Methods for treating multiple myeloma

Abstract

Embodiments of the present invention relate to a method for treating multiple myeloma in subjects requiring treatment for multiple myeloma, comprising administering a therapeutically effective dose of GPRC5D×CD3 bispecific antibody on a monthly administration schedule.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Patent Application No. 63 / 505,640 filed on 1 June 2023, U.S. Provisional Patent Application No. 63 / 588,520 filed on 6 October 2023, and U.S. Provisional Patent Application No. 63 / 594,771 filed on 31 October 2023, the disclosures thereof incorporated herein by reference in their entirety.

[0002] (Reference to electronically submitted sequence listings) This application includes a sequence listing submitted electronically in XML format, the entire sequence listing being incorporated herein by reference. The XML copy was created on 8 May 2024, named "258199061602(JBI6818WOPCT1)Sequence Listing.xml", and has a size of 25,444 bytes.

[0003] (Field of invention) A method for treating multiple myeloma will be disclosed. [Background technology]

[0004] Multiple myeloma (MM) is a type of plasma cell cancer. Mechanistically, multiple myeloma is characterized by the production of monoclonal proteins (M proteins) composed of defunctional pathological immunoglobulins or their fragments. The proliferation of multiple myeloma cells subsequently leads to migration from the normal bone marrow niche, while the overproduction of M proteins causes characteristic osteolytic lesions, increased susceptibility to infection, hypercalcemia, renal dysfunction or failure, and neurological complications.

[0005] Treatment options for multiple myeloma have improved over time and vary depending on the aggressiveness of the disease, underlying prognostic factors, the patient's health status, and existing comorbidities. Therapeutic options include proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), alkylating agents, monoclonal antibodies (mAbs), antibody-drug conjugates, histone deacetylase inhibitors, nucleoprotein transport inhibitors, chimeric antigen receptor (CAR) T-cell therapy, and stem cell transplantation.

[0006] Despite these therapeutic outcomes, the disease relapses and is associated with further risk factors (e.g., comorbidities or aging), thus justifying the need for novel therapeutic approaches, such as new dosages and treatment regimens. Particularly in elderly patients for whom stem cell transplantation is often not a viable option, and in patients with refractory disease who have exhausted numerous therapies, multiple myeloma remains an incurable malignancy with significant morbidity and mortality, representing an unmet medical need. In particular, there is still a need for therapeutic regimens that deliver rapid, deep, and sustained clinical responses while providing a manageable safety profile. [Overview of the project]

[0007] One embodiment of the present invention provides a method for treating multiple myeloma in a subject requiring treatment for the disease, comprising administering to the subject a therapeutically effective dose of a GPRC5D×CD3 bispecific antibody on a monthly (Q4W) administration schedule.

[0008] In a particular embodiment, the GPRC5D × CD3 bispecific antibody comprises a GPRC5D binding domain including HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, HCDR3 of SEQ ID NO: 6, LCDR1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, and LCDR3 of SEQ ID NO: 9, and a CD3 binding domain including HCDR1 of SEQ ID NO: 14, HCDR2 of SEQ ID NO: 15, HCDR3 of SEQ ID NO: 16, LCDR1 of SEQ ID NO: 17, LCDR2 of SEQ ID NO: 18, and LCDR3 of SEQ ID NO: 19.

[0009] In certain embodiments, the GPRC5D binding domain includes a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11, and the CD3 binding domain includes a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 21.

[0010] In certain embodiments, the GPRC5D×CD3 bispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype.

[0011] In certain embodiments, the GPRC5D×CD3 bispecific antibody is of the IgG4 isotype.

[0012] In certain embodiments, the GPRC5D×CD3 bispecific antibody contains one or more substitutions in its Fc region.

[0013] In certain embodiments, the GPRC5D×CD3 bispecific antibody is of the IgG4 isotype and contains proline / alanine / alanine substitutions at amino acid positions 228 / 234 / 235 (according to EU index numbering) of its Fc region, respectively.

[0014] In certain embodiments, the GPRC5D×CD3 bispecific antibody is an IgG4 isotype and contains F405L and R409K substitutions in its Fc region (according to EU index numbering).

[0015] In certain embodiments, the Fc region of the GPRC5D binding arm contains proline / alanine / alanine substitutions at amino acid positions 228 / 234 / 235 (according to EU index numbering), respectively.

[0016] In certain embodiments, the Fc region of the CD3 coupling arm includes S228P, F234A, L235A, F405L, and R409K substitutions in that Fc region (according to EU index numbering).

[0017] In a particular embodiment, the GPRC5D×CD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 23.

[0018] In a particular embodiment, the GPRC5D×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 90% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 90% identity with the amino acid sequence of SEQ ID NO: 23.

[0019] In a particular embodiment, the GPRC5D×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 23.

[0020] In certain embodiments, the GPRC5D×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 98% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 98% identity to the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 98% identity to the amino acid sequence of SEQ ID NO: 23.

[0021] In certain embodiments, the GPRC5D×CD3 bispecific antibody is talquetamab.

[0022] In certain embodiments, the subject has relapsed or refractory multiple myeloma.

[0023] In certain embodiments, the subject has previously received at least 3 lines of therapy.

[0024] In certain embodiments, the subject has previously received at least 4 lines of therapy.

[0025] In certain embodiments, the subject has previously received at least 5 lines of therapy (pentad exposure).

[0026] In certain embodiments, the subject has previously received at least 3 lines of therapy including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

[0027] In certain embodiments, the subject has previously received at least 4 lines of therapy including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

[0028] In certain embodiments, the method comprises subcutaneously administering a therapeutic dose of the GPRC5D×CD3 bispecific antibody on a monthly dosing schedule (Q4W).

[0029] In certain embodiments, a GPRC5D × CD3 bispecific antibody (e.g., talketamab) is administered as monotherapy.

[0030] In certain embodiments, a GPRC5D × CD3 bispecific antibody (e.g., talketamab) is administered as part of a combination therapy with one or more additional antimyeloma agents.

[0031] In certain embodiments, the method includes subcutaneous administration of one or more escalating doses of GPRC5D×CD3 bispecific antibody to the target before administering a first therapeutic dose of GPRC5D×CD3 bispecific antibody.

[0032] In certain embodiments, the method includes subcutaneous administration of a GPRC5D×CD3 bispecific antibody at a therapeutic dose of approximately 400 μg / kg to approximately 800 μg / kg on a monthly administration schedule (Q4W).

[0033] In certain embodiments, the method includes subcutaneous administration of a GPRC5D×CD3 bispecific antibody at a therapeutic dose of approximately 400 μg / kg on a monthly administration schedule (Q4W).

[0034] In certain embodiments, the method includes subcutaneous administration of a GPRC5D×CD3 bispecific antibody at a therapeutic dose of approximately 800 μg / kg on a monthly administration schedule (Q4W).

[0035] In certain embodiments, the method includes subcutaneously administering at least one therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly administration schedule (Q2W), and subsequently administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W).

[0036] In certain embodiments, the method includes subcutaneously administering to a subject at least one therapeutic dose of GPRC5D×CD3 bispecific antibody on a weekly administration schedule (QW), then subcutaneously administering to the subject at least one therapeutic dose of GPRC5D×CD3 bispecific antibody on a bi-weekly administration schedule (Q2W), and then subsequently administering to the subject a therapeutic dose of GPRC5D×CD3 bispecific antibody on a monthly administration schedule (Q4W).

[0037] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject over six treatment cycles on a bi-weekly administration schedule (Q2W), and then, starting in treatment cycle 7, administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W).

[0038] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject over six treatment cycles on a bi-weekly dosing schedule (Q2W), and, if the patient achieves VGPR, CR, or sCR as determined by the IMWG response criteria, starting in treatment cycle 7, administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0039] In a particular embodiment, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject over seven treatment cycles on a bi-weekly administration schedule (Q2W), starting in treatment cycle 8, and administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W).

[0040] In a particular embodiment, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject over seven treatment cycles on a bi-weekly dosing schedule (Q2W), initiating treatment cycle 8 if the patient achieves VGPR, CR, or sCR as determined by the IMWG response criteria, and administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0041] In a particular embodiment, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject over eight treatment cycles on a bi-weekly administration schedule (Q2W), starting in treatment cycle 9, and administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W).

[0042] In a particular embodiment, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject over eight treatment cycles on a bi-weekly dosing schedule (Q2W), initiating treatment cycle 9 if the patient achieves VGPR, CR, or sCR as determined by the IMWG response criteria, and administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0043] In a particular embodiment, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly administration schedule (Q2W), and then subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W) in treatment cycle 7 or treatment cycle 8.

[0044] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly administration schedule (Q2W), and then, if the subject achieves a complete response or a strict complete response as determined by the IMWG response criteria, subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W) in treatment cycle 5.

[0045] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly dosing schedule (Q2W), and then (i) if the subject achieves a very good partial response, complete response, or severe complete response as determined by the IMWG response criteria, subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W) starting in treatment cycle 5, or (ii) regardless of the clinical response in the subject, subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W) starting in treatment cycle 7.

[0046] In certain embodiments, the therapeutic doses of GPRC5D×CD3 bispecific antibody administered on a weekly (QW), bi-weekly (Q2W), or monthly (Q4W) schedule are the same.

[0047] In certain embodiments, the GPRC5D×CD3 bispecific antibody is administered at a therapeutic dose of 800 μg / kg on a bi-weekly (Q2W) and monthly (Q4W) schedule.

[0048] In certain embodiments, the method includes subcutaneous administration of two or three escalating doses of GPRC5D×CD3 bispecific antibody before subcutaneous administration of a first therapeutic dose.

[0049] In certain embodiments, the method includes subcutaneous administration of GPRC5D×CD3 bispecific antibody in escalating doses of 10 μg / kg and 60 μg / kg before subcutaneous administration of a therapeutic dose.

[0050] In certain embodiments, the method includes subcutaneous administration of GPRC5D×CD3 bispecific antibody in escalating doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg before subcutaneous administration of a therapeutic dose.

[0051] In certain embodiments, the method includes subcutaneous administration of escalating doses of a GPRC5D×CD3 bispecific antibody, spaced 2 to 4 days apart.

[0052] In certain embodiments, the subject achieves a clinical response that is PR, VGPR, CR, or sCR.

[0053] In certain embodiments, the subject achieves a clinical response that is a complete response (CR) or sustained complete response (sCR).

[0054] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly dosing schedule (Q2W), and then (i) if the subject achieves a very good partial response, complete response, or severe complete response as determined by the IMWG response criteria, subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W) starting in treatment cycle 5, or (ii) regardless of the clinical response in the subject, subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W) starting in treatment cycle 7.

[0055] In certain embodiments, the method includes subcutaneous administration of two or three escalating doses of GPRC5D×CD3 bispecific antibody before subcutaneous administration of a first therapeutic dose.

[0056] In certain embodiments, the method includes subcutaneous administration of GPRC5D×CD3 bispecific antibody in escalating doses of 10 μg / kg and 60 μg / kg before subcutaneous administration of a therapeutic dose.

[0057] In certain embodiments, the method includes subcutaneous administration of GPRC5D×CD3 bispecific antibody in escalating doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg before subcutaneous administration of a therapeutic dose.

[0058] In certain embodiments, the method includes subcutaneous administration of escalating doses of a GPRC5D×CD3 bispecific antibody, spaced 2 to 4 days apart.

[0059] In certain embodiments, the method comprises treating a subject according to a therapeutically effective regimen comprising a series of 28-day GPRC5D×CD3 treatment cycles, wherein one or more escalating doses of GPRC5D×CD3 bispecific antibody are subcutaneously administered to the subject during the escalation phase, a therapeutic dose of GPRC5D×CD3 bispecific antibody is subcutaneously administered to the subject on a bi-weekly schedule (Q2W) starting from the first GPRC5D×CD3 treatment cycle after the escalation phase, and then a therapeutic dose of GPRC5D×CD3 bispecific antibody is subcutaneously administered to the subject on a monthly schedule (Q4W).

[0060] In certain embodiments, the method comprises treating a subject according to a therapeutically effective regimen comprising a series of 28-day GPRC5D×CD3 treatment cycles, wherein one or more escalating doses of GPRC5D×CD3 bispecific antibody are subcutaneously administered to the subject during the escalation phase, a therapeutic dose of GPRC5D×CD3 bispecific antibody is subcutaneously administered to the subject on a bi-weekly schedule (Q2W) starting from the first GPRC5D×CD3 treatment cycle after the escalation phase, and then a therapeutic dose of GPRC5D×CD3 bispecific antibody is subcutaneously administered to the subject on a monthly schedule (Q4W), either starting in treatment cycle 5 if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) starting in treatment cycle 7 regardless of the clinical response in the subject.

[0061] In certain embodiments, the therapeutic doses of GPRC5D×CD3 bispecific antibody administered on a bi-weekly schedule (Q2W) and a monthly schedule (Q4W) were 800 μg / kg.

[0062] In a particular embodiment, cycle 1 of the regimen includes an escalation phase in which a therapeutic dose of GPRC5D×CD3 bispecific antibody is administered subcutaneously to the subject on a bi-weekly schedule (Q2W) starting from cycle 2, and then a therapeutic dose of GPRC5D×CD3 bispecific antibody is administered subcutaneously to the subject on a monthly schedule (Q4W).

[0063] In a particular embodiment, cycle 1 of the regimen includes an escalation phase in which a therapeutic dose of GPRC5D×CD3 bispecific antibody is administered subcutaneously to the subject on a bi-weekly schedule (Q2W) starting from cycle 2, and then a therapeutic dose of GPRC5D×CD3 bispecific antibody is administered subcutaneously to the subject on a monthly schedule (Q4W), either starting in cycle 5 if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) starting in cycle 7 regardless of the clinical response in the subject.

[0064] In certain embodiments, one to three escalating doses of GPRC5D×CD3 bispecific antibody are administered to the subject during the escalation phase.

[0065] In certain embodiments, two escalating doses of GPRC5D×CD3 bispecific antibody are administered to the subject during the escalation phase.

[0066] In a particular embodiment, three escalating doses of GPRC5D×CD3 bispecific antibody are administered to the subject during the escalation phase.

[0067] In certain embodiments, the dose escalation steps include a first dose escalation of 0.01 mg / kg, a second dose escalation of 0.06 mg / kg, and a third dose escalation of 0.4 mg / kg.

[0068] In certain embodiments, one or more therapeutic doses of GPRC5D×CD3 bispecific antibodies are administered subcutaneously to the subject during the escalation phase, in addition to one or more escalating doses (e.g., on a weekly dosing schedule).

[0069] In certain embodiments, one or two therapeutic doses of GPRC5D×CD3 bispecific antibodies are administered subcutaneously to the subject during the escalation phase, in addition to one or more escalating doses (e.g., on a weekly dosing schedule).

[0070] In a particular embodiment, cycle 1 of the regimen includes a first escalating dose of 0.01 mg / kg, a second escalating dose of 0.06 mg / kg, a third escalating dose of 0.4 mg / kg, and a therapeutic dose of 0.8 mg / kg.

[0071] In a particular embodiment, cycle 1 of the regimen includes a first escalating dose of 0.01 mg / kg, a second escalating dose of 0.06 mg / kg for 2 to 4 days after the first escalating dose, a third escalating dose of 0.4 mg / kg for 4 to 7 days after the second escalating dose, and a therapeutic dose of 0.8 mg / kg for 5 to 9 days after the third escalating dose.

[0072] In a particular embodiment, cycle 1 of the regimen includes a first escalating dose of 0.01 mg / kg on day 1, a second escalating dose of 0.06 mg / kg on day 3, a third escalating dose of 0.4 mg / kg on day 8, and a therapeutic dose of 0.8 mg / kg on day 15.

[0073] In certain embodiments, each of cycles 2-6 of the regimen includes a Q2W therapeutic dose of 0.8 mg / kg on days 1 and 15, and each of cycles 7+ includes a Q4W therapeutic dose of 0.8 mg / kg on day 1.

[0074] In certain embodiments, (i) each of cycles 2-6 of the regimen includes a therapeutic dose of 0.8 mg / kg of Q2W on days 1 and 15, and each of cycles 7+ includes a therapeutic dose of 0.8 mg / kg of Q4W on day 1, or (ii) each of cycles 2-4 of the regimen includes a therapeutic dose of 0.8 mg / kg of Q2W on days 1 and 15, and if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, each of cycles 5+ includes a therapeutic dose of 0.8 mg / kg of Q4W on day 1.

[0075] In a particular embodiment, cycle 1 of the regimen comprises a first escalating dose of 0.01 mg / kg on day 1, a second escalating dose of 0.06 mg / kg on day 3, a third escalating dose of 0.4 mg / kg on day 8, and a therapeutic dose of 0.8 mg / kg on day 15; each of cycles 2-6 of the regimen comprises a Q2W therapeutic dose of 0.8 mg / kg on days 1 and 15; and each of cycles 7+ comprises a Q4W therapeutic dose of 0.8 mg / kg on day 1.

[0076] In a particular embodiment, cycle 1 of the regimen comprises a first escalating dose of 0.01 mg / kg on day 1, a second escalating dose of 0.06 mg / kg on day 3, a third escalating dose of 0.4 mg / kg on day 8, and a therapeutic dose of 0.8 mg / kg on day 15, wherein (i) each of cycles 2-6 of the regimen comprises a therapeutic dose of 0.8 mg / kg of Q2W on days 1 and 15, and each of cycles 7+ comprises a therapeutic dose of 0.8 mg / kg of Q4W on day 1, or (ii) each of cycles 2-4 of the regimen comprises a therapeutic dose of 0.8 mg / kg of Q2W on days 1 and 15, and if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, each of cycles 5+ comprises a therapeutic dose of 0.8 mg / kg of Q4W on day 1.

[0077] In certain embodiments, a dosing regimen including administration of GPRC5D×CD3 bispecific antibody on a monthly (Q4W) dosing schedule improves (i) clinical response rate (e.g., ORR) and / or (ii) adverse event rate and / or severity in the target population compared to a reference population receiving GPRC5D×CD3 bispecific antibody on a weekly (QW) and / or bi-weekly (Q2W) dosing schedule that is not a monthly (Q4W) dosing schedule.

[0078] In certain embodiments, a dosing regimen including a monthly (Q4W) dosing schedule achieves a lower rate and / or shorter duration of adverse events than a dosing regimen including weekly (QW) and / or bi-weekly (Q2W) dosing schedules but not including a monthly (Q4W) dosing schedule.

[0079] In certain embodiments, adverse events include one or more of the following: oral toxicity (e.g., anosmia, dysgeusia, xerostomia, and / or dysphagia), and / or nail toxicity (e.g., nail disorders), and / or skin toxicity (e.g., dry skin, exfoliation, and / or itching).

[0080] In certain embodiments, a dosing regimen including a monthly (Q4W) dosing schedule achieves a stronger and / or longer-lasting clinical response than a dosing regimen including a weekly (QW) and / or bi-weekly (Q2W) dosing schedule but without a monthly (Q4W) dosing schedule. In certain embodiments, a dosing regimen including a monthly (Q4W) dosing schedule achieves a higher overall response rate (ORR) than a dosing regimen including a weekly (QW) and / or bi-weekly (Q2W) dosing schedule but without a monthly (Q4W) dosing schedule. In certain embodiments, a dosing regimen including a monthly (Q4W) dosing schedule achieves a longer progression-free survival (PFS) than a dosing regimen including a weekly (QW) and / or bi-weekly (Q2W) dosing schedule but without a monthly (Q4W) dosing schedule.

[0081] All methods described herein, regardless of how they are expressed, may be described as corresponding uses, specifically medical uses. Detailed Description of the Invention

[0082] The methods disclosed herein may be more readily understood by referring to the detailed description below. It should be understood that the methods disclosed herein are not limited to any particular methods described and / or shown herein, and furthermore, that the terms used herein are intended solely to illustrate specific embodiments and are not intended to limit the claimed methods. All patents, published patent applications and publications referenced herein are incorporated by reference as if they were described herein in their entirety.

[0083] As used herein, the singular forms "a," "an," and "the" are to be interpreted as including the plural form.

[0084] Various terms relating to aspects of this specification will be used throughout this specification and the claims. Unless otherwise indicated, such terms shall be given their common meanings in the art. Other specifically defined terms shall be construed to be consistent with the definitions provided herein.

[0085] When used in reference to a numerical range, cutoff, or specific value, "approximately" means within the allowable margin of error for that specific value as determined by those skilled in the art, which in part depends on the method by which the value is measured or determined, i.e., the limitations of the measurement system. Unless otherwise specified in the examples or elsewhere in this specification in the context of an assay, result, or embodiment, "approximately" means within one standard deviation or within a maximum of 5%, whichever is greater, in accordance with the practices of the art.

[0086] The term "antibody" has a broad meaning and includes monoclonal antibodies, including mouse, human, humanized, and chimeric monoclonal antibodies; antigen-binding fragments; multispecific antibodies such as bispecific, triplicate, and quadruplicate antibodies; dimers, tetramers, or multimers; single-chain antibodies; domain antibodies; and immunoglobulin molecules, including any other modified forms of immunoglobulin molecules containing antigen-binding sites of the required specificity. A "full-length antibody" consists of two heavy chains (HC) and two light chains (LC), interconnected by disulfide bonds, and a multimer thereof (e.g., IgM). Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (composed of domains CH1, hinge, CH2, and CH3). Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions can be further subdivided into hypervariable regions called complementarity determining regions (CDRs), which are interspersed with framework regions (FRs). Each VH and VL consists of three CDR and four FR segments arranged in the order FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 from the amino terminus to the carboxy terminus. Immunoglobulins can be assigned to five main classes, IgA, IgD, IgE, IgG, and IgM, depending on the amino acid sequence of the heavy chain constant domain. IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. The antibody light chains of any vertebrate species can be assigned to one of two distinct types, namely kappa (κ) and lambda (λ), based on the amino acid sequence of their constant domains.

[0087] An "antigen-binding fragment" or "antigen-binding domain" refers to a portion of an immunoglobulin molecule that binds to an antigen. Antigen-binding fragments can be synthetic polypeptides, enzyme-available polypeptides, or genetically modified polypeptides, and include VH, VL, VH and VL, Fab, F(ab')2, Fd and Fv fragments, domain antibodies (dAb) consisting of one VH domain or one VL domain, shark variable IgNAR domains, camelid VH domains, the smallest recognition units consisting of amino acid residues that reproduce the CDR of an antibody, such as the FR3-CDR3-FR4 moiety, HCDR1, HCDR2, and / or HCDR3, and LCDR1, LCDR2, and / or LCDR3. The VH and VL domains can bind to each other via synthetic linkers to form various types of single-chain antibody designs. When the VH and VL domains are expressed by separate single-chain antibody constructs, the VH / VL domains can pair intramolecularly or intermolecularly to form monovalent antigen-binding sites, such as single-chain Fv (scFv) or diabodies. These are described, for example, in International Publications 1998 / 44001, 1988 / 01649, 1994 / 13804, and 1992 / 01047.

[0088] "Bispecificity" refers to an antibody that specifically binds to two different antigens, or to two different epitopes within the same antigen. Bispecific antibodies can cross-react to other related antigens, such as the same antigen (homolog) from other species, such as humans or monkeys, for example, cynomolgus monkeys (Macaca cynomolgus, cyno) or chimpanzees (Pan troglodytes), or they can bind to epitopes shared between two or more different antigens.

[0089] "Cancer" refers to a broad group of diseases characterized by the uncontrolled proliferation of abnormal cells in the body. Uncontrolled cell division and proliferation can lead to the formation of malignant tumors that invade adjacent tissues and can metastasize to distal parts of the body via the lymphatic system or bloodstream. "Cancer" or "cancer tissue" may include tumors.

[0090] "CD3" refers to a human antigen expressed on T cells as part of a multimolecular T cell receptor (TCR) complex, consisting of a homodimer or heterodimer formed from the association of two or four receptor chains: CD3 epsilon, CD3 delta, CD3 zeta, and CD3 gamma. Human CD3 epsilon contains the amino acid sequence shown in SEQ ID NO: 2. SEQ ID NO: 3 shows the extracellular domain of CD3 epsilon.

[0091] Sequence ID 2 MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGS KPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI

[0092] Sequence ID 3 DGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMD

[0093] The "CH3 region" or "CH3 domain" refers to the CH3 region of an immunoglobulin. In human IgG1 antibodies, the CH3 region corresponds to amino acid residues 341-446. However, the CH3 region may also be any of the other antibody isotypes described herein.

[0094] "Combination" means administering two or more therapeutic drugs to a subject together in a mixture, simultaneously as single agents, or sequentially as single agents in any order.

[0095] A “combination regimen” (also referred to as a “combination regimen” or “combination therapy”), as used herein, means a therapeutically effective regimen comprising the administration of two or more anti-multiple myeloma agents to a subject for the treatment of multiple myeloma. The two or more agents are administered to the subject over a period of time according to the respective administration schedules of each agent (for example, a period may include one or more treatment cycles, such as one or more 28-day treatment cycles). For example, a combination regimen may include administering to a subject (i) “agent #1” on its weekly, bi-weekly, or monthly administration schedule, beginning on day 1 of the treatment cycle, and (ii) “agent #2” on its weekly, bi-weekly, or monthly administration schedule, or in subsequent treatment cycles, beginning on day 1 of the same treatment cycle.

[0096] A "complementarity-determining region (CDR)" is the region of an antibody that binds to an antigen. CDRs can be defined using various descriptive methods, such as Kabat (Wu et al. J Exp Med 132:211-50, 1970) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al. J Mol Biol 196:901-17, 1987), IMGT (Lefranc et al. Dev Comp Immunol 27:55-77, 2003), and AbM (Martin and Thornton J Bmol Biol 263:800-15, 1996). Correspondence between various descriptions and variable region numbering is provided (see, for example, Lefranc et al. Dev Comp Immunol 27:55-77, 2003; Honegger and Pluckthun, J Mol Biol 309:657-70, 2001; International ImMunoGeneTics (IMGT) database; web resource, http: / / www_imgt_org). CDRs can be described using available programs such as abYsis by UCL Business PLC. As used herein, the terms “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2”, and “LCDR3”, include CDRs defined by any of the Kabat, Chothia, IMGT, or AbM methods described above, unless otherwise specified herein. Preferably, as used herein, the terms “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2”, and “LCDR3”, include CDRs defined by the Kabat method.

[0097] "Comprising" is intended to include examples that are encompassed by the terms "consisting essentially of" and "consisting of." Similarly, the term "consisting essentially of" is intended to include examples that are encompassed by the term "consisting of." Unless the context clearly indicates otherwise, throughout the specification and claims, words such as "comprise" and "comprising" should be interpreted in a comprehensive sense, as opposed to an exclusive or exhaustive sense, i.e., "including but not limited to."

[0098] The term "Fc gamma receptor" (FcγR) refers to the well-known FcγRI, FcγRIIa, FcγRIIb, or FcγRIII. Activated FcγR includes FcγRI, FcγRIIa, and FcγRIII.

[0099] A "GPRC5D x CD3 bispecific antibody" refers to a bispecific antibody that specifically binds to both GPRC5D and CD3.

[0100] A “human antibody” refers to an antibody optimized to minimize the immune response when administered to a human subject. The variable region of a human antibody is derived from a human immunoglobulin sequence. If a human antibody contains a constant region or a portion of a constant region, that constant region is also derived from a human immunoglobulin sequence. A human antibody contains heavy-chain and light-chain variable regions that “derive” from a human-derived sequence if the variable region of the human antibody is obtained from a system using human germline immunoglobulin or a rearranged immunoglobulin gene. Examples of such systems include human immunoglobulin gene libraries presented to phages, and transgenic non-human animals possessing human immunoglobulin loci, such as mice or rats. A “human antibody” typically contains amino acid differences compared to immunoglobulin expressed in humans, due to differences in the system used to obtain the human antibody and the human immunoglobulin locus, or intentional introduction of somatic mutations or substitutions into the framework or CDR, or both. Typically, a “human antibody” is at least approximately 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical in amino acid sequence to the amino acid sequence encoded by a human germline immunoglobulin or rearranged immunoglobulin gene. In some cases, a “human antibody” may include a consensus framework sequence derived from human framework sequence analysis, for example, Knappik et al., (2000) J Mol Biol 296:57-86, or synthetic HCDR3 incorporated into a human immunoglobulin gene library presented on phages, for example, Shi et al., (2010) J Mol Biol 397:385-96 and International Publication No. 2009 / 085462. Antibodies in which at least one CDR originates from a non-human species are not included in the definition of "human antibodies."

[0101] A "humanized antibody" refers to an antibody in which at least one CDR is derived from a non-human species and at least one framework is derived from a human immunoglobulin sequence. Because humanized antibodies can contain substitutions in their framework, the framework may not be an exact copy of the expressed human immunoglobulin or human immunoglobulin germline gene sequence.

[0102] "Identity" refers to the relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules, determined by aligning and comparing their sequences. The "percentage of sequence identity (%)" relative to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in the reference polypeptide sequence, after aligning the sequences and introducing gaps as necessary, without considering any conservative substitutions as part of the sequence identity, to achieve the maximum possible sequence identity percentage. Alignment for the purpose of determining the amino acid sequence identity percentage can be achieved using various methods within the scope of skill in the art, such as publicly available computer software like BLAST, BLAST-2, ALIGN, or MEGALIGN (DNAStar, Inc.) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithm necessary to achieve the maximum alignment over the entire length of the sequences being compared.

[0103] "Isolated" refers to a homogeneous population of molecules (e.g., synthetic polynucleotides or proteins such as antibodies) that has been substantially separated and / or purified from other components of a system in which molecules are produced, such as recombinant cells, in addition to proteins subjected to at least one purification or isolation step. "Isolated antibody" refers to an antibody that is substantially free of other cellular material and / or chemical substances, and includes antibodies isolated to higher purities, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.

[0104] A "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibody molecules that is identical except for possible known modifications such as removal of the C-terminal lysine from the antibody heavy chain, isomerization or deamidementation of amino acids, oxidation of methionine, or post-translational modifications such as deamidementation of asparagine or glutamine; in other words, an individual antibody that constitutes a population. Monoclonal antibodies typically bind to one antigenic epitope. Bispecific monoclonal antibodies bind to two different antigenic epitopes. Monoclonal antibodies can have heterogeneous glycosylation within the antibody population. Monoclonal antibodies can be monospecific or bispecific, and can be monovalent, bivalent, or polyvalent.

[0105] A "mutation" refers to a genetically engineered or naturally occurring alteration of a polypeptide or polynucleotide sequence compared to a reference sequence. An alteration can be the substitution, insertion, or deletion of one or more amino acids or polynucleotides.

[0106] "Negative minimal residual disease (MRD) status," "negative MRD status," or "MRD-negative" refers to the permillion count (i.e., the point estimate of malignant myeloma cells per million nucleated cells) in the patient's bone marrow sample being examined, relative to the patient's reference bone marrow sample (i.e., a tecristamab-naïve bone marrow sample). Based on this permillion count, each sample is determined to be positive or negative. If the permillion count is above the sensitivity limit, the sample is positive; otherwise, the sample is negative. A negative minimal residual disease status occurs in 0.01% (10%). -4 ), 0.001% (10 -5 ), or 0.0001% (10 -6 The diagnosis can be made with the following sensitivity. Negative minimal residual disease status was determined using next-generation sequencing (NGS).

[0107] A "pharmaceutical composition" refers to a composition containing an active ingredient and a pharmaceutically acceptable carrier.

[0108] "Pharmacologically acceptable carriers" or "excipients" refer to components in a pharmaceutical composition other than the active ingredient that are non-toxic to the target.

[0109] "Recombinant" refers to DNA, antibodies, and other proteins prepared, expressed, created, or isolated by recombinant means when segments from different sources join together to produce recombinant DNA, antibodies, or proteins.

[0110] "Refractory" cancer refers to cancer that cannot be repaired even with surgical intervention and does not respond to therapy from the outset.

[0111] "Recurrent" cancer refers to cancer that responds to treatment but subsequently recurs.

[0112] A “sequential dose” refers to the dose of the active drug administered to the subject before the therapeutic dose. Sequential doses are lower than therapeutic doses. A “priming” dosing strategy to prevent or mitigate certain toxicities, such as cytokine release syndrome (CRS), may include one or more lower sequential doses followed by a higher therapeutic dose. A “sequential phase” refers to the initial phase of a therapeutically effective regime in which at least one sequential dose of the therapeutic agent is administered to the subject. A sequential phase may also include one or more therapeutic doses, i.e., a sequential phase may include one or more sequential doses followed by one or more therapeutic doses, for example, a sequential phase may include two sequential doses followed by two therapeutic doses. In certain embodiments, a sequential phase is 28 days, i.e., a sequential phase is a therapeutically effective regimen in 28-day cycles.

[0113] "Subject" includes any human or non-human animal. "Non-human animal" includes, for example, non-human primates, mammals such as sheep, dogs, cats, horses, cattle, chickens, amphibians, and reptiles, and all non-mammalian vertebrates. Unless otherwise noted, the terms "patient" and "subject" are used interchangeably.

[0114] A "T-cell redirecting therapeutic agent" refers to a molecule containing two or more binding domains, one of which specifically binds to a cell surface antigen on a target cell or tissue, and the second binding domain of the molecule specifically binds to a T-cell antigen. Examples of cell surface antigens include tumor-associated antigens such as GPRC5D. An example of a T-cell antigen is CD3. This dual / multi-target binding ability recruits T cells to target cells or tissues, resulting in their eradication.

[0115] The "therapeutic dose" refers to the amount effective in achieving the desired therapeutic outcome at the required dosage and duration. The therapeutic dose may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the drug or combination of drugs to induce the desired response in the individual. An exemplary indicator of an effective drug or combination of drugs is, for example, the patient's improved health status.

[0116] "To treat" or "treatment" refers to both therapeutic treatment and prophylactic or preventative measures, in which an undesirable physiological change or impairment is prevented or slowed (reduced). Beneficial or desired clinical outcomes include, whether detectable or undetectable, relief of symptoms, reduction of disease severity, a stable (i.e., non-worsening) disease state, delay or slowing of disease progression, improvement or relief of the disease state, and remission (whether partial or complete). "Treatment" may also mean extending survival compared to the expected survival time if the subject were not treated. Those who require treatment include those who already have a condition or disease, those who are susceptible to a condition or impairment, or those seeking to prevent a condition or impairment.

[0117] The "therapeutic dose" refers to the amount of active drug administered to a target to treat a disease. Therapeutic doses may be administered repeatedly (e.g., weekly, bi-weekly, monthly) at regular intervals. One or more dose escalations may precede the therapeutic dose.

[0118] A patient described as "triple-class exposed" refers to a patient diagnosed with multiple myeloma (MM) who has been previously treated with (at least) proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0119] "Tumor cells" or "cancer cells" refer to cancerous, precancerous, or transformed cells that exhibit spontaneous or induced phenotypic changes in vivo, ex vivo, or tissue culture. These changes do not necessarily involve the uptake of new genetic material. Transformation may occur through infection with transforming viruses and the incorporation of new genomic nucleic acids, the uptake of exogenous nucleic acids, or spontaneously or after exposure to carcinogens, thereby mutating endogenous genes. Transformation / cancer is exemplified by morphological changes, cell immortalization, abnormal growth control, lesion formation, proliferation, malignant lesions, regulation of tumor-specific marker levels, invasiveness, and tumor growth in suitable animal hosts such as nude mice, in vitro, in vivo, and ex vivo.

[0120] Throughout this specification, unless otherwise specified, the numbering of amino acid residues in the antibody constant region follows the EU index described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed., Public Health Service, National Institutes of Health, Bethesda, MD. (1991). The numbering of the antibody constant chain can be found, for example, in the IMGT Web resource of the IMGT Scientific chart on the ImMunoGeneTics website.

[0121] Conventional one-letter and three-letter amino acid codes are used herein as shown in Table 1.

[0122] [Table 1]

[0123] GPRC5D×CD3 bispecific antibody and its use It is well known in the field of drug development that it is an unpredictable area. This lack of predictability is demonstrated, for example, by the requirements of health organizations (such as the Food and Drug Administration) for establishing safe and effective dosing regimens for each individual drug candidate in clinical trials. Over the past decade (2011–2020), only 7.9% of all drug candidates in development achieved FDA approval from Phase I clinical trials. See Clinical Development Success Rates and Contributing Factors 2011–2020. Success rates are even lower in oncology, with only 5.3% of oncology drug candidates succeeding.

[0124] In the field of oncology, even for drugs with established dosages for specific indications, the Food and Drug Administration (FDA) recommends further clinical trials to identify optimal dosages for new indications. Otherwise, patients may be exposed to unreasonable and significant risks, among other potential drawbacks. See, for example, Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases; Draft Guidance for Industry; January 2023.

[0125] In patients with relapsed or refractory disease who have exhausted numerous therapies, multiple myeloma remains an incurable malignancy, representing an unmet medical need with significant morbidity and mortality rates. We have developed a novel dosing regimen for GPRC5D × CD3 bispecific antibody that provides an improved safety profile compared to currently approved regimens while maintaining deep and sustained efficacy.

[0126] The inventors have discovered that a specific dosing schedule containing talketamab at a lower frequency can reduce adverse events (AEs) associated with the GPRC5D target, such as oral toxicity (e.g., anosmia, dysgeusia, xerostomia, and / or dysphagia), nail toxicity (e.g., nail disorders), and skin toxicity (e.g., dry skin, exfoliation, and / or itching), while still achieving an effective response. Furthermore, it has been found that, following the dosing schedule described herein, sufficient exposure to talketamab and the shortest time to the best response can be achieved after approximately four 28-day treatment cycles, resulting in patients experiencing reduced AEs while still having a deep and sustained response and the shortest time to clinical response.

[0127] Monthly (Q4W) administration of talketamab was selected based on pharmacokinetic (PK), pharmacodynamic, safety, and efficacy findings from a subset of the core RP2D population in initial data from the MonumtanTAL-1 clinical trial (combination therapy in a relapsed / refractory population), the Phase 1b TriMM-2 clinical trial (combination therapy in a relapsed / refractory population), and MonumINal-2 (combination therapy in a relapsed / refractory population), which switched to less frequent administration (e.g., as described in the Examples section of this specification). In these studies, TEAEs were tolerable and manageable. CRS was generally low-grade, and neurotoxic events were rare. In addition, data from MonumanTAL-1 (e.g., as described in the Examples section of this specification) show that participants who switched to reduced-frequency dosing after achieving a response with talketamab monotherapy had improved progression-free survival (PFS) compared to the overall core population, experienced fewer study drug-related TEAEs and grade 3 or 4 TEAEs after the switch, and experienced improved resolution of on-target toxicities (e.g., oral, cutaneous, and rash AEs). Overall, data from MonumanTAL-1 participants receiving Q4W dosing showed sustained response after switching, with a trend toward improved resolution of oral, cutaneous (rash and non-rash), and nail toxicities associated with GPRC5D.

[0128] PK simulations showed that talketamab trough levels after the first 0.8 mg / kg SC administration were the maximum EC levels identified in the ex vivo cytotoxic assay. 90 The values ​​were equivalent to or higher than the specified values. In this assay, the killing ability of talketamab was evaluated using mononuclear cells derived from bone marrow samples of multiple myeloma patients co-cultured with T cells from healthy donors. The trough concentration at steady state was also measured by the maximum EC2. 90It was equivalent to or higher than that. Embodiments of the Q4W dosing schedule disclosed herein are thought to maintain the efficacy of talketamab by balancing the maximization of disease burden reduction through bi-weekly dosing in the first six treatment cycles with the convenience of the participant, with the reduction of exposure through Q4W dosing from cycle 7 onward (or as early as cycle 5 for participants who achieved a confirmed PR or better response).

[0129] The antibody of the present invention In consideration of this disclosure, any suitable GPRC5D×CD3 bispecific antibody known to those skilled in the art can be used in the present invention.

[0130] Various bispecific antibody formats include the formats described herein, as well as recombinant IgG-like bitarget molecules in which each of the two sides of the molecule contains Fab fragments or portions of Fab fragments of at least two different antibodies; IgG fusion molecules in which a full-length IgG antibody is fused to an extra Fab fragment or portion of a Fab fragment; Fc fusion molecules in which a single-chain Fv molecule or stabilized diabody is fused to a heavy chain constant domain, Fc region, or portion thereof; Fab fusion molecules in which different Fab fragments are fused together; and ScFv and diabody-based heavy chain antibodies (e.g., domain antibodies, nanobodies) in which different single-chain Fv molecules, different diabodies, or different heavy chain antibodies (e.g., domain antibodies, nanobodies) are fused to each other or to another protein or carrier molecule, or to a bispecific antibody produced by arm exchange.Exemplary bispecific antibody formats include dual-targeting (DT)-Ig (GSK / Domantis) molecules, two-in-one antibodies (Genentech) and mAb2 (F-Star), dual variable domain (DVD)-Ig (Abbott), DuoBody (Genmab), Ts2Ab (MedImmune / AZ) and BsAb (Zymogenetics), HERCULES (Biogen Idec) and TvAb (Roche), ScFv / Fc fusions (Academic Institution), SCORPION (Emergent BioSolutions / Trubion, Zymogenetics / BMS), and dual-affinity retargeting technology. Examples include Technology, Fc-DART) (MacroGenics), F(ab)2 (Medarex / AMGEN), dual-activating or Bis-Fab (Genentech), Dock-and-Lock (DNL) (ImmunoMedics), bivalent bispecificity (Biotecnol) and Fab-Fv (UCB-Celltech), bispecific T cell engager (BITE) (Micromet), tandem diabody (Tandab) (Affimed), dual-affinity retargeting technology (DART) (MacroGenics), single-chain diabody (Academic), TCR-like antibody (AIT, ReceptorLogics), human serum albumin ScFv fusion (Merrimack) and COMBODY (Epigen Biotech), dual-target nanobody (Ablynx), and dual-target heavy chain-only domain antibody. Various formats of bispecific antibodies are described, for example, in Chames and Baty (2009) Curr Opin Drug Disc Dev 12:276 and Nunez-Prado et al., (2015) Drug Discovery Today 20(5):588-594.

[0131] In some embodiments, the GPRC5D×CD3 bispecific antibody comprises one of the GPRC5D binding domains described in U.S. Patent No. 10,562,968 (the entire contents of which are incorporated herein by reference). In some embodiments, the GPRC5D×CD3 bispecific antibody comprises one of the CD3 binding domains described in U.S. Patent No. 10,562,968. In some embodiments, the GPRC5D×CD3 bispecific antibody comprises one of the GPRC5D×CD3 bispecific antibodies described in U.S. Patent No. 10,562,968.

[0132] In some embodiments, the GPRC5D×CD3 bispecific antibody is chimeric, humanized, or human.

[0133] In some embodiments, the bispecific antibody is an IgG1, IgG2, IgG3, or IgG4 isotype. In preferred embodiments, the bispecific antibody is an IgG4 isotype. An exemplary wild-type IgG4 contains the amino acid sequence of SEQ ID NO: 34.

[0134] Sequence ID 34: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0135] Bispecific antibodies can be of any allotype. Allotype is not expected to affect the properties of bispecific antibodies, such as binding or Fc-mediated effector function. The immunogenicity of therapeutic antibodies is associated with a higher risk of injection reaction and a shorter duration of the therapeutic response (Baert et al., (2003) N Engl J Med 348:602-08). The extent to which a therapeutic antibody induces an immune response in the host may be partially determined by the antibody allotype (Stickler et al., (2011) Genes and Immunity 12:213-21). Antibody allotype is related to variations in the amino acid sequence at specific positions within the antibody's constant region sequence. Table 2 shows the selected IgG1, IgG2, and IgG4 allotypes.

[0136] [Table 2]

[0137] In some embodiments, the bispecific antibody includes one or more Fc substitutions that reduce the binding of the bispecific antibody to the Fcγ receptor (FcγR) and / or reduce Fc effector functions such as C1q binding, complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), or antibody-dependent cell-mediated phagocytosis (ADCP). Specific substitutions can be produced by comparing with wild-type IgG4 of SEQ ID NO: 34.

[0138] Fc positions that can be substituted to reduce the binding of Fc to activated FcγR and subsequently reduce effector function include L234A / L235A on IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N297A on all Ig isotypes, V234A / G237A on IgG2, K214T / E233P / L234V / L235A / G236 deletion / A327G / P331A / on IgG1 These are substitutions of D365E / L358M, H268Q / V309L / A330S / P331S on IgG2, S267E / L328F on IgG1, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236 deletion / G237A / P238S on IgG4, where residue numbering follows the EU index.

[0139] The Fc substitution that can be used to reduce CDC is K322A substitution.

[0140] To improve the stability of IgG4, the well-known S228P substitution can be further applied to the IgG4 antibody.

[0141] In some embodiments, the bispecific antibody contains one or more asymmetric substitutions in the first CH3 domain, the second CH3 domain, or both the first and second CH3 domains.

[0142] In some embodiments, one or more asymmetric substitutions are F405L / K409R, wild-type / F405L_R409K, T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S and The selection is made from the group consisting of T366W / T366S_L368A_Y407V, L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, and T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0143] In some embodiments, the GPRC5D×CD3 bispecific antibody is of the IgG4 isotype and contains phenylalanine at position 405 and arginine at position 409 of the first heavy chain (HC1), and leucine at position 405 and lysine at position 409 of the second heavy chain (HC2), with residue numbering following the EU index.

[0144] In some embodiments, the GPRC5D×CD3 bispecific antibody further comprises proline at position 228, alanine at position 234, and alanine at position 235 of both HC1 and HC2.

[0145] Tables 3 and 4 provide sequences of exemplary embodiments of GPRC5D×CD3 bispecific antibodies according to the Kabat numbering system.

[0146] [Table 3]

[0147] [Table 4]

[0148] In some embodiments, the GPRC5D×CD3 bispecific antibody is JNJ-64407564 or talketamab (also referred to herein as Tal) and has the sequences described in Tables 3 and 4.

[0149] Talketamab is a GPRC5D-targeted bispecific antibody developed for the treatment of patients with relapsed or refractory multiple myeloma. See, for example, Chari A, et al. Blood 2022;140(suppl 1):384-387 (which is incorporated herein by reference). Talketamab is a bispecific GPRC5D-targeted CD3 T-cell engager developed as monotherapy for adult patients with relapsed or refractory multiple myeloma who have previously received at least three or four prior treatments, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0150] Talketamab and its uses are described, for example, in International Publication No. 2018 / 017786 and International Publication No. 2022 / 058445, which are incorporated herein by reference. According to certain embodiments, the GPRC5D×CD3 bispecific antibody has an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with the amino acid sequence of talketamab.

[0151] Further embodiments of the GPRC5D×CD3 bispecific antibody that can be used in accordance with the present invention are described below.

[0152] In a particular embodiment, the GPRC5D × CD3 bispecific antibody comprises a GPRC5D binding domain including HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, HCDR3 of SEQ ID NO: 6, LCDR1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, and LCDR3 of SEQ ID NO: 9, and a CD3 binding domain including HCDR1 of SEQ ID NO: 14, HCDR2 of SEQ ID NO: 15, HCDR3 of SEQ ID NO: 16, LCDR1 of SEQ ID NO: 17, LCDR2 of SEQ ID NO: 18, and LCDR3 of SEQ ID NO: 19.

[0153] In certain embodiments, the GPRC5D binding domain includes a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11, and the CD3 binding domain includes a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 21.

[0154] In certain embodiments, the GPRC5D×CD3 bispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype.

[0155] In certain embodiments, the GPRC5D×CD3 bispecific antibody is of the IgG4 isotype.

[0156] In certain embodiments, the GPRC5D×CD3 bispecific antibody contains one or more substitutions in its Fc region.

[0157] In certain embodiments, the GPRC5D×CD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A, and L235A substitutions in its Fc region.

[0158] In certain embodiments, the GPRC5D×CD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A, L235A, F405L, and R409K substitutions in its Fc region.

[0159] In certain embodiments, the GPRC5D coupling arm includes S228P, F234A, and L235A substitutions in its Fc region (according to EU index numbering).

[0160] In certain embodiments, the Fc region of the CD3 coupling arm includes S228P, F234A, L235A, F405L, and R409K substitutions in that Fc region (according to EU index numbering).

[0161] In a particular embodiment, the GPRC5D×CD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 23.

[0162] In a particular embodiment, the GPRC5D×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 90% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 90% identity with the amino acid sequence of SEQ ID NO: 23.

[0163] In a particular embodiment, the GPRC5D×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 23.

[0164] In a particular embodiment, the GPRC5D×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 98% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 98% identity with the amino acid sequence of SEQ ID NO: 23.

[0165] In certain embodiments, the GPRC5D×CD3 bispecific antibody is talketamab.

[0166] Patient population with multiple myeloma The GPRC5D×CD3 bispecific antibodies disclosed herein are intended for use in the treatment of multiple myeloma in subjects, for example, human subjects. In certain embodiments, the subjects are relapsed or refractory to treatment with one or more prior anti-cancer therapies. Relapsed disease means that cancer has come back. Refractory disease means that the cancer has not improved with treatment or has become unresponsive to treatment.

[0167] In some embodiments, the subject is relapsed or refractory to treatment with therapeutic agents used to treat multiple myeloma or other hematological malignancies.

[0168] In certain embodiments, the subject has been treated in 1 to 11 previous treatment lines, or in 1 to 10 previous treatment lines.

[0169] In certain embodiments, the subjects have previously undergone autologous stem cell transplantation (ASCT).

[0170] In certain embodiments, the subject has previously received at least three lines of treatment.

[0171] In certain embodiments, the subject has previously received at least four lines of treatment.

[0172] In certain embodiments, the subject has previously received at least five lines of treatment (pentad exposure).

[0173] In certain embodiments, the subject has previously received at least three lines of treatment, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0174] In certain embodiments, the subject has previously received at least four lines of treatment, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0175] In certain embodiments, patients had relapsed, refractory, or last-line of therapy (LOT) intolerance, had been exposed to proteasome inhibitors, immunomodulators, and anti-CD38 therapies, and had measurable disease.

[0176] In some embodiments, subjects had received three anticancer therapies prior to administration of the GPRC5D×CD3 bispecific antibody.

[0177] In one embodiment, the three prior anticancer therapies are a proteasome inhibitor (PI), an immunomodulatory drug (ImiD), and an anti-CD38 antibody. In certain such embodiments, the proteasome inhibitor is bortezomib, carfilzomib, or ixazomib; the immunomodulatory drug (ImiD) is lenalidomide, pomalidomide, or thalidomide; and the anti-CD38 antibody is daratumumab or isatuximab.

[0178] In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory agent (ImiD) is lenalidomide, and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory agent (ImiD) is lenalidomide, and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory agent (ImiD) is pomalidomide, and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory agent (ImiD) is pomalidomide, and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory agent (ImiD) is thalidomide, and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulator (ImiD) is thalidomide, and the anti-CD38 antibody is isatuximab.

[0179] In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory agent (ImiD) is lenalidomide, and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory agent (ImiD) is lenalidomide, and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory agent (ImiD) is pomalidomide, and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory agent (ImiD) is pomalidomide, and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory agent (ImiD) is thalidomide, and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory agent (ImiD) is thalidomide, and the anti-CD38 antibody is isatuximab.

[0180] In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory agent (ImiD) is lenalidomide, and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory agent (ImiD) is lenalidomide, and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory agent (ImiD) is pomalidomide, and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory agent (ImiD) is pomalidomide, and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory agent (ImiD) is thalidomide, and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulator (ImiD) is thalidomide, and the anti-CD38 antibody is isatuximab.

[0181] In some embodiments, the subjects are refractory or relapsed to treatment with one or more therapies, such as THALOMID® (thalidomide), REVLIMID® (lenalidomide), POMALYST® (pomaridomide), VELCADE® (bortezomib), NINLARO (ixazomib), KYPROLIS® (carfilzomib), FARADYK® (panobinostat), AREDIA® (pamidronate), ZOMETA® (zoledronic acid), DARZALEX® (daratumumab), erotozumab or melphalan, Xpovio® (selinexol), Venclexta® (venetoclax), GSK916, CAR-T therapy, or other BCMA-targeted therapies.

[0182] Various qualitative and / or quantitative methods can be used to determine the recurrence or refractory nature of the disease. Possible related symptoms include, for example, a decline or stabilization of the patient's health, recurrence or exacerbation of various symptoms associated with solid tumors, and / or metastasis of cancer cells within the body from one site to other organs, tissues, or cells.

[0183] In some embodiments, multiple myeloma is relapsed or refractory to treatment with anti-CD38 antibodies, selinexol, venetoclax, lenalidomide, bortezomib, pomalidomidocarfilzomib, elotozumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[0184] In one embodiment, the anti-CD38 antibody is daratumumab.

[0185] In another embodiment, the anti-CD38 antibody is isatuximab.

[0186] In some embodiments, multiple myeloma is high-risk multiple myeloma. Subjects with high-risk multiple myeloma are known to experience early relapses and have a poor prognosis and outcome. Subjects may be classified as having high-risk multiple myeloma if they have one or more of the following cytogenetic abnormalities: t(4;14)(p16;q32), t(14;16)(q32;q23), del17p, 1qAmp, t(4;14)(p16;q32) and t(14;16)(q32;q23), t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p. In some embodiments, subjects may be classified as having high-risk multiple myeloma if they have one or more of the following chromosomal abnormalities: t(4;14)(p16;q32), t(14;16)(q32;q23), del17p, 1qAmp, t(4;14)(p16;q32) and t(14;16)(q32;q23), t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof.

[0187] Cytogenetic abnormalities can be detected, for example, by fluorescence in situ hybridization (FISH). In chromosomal translocations, oncogenes are translocated to the IgH region on chromosome 14q32, resulting in dysregulation of these genes. T(4;14)(p16;q32) involves translocations of fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain-containing protein (MMSET) (also known as WHSC1 / NSD2), while t(14;16)(q32;q23) involves a translocation of the MAF transcription factor C-MAF. Deletion of 17p (del17p) involves the loss of the p53 locus.

[0188] Chromosome rearrangements can be identified using well-known methods, such as fluorescence in situ hybridization, karyotype analysis, pulsed-field gel electrophoresis, or sequencing.

[0189] Monthly administration of GPRC5D x CD3 bispecific antibody The inventors have developed a novel dosing regimen for GPRC5D×CD3 bispecific antibodies that provides an improved safety profile compared to currently approved regimens while maintaining a deep and sustained clinical response over time. The regimen provides reduced or reduced doses that decrease the rate and / or severity of adverse events while maintaining a clinical response.

[0190] As used herein, “body weight-based” refers to a dosage based on the specific body weight of the subject; for example, 3 mg / kg refers to a dose of 3 milligrams of antibody per kilogram of body weight of the subject. Unless otherwise specified herein, body weight-based dosages are used when the dosage is given in units of “mg / kg” or “μg / kg”.

[0191] Unless otherwise specified herein, GPRC5D×CD3 bispecific antibodies such as talketamab are administered in a dosing schedule based on consecutive 28-day cycles, for example, Cycle 1 begins on Day 1 of Cycle 1 and ends on Day 28 of Cycle 1, then Day 1 of Cycle 2 begins the day after Day 28 of Cycle 1 and ends on Day 28 of Cycle 2, then Day 1 of Cycle 3 begins the day after Day 28 of Cycle 2 and ends on Day 28 of Cycle 3, and so on. In certain embodiments, one or more escalating doses are administered prior to the first treatment cycle, i.e., prior to Day 1 of Cycle 1. Thus, as used herein, a treatment cycle refers to a 28-day treatment cycle. As used herein with respect to treatment cycles, "C1" refers to Cycle 1, "C2" refers to Cycle 2, "C3" refers to Cycle 3, and so on. Multiple cycles may also be described, for example, "C3-6" refers to Cycles 3-6 (Cycles 3, 4, 5, and 6). Cycle numbers with a "+" symbol refer to that cycle and all subsequent cycles. For example, "C5+" refers to cycle 5 and all subsequent cycles (i.e., C5, C6, C7, C8, C9, etc.).

[0192] As used herein, “Q4W” means once every four weeks, “Q2W” (also known as “bi-weekly” or “biweekly”) means once every two weeks, and “QW” (also known as “weekly”) means once a week. In this specification, Q4W may refer to “monthly,” but strictly speaking, it refers to once every four weeks or once every 28 days (for example, in a 28-day cycle, the first therapeutic dose is administered on day 1 of cycle 1, and the second therapeutic dose is administered on day 1 of cycle 2). Administration of a once-weekly (QW) therapeutic dose is also referred to herein as a weekly administration schedule, and for example, a 28-day treatment cycle may have a weekly administration schedule including four doses spaced one week apart from each other (e.g., days 1, 8, 15, and 22), or three doses spaced one week apart from each other (e.g., days 8, 15, and 22), or two doses spaced one week apart from each other (e.g., days 8 and 15). A therapeutic dose administered every two weeks (Q2W) is also referred to herein as a bi-weekly dosing schedule. A therapeutic dose administered every four weeks (Q4W) is also referred to herein as a monthly dosing schedule. Dosing regimens may be described herein in terms of dosage and frequency. For example, "C1: 0.4 mg / kg QW" refers to an administration of 0.4 mg / kg once a week in cycle 1 of a therapeutically effective regimen, "C3~6: 0.8 mg / kg Q2W" refers to an administration of 0.8 mg / kg once every two weeks from cycle 3 to cycle 6, and "C7+: 0.8 mg / kg Q4W" refers to an administration of 0.8 mg / kg once every four weeks starting from cycle 7.

[0193] As used herein, “GPRC5D×CD3 therapeutic cycle” refers to each therapeutic cycle in a therapeutically effective regime in which at least one therapeutic dose of the GPRC5D×CD3 bispecific antibody is administered to the subject. In a preferred embodiment, there is an escalation phase prior to the first GPRC5D×CD3 therapeutic cycle in the therapeutically effective regime.

[0194] According to embodiments of the present invention, a method for treating multiple myeloma is effective in inducing a clinical response in a population as determined by the International Myeloma Working Group (IMWG) response criteria. According to certain embodiments, the treatment method is effective in inducing a partial response, very good partial response, complete response, or exact complete response, as determined by the IMWG response criteria. As used herein, overall response rate (ORR) refers to the percentage of patients in the population that achieve a partial response (PR) or better, i.e., a partial response, very good partial response, complete response, or exact complete response. The IMWG criteria for response to the treatment of multiple myeloma are provided in Table 7 below.

[0195] [Table 5] CR = Complete Response, FLC = Free Light Chain, IMWG = International Myeloma Working Group, M Protein = Monoclonal Paraprotein, MR = Minimal Response, PC = Plasma Cell, PD = Progressive Disease, PR = Partial Response, sCR = Strict Complete Response, SD = Stable Disease, VGPR = Very Good Partial Response a The presence or absence of clonal cells is based on the kappa / lambda ratio. Abnormal kappa / lambda ratios by immunohistochemistry or immunofluorescence require a minimum of 100 plasma cells for analysis. Abnormal ratios reflecting the presence of abnormal clones are kappa / lambda greater than 4:1 or less than 1:2. * Clarification of IMWG criteria for coding CR and VGPR in subjects where the only measurable disease is due to serum FLC levels: CR in such subjects exhibits a normal FLC ratio of 0.26–1.65, in addition to the CR criteria listed above. VGPR in such subjects requires a reduction of more than 90% in the difference between the involved FLC level and the uninvolved FLC level.

[0196] The IMWG criteria for response to multiple myeloma treatment are also described, for example, in Durie et al., Kumar et al. and Rajkumar et al.: Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9):1467-1473; Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-346, Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform reporting of clinical Trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117(18):4691-4695.

[0197] In certain embodiments, prior to switching to subcutaneous monthly (Q4W) administration at a therapeutic dose amount of 0.8 mg / kg, talquetamab may be administered subcutaneously according to one or both of the following weight-based dosing schedules (QW and / or Q2W) shown in Tables 9 and 10, where mg / kg refers to the number of mg of talquetamab per kg of the patient's body weight.

[0198]

Table 6

[0199] [Table 7] a Based on actual weight. b The dose may be administered 2 to 4 days after the previous dose, or up to 7 days after the previous dose to allow time for the resolution of adverse reactions. c Maintenance should be maintained for a minimum of 6 days between weekly doses and for a minimum of 12 days between bi-weekly (every two weeks) doses.

[0200] According to certain embodiments, the frequency of administration of GPRC5D×CD3 bispecific monoclonal antibody can be reduced from every other week to every month. For example, the frequency of administration of GPRC5D×CD3 bispecific antigen can be reduced from every other week to every month if the subject achieves a clinical response.

[0201] According to one embodiment, the frequency of administration of the GPRC5D×CD3 bispecific antibody may be reduced from weekly to bi-weekly after 4 treatment cycles if the patient achieves a partial response, and may be further reduced from bi-weekly to monthly after 8 cycles if the patient achieves a very good partial response.

[0202] In another embodiment, the administration regimen of the GPRC5D×CD3 bispecific antibody may include a bi-weekly therapeutic dose of 0.8 mg / kg, followed by a switch to 0.8 mg / kg monthly in treatment cycle 7, or, if the subject achieves a complete response, a switch to 0.8 mg / kg monthly in treatment cycle 5.

[0203] According to another embodiment, a GPRC5D×CD3 bispecific antibody administration regimen may include subcutaneous administration of a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly administration schedule (Q2W), and then (i) if the subject achieves a very good partial response, complete response, or strict complete response as determined by the IMWG response criteria, subcutaneous administration of a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W) starting in treatment cycle 5, or (ii) regardless of the clinical response in the subject, subcutaneous administration of a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W) starting in treatment cycle 7.

[0204] In another embodiment, a GPRC5D×CD3 bispecific antibody administration regimen may include subcutaneous administration of a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly administration schedule (Q2W), and then (i) if the subject achieves a very good partial response, complete response, or strict complete response as determined by the IMWG response criteria, subcutaneous administration of a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W) starting in treatment cycle 5 or 6, or (ii) regardless of the clinical response in the subject, subcutaneous administration of a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W) starting in treatment cycle 7.

[0205] According to another embodiment, a GPRC5D×CD3 bispecific antibody administration regimen may include subcutaneous administration of a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly administration schedule (Q2W), and then (i) if the subject achieves a very good partial response, complete response, or severe complete response as determined by the IMWG response criteria, the subject is subcutaneously administered a therapeutic dose of GPRC5D×CD3 bispecific antibody on a monthly administration schedule (Q4W) starting in treatment cycle 5 or 6, or (ii) if the subject achieves a partial response, very good partial response, complete response, or severe complete response as determined by the IMWG response criteria, the subject is subcutaneously administered a therapeutic dose of GPRC5D×CD3 bispecific antibody on a monthly administration schedule (Q4W) starting in treatment cycle 7 or later.

[0206] Additional embodiments of the present invention are described below.

[0207] In certain embodiments, a method for treating a subject requiring treatment for multiple myeloma includes administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0208] In certain embodiments, the method includes subcutaneous administration of a therapeutic dose of GPRC5D×CD3 bispecific antibody on a monthly administration schedule (Q4W).

[0209] In certain embodiments, the method includes subcutaneous administration of one or more escalating doses of GPRC5D×CD3 bispecific antibody to the target before administering a first therapeutic dose of GPRC5D×CD3 bispecific antibody.

[0210] In certain embodiments, the method includes subcutaneous administration of a GPRC5D×CD3 bispecific antibody at a therapeutic dose of approximately 400 μg / kg to approximately 800 μg / kg on a monthly administration schedule (Q4W).

[0211] In certain embodiments, the method includes subcutaneous administration of a GPRC5D×CD3 bispecific antibody at a therapeutic dose of approximately 400 μg / kg on a monthly administration schedule (Q4W).

[0212] In certain embodiments, the method includes subcutaneous administration of a GPRC5D×CD3 bispecific antibody at a therapeutic dose of approximately 800 μg / kg on a monthly administration schedule (Q4W).

[0213] In certain embodiments, the method includes subcutaneously administering at least one therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly administration schedule (Q2W), and subsequently administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W).

[0214] In certain embodiments, the method includes subcutaneously administering to a subject at least one therapeutic dose of GPRC5D×CD3 bispecific antibody on a weekly administration schedule (QW), then subcutaneously administering to the subject at least one therapeutic dose of GPRC5D×CD3 bispecific antibody on a bi-weekly administration schedule (Q2W), and then subsequently administering to the subject a therapeutic dose of GPRC5D×CD3 bispecific antibody on a monthly administration schedule (Q4W).

[0215] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject over six treatment cycles on a bi-weekly administration schedule (Q2W), and then, starting in treatment cycle 7, administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W).

[0216] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly administration schedule (Q2W), and if the patient achieves PR, VGPR, CR, or sCR as determined by the IMWG response criteria, administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W).

[0217] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly dosing schedule (Q2W), and if the patient achieves PR, VGPR, CR, or sCR as determined by the IMWG response criteria, administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W) starting in treatment cycle 3, 4, or 5.

[0218] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject over six treatment cycles on a bi-weekly dosing schedule (Q2W), and, if the patient achieves VGPR, CR, or sCR as determined by the IMWG response criteria, starting in treatment cycle 7, administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0219] In a particular embodiment, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject over seven treatment cycles on a bi-weekly administration schedule (Q2W), starting in treatment cycle 8, and administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W).

[0220] In a particular embodiment, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject over seven treatment cycles on a bi-weekly dosing schedule (Q2W), initiating treatment cycle 8 if the patient achieves VGPR, CR, or sCR as determined by the IMWG response criteria, and administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0221] In a particular embodiment, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject over eight treatment cycles on a bi-weekly administration schedule (Q2W), starting in treatment cycle 9, and administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W).

[0222] In a particular embodiment, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject over eight treatment cycles on a bi-weekly dosing schedule (Q2W), initiating treatment cycle 9 if the patient achieves VGPR, CR, or sCR as determined by the IMWG response criteria, and administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0223] In a particular embodiment, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly administration schedule (Q2W), and then subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W) in treatment cycle 7 or treatment cycle 8.

[0224] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly administration schedule (Q2W), and then, if the subject achieves a complete response or a strict complete response as determined by the IMWG response criteria, subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W) in treatment cycle 5.

[0225] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly dosing schedule (Q2W), and then (i) if the subject achieves a very good partial response, complete response, or severe complete response as determined by the IMWG response criteria, subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W) starting in treatment cycle 5, or (ii) regardless of the clinical response in the subject, subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W) starting in treatment cycle 7.

[0226] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly dosing schedule (Q2W), and then (i) if the subject achieves a very good partial response, complete response, or severe complete response as determined by the IMWG response criteria, subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W) starting in treatment cycle 5 or 6, or (ii) regardless of the clinical response in the subject, subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W) starting in treatment cycle 7.

[0227] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly administration schedule (Q2W), and then (i) if the subject achieves a very good partial response, complete response, or severe complete response as determined by the IMWG response criteria, subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W) starting in treatment cycle 5 or 6, or (ii) if the subject achieves a partial response, very good partial response, complete response, or severe complete response as determined by the IMWG response criteria, subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W) starting in treatment cycle 7 or later.

[0228] In certain embodiments, the therapeutic doses of GPRC5D×CD3 bispecific antibody administered on a weekly (QW), bi-weekly (Q2W), or monthly (Q4W) schedule are the same.

[0229] In certain embodiments, the GPRC5D×CD3 bispecific antibody is administered at a therapeutic dose of 800 μg / kg on a bi-weekly (Q2W) and monthly (Q4W) schedule.

[0230] In certain embodiments, the method includes subcutaneous administration of two or three escalating doses of GPRC5D×CD3 bispecific antibody before subcutaneous administration of a first therapeutic dose.

[0231] In certain embodiments, the method includes subcutaneous administration of GPRC5D×CD3 bispecific antibody in escalating doses of 10 μg / kg and 60 μg / kg before subcutaneous administration of a therapeutic dose.

[0232] In certain embodiments, the method includes subcutaneous administration of GPRC5D×CD3 bispecific antibody in escalating doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg before subcutaneous administration of a therapeutic dose.

[0233] In certain embodiments, the method includes subcutaneous administration of escalating doses of a GPRC5D×CD3 bispecific antibody, spaced 2 to 4 days apart.

[0234] In certain embodiments, the subject achieves a clinical response that is PR, VGPR, CR, or sCR.

[0235] In certain embodiments, the subject achieves a clinical response that is a complete response (CR) or sustained complete response (sCR).

[0236] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly dosing schedule (Q2W), and then (i) if the subject achieves a very good partial response, complete response, or severe complete response as determined by the IMWG response criteria, subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W) starting in treatment cycle 5, or (ii) regardless of the clinical response in the subject, subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W) starting in treatment cycle 7.

[0237] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly dosing schedule (Q2W), and then (i) if the subject achieves a very good partial response, complete response, or severe complete response as determined by the IMWG response criteria, subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W) starting in treatment cycle 5 or 6, or (ii) regardless of the clinical response in the subject, subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W) starting in treatment cycle 7.

[0238] In certain embodiments, the method includes subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly dosing schedule (Q2W), and then (i) if the subject achieves a very good partial response, complete response, or severe complete response as determined by the IMWG response criteria, subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W) starting in treatment cycle 5 or 6, or (ii) if the subject achieves a partial response, very good partial response, complete response, or severe complete response as determined by the IMWG response criteria, subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W) starting in treatment cycle 7. In certain embodiments, the method includes subcutaneously administering two or three escalating doses of GPRC5D×CD3 bispecific antibody before subcutaneously administering the first therapeutic dose.

[0239] In certain embodiments, the method includes subcutaneous administration of GPRC5D×CD3 bispecific antibody in escalating doses of 10 μg / kg and 60 μg / kg before subcutaneous administration of a therapeutic dose.

[0240] In certain embodiments, the method includes subcutaneous administration of GPRC5D×CD3 bispecific antibody in escalating doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg before subcutaneous administration of a therapeutic dose.

[0241] In certain embodiments, the method includes subcutaneous administration of escalating doses of a GPRC5D×CD3 bispecific antibody, spaced 2 to 4 days apart.

[0242] In certain embodiments, the method comprises treating a subject according to a therapeutically effective regimen comprising a series of 28-day GPRC5D×CD3 treatment cycles, wherein one or more escalating doses of GPRC5D×CD3 bispecific antibody are subcutaneously administered to the subject during the escalation phase, a therapeutic dose of GPRC5D×CD3 bispecific antibody is subcutaneously administered to the subject on a bi-weekly schedule (Q2W) starting from the first GPRC5D×CD3 treatment cycle after the escalation phase, and then a therapeutic dose of GPRC5D×CD3 bispecific antibody is subcutaneously administered to the subject on a monthly schedule (Q4W).

[0243] In certain embodiments, the method comprises treating a subject according to a therapeutically effective regimen comprising a series of 28-day GPRC5D×CD3 treatment cycles, wherein one or more escalating doses of GPRC5D×CD3 bispecific antibody are subcutaneously administered to the subject during the escalation phase, a therapeutic dose of GPRC5D×CD3 bispecific antibody is subcutaneously administered to the subject on a bi-weekly schedule (Q2W) starting from the first GPRC5D×CD3 treatment cycle after the escalation phase, and then a therapeutic dose of GPRC5D×CD3 bispecific antibody is subcutaneously administered to the subject on a monthly schedule (Q4W), either starting in treatment cycle 5 if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) starting in treatment cycle 7 regardless of the clinical response in the subject.

[0244] In certain embodiments, the method comprises treating a subject according to a therapeutically effective regimen comprising a series of 28-day GPRC5D×CD3 treatment cycles, wherein one or more escalating doses of GPRC5D×CD3 bispecific antibody are subcutaneously administered to the subject during the escalation phase, a therapeutic dose of GPRC5D×CD3 bispecific antibody is subcutaneously administered to the subject on a bi-weekly schedule (Q2W) starting from the first GPRC5D×CD3 treatment cycle after the escalation phase, and then a therapeutic dose of GPRC5D×CD3 bispecific antibody is subcutaneously administered to the subject on a monthly schedule (Q4W), either starting in treatment cycle 5 if (i) the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) starting in treatment cycle 7 if the subject achieves a partial response, very good partial response, complete response, or exact complete response as determined by the IMWG response criteria.

[0245] In certain embodiments, the therapeutic doses of GPRC5D×CD3 bispecific antibody administered on a bi-weekly schedule (Q2W) and a monthly schedule (Q4W) were 800 μg / kg.

[0246] In a particular embodiment, cycle 1 of the regimen includes an escalation phase in which a therapeutic dose of GPRC5D×CD3 bispecific antibody is administered subcutaneously to the subject on a bi-weekly schedule (Q2W) starting from cycle 2, and then a therapeutic dose of GPRC5D×CD3 bispecific antibody is administered subcutaneously to the subject on a monthly schedule (Q4W).

[0247] In certain embodiments, the administration regimen includes an escalation phase, followed by the subcutaneous administration of a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W) starting from the treatment cycle immediately following the escalation phase (regardless of whether or not there is a clinical response in the subject). In certain embodiments, cycle 1 of the regimen includes an escalation phase, followed by the subcutaneous administration of a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W) starting from cycle 2 (e.g., 0.8 mg / kg on day 1 of each cycle, starting in cycle 2). In certain embodiments, the escalation phase includes two or three escalating doses, preferably spaced 2 to 4 days apart from each other, followed by at least one therapeutic dose of 0.8 mg / kg (e.g., one therapeutic dose on day 15 of cycle 1). In certain embodiments, the dose escalation phase includes, for example, three escalating doses (0.01, 0.06, and 0.4 mg / kg) on ​​days 2, 4, and 8 of cycle 1, followed by a therapeutic dose of 0.8 mg / kg on day 15 of cycle 1.

[0248] In a particular embodiment, cycle 1 of the regimen includes an escalation phase in which a therapeutic dose of GPRC5D×CD3 bispecific antibody is administered subcutaneously to the subject on a bi-weekly schedule (Q2W) starting from cycle 2, and then a therapeutic dose of GPRC5D×CD3 bispecific antibody is administered subcutaneously to the subject on a monthly schedule (Q4W), either starting in cycle 5 if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) starting in cycle 7 regardless of the clinical response in the subject.

[0249] In certain embodiments, one to three escalating doses of GPRC5D×CD3 bispecific antibody are administered to the subject during the escalation phase.

[0250] In certain embodiments, two escalating doses of GPRC5D×CD3 bispecific antibody are administered to the subject during the escalation phase.

[0251] In a particular embodiment, three escalating doses of GPRC5D×CD3 bispecific antibody are administered to the subject during the escalation phase.

[0252] In certain embodiments, the dose escalation steps include a first dose escalation of 0.01 mg / kg, a second dose escalation of 0.06 mg / kg, and a third dose escalation of 0.4 mg / kg.

[0253] In certain embodiments, one or more therapeutic doses of GPRC5D×CD3 bispecific antibodies are administered subcutaneously to the subject during the escalation phase, in addition to one or more escalating doses (e.g., on a weekly dosing schedule).

[0254] In certain embodiments, one or two therapeutic doses of GPRC5D×CD3 bispecific antibodies are administered subcutaneously to the subject during the escalation phase, in addition to one or more escalating doses (e.g., on a weekly dosing schedule).

[0255] In a particular embodiment, cycle 1 of the regimen includes a first escalating dose of 0.01 mg / kg, a second escalating dose of 0.06 mg / kg, a third escalating dose of 0.4 mg / kg, and a therapeutic dose of 0.8 mg / kg.

[0256] In a particular embodiment, cycle 1 of the regimen includes a first escalating dose of 0.01 mg / kg, a second escalating dose of 0.06 mg / kg for 2 to 4 days after the first escalating dose, a third escalating dose of 0.4 mg / kg for 4 to 7 days after the second escalating dose, and a therapeutic dose of 0.8 mg / kg for 5 to 9 days after the third escalating dose.

[0257] In a particular embodiment, cycle 1 of the regimen includes a first escalating dose of 0.01 mg / kg on day 1, a second escalating dose of 0.06 mg / kg on day 3, a third escalating dose of 0.4 mg / kg on day 8, and a therapeutic dose of 0.8 mg / kg on day 15.

[0258] In certain embodiments, each of cycles 2-6 of the regimen includes a Q2W therapeutic dose of 0.8 mg / kg on days 1 and 15, and each of cycles 7+ includes a Q4W therapeutic dose of 0.8 mg / kg on day 1.

[0259] In certain embodiments, (i) each of cycles 2-6 of the regimen includes a therapeutic dose of 0.8 mg / kg of Q2W on days 1 and 15, and each of cycles 7+ includes a therapeutic dose of 0.8 mg / kg of Q4W on day 1, or (ii) each of cycles 2-4 of the regimen includes a therapeutic dose of 0.8 mg / kg of Q2W on days 1 and 15, and if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, each of cycles 5+ includes a therapeutic dose of 0.8 mg / kg of Q4W on day 1.

[0260] In a particular embodiment, cycle 1 of the regimen comprises a first escalating dose of 0.01 mg / kg on day 1, a second escalating dose of 0.06 mg / kg on day 3, a third escalating dose of 0.4 mg / kg on day 8, and a therapeutic dose of 0.8 mg / kg on day 15; each of cycles 2-6 of the regimen comprises a Q2W therapeutic dose of 0.8 mg / kg on days 1 and 15; and each of cycles 7+ comprises a Q4W therapeutic dose of 0.8 mg / kg on day 1.

[0261] In a particular embodiment, cycle 1 of the regimen comprises a first escalating dose of 0.01 mg / kg on day 1, a second escalating dose of 0.06 mg / kg on day 3, a third escalating dose of 0.4 mg / kg on day 8, and a therapeutic dose of 0.8 mg / kg on day 15, wherein (i) each of cycles 2-6 of the regimen comprises a therapeutic dose of 0.8 mg / kg of Q2W on days 1 and 15, and each of cycles 7+ comprises a therapeutic dose of 0.8 mg / kg of Q4W on day 1, or (ii) each of cycles 2-4 of the regimen comprises a therapeutic dose of 0.8 mg / kg of Q2W on days 1 and 15, and if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, each of cycles 5+ comprises a therapeutic dose of 0.8 mg / kg of Q4W on day 1.

[0262] Table 11 provides non-limiting examples of exemplary administration regimens of the present invention.

[0263] [Table 8]

[0264] Table 12 provides another non-limiting example of an exemplary administration regimen of the present invention.

[0265] [Table 9] * Patients who achieve VGPR or a better response may switch to 0.8 mg / kg Q4W, initiated on day 1 of cycle 5.

[0266] Another non-limiting example of an exemplary dosing regimen of the present invention is provided below, in which talketamab is administered in a 28-day treatment cycle.

[0267] - In Cycle 1, the following doses of talketamab will be administered subcutaneously. ○ Tarketamab step-up dose 1 (SU1): 0.01 mg / kg, administered on day 1. ○ Tarketamab step-up dose 2 (SU2): 0.06 mg / kg, administered at least 2 days after SU1. ○ Talketamab therapeutic dose (sometimes referred to as dose escalation 3): 0.4 mg / kg, administered at least 2 days after SU2. ○ Tarketamab therapeutic dose: Administered on days 7-15, at least 2 days after the first therapeutic dose (elevation dose 3) of 0.8 mg / kg or 0.4 mg / kg. -In subsequent treatment cycles following Cycle 1, a therapeutic dose of 0.8 mg / kg of talketamab is administered subcutaneously as follows: ○ Cycles 2 to 4 (C2 - C4), talquetamab SC is administered every other week (Q2W), i.e., 14 days (±3 days) after the previous treatment dose. ○ From Cycle 5 (C5), if VGPR or better is confirmed, the schedule can be changed to Q4W dosing (only on Day 1 of each 28 - day cycle), and the change to Q4W is made on Day 1 of Cycle 5 or Cycle 6 (±3 days). ○ If PR or better is confirmed on Day 1 of Cycle 7 (±3 days), the schedule must be changed to Q4W dosing. ○ If it is confirmed on Day 1 of Cycle 7 (±3 days) that PR or better is not achieved, continue Q2W dosing until PR or better is achieved.

[0268] Another non - limiting example of an exemplary dosing regimen of the present invention is provided in Table 13.

[0269]

Table 10

[0270] In certain embodiments, a dosing regimen comprising administration of a GPRC5D×CD3 bispecific antibody on a monthly (Q4W) dosing schedule improves (i) clinical response rates (e.g., ORR and / or PFS) and / or (ii) the rate and / or severity of adverse events in a population of subjects receiving the GPRC5D×CD3 bispecific antibody on a dosing schedule that is weekly (QW) and / or every other week (Q2W) and not a monthly (Q4W) dosing schedule, as compared to a reference population of subjects receiving the GPRC5D×CD3 bispecific antibody on a dosing schedule that is weekly (QW) and / or every other week (Q2W) and not a monthly (Q4W) dosing schedule.

[0271] In certain embodiments, a dosing regimen comprising a monthly (Q4W) dosing schedule achieves a lower rate and / or shorter duration of adverse events than a dosing regimen that comprises a weekly (QW) and / or every other week (Q2W) dosing schedule but does not comprise a monthly (Q4W) dosing schedule.

[0272] In certain embodiments, the adverse event includes one or more of oral toxicity (e.g., ageusia, dysgeusia, xerostomia, and / or dysphagia), and / or nail toxicity (e.g., nail disorder), and / or skin toxicity (e.g., dry skin, skin exfoliation, and / or pruritus).

[0273] In certain embodiments, a dosing regimen that includes a monthly (Q4W) dosing schedule achieves a stronger and / or longer-lasting clinical response than a dosing regimen that includes a weekly (QW) and / or bi-weekly (Q2W) dosing schedule but does not include a monthly (Q4W) dosing schedule.

[0274] Exemplary embodiments The embodiments of the invention listed are provided below. These embodiments are for illustrative purposes only and do not limit the present disclosure or the claims appended hereto. 1. A method of treating multiple myeloma in a subject who needs treatment for multiple myeloma, the method comprising administering to the subject a therapeutically effective amount of a GPRC5D×CD3 bispecific antibody on a monthly (Q4W) dosing schedule. 2. The method according to embodiment 1, wherein the GPRC5D×CD3 bispecific antibody comprises a GPRC5D binding domain comprising HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, HCDR3 of SEQ ID NO: 6, LCDR1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, and LCDR3 of SEQ ID NO: 9, and a CD3 binding domain comprising HCDR1 of SEQ ID NO: 14, HCDR2 of SEQ ID NO: 15, HCDR3 of SEQ ID NO: 16, LCDR1 of SEQ ID NO: 17, LCDR2 of SEQ ID NO: 18, and LCDR3 of SEQ ID NO: 19. 3. The method according to embodiment 1 or 2, wherein the GPRC5D×CD3 bispecific antibody comprises a GPRC5D binding domain comprising a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11, and a CD3 binding domain comprising a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 21. 4. The method according to any one of Embodiments 1 to 3, wherein the GPRC5D×CD3 bispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype. 5. The method according to any one of Embodiments 1 to 4, wherein the GPRC5D×CD3 bispecific antibody is of the IgG4 isotype. 6. The method according to any one of Embodiments 1 to 5, wherein the GPRC5D×CD3 bispecific antibody contains one or more substitutions in its Fc region. 7. The method according to any one of Embodiments 1 to 6, wherein the GPRC5D×CD3 bispecific antibody is of the IgG4 isotype and contains S228P, F234A and L235A substitutions in its Fc region (according to EU numbering). 8. The method according to any one of Embodiments 1 to 7, wherein the GPRC5D×CD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A, L235A F405L and R409K substitutions in its Fc region (according to EU numbering). 9. The method according to any one of Embodiments 1 to 8, wherein the Fc region of the GPRC5D coupling arm includes S228P, F234A and L235A substitutions in the Fc region (according to EU numbering). 10. The method according to any one of Embodiments 1 to 9, wherein the Fc region of the CD3 coupling arm includes S228P, F234A, L235A, F405L, and R409K substitutions in the Fc region (according to EU numbering). 11. The method according to any one of Embodiments 1 to 10, wherein the GPRC5D×CD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 23. 12. The method according to any one of Embodiments 1 to 10, wherein the GPRC5D×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 90% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 90% identity with the amino acid sequence of SEQ ID NO: 23. 13. The method according to any one of Embodiments 1 to 10, wherein the GPRC5D×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 23. 14. The method according to any one of Embodiments 1 to 10, wherein the GPRC5D×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 98% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 98% identity with the amino acid sequence of SEQ ID NO: 23. 15. The method according to any one of Embodiments 1 to 10, wherein the GPRC5D×CD3 bispecific antibody is talketamab. 16. The method according to any one of Embodiments 1 to 15, wherein the subject has relapsed or refractory multiple myeloma. 17. The method according to any one of Embodiments 1 to 16, wherein the subject has previously received at least three lines of treatment. 18. The method according to any one of Embodiments 1 to 16, wherein the subject has previously received at least four lines of treatment. 19. The method according to any one of Embodiments 1 to 16, wherein the subject has previously received at least five lines of treatment (pentad exposure). 20. The method according to any one of Embodiments 1 to 16, wherein the subject has previously received at least three lines of treatment comprising a proteasome inhibitor, an immunomodulator, and an anti-CD38 monoclonal antibody. 21. The method according to any one of Embodiments 1 to 16, wherein the subject has previously received at least four lines of treatment comprising a proteasome inhibitor, an immunomodulator, and an anti-CD38 monoclonal antibody. 22. The method according to any one of Embodiments 1 to 21, comprising subcutaneous administration of a therapeutic dose of GPRC5D×CD3 bispecific antibody on a monthly administration schedule (Q4W). 23. The method according to any one of Embodiments 1 to 22, comprising subcutaneously administering one or more escalating doses of GPRC5D×CD3 bispecific antibody to the target before administering a first therapeutic dose of GPRC5D×CD3 bispecific antibody. 24. The method according to any one of Embodiments 1 to 23, comprising subcutaneous administration of a GPRC5D×CD3 bispecific antibody at a therapeutic dose of approximately 400 μg / kg to approximately 800 μg / kg on a monthly administration schedule (Q4W). 25. The method according to any one of Embodiments 1 to 23, comprising subcutaneous administration of a GPRC5D×CD3 bispecific antibody at a therapeutic dose of approximately 400 μg / kg on a monthly administration schedule (Q4W). 26. The method according to any one of Embodiments 1 to 23, comprising subcutaneous administration of a GPRC5D×CD3 bispecific antibody at a therapeutic dose of approximately 800 μg / kg on a monthly administration schedule (Q4W). 27. The method according to any one of Embodiments 1 to 26, comprising subcutaneously administering at least one therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly administration schedule (Q2W), and subsequently administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W). 28. The method according to any one of Embodiments 1 to 27, comprising: subcutaneously administering at least one therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a weekly administration schedule (QW); then subcutaneously administering at least one therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a bi-weekly administration schedule (Q2W); and then administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W). 29. The method according to any one of Embodiments 1 to 28, comprising: subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject over six treatment cycles on a bi-weekly administration schedule (Q2W); and starting in treatment cycle 7, administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W). 30. The method according to any one of Embodiments 1 to 28, comprising: subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject over six treatment cycles on a bi-weekly administration schedule (Q2W); and, if the patient achieves VGPR, CR, or sCR as determined by the IMWG response criteria, starting in treatment cycle 7, administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W). 31. The method according to any one of Embodiments 1 to 28, comprising: subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject over seven treatment cycles on a bi-weekly administration schedule (Q2W), starting in treatment cycle 8; and administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W). 32. The method according to any one of Embodiments 1 to 28, comprising: subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject over seven treatment cycles on a bi-weekly administration schedule (Q2W); starting treatment cycle 8 if the patient achieves VGPR, CR, or sCR as determined by the IMWG response criteria; and administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W). 33. The method according to any one of Embodiments 1 to 28, comprising: subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject over eight treatment cycles on a bi-weekly administration schedule (Q2W), starting in treatment cycle 9; and administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W). 34. The method according to any one of Embodiments 1 to 28, comprising: subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject over eight treatment cycles on a bi-weekly administration schedule (Q2W); starting treatment cycle 9 if the patient achieves VGPR, CR, or sCR as determined by the IMWG response criteria; and administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W). 35. The method according to any one of Embodiments 1 to 27, comprising subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly administration schedule (Q2W), and then subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W) in treatment cycle 7 or treatment cycle 8. 36. The method according to any one of Embodiments 1 to 27, comprising: subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly administration schedule (Q2W); and then, if the subject achieves a complete response or a strict complete response as determined by the IMWG response criteria, subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W) in treatment cycle 5. 37. The method according to any one of Embodiments 27 to 36, wherein the therapeutic doses of the GPRC5D×CD3 bispecific antibody administered on a weekly (QW), bi-weekly (Q2W), or monthly (Q4W) schedule are the same. 38. The method according to any one of Embodiments 27 to 36, wherein a GPRC5D × CD3 bispecific antibody is administered at a therapeutic dose of 800 μg / kg in a bi-weekly administration schedule (Q2W) and a monthly administration schedule (Q4W). 39. The method according to any one of Embodiments 1 to 38, comprising subcutaneously administering two or three escalating doses of a GPRC5D×CD3 bispecific antibody before subcutaneously administering a first therapeutic dose. 40. The method according to any one of Embodiments 1 to 38, comprising subcutaneously administering GPRC5D×CD3 bispecific antibody in escalating doses of 10 μg / kg and 60 μg / kg before subcutaneously administering a therapeutic dose. 41. The method according to any one of Embodiments 1 to 38, comprising subcutaneously administering GPRC5D×CD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg before subcutaneously administering a therapeutic dose. 42. The method according to any one of Embodiments 1 to 41, comprising subcutaneously administering GPRC5D×CD3 bispecific antibodies in gradually increasing doses, with intervals of 2 to 4 days between administrations. 43. The method according to any one of Embodiments 1 to 42, wherein the subject achieves a clinical response which is PR, VGPR, CR, or sCR. 44. The method according to any one of Embodiments 1 to 42, wherein the subject achieves a clinical response of CR or sCR. 45. The method according to any one of Embodiments 1 to 27, comprising: subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to a subject on a bi-weekly administration schedule (Q2W); and then, if the subject achieves a very good partial response, complete response, or severe complete response as determined by the IMWG response criteria, subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W) starting in treatment cycle 5; or (ii) regardless of the clinical response in the subject, subcutaneously administering a therapeutic dose of GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W) starting in treatment cycle 7. 46. ​​The method according to Embodiment 45, wherein a GPRC5D×CD3 bispecific antibody is administered at a therapeutic dose of 800 μg / kg on a bi-weekly administration schedule (Q2W) and a monthly administration schedule (Q4W). 47. The method according to any one of Embodiments 45 to 46, comprising subcutaneously administering two or three escalating doses of a GPRC5D×CD3 bispecific antibody before subcutaneously administering a first therapeutic dose. 48. The method according to any one of Embodiments 45 to 47, comprising subcutaneously administering GPRC5D×CD3 bispecific antibody in escalating doses of 10 μg / kg and 60 μg / kg before subcutaneously administering a therapeutic dose. 49. The method according to any one of Embodiments 45 to 48, comprising subcutaneously administering GPRC5D×CD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg before subcutaneously administering a therapeutic dose. 50. The method according to any one of Embodiments 45 to 49, comprising subcutaneously administering GPRC5D×CD3 bispecific antibodies in gradually increasing doses, with intervals of 2 to 4 days between administrations. 51. The method according to any one of Embodiments 45 to 50, for achieving a clinical response in which the subject is PR, VGPR, CR, or sCR. 52. The method according to any one of Embodiments 45 to 51, wherein the subject achieves a clinical response of CR or sCR. 53. Treatment of the subject according to a therapeutically effective regimen including a consecutive 28-day GPRC5D×CD3 treatment cycle, One or more escalating doses of GPRC5D×CD3 bispecific antibodies are administered subcutaneously to the subject during the escalation phase. The method according to any one of Embodiments 1 to 52, wherein a therapeutic dose of GPRC5D×CD3 bispecific antibody is subcutaneously administered to the subject on a bi-weekly administration schedule (Q2W) starting from the first GPRC5D×CD3 treatment cycle after the escalation phase, and then a therapeutic dose of GPRC5D×CD3 bispecific antibody is subcutaneously administered to the subject on a monthly administration schedule (Q4W). 54. Treatment of the subject according to a therapeutically effective regimen including a consecutive 28-day GPRC5D×CD3 treatment cycle, One or more escalating doses of GPRC5D×CD3 bispecific antibodies are administered subcutaneously to the subject during the escalation phase. The method according to any one of Embodiments 1 to 53, wherein a therapeutic dose of GPRC5D×CD3 bispecific antibody is administered subcutaneously to the subject on a bi-weekly schedule (Q2W) starting with the first GPRC5D×CD3 treatment cycle after the escalation phase, and then a therapeutic dose of GPRC5D×CD3 bispecific antibody is administered subcutaneously to the subject on a monthly schedule (Q4W), either starting in treatment cycle 5 if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) starting in treatment cycle 7 regardless of the clinical response in the subject. 55. The method according to Embodiment 53 or 54, wherein the therapeutic dose of GPRC5D×CD3 bispecific antibody administered on a bi-weekly schedule (Q2W) and a monthly schedule (Q4W) is 800 μg / kg. 56. The method according to any one of Embodiments 53 to 55, wherein Cycle 1 of the regimen includes an escalation phase, in which a therapeutic dose of GPRC5D×CD3 bispecific antibody is administered subcutaneously to the subject on a bi-weekly schedule (Q2W) starting from Cycle 2, and then a therapeutic dose of GPRC5D×CD3 bispecific antibody is administered subcutaneously to the subject on a monthly schedule (Q4W). 57. The method according to any one of Embodiments 53 to 56, wherein Cycle 1 of the regimen includes an escalation phase, with a therapeutic dose of GPRC5D×CD3 bispecific antibody being administered subcutaneously to the subject on a bi-weekly schedule (Q2W) starting from Cycle 2, and then a therapeutic dose of GPRC5D×CD3 bispecific antibody being administered subcutaneously to the subject on a monthly schedule (Q4W), either starting in Cycle 5 if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) starting in Cycle 7 regardless of the clinical response in the subject. 58. The method according to any one of embodiments 53-57, wherein 1 to 3 escalating doses of the GPRC5D×CD3 bispecific antibody are administered to the subject during the escalation phase. 59. The method according to any one of embodiments 53-58, wherein 2 escalating doses of the GPRC5D×CD3 bispecific antibody are administered to the subject during the escalation phase. 60. The method according to any one of embodiments 53-58, wherein 3 escalating doses of the GPRC5D×CD3 bispecific antibody are administered to the subject during the escalation phase. 61. The method according to any one of embodiments 53-60, wherein the escalation phase comprises a first escalating dose of 0.01 mg / kg, a second escalating dose of 0.06 mg / kg, and a third escalating dose of 0.4 mg / kg. 62. The method according to any one of embodiments 53-61, wherein one or more therapeutic doses of the GPRC5D×CD3 bispecific antibody are administered subcutaneously to the subject during the escalation phase in addition to one or more escalating doses (e.g., on a weekly dosing schedule). 63. The method according to any one of embodiments 53-61, wherein one or two therapeutic doses of the GPRC5D×CD3 bispecific antibody are administered subcutaneously to the subject during the escalation phase in addition to one or more escalating doses (e.g., on a weekly dosing schedule). 64. The method according to any one of embodiments 53-63, wherein cycle 1 of the regimen comprises a first escalating dose of 0.01 mg / kg, a second escalating dose of 0.06 mg / kg, a third escalating dose of 0.4 mg / kg, and a therapeutic dose of 0.8 mg / kg. 65. The method according to any one of embodiments 53-64, wherein cycle 1 of the regimen comprises a first escalating dose of 0.01 mg / kg, a second escalating dose of 0.06 mg / kg 2 to 4 days after the first escalating dose, a third escalating dose of 0.4 mg / kg 4 to 7 days (or 5 to 7 days) after the second escalating dose, and a therapeutic dose of 0.8 mg / kg 5 to 9 days (or 7 to 9 days) after the third escalating dose. 66. The method according to any one of Embodiments 53 to 65, wherein cycle 1 of the regimen comprises a first escalating dose of 0.01 mg / kg on day 1, a second escalating dose of 0.06 mg / kg on day 3, a third escalating dose of 0.4 mg / kg on day 8, and a therapeutic dose of 0.8 mg / kg on day 15. 67. The method according to any one of embodiments 53 to 66, wherein each of cycles 2 to 6 of the regimen contains a therapeutic dose of 0.8 mg / kg of Q2W on days 1 and 15, and each of cycles 7+ contains a therapeutic dose of 0.8 mg / kg of Q4W on day 1. 68. The method according to any one of Embodiments 53 to 66, wherein (i) each of cycles 2 to 6 of the regimen contains a therapeutic dose of 0.8 mg / kg of Q2W on days 1 and 15, and each of cycles 7+ contains a therapeutic dose of 0.8 mg / kg of Q4W on day 1, or (ii) each of cycles 2 to 4 of the regimen contains a therapeutic dose of 0.8 mg / kg of Q2W on days 1 and 15, and if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, each of cycles 5+ contains a therapeutic dose of 0.8 mg / kg of Q4W on day 1. 69. The method according to any one of embodiments 53 to 68, wherein cycle 1 of the regimen comprises a first escalating dose of 0.01 mg / kg on day 1, a second escalating dose of 0.06 mg / kg on day 3, a third escalating dose of 0.4 mg / kg on day 8, and a therapeutic dose of 0.8 mg / kg on day 15, each of cycles 2 to 6 of the regimen comprises a Q2W therapeutic dose of 0.8 mg / kg on days 1 and 15, and each of cycles 7+ comprises a Q4W therapeutic dose of 0.8 mg / kg on day 1. 70. Cycle 1 of the regimen includes a first escalating dose of 0.01 mg / kg on day 1, a second escalating dose of 0.06 mg / kg on day 3, a third escalating dose of 0.4 mg / kg on day 8, and a therapeutic dose of 0.8 mg / kg on day 15. (i) Each of cycles 2-6 of the regimen contains a Q2W therapeutic dose of 0.8 mg / kg on day 1 and day 15, and each of cycles 7+ contains a Q4W therapeutic dose of 0.8 mg / kg on day 1, or (ii) The method according to any one of Embodiments 53 to 68, wherein each of cycles 2 to 4 of the regimen contains a therapeutic dose of 0.8 mg / kg of Q2W on day 1 and day 15, and each of cycles 5+ contains a therapeutic dose of 0.8 mg / kg of Q4W on day 1 if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria. 71. Treatment of the subject according to a therapeutically effective regimen including a consecutive 28-day GPRC5D×CD3 treatment cycle, One or more escalating doses of a GPRC5D×CD3 bispecific antibody (e.g., talketamab) are administered subcutaneously to the subject during the escalation phase. Therapeutic doses of GPRC5D×CD3 bispecific antibody are administered subcutaneously to subjects on a bi-weekly schedule (Q2W), starting with the first GPRC5D×CD3 treatment cycle after the escalation phase. Subsequently, therapeutic doses of GPRC5D×CD3 bispecific antibody are administered subcutaneously to subjects on a monthly schedule (Q4W), either (i) starting in treatment cycle 5 or 6 if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) starting in treatment cycle 7 or later if the subject achieves a partial response, very good partial response, complete response, or exact complete response as determined by the IMWG response criteria. The method according to any one of Embodiments 1 to 53, wherein the therapeutic dose of the GPRC5D×CD3 bispecific antibody administered on a bi-weekly schedule (Q2W) and a monthly schedule (Q4W) is 0.8 mg / kg. 72. The method according to Embodiment 71, wherein the dose escalation step comprises administering two or three doses of GPRC5D×CD3 bispecific antibody, preferably spaced 2 to 4 days apart from each other. 73. The method according to Embodiment 71, wherein the dose escalation step comprises administering two or three escalating doses of GPRC5D×CD3 bispecific antibody and one therapeutic dose of 0.8 mg / kg. 74. The method according to Embodiment 71, wherein the dose escalation step includes administering three dose escalating doses of GPRC5D×CD3 bispecific antibody (e.g., 0.01 mg / kg, 0.06 mg / kg, and 0.4 mg / kg) and one therapeutic dose of 0.8 mg / kg. 75. The method according to any one of embodiments 71 to 74, wherein cycle 1 of the regimen includes an escalation phase and a bi-weekly dosing schedule (Q2W) begins in cycle 2. 76. Treatment of the subject according to a therapeutically effective regimen including consecutive 28-day GPRC5D×CD3 treatment cycles, wherein one or more escalating doses of a GPRC5D×CD3 bispecific antibody (e.g., talketamab) are subcutaneously administered to the subject during the escalation phase, and then a therapeutic dose of the GPRC5D×CD3 bispecific antibody is subcutaneously administered to the subject on a monthly dosing schedule (Q4W) starting from the treatment cycle immediately following the escalation phase (regardless of whether or not there is a clinical response in the subject). The method according to any one of Embodiments 1 to 53, wherein the therapeutic dose of the GPRC5D×CD3 bispecific antibody administered on a bi-weekly schedule (Q2W) and a monthly schedule (Q4W) is 0.8 mg / kg. 77. The method according to Embodiment 76, wherein the dose escalation step comprises administering two or three doses of GPRC5D×CD3 bispecific antibody, preferably spaced 2 to 4 days apart from each other. 78. The method according to Embodiment 76, wherein the dose escalation step comprises administering two or three doses of GPRC5D×CD3 bispecific antibody and one therapeutic dose of 0.8 mg / kg. 79. The method according to Embodiment 76, wherein the dose escalation step includes administering three dose escalating doses of GPRC5D×CD3 bispecific antibody (e.g., 0.01 mg / kg, 0.06 mg / kg, and 0.4 mg / kg) and one therapeutic dose of 0.8 mg / kg. 80. The method according to any one of embodiments 76 to 79, wherein cycle 1 of the regimen includes an escalation phase, and a monthly dosing schedule (Q4W) begins in cycle 2. 81. The method according to any one of Embodiments 1 to 80, wherein a GPRC5D × CD3 bispecific antibody (e.g., talketamab) is administered as monotherapy. 82. The method according to any one of Embodiments 1 to 80, wherein a GPRC5D × CD3 bispecific antibody (e.g., talketamab) is administered as part of a combination therapy with one or more additional antimyeloma agents. 83. The method according to any one of Embodiments 1 to 82, wherein a dosing regimen including a monthly (Q4W) dosing schedule achieves a lower rate and / or shorter duration of adverse events than a dosing regimen including a weekly (QW) and / or bi-weekly (Q2W) dosing schedule but not a monthly (Q4W) dosing schedule. 84. The method according to Embodiment 83, wherein the adverse event includes one or more of the following: oral toxicity (e.g., anosmia, dysgeusia, xerostomia, and / or dysphagia), and / or nail toxicity (e.g., nail disorders), and / or skin toxicity (e.g., dry skin, exfoliation, and / or itching). 85. The method according to any one of Embodiments 1 to 84, wherein a dosing regimen including a monthly (Q4W) dosing schedule achieves a stronger and / or longer-lasting clinical response than a dosing regimen including a weekly (QW) and / or bi-weekly (Q2W) dosing schedule but not a monthly (Q4W) dosing schedule. 86. The method according to any one of Embodiments 1 to 85, wherein a dosing regimen including a monthly (Q4W) dosing schedule achieves a higher overall response rate (ORR) than a dosing regimen including a weekly (QW) and / or bi-weekly (Q2W) dosing schedule but not a monthly (Q4W) dosing schedule. 87. The method according to any one of Embodiments 1 to 86, wherein a dosing regimen including a monthly (Q4W) dosing schedule achieves a longer progression-free survival (PFS) than a dosing regimen including a weekly (QW) and / or bi-weekly (Q2W) dosing schedule but not a monthly (Q4W) dosing schedule.

[0275] Those skilled in the art will understand that numerous changes and modifications can be made to preferred embodiments of the present invention, and that such changes and modifications can be made without departing from the spirit of the invention. Accordingly, the appended claims are intended to cover all such equivalent variations that fall within the true spirit and scope of the invention.

[0276] Any patent, patent application, and publication disclosure cited or referenced herein is incorporated herein by reference in its entirety. [Examples]

[0277] To further illustrate some of the embodiments disclosed herein, the following examples are provided. These examples are illustrative and not intended to limit the embodiments of the present disclosure.

[0278] Example 1: Efficacy and safety of lower frequency / lower intensity talketamab dosing in patients with relapsed / refractory multiple myeloma: Results from the Phase 1 / 2 MonumenTAL-1 study antibody The anti-GPRC5D / anti-CD3 antibody talketamab (also known as Tal) was manufactured by Janssen Pharmaceuticals. Talketamab contains a GPRC5D-binding arm and a CD3-binding arm, the amino acid sequences of which are shown in Tables 5 and 6, respectively.

[0279] [Table 11]

[0280] [Table 12]

[0281] background Talketamab (tal) is a commercially available T-cell redirecting bispecific antibody that targets G protein-coupled receptor family C group 5 member D (GPRC5D) and CD3. The results of the Phase 1 / 2 MonumenTAL-1 (NCT03399799 / NCT04634552) trial showed an overall response rate (ORR) of over 71% and a manageable safety profile at the recommended Phase 2 dose (RP2D) of subcutaneous tal (0.4 mg / kg weekly [QW] or 0.8 mg / kg every other week [Q2W]) in patients with relapsed / refractory multiple myeloma (RRMM). The impact of dose-intensity reduction using a bispecific antibody on safety and efficacy is a clinically interesting area. This example reports the safety and efficacy in patients from MonumenTAL-1 who were switched to reduced-frequency or reduced-dose tal.

[0282] method In Phase 1, patients were either intolerant to established therapies or had progressed during those therapies and had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. In Phase 2, patients had previously received three or more lines of treatment including one or more proteasome inhibitors, one or more immunomodulators, and one or more anti-CD38 monoclonal antibodies and had an ECOG PS of 0–2. Phase 1 included two prospectively designed cohorts: (A) a reduced dosing cohort in which patients treated with tal 0.8 mg / kg Q2W were permitted to switch to 0.4 mg / kg Q2W in the next cycle after a confirmed partial response or better (PR or better); and (B) a reduced frequency dosing cohort in which patients treated with tal 0.8 mg / kg Q2W were permitted to switch to 0.8 mg / kg monthly (Q4W) in the next cycle after a confirmed PR or better. The results of these Phase 1 prospective cohorts were pooled. Confirmatory analyses were also performed based on Phase 1 / 2 patients who received RP2D and were switched to reduced doses based on meeting response criteria or mitigating treatment-emergent adverse events (TEAEs). Dose reduction can be achieved by reducing the frequency of administration or by reducing the dose. ORR was evaluated according to IMWG criteria. TEAEs were graded according to CTCAE v4.03.

[0283] result In total, 45 patients were switched to reduced-intensity medication. As of June 20, 2023, 24 patients were included in the prospective cohort with a median follow-up period of 9.7 months. In total, 9 out of 12 patients achieved a partial response (PR) or better and were switched from 0.8 mg / kg Q2W to 0.4 mg / kg Q2W, and 10 out of 12 patients achieved a PR or better and were switched from Q2W to 0.8 mg / kg Q4W. Generally, patients were switched to reduced-intensity medication between cycles 3 and 5. After the change in dosage, the response deepened in 11 out of 19 patients and was maintained in 5 out of 19 patients. 3 out of 19 patients had disease progression. Six months after the switch, an estimated 88.9% of respondents maintained their response. Oral-related TEAEs, reported in 16 / 19 (84.2%) of patients, improved or resolved in 4 patients 1–6 months after switching to a reduced dose. Nail-related TEAEs were reported in 7 / 19 (36.8%) of patients and improved or resolved in 2 patients 3–4 months later. Skin-related TEAEs were reported in 8 / 19 (42.1%) of patients and resolved in 3 patients 1–3 months later. Overall, improvement or resolution of oral, nail, and skin-related TEAEs was observed over time in some patients in the promising dose-reduced and reduced-frequency dosing cohorts. No patients discontinued tal due to these TEAEs. As of January 17, 2023, the Phase 1 / 2 confirmatory analysis included 20 patients switched from tal 0.4 mg / kg QW to a reduced dose (TEAE reduction, n=16; response, n=3; both, n=1), and 6 patients switched from tal 0.8 mg / kg Q2W to a reduced dose (TEAE reduction, n=4; response, n=2). In patients switched from tal 0.4 mg / kg to a reduced dose, an estimated 84.2% and 78.9% of respondents maintained their response at 9 and 12 months, respectively. In patients switched from tal 0.8 mg / kg Q2W to a reduced dose, an estimated 100% and 80.0% of respondents maintained their response at 9 and 12 months, respectively.

[0284] Updated results: As of September 17, 2023, 17 participants in the core RP2D population of talketamab in MonumenTAL-1 reduced their talketamab dosing frequency from 0.8 mg / kg Q2W to 0.8 mg / kg Q4W due to their response to and / or management of adverse events (AEs). For participants who reduced their dosing frequency to Q4W, the median progression-free survival (PFS) was 17.8 months, compared to the median PFS of 14.2 months for all participants in MonumenTAL-1 (0.8 mg / kg Q2W). Prior to switching to Q4W dosing, all 17 participants (100%) experienced one or more study drug-related TEAEs, while study drug-related TEAEs occurred in 12 participants (70.6%) after the switch. Grade 3 or 4 events occurred in 16 participants (94.1%) before switching to Q4W dosing and in 6 participants (35.3%) after the switch. To further address the reduced frequency of talketamab administration, a Phase 1 dose reduction cohort was established in MonumenTAL-1, where participants were treated with talketamab 0.8 mg / kg SC Q2W until a confirmed partial response (PR) or better response was achieved, and then the frequency of talketamab administration was reduced to Q4W. As of October 11, 2023, this cohort showed the median time to first response at 1.2 months and the median time to best response at 2.2 months for participants treated with talketamab 0.8 mg / kg SC Q2W. Of the 12 participants enrolled in this cohort, 10 achieved a PR or better response and subsequently changed the administration frequency to 0.8 mg / kg SC Q4W, with 2 participants achieving the best response in PD. The change in administration frequency for the 10 participants with a PR or better response was performed on day 1 of cycles 3–5. Eight out of ten participants maintained or deepened their response after switching to Q4W administration.The proposed Q4W dosing schedule for talketamab would maintain efficacy by balancing the maximal reduction of disease burden through bi-weekly dosing during the first six treatment cycles, which offers participant convenience, with reduced exposure through Q4W dosing from cycle 7 onward (or as early as cycle 5 for participants who achieve a confirmed partial response or better), for participants who achieve a significant partial response or better.

[0285] Conclusion: In MonumenTAL-1, the majority of patients who switched to a reduced dose deepened or maintained their response to Tal. GPRC5D-related TEAEs generally improved over time in the prospectively designed cohort. Overall, reduced frequency or reduced doses of Tal may help mitigate these TEAEs while maintaining the response.

Claims

1. A method for treating multiple myeloma in a subject requiring treatment for the disease, comprising administering a therapeutically effective dose of a GPRC5D x CD3 bispecific antibody to the subject on a monthly (Q4W) administration schedule.

2. The method according to claim 1, wherein the GPRC5D × CD3 bispecific antibody comprises a GPRC5D binding domain including HCDR1 of SEQ ID NO: 4, HCDR2 of SEQ ID NO: 5, HCDR3 of SEQ ID NO: 6, LCDR1 of SEQ ID NO: 7, LCDR2 of SEQ ID NO: 8, and LCDR3 of SEQ ID NO: 9, and a CD3 binding domain including HCDR1 of SEQ ID NO: 14, HCDR2 of SEQ ID NO: 15, HCDR3 of SEQ ID NO: 16, LCDR1 of SEQ ID NO: 17, LCDR2 of SEQ ID NO: 18, and LCDR3 of SEQ ID NO:

19.

3. The method according to claim 1 or 2, wherein the GPRC5D × CD3 bispecific antibody comprises a GPRC5D binding domain having a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11, and a CD3 binding domain having a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO:

21.

4. The method according to any one of claims 1 to 3, wherein the GPRC5D × CD3 bispecific antibody is an IgG1, IgG2, IgG3, or IgG4 isotype.

5. The method according to any one of claims 1 to 4, wherein the GPRC5D × CD3 bispecific antibody is an IgG4 isotype.

6. The method according to any one of claims 1 to 5, wherein the GPRC5D×CD3 bispecific antibody comprises one or more substitutions in its Fc region.

7. The method according to any one of claims 1 to 6, wherein the GPRC5D×CD3 bispecific antibody is of the IgG4 isotype and comprises S228P, F234A and L235A substitutions in its Fc region (according to EU numbering).

8. The method according to any one of claims 1 to 7, wherein the GPRC5D×CD3 bispecific antibody is of the IgG4 isotype and comprises S228P, F234A, L235A F405L and R409K substitutions in its Fc region (according to EU numbering).

9. The method according to any one of claims 1 to 8, wherein the Fc region of the GPRC5D coupling arm includes S228P, F234A and L235A substitutions in the Fc region (according to EU numbering).

10. The method according to any one of claims 1 to 9, wherein the Fc region of the CD3 coupling arm includes substitutions of S228P, F234A, L235A, F405L, and R409K in the Fc region (according to EU numbering).

11. The method according to any one of claims 1 to 10, wherein the GPRC5D×CD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having the amino acid sequence of SEQ ID NO:

23.

12. The method according to any one of claims 1 to 10, wherein the GPRC5D×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 90% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 90% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 90% identity with the amino acid sequence of SEQ ID NO:

23.

13. The method according to any one of claims 1 to 10, wherein the GPRC5D×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 95% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 95% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 95% identity with the amino acid sequence of SEQ ID NO:

23.

14. The method according to any one of claims 1 to 10, wherein the GPRC5D×CD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 98% identity with the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 98% identity with the amino acid sequence of SEQ ID NO: 22, and a second light chain (LC2) having at least 98% identity with the amino acid sequence of SEQ ID NO:

23.

15. The method according to any one of claims 1 to 10, wherein the GPRC5D × CD3 bispecific antibody is talketamab.

16. The method according to any one of claims 1 to 15, wherein the subject has relapsed or refractory multiple myeloma.

17. The method according to any one of claims 1 to 16, wherein the subject has previously received at least three treatment lines.

18. The method according to any one of claims 1 to 16, wherein the subject has previously received at least four treatment lines.

19. The method according to any one of claims 1 to 16, wherein the subject has previously received at least five treatment lines (five-drug exposure).

20. The method according to any one of claims 1 to 16, wherein the subject has previously received at least three lines of treatment comprising a proteasome inhibitor, an immunomodulator, and an anti-CD38 monoclonal antibody.

21. The method according to any one of claims 1 to 16, wherein the subject has previously received at least four lines of treatment comprising a proteasome inhibitor, an immunomodulator, and an anti-CD38 monoclonal antibody.

22. The method according to any one of claims 1 to 21, comprising subcutaneously administering a therapeutic dose of the GPRC5D x CD3 bispecific antibody according to the monthly administration schedule (Q4W).

23. The method according to any one of claims 1 to 22, comprising subcutaneously administering one or more incremental doses of the GPRC5D×CD3 bispecific antibody to the subject before administering a first therapeutic dose of the GPRC5D×CD3 bispecific antibody.

24. The method according to any one of claims 1 to 23, comprising subcutaneously administering the GPRC5D×CD3 bispecific antibody at a therapeutic dose of approximately 400 μg / kg to approximately 800 μg / kg according to the monthly administration schedule (Q4W).

25. The method according to any one of claims 1 to 23, comprising subcutaneously administering the GPRC5D x CD3 bispecific antibody at a therapeutic dose of approximately 400 μg / kg according to the monthly administration schedule (Q4W).

26. The method according to any one of claims 1 to 23, comprising subcutaneously administering the GPRC5D×CD3 bispecific antibody at a therapeutic dose of approximately 800 μg / kg according to the monthly administration schedule (Q4W).

27. The method according to any one of claims 1 to 26, comprising subcutaneously administering at least one therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject on a bi-weekly administration schedule (Q2W), and subsequently administering a therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W).

28. The method according to any one of claims 1 to 27, comprising: subcutaneously administering at least one therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject on a weekly administration schedule (QW); subcutaneously administering at least one therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject on a bi-weekly administration schedule (Q2W); and subsequently administering a therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W).

29. The method according to any one of claims 1 to 28, comprising: subcutaneously administering a therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject over six treatment cycles on a bi-weekly administration schedule (Q2W); and administering a therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W), starting in treatment cycle 7.

30. The method according to any one of claims 1 to 28, comprising: subcutaneously administering a therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject over six treatment cycles on a bi-weekly administration schedule (Q2W); and, if the patient achieves VGPR, CR, or sCR as determined by the IMWG response criteria, administering a therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject starting in treatment cycle 7 on a monthly administration schedule (Q4W).

31. The method according to any one of claims 1 to 28, comprising: subcutaneously administering a therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject over seven treatment cycles on a bi-weekly administration schedule (Q2W); and starting in treatment cycle 8, administering a therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W).

32. The method according to any one of claims 1 to 28, comprising: subcutaneously administering a therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject over seven treatment cycles on a bi-weekly administration schedule (Q2W); and, if the patient achieves VGPR, CR, or sCR as determined by the IMWG response criteria, administering a therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject starting in treatment cycle 8 on a monthly administration schedule (Q4W).

33. The method according to any one of claims 1 to 28, comprising: subcutaneously administering a therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject over eight treatment cycles on a bi-weekly administration schedule (Q2W); and administering a therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W), starting in treatment cycle 9.

34. The method according to any one of claims 1 to 28, comprising: subcutaneously administering a therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject over eight treatment cycles on a bi-weekly administration schedule (Q2W); and, if the patient achieves VGPR, CR, or sCR as determined by the IMWG response criteria, administering a therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject starting in treatment cycle 9 on a monthly administration schedule (Q4W).

35. The method according to any one of claims 1 to 27, comprising: subcutaneously administering a therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject on a bi-weekly administration schedule (Q2W); and then subcutaneously administering a therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W) in treatment cycle 7 or treatment cycle 8.

36. The method according to any one of claims 1 to 27, comprising: subcutaneously administering a therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject on a bi-weekly administration schedule (Q2W); and then, if the subject achieves a complete response or a strict complete response as determined by the IMWG response criteria, subcutaneously administering a therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W) in treatment cycle 5.

37. The method according to any one of claims 27 to 36, wherein the amount of each therapeutic dose of the GPRC5D×CD3 bispecific antibody administered according to a weekly administration schedule (QW), a bi-weekly administration schedule (Q2W), or the monthly administration schedule (Q4W) is the same.

38. The method according to any one of claims 27 to 36, wherein the GPRC5D × CD3 bispecific antibody is administered in a therapeutic dose of 800 μg / kg according to the bi-weekly administration schedule (Q2W) and the monthly administration schedule (Q4W).

39. The method according to any one of claims 1 to 38, comprising subcutaneously administering two or three escalating doses of the GPRC5D×CD3 bispecific antibody before subcutaneously administering a first therapeutic dose.

40. The method according to any one of claims 1 to 38, comprising subcutaneously administering the GPRC5D×CD3 bispecific antibody in gradually increasing doses of 10 μg / kg and 60 μg / kg before subcutaneously administering a therapeutic dose.

41. The method according to any one of claims 1 to 38, comprising subcutaneously administering the GPRC5D×CD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg before subcutaneously administering a therapeutic dose.

42. The method according to any one of claims 1 to 41, comprising subcutaneously administering the GPRC5D×CD3 bispecific antibodies in gradually increasing doses, with a gap of 2 to 4 days between doses.

43. The method according to any one of claims 1 to 42, wherein the subject achieves a clinical response in which PR, VGPR, CR, or sCR.

44. The method according to any one of claims 1 to 42, wherein the subject achieves a clinical response in which CR or sCR.

45. The method according to any one of claims 1 to 27, comprising: subcutaneously administering a therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject on a bi-weekly administration schedule (Q2W); and then, if the subject achieves a very good partial response, complete response, or severe complete response as determined by the IMWG response criteria, subcutaneously administering a therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W) starting in treatment cycle 5; or (ii) regardless of the clinical response in the subject, subcutaneously administering a therapeutic dose of the GPRC5D×CD3 bispecific antibody to the subject on a monthly administration schedule (Q4W) starting in treatment cycle 7.

46. The method according to claim 45, wherein the GPRC5D × CD3 bispecific antibody is administered in a therapeutic dose of 800 μg / kg according to the bi-weekly administration schedule (Q2W) and the monthly administration schedule (Q4W).

47. The method according to any one of claims 45 to 46, comprising subcutaneously administering two or three escalating doses of the GPRC5D×CD3 bispecific antibody before subcutaneously administering a first therapeutic dose.

48. The method according to any one of claims 45 to 47, comprising subcutaneously administering the GPRC5D×CD3 bispecific antibody in gradually increasing doses of 10 μg / kg and 60 μg / kg before subcutaneously administering a therapeutic dose.

49. The method according to any one of claims 45 to 48, comprising subcutaneously administering the GPRC5D×CD3 bispecific antibody in gradually increasing doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg before subcutaneously administering a therapeutic dose.

50. The method according to any one of claims 45 to 49, comprising subcutaneously administering the GPRC5D × CD3 bispecific antibody in gradually increasing doses, with intervals of 2 to 4 days between each dose.

51. The method according to any one of claims 45 to 50, wherein the subject achieves a clinical response in which PR, VGPR, CR, or sCR.

52. The method according to any one of claims 45 to 51, wherein the subject achieves a clinical response in which CR or sCR.

53. This includes treating the subject according to a therapeutically effective regimen that includes a continuous 28-day GPRC5D x CD3 treatment cycle, One or more escalating doses of the GPRC5D×CD3 bispecific antibody are subcutaneously administered to the subject during the escalation phase. The method according to any one of claims 1 to 52, wherein a therapeutic dose of the GPRC5D x CD3 bispecific antibody is subcutaneously administered to the subject on a bi-weekly administration schedule (Q2W) starting from the first GPRC5D x CD3 treatment cycle after the escalation stage, and then a therapeutic dose of the GPRC5D x CD3 bispecific antibody is subcutaneously administered to the subject on a monthly administration schedule (Q4W).

54. This includes treating the subject according to a therapeutically effective regimen that includes a continuous 28-day GPRC5D x CD3 treatment cycle, One or more escalating doses of the GPRC5D×CD3 bispecific antibody are subcutaneously administered to the subject during the escalation phase. The method according to any one of claims 1 to 53, wherein a therapeutic dose of the GPRC5D x CD3 bispecific antibody is subcutaneously administered to the subject on a bi-weekly administration schedule (Q2W) starting from the first GPRC5D x CD3 treatment cycle after the escalation stage, and then a therapeutic dose of the GPRC5D x CD3 bispecific antibody is subcutaneously administered to the subject on a monthly administration schedule (Q4W), which either starts in treatment cycle 5 if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) starts in treatment cycle 7 regardless of the clinical response in the subject.

55. The method according to claim 53 or 54, wherein each therapeutic dose of the GPRC5D×CD3 bispecific antibody administered according to the bi-weekly administration schedule (Q2W) and the monthly administration schedule (Q4W) is 800 μg / kg.

56. The method according to any one of claims 53 to 55, wherein cycle 1 of the regimen includes the escalation step, the therapeutic dose of the GPRC5D x CD3 bispecific antibody is administered subcutaneously to the subject in the bi-weekly administration schedule (Q2W) starting from cycle 2, and then the therapeutic dose of the GPRC5D x CD3 bispecific antibody is administered subcutaneously to the subject in the monthly administration schedule (Q4W).

57. The method according to any one of claims 53 to 56, wherein cycle 1 of the regimen includes the escalation step, and the therapeutic dose of the GPRC5D×CD3 bispecific antibody is administered subcutaneously to the subject in the bi-weekly administration schedule (Q2W) starting from cycle 2, and then the therapeutic dose of the GPRC5D×CD3 bispecific antibody is administered subcutaneously to the subject in the monthly administration schedule (Q4W), which either starts in treatment cycle 5 if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria, or (ii) starts in treatment cycle 7 regardless of the clinical response in the subject.

58. The method according to any one of claims 53 to 57, wherein one to three gradually increasing doses of the GPRC5D × CD3 bispecific antibody are administered to the subject during the escalation stage.

59. The method according to any one of claims 53 to 58, wherein two escalating doses of the GPRC5D × CD3 bispecific antibody are administered to the subject during the escalation stage.

60. The method according to any one of claims 53 to 58, wherein three escalating doses of the GPRC5D × CD3 bispecific antibody are administered to the subject during the escalation stage.

61. The method according to any one of claims 53 to 60, wherein the escalation step includes a first escalating dose of 0.01 mg / kg, a second escalating dose of 0.06 mg / kg, and a third escalating dose of 0.4 mg / kg.

62. The method according to any one of claims 53 to 61, wherein one or more therapeutic doses of the GPRC5D×CD3 bispecific antibody are administered subcutaneously to the subject during the escalation stage, in addition to the one or more escalating doses (for example, on a weekly administration schedule).

63. The method according to any one of claims 53 to 61, wherein one or two therapeutic doses of the GPRC5D×CD3 bispecific antibody are administered subcutaneously to the subject during the escalation stage, in addition to the one or more escalating doses (for example, on a weekly administration schedule).

64. The method according to any one of claims 53 to 63, wherein cycle 1 of the regimen comprises a first escalating dose of 0.01 mg / kg, a second escalating dose of 0.06 mg / kg, a third escalating dose of 0.4 mg / kg, and a therapeutic dose of 0.8 mg / kg.

65. The method according to any one of claims 53 to 64, wherein cycle 1 of the regimen comprises a first escalating dose of 0.01 mg / kg, a second escalating dose of 0.06 mg / kg for 2 to 4 days after the first escalating dose, a third escalating dose of 0.4 mg / kg for 4 to 7 days (or 5 to 7 days) after the second escalating dose, and a therapeutic dose of 0.8 mg / kg for 5 to 9 days (or 7 to 9 days) after the third escalating dose.

66. The method according to any one of claims 53 to 65, wherein cycle 1 of the regimen comprises a first escalating dose of 0.01 mg / kg on day 1, a second escalating dose of 0.06 mg / kg on day 3, a third escalating dose of 0.4 mg / kg on day 8, and a therapeutic dose of 0.8 mg / kg on day 15.

67. The method according to any one of claims 53 to 66, wherein each of cycles 2 to 6 of the regimen comprises a Q2W therapeutic dose of 0.8 mg / kg on day 1 and day 15, and each of cycles 7+ comprises a Q4W therapeutic dose of 0.8 mg / kg on day 1.

68. (i) Each of cycles 2 to 6 of the regimen includes a therapeutic dose of 0.8 mg / kg of Q2W on day 1 and day 15, and each of cycles 7+ includes a therapeutic dose of 0.8 mg / kg of Q4W on day 1, or (ii) Each of cycles 2 to 4 of the regimen includes a therapeutic dose of 0.8 mg / kg of Q2W on day 1 and day 15, and each of cycles 5+ includes a therapeutic dose of 0.8 mg / kg of Q4W on day 1 if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria.

69. The method according to any one of claims 53 to 68, wherein cycle 1 of the regimen comprises a first escalating dose of 0.01 mg / kg on day 1, a second escalating dose of 0.06 mg / kg on day 3, a third escalating dose of 0.4 mg / kg on day 8, and a therapeutic dose of 0.8 mg / kg on day 15, each of cycles 2 to 6 of the regimen comprises a therapeutic dose of Q2W of 0.8 mg / kg on day 1 and day 15, and each of cycles 7+ comprises a therapeutic dose of Q4W of 0.8 mg / kg on day 1.

70. Cycle 1 of the regimen includes a first escalating dose of 0.01 mg / kg on day 1, a second escalating dose of 0.06 mg / kg on day 3, a third escalating dose of 0.4 mg / kg on day 8, and a therapeutic dose of 0.8 mg / kg on day 15. (i) Each of cycles 2 to 6 of the regimen contains a therapeutic dose of Q2W of 0.8 mg / kg on day 1 and day 15, and each of cycles 7+ contains a therapeutic dose of Q4W of 0.8 mg / kg on day 1, or (ii) The method according to any one of claims 53 to 68, wherein each of cycles 2 to 4 of the regimen comprises a therapeutic dose of Q2W of 0.8 mg / kg on day 1 and day 15, and each of cycles 5+ comprises a therapeutic dose of Q4W of 0.8 mg / kg on day 1 if the subject achieves a very good partial response, complete response, or exact complete response as determined by the IMWG response criteria.

71. The method according to any one of claims 1 to 70, wherein the dosing regimen including the monthly (Q4W) dosing schedule achieves a lower rate and / or shorter duration of adverse events than a dosing regimen including weekly (QW) and / or bi-weekly (Q2W) dosing schedules but not including the monthly (Q4W) dosing schedule.

72. The method according to claim 71, wherein the adverse event includes one or more of the following: oral toxicity (e.g., anosmia, dysgeusia, xerostomia, and / or dysphagia), and / or nail toxicity (e.g., nail disorders), and / or skin toxicity (e.g., dry skin, exfoliation, and / or itching).

73. The method according to any one of claims 1 to 72, wherein the administration regimen including the monthly (Q4W) administration schedule achieves a stronger and / or longer-lasting clinical response than an administration regimen including weekly (QW) and / or bi-weekly (Q2W) administration schedules but not including the monthly (Q4W) administration schedule.

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