every 6 weeks.
  • the method of treating Multiple Myeloma (MM) in a subject disclosed herein comprises administering the anti-BCMA ADC at a dose of about 0.14 mg/kg once every 3 weeks. In some aspects, the method of treating Multiple Myeloma (MM) in a subject comprises administering the anti-BCMA ADC at a dose of about 0.14 mg/kg once every 6 weeks. In some aspects, the method of treating Multiple Myeloma (MM) in a subject comprises administering the anti-BCMA ADC at a dose of about 0.14 mg/kg once every 3 weeks for two cycles, and then the anti-BCMA ADC is administered at a maintenance dose once every 6 weeks. In some aspects, the maintenance dose is about 0.07 mg/kg.
  • the subject is human.
  • the method of treating Multiple Myeloma (MM) in a subject disclosed herein comprises administering a dose of the anti-BCMA ADC to the subject, the administration is intravenous. In some aspects, the administration is intraperitoneal. In some aspects, the administration is subcutaneous.
  • the methods of treating Multiple Myeloma (MM) in a subject in need thereof disclosed herein comprises the administration of one or more additional therapeutic agents.
  • the additional therapeutic agents are bortezomib and dexamethasone.
  • the additional therapeutic agent is Daratumumab.
  • the additional therapeutic agents are Lenalidomide and dexamethasone.
  • the anti-BCMA ADC and the one or more additional therapeutic agents are administered simultaneously.
  • the anti-BCMA ADC and the one or more additional therapeutic agents are administered sequentially.
  • the ADC for use in the methods described herein specifically binds to human BCMA and comprises the amino acid sequences of the antibody provided in Table 1.
  • anti-BCMA antibody or antigen-biding fragment thereof of the present disclosure and methods of producing the anti-BCMA antibody or antigen-biding fragment thereof are disclosed in published U.S. Patent Application Pub. No. 2019/0040152 Al, the entirety of which is hereby incorporated by reference.
  • the ADC described herein comprises the monoclonal antibody, or an antigen-binding fragment thereof, directed against BCMA.
  • the anti-BCMA antibody or antigen-biding fragment thereof comprises (a) a heavy chain variable region comprising a complementarity determining region 1 (HCDR1) amino acid sequence of SEQ ID NO: 1, an HCDR2 amino acid sequence of SEQ ID NO: 2, and an HCDR3 amino acid sequence of SEQ ID NO: 3 and (b) a light chain variable region comprising a complementarity determining region 1 (LCDR1) amino acid sequence of SEQ ID NO: 4, an LCDR2 amino acid sequence of SEQ ID NO: 5, and an LCDR3 amino acid sequence of SEQ ID NO: 6.
  • the anti-BCMA antibody or antigen-biding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 7 and/or a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 8.
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-BCMA antibody or antigen-biding fragment thereof comprises a full-length heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 9 and/or a full-length light chain (LC) comprising the amino acid sequence of SEQ ID NO: 10.
  • the anti-BCMA antibody or antigen-biding fragment thereof comprises a full-length antibody.
  • the anti-BCMA antibody or antigen-biding fragment thereof comprises an antigen binding fragment.
  • the antigen binding fragment comprises a single chain Fv (scFv).
  • the antibody, or antigen-binding fragment thereof, directed against BCMA may comprise any suitable binding affinity to BCMA or an epitope thereof.
  • affinity refers to the equilibrium constant for the reversible binding of two agents and is expressed as the dissociation constant (KD).
  • KD dissociation constant
  • the affinity of an antibody or antigen-binding fragment thereof for an antigen or epitope of interest can be measured using any method known in the art. Such methods include, for example, fluorescence activated cell sorting (FACS), surface plasmon resonance (e.g., BiacoreTM, ProteOnTM), biolayer interferometry (BLI, e.g.
  • sBCMA soluble form of BCMA
  • serum of multiple myeloma patients with reported values ranging from 3.8 to 1062 ng/mL (Lee et al Br J Haematol 2016, Sanchez et al Br J Haematol 2012), and is comprised of the entire extracellular domain of the molecule (Laurent et. al. Nat Commun 2015). Therefore, sBCMA could diminish the effects of antibody-based therapies.
  • the functional features of sBCMA and recombinant monomeric human BCMA are similar (Laurent et. al. Nat Commun 2015).
  • Affinity of a binding agent to a ligand can be, for example, from about 1 picomolar (pM) to about 1 micromolar (pM) (e.g., from about 1 picomolar (pM) to about 1 nanomolar (nM), or from about 1 nM to about 1 micromolar (pM)).
  • the monoclonal antibody or an antigen-binding fragment thereof may bind to BCMA with a KD less than or equal to 100 nanomolar (e.g., 100 nM, about 90 nM, about 80 nM, about 70 nM, about 60 nM, about 50 nM, about 40 nM, about 30 nM, about 20 nM, or about 10 nM, or a range defined by any two of the foregoing values).
  • 100 nanomolar e.g., 100 nM, about 90 nM, about 80 nM, about 70 nM, about 60 nM, about 50 nM, about 40 nM, about 30 nM, about 20 nM, or about 10 nM, or a range defined by any two of the foregoing values.
  • the monoclonal antibody may bind to BCMA with a KD less than or equal to 10 nanomolar (e.g., about 9 nM, about 8.5 nM, about 8 nM, about 7.5 nM, about 7 nM, about 6.5 nM, about 6 nM, about 5.5 nM, about 5 nM, about 4.5 nM, about 4 nM, about 3.5 nM, about 3 nM, about 2.5 nM, about 2 nM, about 1.5 nM, about 1 nM, about 0.9 nM, about 0.8 nM, about 0.7 nM, about 0.6 nM, about 0.5 nM, about 0.4 nM, about 0.3 nM, about 0.2 nM, about 0.1 nM, about 0.05 nM, about 0.025 nM, about 0.01 nM, about 0.001 nM, or a range defined by any two of the foregoing values).
  • 10 nanomolar
  • the monoclonal antibody may bind to BCMA with a KD less than or equal to 200 pM (e.g., about 190 pM, about 175 pM, about 150 pM, about 125 pM, about 110 pM, about 100 pM, about 90 pM, about 80 pM, about 75 pM, about 60 pM, about 50 pM, about 40 pM, about 30 pM, about 25 pM, about 20 pM, about 15 pM, about 10 pM, about 5 pM, about 1 pM, or a range defined by any two of the foregoing values).
  • 200 pM e.g., about 190 pM, about 175 pM, about 150 pM, about 125 pM, about 110 pM, about 100 pM, about 90 pM, about 80 pM, about 75 pM, about 60 pM, about 50 pM, about 40 pM, about 30
  • the affinity of the anti-BCMA antibody or antigen-binding fragment thereof to monomeric (soluble) BCMA is about 90 nM, about 80 nM, about 70 nM, about 60 nM, about 50 nM, about 40 nM, about 30 nM, or a range defined by any two of the foregoing values, for example, about 50 nM to about 70 nM, about 55 nM to about 65 nM, or about 58 nM to about 62 nM.
  • the ADC comprises an anti-BCMA antibody or antigen-biding fragment thereof that binds strongly to membrane-bound BCMA.
  • the ADC comprises an anti-BCMA antibody or antigen-biding fragment thereof that binds to monomeric (soluble) BCMA with a binding affinity of about 60 nM, as measured by SPR. In some aspects, the anti-BCMA antibody or antigen-biding fragment thereof binds to monomeric (soluble) BCMA with a binding affinity of 60.7 nM, as measured by SPR.
  • the affinity of the anti-BCMA antibody or antigen-binding fragment thereof to membrane-bound BCMA, as measured by flow cytometry (FACS), is less than or equal to 10 nanomolar (e.g., about 9 nM, about 8.5 nM, about 8 nM, about 7.5 nM, about 7 nM, about 6.5 nM, about 6 nM, about 5.5 nM, about 5 nM, about 4.5 nM, about 4 nM, about 3.5 nM, about 3 nM, about 2.5 nM, about 2 nM, about 1.5 nM, about 1 nM, about 0.9 nM, about 0.8 nM, about 0.7 nM, about 0.6 nM, about 0.5 nM, about 0.4 nM, about 0.3 nM, about 0.2 nM, about 0.1 nM, about 0.05
  • 10 nanomolar e.g., about 9 nM, about 8.5 nM, about 8 n
  • the ADC comprises an anti-BCMA antibody or antigen-biding fragment thereof that binds weakly to monomeric (soluble) BCMA.
  • the ADC comprises an anti-BCMA antibody or antigen-biding fragment thereof that binds to cell-bound BCMA with a binding affinity of between about 2 nM and 4 nM, as measured by FACS. In some aspects, the ADC comprises an anti-BCMA antibody or antigenbiding fragment thereof that binds to cell-bound BCMA with a binding affinity of about 3 nM, as measured by FACS.
  • an antigen-binding portion or fragment of an anti-BCMA antibody or antigenbinding fragment thereof can be of any size so long as the portion binds to BCMA.
  • an antigen binding portion or fragment of the monoclonal antibody directed against BCMA can comprise between about 5 and 18 amino acids (e.g., about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or a range defined by any two of the foregoing values).
  • cytotoxin and “cytotoxic agent” refer to any molecule that inhibits or prevents the function of cells and/or causes destruction of cells (cell death), and/or exerts anti- proliferative effects.
  • a cytotoxin or cytotoxic agent of an ADC also is referred to in the art as the “payload” of the ADC.
  • a number of classes of cytotoxic agents are known in the art to have potential utility in ADC molecules and can be used in the ADC described herein.
  • cytotoxic agents include, for example, anti-microtubule agents (e.g., auristatins and maytansinoids), pyrrolobenzodiazepines (PBDs), RNA polymerase II inhibitors (e.g., amatoxins), and DNA alkylating agents (e.g., indolinobenzodiazepine pseudodimers).
  • anti-microtubule agents e.g., auristatins and maytansinoids
  • PBDs pyrrolobenzodiazepines
  • RNA polymerase II inhibitors e.g., amatoxins
  • DNA alkylating agents e.g., indolinobenzodiazepine pseudodimers
  • cytotoxic agents examples include, but are not limited to, amanitins, auristatins, calicheamicin, daunomycins, doxorubicins, duocarmycins, dolastatins, enediynes, lexitropsins, taxanes, puromycins, maytansinoids, vinca alkaloids, tubulysins, and pyrrolobenzodiazepines (PBDs).
  • amanitins examples include, but are not limited to, amanitins, auristatins, calicheamicin, daunomycins, doxorubicins, duocarmycins, dolastatins, enediynes, lexitropsins, taxanes, puromycins, maytansinoids, vinca alkaloids, tubulysins, and pyrrolobenzodiazepines (PBDs).
  • PBDs pyrrolobenzodiazepines
  • the cytotoxic agent may be, for example AFP, MMAF, MMAE, AEB, AEVB, auristatin E, paclitaxel, docetaxel, CC-1065, SN-38, topotecan, morpholino-doxorubicin, rhizoxin, cyanomorpholino-doxorubicin, dolastatin- 10, echinomycin, combretatstatin, chalicheamicin, maytansine, DM1, DM4, vinblastine, methotrexate, netropsin, or derivatives or analogs thereof. Cytotoxins suitable for use in ADCs are also described in, for example, International Patent Application Publication Nos. WO 2015/155345 and WO 2015/157592.
  • the cytotoxic agent may be a pyrrolobenzodiazepine (PBD) or a PBD derivative.
  • PBD pyrrolobenzodiazepine
  • PBD derivative a PBD derivative.
  • PBD translocates to the nucleus where it crosslinks DNA, preventing replication during mitosis, damaging DNA by inducing single strand breaks, and subsequently leading to apoptosis.
  • Some PBDs also have the ability to recognize and bind to specific sequences of DNA.
  • PBDs are of the general structure:
  • PBDs differ in the number, type, and position of substituents, in both their aromatic A rings and pyrrolo C rings, and in the degree of saturation of the C ring.
  • All of the known natural products have an (S)-configuration at the chiral Cl la position which provides them with a right-handed twist when viewed from the C ring towards the A ring.
  • PBDs the appropriate three-dimensional shape for isohelicity with the minor groove of B-form DNA, leading to a snug fit at the binding site (Kohn, In: Antibiotics III. Springer- Verlag, New York, pp. 3-11 (1975); and Hurley and Needham-VanDevanter, Acc. Chem. Res., 19: 230-237 (1986)). PBDs can form adducts in the minor groove, leading to interference with DNA processing.
  • the PBD is PBD 3249, also referred to herein as “SG3249” and described in detail in WO 2014/057074, which has the following structure:
  • the PBD is PBD 3315, also referred to herein as “SG3315” and described in detail in WO 2015/052322, which has the following structure:
  • the PBD is SG3400, also referred to as Compound 23, which is described in detail in PCT/EP2017/052988, filed on 10 February 2017, and has the following structure:
  • the anti-BCMA antibody, or antigen-binding fragment thereof may be conjugated to a cytotoxin using any suitable method known in the art, including site-specific or non-site specific conjugation methods.
  • Conventional conjugation strategies for antibodies typically rely on randomly (i.e., non-specifically) conjugating the payload to the antibody or antigen-binding fragment thereof, through lysines or cysteines.
  • the cytotoxic agent may be conjugated to the BCMA monoclonal antibody using site-specific conjugation methods at specific reactive amino acid residues, yielding homogeneous ADC preparations with uniform stoichiometry.
  • Site-specific conjugation may be through a cysteine residue or a non-natural amino acid.
  • the cytotoxic agent may be conjugated to the antibody, or antigen binding fragment thereof, through at least one cysteine residue.
  • a cytotoxic agent may be chemically conjugated to the side chain of an amino acid at a specific Kabat position in the Fc region of the anti-BCMA antibody.
  • the cytotoxic agent may be conjugated to the anti-BCMA antibody through a cysteine residue at any suitable position in the Fc region of the antibody, including but not limited to, a cysteine at least one of positions 239, 248, 254, 273, 279, 282, 284, 286, 287, 289, 297, 298, 312, 324, 326, 330, 335, 337, 339, 350, 355, 356, 359, 360, 361, 375, 383, 384, 389, 398, 400, 413, 415, 418, 422, 440, 441, 442, 443 and 446, wherein the numbering corresponds to the EU index in Kabat.
  • the cytotoxic agent may be conjugated to the anti-BCMA antibody through a cysteine residue at the specific Kabat positions 239 and/or 442 of the BCMA monoclonal antibody, and/or through an amino acid residue inserted between Kabat positions 239 and 240 of the BCMA antibody (Dimasi et al., Mol Pharm, 14(5): 1501 - 1516 (2017).
  • the cytotoxic agent may be conjugated to the anti-BCMA antibody or antigen binding fragment thereof through a thiol-maleimide linkage, such as, for example, via a sulfhydryl reactive group at the hinge and heavy-light chains.
  • the anti-BCMA antibody described herein comprises at least one cytotoxin molecule conjugated thereto; however, the anti-BCMA antibody may comprise any suitable number of cytotoxin molecules conjugated thereto (e.g., 1, 2, 3, 4, or more cytotoxin molecules) to achieve a desired therapeutic effect.
  • the ADC described herein comprises two cytotoxin molecules conjugated to a BCMA monoclonal antibody.
  • the ADC is site-specifically conjugated to a DNA cross-linking pyrrolobenzodiazepine (PBD) dimer via a protease-cleavable linker.
  • PBD DNA cross-linking pyrrolobenzodiazepine
  • the ADC comprises an anti-BCMA antibody or antigen-biding fragment thereof conjugated to a cytotoxin via a linker.
  • the linker is a protease- cleavable linker.
  • the cytotoxin is a pyrrolobenzodiazepine (PBD).
  • the PBD is a DNA cross-linking PBD dimer.
  • the ADC comprises an anti-BCMA antibody or antigen-biding fragment thereof, wherein the Fc effector function of the anti-BCMA antibody or antigen-biding fragment thereof is eliminated.
  • the method of treating Multiple Myeloma (MM) in a subject disclosed herein comprises intravenously administering 0.14 mg/kg of an antibody-drug conjugate (ADC) directed against B-Cell Maturation Antigen (BCMA) every 3 weeks, wherein the ADC comprises: (a) an anti-BCMA antibody or antigen-biding fragment thereof comprising (a) a heavy chain variable region comprising a complementarity determining region 1 (HCDR1) amino acid sequence of SEQ ID NO: 1, an HCDR2 amino acid sequence of SEQ ID NO: 2, and an HCDR3 amino acid sequence of SEQ ID NO: 3 and (b) a light chain variable region comprising a complementarity determining region 1 (LCDR1) amino acid sequence of SEQ ID NO: 4, an LCDR2 amino acid sequence of SEQ ID NO: 5, and an LCDR3 amino acid sequence of SEQ ID NO: 6; (b) a protease-cleavable linker; and (c) a DNA cross-linking
  • ADC antibody-d
  • the method of treating Multiple Myeloma (MM) in a subject disclosed herein comprises intravenously administering 0.14 mg/kg of an antibody-drug conjugate (ADC) directed against B-Cell Maturation Antigen (BCMA) every 6 weeks, wherein the ADC comprises: (a) an anti-BCMA antibody or antigen-biding fragment thereof comprising (a) a heavy chain variable region comprising a complementarity determining region 1 (HCDR1) amino acid sequence of SEQ ID NO: 1, an HCDR2 amino acid sequence of SEQ ID NO: 2, and an HCDR3 amino acid sequence of SEQ ID NO: 3 and (b) a light chain variable region comprising a complementarity determining region 1 (LCDR1) amino acid sequence of SEQ ID NO: 4, an LCDR2 amino acid sequence of SEQ ID NO: 5, and an LCDR3 amino acid sequence of SEQ ID NO: 6; (b) a protease-cleavable linker; and (c) a DNA cross-linking
  • ADC antibody-d
  • the method of treating Multiple Myeloma (MM) in a subject disclosed herein comprises intravenously administering 0.14 mg/kg of an antibody-drug conjugate (ADC) directed against B-Cell Maturation Antigen (BCMA) every 3 weeks for 2 cycles, and then intravenously administering 0.07 mg/kg of the ADC every 6 weeks, wherein the ADC comprises: (a) an anti-BCMA antibody or antigen-biding fragment thereof comprising (a) a heavy chain variable region comprising a complementarity determining region 1 (HCDR1) amino acid sequence of SEQ ID NO: 1, an HCDR2 amino acid sequence of SEQ ID NO: 2, and an HCDR3 amino acid sequence of SEQ ID NO: 3 and (b) a light chain variable region comprising a complementarity determining region 1 (LCDR1) amino acid sequence of SEQ ID NO: 4, an LCDR2 amino acid sequence of SEQ ID NO: 5, and an LCDR3 amino acid sequence of SEQ ID NO: 6; (b) a) an anti-BCMA antibody
  • the method of treating Multiple Myeloma (MM) in a subject disclosed herein comprises intravenously administering 0.10 mg/kg of an antibody-drug conjugate (ADC) directed against B-Cell Maturation Antigen (BCMA) every 3 weeks for at least 6 months, wherein the ADC comprises: (a) an anti-BCMA antibody or antigen-biding fragment thereof comprising (a) a heavy chain variable region comprising a complementarity determining region 1 (HCDR1) amino acid sequence of SEQ ID NO: 1, an HCDR2 amino acid sequence of SEQ ID NO: 2, and an HCDR3 amino acid sequence of SEQ ID NO: 3 and (b) a light chain variable region comprising a complementarity determining region 1 (LCDR1) amino acid sequence of SEQ ID NO: 4, an LCDR2 amino acid sequence of SEQ ID NO: 5, and an LCDR3 amino acid sequence of SEQ ID NO: 6; (b) a protease-cleavable linker; and (c) a
  • the method of treating Multiple Myeloma (MM) in a subject disclosed herein results in a response in the subject for a duration of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months.
  • the method of treating Multiple Myeloma (MM) in a subject disclosed herein results in a response in the subject for a duration of at least one year.
  • MM Multiple Myeloma
  • ADC antibody-drug conjugate
  • BCMA B-Cell Maturation Antigen
  • the ADC described herein inhibits or suppresses proliferation of BCMA-expressing myeloma cells by at least about 10% (e.g., at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100%).
  • Cell proliferation can be measured using any suitable method known in the art, such as measuring incorporation of labeled nucleosides (e.g., 3H- thymidine or bromodeoxyuridine Brd(U)) into genomic DNA (see, e.g., Madhavan, H.N., J. Stem Cells Regen. Med., 3(1): 12-14 (2007)).
  • a known drawback of available MM treatment is eye toxicity.
  • administration of an antibody-drug conjugate (ADC) directed against B-Cell Maturation Antigen (BCMA) described herein does not result in significant epithelial changes in the cornea.
  • compositions suitable for administration to human patients are typically formulated for parenteral administration, e.g., in a liquid carrier, or suitable for reconstitution into liquid solution or suspension for intravenous administration.
  • compositions typically comprise a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable means approved by a government regulatory agency or listed in the U.S. Pharmacopeia or another generally recognized pharmacopeia for use in animals, particularly in humans.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, glycerol polyethylene glycol ricinoleate, and the like.
  • Liquid compositions for parenteral administration can be formulated for administration by injection or continuous infusion. Routes of administration by injection or infusion include intravenous, intraperitoneal, intramuscular, intrathecal and subcutaneous.
  • Example 1 Phase 1, First-in-Human Study of a BCMA-Targeted ADC in Patients With Relapsed/Refractory Multiple Myeloma
  • Pls proteasome inhibitors
  • IMDs immunomodulatory drugs
  • mAbs monoclonal antibodies
  • ORR Objective response rate
  • CBR clinical benefit rate
  • DoR duration of response
  • PFS progression-free survival
  • OS overall survival
  • the endpoints for assessment of PK include individual subject concentrations (including active anti-BCMA ADC, total antibody, and free warhead) in plasma at different time points after administration.
  • Pharmacokinetic parameters include, but are not limited to, maximum observed concentration (Cmax), area under the concentration-time curve (AUC), clearance (CL), and terminal half-life (tl/2).
  • the endpoints for assessment of immunogenicity include the number and percentage of subjects who develop treatment-emergent anti-drug antibodies (AD As).
  • MRD Minimal residual disease
  • BM refers to bone marrow biopsies and/or bone marrow aspirates.
  • Baseline refers to fresh BM samples collected at study entry.
  • the sequentially ascending dose levels start from a starting dose of 0.025 mg/kg administered via intravenous infusion on Day 1 of each 3-week cycle (Q3W).
  • the 8 main dose levels are 0.025 mg/kg, 0.05 mg/kg, 0.10 mg/kg, 0.20 mg/kg, 0.31 mg/kg, 0.51 mg/kg, 0.80 mg/kg, and 1.25 mg/kg.
  • Intermediate dose levels of 0.035 mg/kg, 0.07 mg/kg, 0.14 mg/kg, 0.24 mg/kg, 0.37 mg/kg, 0.55 mg/kg, and 0.82 mg/kg were de-escalation doses, /kg and 1.5 mg/kg; 25% and 20% escalation increments respectively) may be evaluated.
  • Subjects must have a confirmed diagnosis of multiple myeloma with measurable disease per IMWG criteria (Kumar et al, 2016) requiring systemic therapy.
  • Relapsed myeloma previously treated myeloma that progresses and requires the initiation of salvage therapy but does not meet criteria for either “primary refractory myeloma” or “relapsed-and-refractory myeloma” categories.
  • Refractory myeloma disease that is nonresponsive while on primary or salvage therapy, or progresses within 60 days of last therapy.
  • Nonresponsive disease is defined as either failure to achieve minimal response or development of progressive disease (PD) while on therapy.
  • PD progressive disease
  • NCLCTCAE National Cancer Institute - Common Toxicity Criteria for Adverse Events
  • At least 21 days must have elapsed following treatment with Mab treatment of MM • At least 21 days must have elapsed or complete healing of incision must have occurred (whichever occurs sooner) after major surgery
  • the anti-BCMA ADC was administered in sequentially ascending dose levels (0.0125, 0.025, 0.05, 0.1, and 0.2 mg/kg) intravenously every 3 weeks (Q3W) (FIG. 1). Due to dose-limiting toxicities (DLTs), the 0.2 mg/kg dose was de-escalated to an intermediate dose level of 0.14 mg/kg.
  • the maximum tolerated dose was 0.14 mg/kg administered every three weeks. This dose was used as a basis for expansion Cohorts A, B, and C.
  • the IHC readouts indicated (1) the % CD 138+ that are BCMA+ and (2) the % of tumor cells that are 1+ and 2+ intensity.
  • a BCMA modified H-score was calculated based on % BCMA and intensity.
  • IHC expression also confirmed that levels of BCMA are similar in patients pretreated with daratumumab compared to those not previously treated with daratumumab (but may have been treated with other agents).
  • Treatment-related adverse events that occurred in >20% of patients in the 0.14 mg/kg cohort in the dose expansion phase were photophobia (53.7%), thrombocytopenia (31.7%), rash (29.3%), increased gamma-glutamyltransferase (24.4%), dry eye (20.0%), and pleural effusion (20.0%). Keratopathy or visual acuity loss were not observed in this cohort.
  • the TEAE profiles at lower-dose levels were similar but with lower incidences compared with the 0.14 mg/kg level.
  • Treatment related adverse events by grade and frequency in Cohort A are provided below in Table 3.
  • Photophobia (discomfort or pain to the eyes due to light exposure) is a key factor affecting quality of life for patients undergoing treatment for Multiple Myeloma. Eye toxicity is not a known class effect of the DNA cross-linking pyrrolobenzodiazepine (PBD) payload in the anti-BCMA ADC.
  • PPD DNA cross-linking pyrrolobenzodiazepine
  • a key symptom discovered during the Phase 1, first-in-human study described herein related to drug administration is photophobia.
  • patients were symptomatic (i.e., they reported photophobia, eye pain, dry eye, blepharitis, inability to read, drive, look at tv, dark glasses indoors sitting in dark rooms) no significant corneal changes were found upon ophthalmology examinations.

Landscapes

  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Cell Biology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne des méthodes de traitement de cancers chez un patient humain (par exemple, le myélome multiple (MM)), qui consistent à administrer un conjugué anticorps-médicament (ADC) comprenant un anticorps monoclonal, ou un fragment de liaison à l'antigène correspondant, dirigé contre l'antigène de maturation des lymphocytes B (BCMA) conjugué à une cytotoxine. L'invention concerne également des compositions comprenant le conjugué anticorps-médicament et des procédés de destruction de cellules de myélome multiple (y compris des cellules souches de myélome multiple) qui expriment BCMA par la mise en contact de cellules de myélome multiple avec l'ADC.
PCT/IB2021/060187 2020-11-04 2021-11-03 Méthodes de traitement utilisant des conjugués anticorps-médicament anti-bcma Ceased WO2022097047A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063109805P 2020-11-04 2020-11-04
US63/109,805 2020-11-04

Publications (1)

Publication Number Publication Date
WO2022097047A1 true WO2022097047A1 (fr) 2022-05-12

Family

ID=81456982

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2021/060187 Ceased WO2022097047A1 (fr) 2020-11-04 2021-11-03 Méthodes de traitement utilisant des conjugués anticorps-médicament anti-bcma

Country Status (1)

Country Link
WO (1) WO2022097047A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140161828A1 (en) * 2012-12-07 2014-06-12 Amgen Inc. Bcma antigen binding proteins
US20160130362A1 (en) * 2005-03-23 2016-05-12 Genmab A/S Antibodies against cd38 for treatment of multiple myeloma
US20160250346A1 (en) * 2013-10-11 2016-09-01 Medimmune Limited Pyrrolobenzodiazepine-antibody conjugates
US20190040152A1 (en) * 2017-08-01 2019-02-07 Medimmune, Llc BCMA Monoclonal Antibody-Drug Conjugate

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160130362A1 (en) * 2005-03-23 2016-05-12 Genmab A/S Antibodies against cd38 for treatment of multiple myeloma
US20140161828A1 (en) * 2012-12-07 2014-06-12 Amgen Inc. Bcma antigen binding proteins
US20160250346A1 (en) * 2013-10-11 2016-09-01 Medimmune Limited Pyrrolobenzodiazepine-antibody conjugates
US20190040152A1 (en) * 2017-08-01 2019-02-07 Medimmune, Llc BCMA Monoclonal Antibody-Drug Conjugate

Similar Documents

Publication Publication Date Title
JP7222024B2 (ja) 上皮増殖因子受容体変異体ｉｉｉおよびｃｄ３の単一および二重特異性抗体およびそれらの使用
JP7401126B2 (ja) 抗ｃｕｂドメイン含有タンパク質１（ｃｄｃｐ１）抗体、抗体薬物コンジュゲート、およびその使用方法
KR102624564B1 (ko) 항-ctla4 항체 단독의, 및 프로그램화된 사멸 수용체 1 (pd-1) 항체와 조합된 항-ctla4 항체의 안정한 제제 및 그의 사용 방법
CN111378041B (zh) 抗-egfr抗体及抗体药物偶联物
JP7522477B2 (ja) 抗ｓｅｚ６ｌ２抗体および抗体薬物コンジュゲート
EP3188758A1 (fr) Protéines de fusion sirp alpha-anticorps
JP2024001187A (ja) 乳がんの処置のためのヒト化抗ｌｉｖ１抗体
JP7607564B2 (ja) Ｐｍｅｌ１７に対する抗体及びその結合体
CN114173823A (zh) 抗ceacam5免疫缀合物用于治疗肺癌的用途
KR20210014684A (ko) 항-cd37 면역접합체 투약 용법
KR20230023650A (ko) 항-cd30 항체-약물 컨쥬게이트의 조합을 사용하여 암을 치료하는 방법
CN114641498A (zh) 结合amhrii的抗体药物缀合物及其在治疗癌症中的用途
CN116940387A (zh) 使用抗cd30抗体-药物缀合物调节免疫反应
WO2022097047A1 (fr) Méthodes de traitement utilisant des conjugués anticorps-médicament anti-bcma
WO2022245978A1 (fr) Polythérapie à conjugué de récepteur anti-folate avec du bévacizumab
CA3197158A1 (fr) Anticorps anti-liv1 humanises destines au traitement du cancer
KR20220146488A (ko) 항-cd30 항체-약물 컨쥬게이트 및 비-호지킨 림프종의 치료를 위한 그의 용도
CA2965362A1 (fr) Polytherapie a base d'anticorps anti-egfr
RU2828374C2 (ru) Применение иммуноконъюгатов к ceacam5 для лечения рака легкого
KR20240158391A (ko) 항-프로그래밍된 사멸-리간드 1(pd-l1) 항체 분자, 암호화 폴리뉴클레오티드 및 사용 방법
WO2023102077A1 (fr) Thérapie anticancéreuse basée sur un conjugué de récepteur anti-folate
WO2025216949A1 (fr) Méthodes de traitement d'une tumeur avec des conjugués médicament-anticorps anti-cdh6
CA2957531C (fr) Proteines de fusion sirp alpha-anticorps

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21888791

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21888791

Country of ref document: EP

Kind code of ref document: A1