Methods for treating multiple myeloma

Abstract

Embodiments of the invention relate to methods of treating multiple myeloma in a subject in need thereof, comprising administering a therapeutically effective amount of a GPRC5DxCD3 bispecific antibody according to a monthly administration schedule.

Description

[0001] Cross-references to related applications This application claims priority to U.S. Provisional Application No. 63 / 505,640, filed June 1, 2023; U.S. Provisional Application No. 63 / 588,520, filed October 6, 2023; and U.S. Provisional Application No. 63 / 594,771, filed October 31, 2023, the entire contents of which are incorporated herein by reference.

[0002] Reference sequence list submitted electronically This application contains a sequence list electronically filed in XML format, the entire contents of which are incorporated herein by reference. The XML copy was created on May 8, 2024, named "258199061602(JBI6818WOPCT1)SequenceListing.xml", and has a size of 25,444 bytes. Technical Field

[0003] A method for treating multiple myeloma has been disclosed. Background Technology

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

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

[0006] Despite these therapeutic achievements, the disease relapses and is associated with additional risk factors (e.g., comorbidities or increasing age), thus ensuring the need for novel treatments, such as new dosages and regimens. Especially in older populations, stem cell transplantation is often not a viable option, and in patients with refractory disease who have tried several therapies, multiple myeloma remains an incurable malignancy and an unmet medical need, with significant morbidity and mortality. Specifically, there remains a need for treatment regimens that can achieve rapid, deep, and durable clinical remission while providing manageable safety profiles. Summary of the Invention

[0007] Embodiments of the present invention provide a method for treating multiple myeloma in a subject in need, the method comprising administering a therapeutically effective amount of GPRC5DxCD3 bispecific antibody to the subject according to a monthly (Q4W) dosing schedule.

[0008] In some embodiments, the GPRC5DxCD3 bispecific antibody comprises: a GPRC5D binding domain of HCDR1 (SEQ ID NO: 4), HCDR2 (SEQ ID NO: 5), HCDR3 (SEQ ID NO: 6), LCDR1 (SEQ ID NO: 7), LCDR2 (SEQ ID NO: 8), and LCDR3 (SEQ ID NO: 9), and a CD3 binding domain of HCDR1 (SEQ ID NO: 14), HCDR2 (SEQ ID NO: 15), HCDR3 (SEQ ID NO: 16), LCDR1 (SEQ ID NO: 17), LCDR2 (SEQ ID NO: 18), and LCDR3 (SEQ ID NO: 19).

[0009] In some embodiments, the GPRC5D binding domain comprises 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 comprises 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 some implementations, the GPRC5DxCD3 bispecific antibody is an IgG1, IgG2, IgG3, or IgG4 isotype.

[0011] In some implementations, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype.

[0012] In some implementations, the GPRC5DxCD3 bispecific antibody contains one or more substitutions in its Fc region.

[0013] In some embodiments, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and contains proline / alanine / alanine substitutions at amino acid positions 228 / 234 / 235 in its Fc region (according to EU index number).

[0014] In some implementations, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and contains F405L and R409K substitutions (according to EU index number) in its Fc region.

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

[0016] In some implementations, the Fc region of the CD3 binding arm contains S228P, F234A, L235A, F405L, and R409K replacements (according to EU index numbers) in its Fc region.

[0017] In some embodiments, the GPRC5DxCD3 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 some embodiments, the GPRC5DxCD3 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 some embodiments, the GPRC5DxCD3 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 some embodiments, the GPRC5DxCD3 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.

[0021] In some implementations, the GPRC5DxCD3 bispecific antibody is talquetamab.

[0022] In some implementations, the subjects have relapsed or refractory multiple myeloma.

[0023] In some implementations, the subject has received at least three lines of prior treatment.

[0024] In some implementations, the subject has received at least four lines of prior treatment.

[0025] In some implementation schemes, the subject has received at least five lines of prior treatment (five drug exposures).

[0026] In some implementations, the subject has received at least three lines of prior treatment, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0027] In some implementations, the subject has received at least four lines of prior treatment, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0028] In some implementations, the method includes subcutaneous administration of a therapeutic dose of the GPRC5DxCD3 bispecific antibody according to a monthly dosing schedule (Q4W).

[0029] In some implementations, a GPRC5DxCD3 bispecific antibody (e.g., taquituzumab) is administered as a monotherapy.

[0030] In some implementations, a GPRC5DxCD3 bispecific antibody (e.g., taquituzumab) is administered as part of a combination therapy with one or more other antimyeloma agents.

[0031] In some embodiments, the method includes subcutaneously administering one or more escalating doses of the GPRC5DxCD3 bispecific antibody to the subject prior to administering a first therapeutic dose of the GPRC5DxCD3 bispecific antibody.

[0032] In some implementations, the method includes subcutaneous administration of the GPRC5DxCD3 bispecific antibody at a therapeutic dose of about 400 μg / kg to about 800 μg / kg according to a monthly dosing schedule (Q4W).

[0033] In some implementations, the method includes subcutaneous administration of the GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 400 μg / kg according to a monthly dosing schedule (Q4W).

[0034] In some implementations, the method includes subcutaneous administration of the GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 800 μg / kg according to a monthly dosing schedule (Q4W).

[0035] In some implementations, the method includes subcutaneously administering at least one therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W) and subsequently administering the therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0036] In some embodiments, the method includes administering at least one therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a weekly dosing schedule (QW), followed by administering at least one therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a bi-weekly dosing schedule (Q2W), followed by administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0037] In some implementations, the method includes administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a two-week dosing schedule (Q2W) for six treatment cycles, and, starting in the seventh treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0038] In some implementations, the method includes administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a two-week dosing schedule (Q2W) for six treatment cycles, and if the patient has achieved VGPR, CR, or sCR as determined by the IMWG remission criteria, then, starting in the seventh treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0039] In some implementations, the method includes administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a two-week dosing schedule (Q2W) for seven treatment cycles, and, starting in the eighth treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0040] In some implementations, the method includes administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a bi-weekly dosing schedule (Q2W) for seven treatment cycles, and if the patient has achieved VGPR, CR, or sCR as determined by the IMWG remission criteria, then, starting in the eighth treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0041] In some implementations, the method includes administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a two-week dosing schedule (Q2W) for eight treatment cycles, and, starting in the ninth treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0042] In some implementations, the method includes administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a bi-weekly dosing schedule (Q2W) for eight treatment cycles, and if the patient has achieved VGPR, CR, or sCR as determined by the IMWG remission criteria, then, starting in the ninth treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0043] In some embodiments, the method includes subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a two-week dosing schedule (Q2W), and subsequently administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a monthly dosing schedule (Q4W) during the 7th or 8th treatment cycle.

[0044] In some implementations, the method includes subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W), and subsequently, if the subject has achieved complete or strict complete remission as determined by the IMWG remission criteria, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a monthly dosing schedule (Q4W) during the fifth treatment cycle.

[0045] In some implementations, the method includes subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W), and subsequently (i) if the subject has achieved a very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, at the start of the fifth treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a monthly dosing schedule (Q4W); or (ii) regardless of the subject's clinical remission, at the start of the seventh treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a monthly dosing schedule (Q4W).

[0046] In some implementations, the amount of each therapeutic dose of the GPRC5DxCD3 bispecific antibody administered according to a weekly dosing schedule (QW), a bi-weekly dosing schedule (Q2W), or a monthly dosing schedule (Q4W) is the same.

[0047] In some implementations, the GPRC5DxCD3 bispecific antibody is administered at a therapeutic dose of 800 μg / kg according to a bi-weekly dosing schedule (Q2W) and a monthly dosing schedule (Q4W).

[0048] In some implementations, the method includes subcutaneously administering two or three escalating doses of the GPRC5DxCD3 bispecific antibody prior to the first therapeutic dose.

[0049] In some embodiments, the method includes subcutaneously administering escalating doses of GPRC5DxCD3 bispecific antibody at 10 μg / kg and 60 μg / kg prior to the administration of a therapeutic dose.

[0050] In some embodiments, the method includes subcutaneously administering escalating doses of GPRC5DxCD3 bispecific antibody at 10 μg / kg, 60 μg / kg, and 400 μg / kg prior to the administration of a therapeutic dose.

[0051] In some implementations, the method includes subcutaneous administration of escalating doses of the GPRC5DxCD3 bispecific antibody at intervals of 2 to 4 days.

[0052] In some implementations, the subject achieves a clinical response of PR, VGPR, CR, or sCR.

[0053] In some implementations, the subject achieves clinical remission as CR or sCR.

[0054] In some implementations, the method includes subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W), and subsequently (i) if the subject has achieved a very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, at the start of the fifth treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a monthly dosing schedule (Q4W); or (ii) regardless of the subject's clinical remission, at the start of the seventh treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a monthly dosing schedule (Q4W).

[0055] In some implementations, the method includes subcutaneously administering two or three escalating doses of the GPRC5DxCD3 bispecific antibody prior to the first therapeutic dose.

[0056] In some embodiments, the method includes subcutaneously administering escalating doses of GPRC5DxCD3 bispecific antibody at 10 μg / kg and 60 μg / kg prior to the administration of a therapeutic dose.

[0057] In some embodiments, the method includes subcutaneously administering escalating doses of GPRC5DxCD3 bispecific antibody at 10 μg / kg, 60 μg / kg, and 400 μg / kg prior to the administration of a therapeutic dose.

[0058] In some implementations, the method includes subcutaneous administration of escalating doses of the GPRC5DxCD3 bispecific antibody at intervals of 2 to 4 days.

[0059] In some embodiments, the method includes treating a subject according to a treatment-effective regimen comprising consecutive 28-day GPRC5DxCD3 treatment cycles, wherein: during the escalation phase, one or more escalating doses of the GPRC5DxCD3 bispecific antibody are administered subcutaneously to the subject, and after the escalation phase, starting from the first GPRC5DxCD3 treatment cycle, a therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject on a bi-weekly dosing schedule (Q2W), and subsequently on a monthly dosing schedule (Q4W).

[0060] In some embodiments, the method includes treating a subject according to a treatment-effective regimen comprising consecutive 28-day GPRC5DxCD3 treatment cycles, wherein: during the escalation phase, one or more escalating doses of the GPRC5DxCD3 bispecific antibody are administered subcutaneously to the subject, and after the escalation phase, starting from the first GPRC5DxCD3 treatment cycle, a therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject on a bi-weekly dosing schedule (Q2W), and subsequently on a monthly dosing schedule (Q4W): (i) if the subject has achieved a very good partial remission, complete remission, or strictly complete remission as determined by the IMWG remission criteria, then starting at the 5th treatment cycle; or (ii) regardless of the subject's clinical remission, starting at the 7th treatment cycle.

[0061] In some implementations, each treatment dose of the GPRC5DxCD3 bispecific antibody, administered according to a bi-weekly dosing schedule (Q2W) and a monthly dosing schedule (Q4W), is 800 μg / kg.

[0062] In some implementations, the first cycle of the regimen includes an escalation period, and starting from the second cycle, a therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject on a two-week dosing schedule (Q2W), and subsequently on a monthly dosing schedule (Q4W).

[0063] In some implementations, the first cycle of the regimen includes an escalation period, and starting from the second cycle, a therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject on a two-week dosing schedule (Q2W), and subsequently on a monthly dosing schedule (Q4W): (i) if the subject has achieved a very good partial response, complete response, or strict complete response as determined by the IMWG response criteria, then the fifth treatment cycle is initiated; or (ii) regardless of the subject's clinical response, the seventh treatment cycle is initiated.

[0064] In some implementations, subjects are administered one to three incremental doses of the GPRC5DxCD3 bispecific antibody during the escalation period.

[0065] In some implementations, two incremental doses of the GPRC5DxCD3 bispecific antibody are administered to the subject during the escalation period.

[0066] In some implementations, subjects are administered three incremental doses of the GPRC5DxCD3 bispecific antibody during the escalation period.

[0067] In some implementations, the escalation period includes a first escalation dose of 0.01 mg / kg, a second escalation dose of 0.06 mg / kg, and a third escalation dose of 0.4 mg / kg.

[0068] In some implementations, in addition to one or more escalation doses, one or more therapeutic doses of the GPRC5DxCD3 bispecific antibody are administered subcutaneously to the subject during the escalation period (e.g., according to a weekly dosing schedule).

[0069] In some implementations, in addition to one or more escalation doses, one or two therapeutic doses of the GPRC5DxCD3 bispecific antibody are administered subcutaneously to the subject during the escalation period (e.g., according to a weekly dosing schedule).

[0070] In some implementations, the first cycle of the regimen includes a first escalation dose of 0.01 mg / kg, a second escalation dose of 0.06 mg / kg, a third escalation dose of 0.4 mg / kg, and a treatment dose of 0.8 mg / kg.

[0071] In some implementations, the first cycle of the regimen includes a first escalation dose of 0.01 mg / kg, a second escalation dose of 0.06 mg / kg for 2 to 4 days after the first escalation dose, a third escalation dose of 0.4 mg / kg for 4 to 7 days after the second escalation dose, and a treatment dose of 0.8 mg / kg for 5 to 9 days after the third escalation dose.

[0072] In some implementations, the first cycle of the regimen includes a first escalation dose of 0.01 mg / kg on day 1, a second escalation dose of 0.06 mg / kg on day 3, a third escalation dose of 0.4 mg / kg on day 8, and a treatment dose of 0.8 mg / kg on day 15.

[0073] In some implementations, each of cycles 2 through 6 of the regimen comprises a Q2W treatment dose of 0.8 mg / kg on days 1 and 15, and each of cycles 7+ comprises a Q4W treatment dose of 0.8 mg / kg on day 1.

[0074] In some implementations, (i) each of cycles 2 through 6 of the regimen comprises a Q2W treatment dose of 0.8 mg / kg on days 1 and 15, and each of cycles 7+ comprises a Q4W treatment dose of 0.8 mg / kg on day 1, or (ii) each of cycles 2 through 4 of the regimen comprises a Q2W treatment dose of 0.8 mg / kg on days 1 and 15, and each of cycles 5+ comprises a Q4W treatment dose of 0.8 mg / kg on day 1 if the subject has achieved a very good partial response, complete response, or strict complete response as determined by the IMWG response criteria.

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

[0076] In some implementations, cycle 1 of the regimen comprises a first escalation dose of 0.01 mg / kg on day 1, a second escalation dose of 0.06 mg / kg on day 3, a third escalation dose of 0.4 mg / kg on day 8, and a treatment dose of 0.8 mg / kg on day 15; and any of the following: (i) each of cycles 2 through 6 of the regimen comprises a Q2W treatment dose of 0.8 mg / kg on days 1 and 15, and each of cycles 7+ comprises a Q4W treatment dose of 0.8 mg / kg on day 1, or (ii) each of cycles 2 through 4 of the regimen comprises a Q2W treatment dose of 0.8 mg / kg on days 1 and 15, and each of cycles 5+ comprises a Q4W treatment dose of 0.8 mg / kg on day 1 if the subject has achieved a very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria.

[0077] In some implementations, dosing regimens including administration of GPRC5DxCD3 bispecific antibodies on a weekly (QW) and / or bi-weekly (Q2W) dosing schedule instead of a monthly (Q4W) dosing schedule improve (i) clinical response rate (e.g., ORR) and / or (ii) the rate and / or severity of adverse events in a reference subject population compared to a reference subject population receiving the GPRC5DxCD3 bispecific antibody on a monthly (Q4W) dosing schedule.

[0078] In some implementations, dosing regimens that include a monthly (Q4W) dosing schedule achieve a lower rate of adverse events and / or a shorter duration of adverse events than dosing regimens that include a weekly (QW) and / or bi-weekly (Q2W) dosing schedule instead of a monthly (Q4W) dosing schedule.

[0079] In some implementations, adverse events include one or more of the following: oral toxicity (e.g., loss of taste, taste disturbance, dry mouth and / or difficulty swallowing) and / or nail toxicity (e.g., nail disease) and / or skin toxicity (e.g., dry skin, skin peeling and / or itching).

[0080] In some implementations, dosing regimens including a monthly (Q4W) dosing schedule achieve stronger clinical responses and / or longer durations of clinical response than dosing regimens including a weekly (QW) and / or bi-weekly (Q2W) dosing schedule instead of a monthly (Q4W) dosing schedule. In some implementations, dosing regimens including a monthly (Q4W) dosing schedule achieve a higher overall response rate (ORR) than dosing regimens including a weekly (QW) and / or bi-weekly (Q2W) dosing schedule instead of a monthly (Q4W) dosing schedule. In some implementations, dosing regimens including a monthly (Q4W) dosing schedule achieve longer progression-free survival (PFS) than dosing regimens including a weekly (QW) and / or bi-weekly (Q2W) dosing schedule instead of a monthly (Q4W) dosing schedule.

[0081] However, all the methods described in this article, however expressed, can be described as having the corresponding uses, especially medical uses. Detailed Implementation

[0082] The disclosed methods can be more readily understood by referring to the following detailed description. It should be understood that the methods disclosed herein are not limited to the specific methods described and / or shown herein, and the terminology used herein is for illustrative purposes only and is not intended to limit the methods protected by the claims. All patents, published patent applications, and publications cited herein are incorporated herein by reference as if fully set forth herein.

[0083] As used in this article, the singular forms “a,” “a,” and “the” include the plural forms.

[0084] Various terms relating to various aspects of the specification are used throughout the specification and claims. Unless otherwise specified, such terms are given their ordinary meaning in the art. Other specifically defined terms should be understood in accordance with the definitions provided herein.

[0085] When used in relation to numerical ranges, cutoff values, or specific values, “about” means within an acceptable range of error for a specific value as determined by one of ordinary skill in the art, which will depend in part on how the value was measured or determined, i.e., the limitations of the measurement system. In the context of a particular measurement, result, or embodiment, unless otherwise expressly stated in the embodiments or elsewhere in the specification, “about” means within one standard deviation or up to 5% (whichever is greater) according to convention in the art.

[0086] "Antibody" broadly refers to and includes immunoglobulin molecules, specifically including monoclonal antibodies (including murine monoclonal antibodies, human monoclonal antibodies, humanized monoclonal antibodies, and chimeric monoclonal antibodies), antigen-binding fragments, multispecific antibodies (such as bispecific antibodies, trispecific antibodies, tetraspecific antibodies, etc.), dimer, tetramer, or multimer antibodies, single-chain antibodies, domain antibodies, and any other modified conformation of immunoglobulin molecules containing an antigen-binding site with desired specificity. A "full-length antibody" comprises two heavy chains (HC) and two light chains (LC) linked by disulfide bonds, as well as their polymers (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), and framework regions (FRs) interspersed therebetween. Each VH and VL consists of three CDR and four FR segments, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Immunoglobulins can be designated into five major classes based on the amino acid sequence of their heavy chain constant domain: IgA, IgD, IgE, IgG, and IgM. IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. Based on the amino acid sequence of their constant domain, antibody light chains of any vertebrate species can be designated into two completely different types, κ and λ.

[0087] An "antigen-binding fragment" or "antigen-binding domain" refers to the portion of an immunoglobulin molecule that binds to an antigen. Antigen-binding fragments can be synthetic, enzymatically obtained, or genetically engineered polypeptides, and contain: VH, VL, VH and VL, Fab, F(ab')2, Fd, and Fv fragments; domain antibodies (dAbs) consisting of a VH domain or a VL domain; shark variable IgNAR domains; humped VH domains; or the smallest recognition unit consisting of amino acid residues of the CDRs of a mimic 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 be linked together via synthetic linkers to form various types of single-chain antibody designs. Where the VH and VL domains are expressed by separate single-chain antibody constructs, the VH / VL domains can be paired intramolecularly or intermolecularly to form monovalent antigen binding sites, such as single-chain Fv (scFv) or bivalent antibodies; as described, for example, in International Patent Publications Nos. WO1998 / 44001, WO1988 / 01649, WO1994 / 13804 and WO1992 / 01047.

[0088] "Bispecificity" refers to antibodies that specifically bind to two different antigens or two different epitopes within the same antigen. Bispecific antibodies may exhibit cross-reactivity with other related antigens, for example, to antigens from other species (homologous) (such as humans or monkeys, such as cynomolgus monkeys). Macaca cynomolgus (cynomolgus, cyno) or chimpanzee ( Pan troglodytes The same antigens have cross-reactivity, or can bind to epitopes shared by two or more different antigens.

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

[0090] "CD3" refers to a human antigen expressed on T cells as part of a multimolecular T-cell receptor (TCR) complex and composed of a homodimer or heterodimer formed by the association of two or four receptor chains: CD3ε, CD3δ, CD3ζ, and CD3γ. Human CD3ε contains the amino acid sequence of SEQ ID NO: 2. SEQ ID NO: 3 shows the extracellular domain of CD3ε.

[0091] SEQ ID NO: 2 MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGS KPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI SEQ ID NO: 3 DGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMD The "CH3 region" or "CH3 domain" refers to the CH3 region of an immunoglobulin. The CH3 region of the human IgG1 antibody corresponds to amino acid residues 341-446. However, the CH3 region can also be any of the other antibody isotypes described herein.

[0092] "Combined with" means administering two or more therapeutic agents together as a mixture to the subject, administering them simultaneously as a single agent to the subject, or administering them sequentially as single agents in any order to the subject.

[0093] As used herein, a “combination dosing regimen” (also referred to as a “combination regimen” or “combination therapy”) means a treatment regimen that is effective and involves administering two or more anti-multiple myeloma therapeutic agents to a subject for the treatment of multiple myeloma. Two or more therapeutic agents are administered to the subject over a period of time according to the appropriate dosing schedule for each therapeutic agent (e.g., a period of time may include one or more treatment cycles, such as one or more 28-day treatment cycles); for example, a combination dosing regimen may include administering to the subject (i) “Therapy Agent #1” with its weekly, bi-weekly, or monthly dosing schedule starting from day 1 of the treatment cycle; and (ii) “Therapy Agent #2” with its weekly, bi-weekly, or monthly dosing schedule starting from day 1 of the same or subsequent treatment cycle.

[0094] The complementarity-determining region (CDR) is the antibody region that binds to the antigen. The CDR can be defined using various descriptive methods, such as Kabat (Wu et al.). J Exp Med132: 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). It describes the correspondence between various depictions and variable area numbering (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). Available programs (such as abYsis for UCL Business PLC) can be used to depict CDRs. Unless otherwise expressly stated in the specification, as used herein, the terms “CDR,” “HCDR1,” “HCDR2,” “HCDR3,” “LCDR1,” “LCDR2,” and “LCDR3” include CDRs defined by any of the foregoing methods (Kabat, Chothia, IMGT, or AbM). Preferably, as used herein, the terms “CDR,” “HCDR1,” “HCDR2,” “HCDR3,” “LCDR1,” “LCDR2,” and “LCDR3” include CDRs defined by the Kabat method.

[0095] The term “comprising” is intended to include examples covered by the terms “substantially consisting of” and “consisting of”; similarly, the term “substantially consisting of” is intended to include examples covered by the term “consisting of”. Unless the context expressly requires otherwise, throughout the specification and claims, the words “comprising,” “including,” etc., shall be understood in an inclusive sense, rather than an exclusive or exhaustive sense; that is, in the sense of “including but not limited to.”

[0096] "Fcγ receptor" (FcγR) refers to the well-known FcγRI, FcγRIIa, FcγRIIb, or FcγRIII. Activation of FcγR includes FcγRI, FcγRIIa, and FcγRIII.

[0097] "GPRC5DxCD3 bispecific antibody" refers to a bispecific antibody that specifically binds to GPRC5D and CD3.

[0098] "Human antibody" refers to an antibody optimized to produce a minimal immune response when administered to human subjects. 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. If the variable region of a human antibody is obtained using a system that uses human germline immunoglobulins or rearranged immunoglobulin genes, the human antibody contains both heavy-chain and light-chain variable regions "derived" from human-origin sequences. Exemplary systems of this kind include human immunoglobulin gene libraries displayed on bacteriophages and transgenic nonhuman animals, such as mice or rats carrying human immunoglobulin loci. Due to differences between the systems used to obtain human antibodies and human immunoglobulin loci, the introduction of somatic mutations, or the intentional substitution of elements introduced into the frame or CDR, or both, "human antibodies" typically contain amino acid differences compared to immunoglobulins expressed in humans. Typically, the amino acid sequence of a “human antibody” has at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence encoded by a human immunoglobulin gene or rearranged immunoglobulin gene. In some cases, a “human antibody” may contain a common frame sequence derived from human frame sequence analysis (e.g., as described in Knappik et al., (2000) J Mol Biol 296:57-86) or a synthetic HCDR3 bound to a human immunoglobulin gene library displayed on a phage (e.g., as described in Shi et al., (2010) J Mol Biol 397:385-96 and International Patent Publication No. WO2009 / 085462). The definition of a “human antibody” does not include antibodies in which at least one CDR is derived from a non-human species.

[0099] "Humanized antibody" refers to an antibody in which at least one CDR is derived from a non-human species and at least one frame is derived from a human immunoglobulin sequence. Humanized antibodies may contain substitutions in the frame such that these frames may not be exact copies of the expressed human immunoglobulin or the germline gene sequence of human immunoglobulin.

[0100] "Identity" refers to the relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules, as determined by sequence alignment and comparison. The "percentage of sequence identity (%)" relative to a reference polypeptide sequence is defined as the percentage of amino acid residues in the candidate sequence that are identical to those in the reference polypeptide sequence, after sequence alignment and the introduction of gaps (if necessary) to achieve the maximum percentage of sequence identity, without considering any conserved substitutions as part of the sequence identity. Alignments performed for the purpose of determining the percentage of amino acid sequence identity can be performed in a variety of ways within the scope of the art, such as using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN (DNAStar, Inc.) software. Those skilled in the art can determine suitable parameters for sequence alignment, including any algorithms required to achieve maximum alignment across the full length of the compared sequences.

[0101] "Separated" refers to a homogeneous group of molecules (such as synthetic polynucleotides or proteins, such as antibodies) that have been substantially separated from and / or purified from other components in a system in which the molecules are produced (such as recombinant cells), as well as proteins that have undergone at least one purification or separation step. "Separated antibodies" refers to antibodies that are substantially free of other cellular material and / or chemicals, and covers antibodies separated to higher purities, such as 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% purity.

[0102] Monoclonal antibodies are antibodies derived from a substantially homogeneous population of antibody molecules, meaning that the individual antibodies within that population are identical, differing only in possible well-known modifications, such as removal of a C-terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation, or asparagine or glutamine deamidation. Monoclonal antibodies typically bind to one antigenic epitope. Bispecific monoclonal antibodies bind to two different antigenic epitopes. Monoclonal antibodies can exhibit heterogeneous glycosylation within an antibody population. Monoclonal antibodies can be monospecific or multispecific, such as bispecific, monovalent, divalent, or multivalent.

[0103] A "mutation" refers to an engineered or naturally occurring change in a polypeptide or polynucleotide sequence compared to a reference sequence. This change can be a substitution, insertion, or deletion of one or more amino acids or polynucleotides.

[0104] "Negative minimal residual disease status" or "negative MRD status" or "MRD negative" refers to the PerMillionCount (a point estimate of malignant myeloma cells per million nucleated cells) of a bone marrow sample in a patient study relative to its reference bone marrow sample (i.e., a bone marrow sample not treated with taquituzumab). Based on this PerMillionCount, each sample is determined to be positive or negative. If the PerMillionCount is greater than or equal to the sensitivity limit, the sample is positive; otherwise, they are negative. It can be 0.01% (10 -4 ), 0.001% (10 -5 ) or 0.0001% (10 -6 The sensitivity of next-generation sequencing (NGS) was used to determine negative minimal residual disease status.

[0105] "Pharmaceutical composition" refers to a composition containing an active ingredient and a pharmaceutically acceptable carrier.

[0106] "Pharmaceutically acceptable carrier" or "excipient" refers to a component in a pharmaceutical composition other than the active ingredient that is non-toxic to the subject.

[0107] "Recombinant" refers to DNA, antibodies, and other proteins that are prepared, expressed, formed, or isolated through recombination when fragments from different sources are joined to produce recombinant DNA, antibodies, or proteins.

[0108] "Refractory" refers to cancers that are not suitable for surgical intervention and do not initially respond to treatment.

[0109] "Recurrent" refers to cancer that responds to treatment but subsequently relapses.

[0110] "Elevation dose" refers to the dose of the active agent administered to the subject prior to the therapeutic dose. The escalation dose is lower than the therapeutic dose. To prevent or mitigate certain toxicities, such as cytokine release syndrome (CRS), an "initiating" dosing strategy may include one or more lower escalation doses followed by a higher therapeutic dose. An "escalation period" refers to the initial phase of a treatment regimen in which at least one escalation dose of the therapeutic agent is administered to the subject. An escalation period may also include one or more therapeutic doses, i.e., an escalation period may include one or more escalation doses followed by one or more therapeutic doses; for example, an escalation period may include two escalation doses followed by two therapeutic doses. In a specific implementation, the escalation period is 28 days, i.e., the escalation period is a 28-day cycle of a treatment regimen.

[0111] "Subject" includes any human or non-human animal. "Non-human animal" includes all vertebrates, such as mammals and non-mammals, including non-human primates, sheep, dogs, cats, horses, cattle, chickens, amphibians, reptiles, etc. Unless otherwise stated, the terms "patient" or "subject" are used interchangeably.

[0112] "T-cell redirection therapy" refers to a molecule containing two or more binding regions, wherein one of these binding regions specifically binds to a cell surface antigen on a target cell or tissue, and wherein a second binding region of the molecule specifically binds to a T-cell antigen. Examples of cell surface antigens include tumor-associated antigens such as GPRC5D. Examples of T-cell antigens include, for example, CD3. This dual-target / multi-target binding capability recruits T cells to the target cells or tissue, thereby eradicating the target cells or tissue.

[0113] "Therapeutic effective dose" refers to the amount that effectively achieves the desired therapeutic outcome at the required dose and time period. Therapeutic effective dose can vary depending on factors such as an individual's disease state, age, sex, and weight, as well as the ability of the therapeutic agent or combination of therapeutic agents to elicit the desired response in the individual. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, improved patient health.

[0114] "Treatment" refers to both therapeutic treatment and preventative or defensive measures, the goal of which is to prevent or mitigate (reduce) undesirable physiological changes or disorders. Beneficial or desired clinical outcomes include symptom relief, reduction of disease severity, stable (i.e., no worsening) state of disease, delay or slowing of disease progression, improvement or mitigation of disease status, and remission (whether partial or complete), whether detectable or undetectable. "Treatment" can also mean extended survival compared to the expected survival of a subject without treatment. Individuals requiring treatment include those already suffering from a condition or disorder, those susceptible to a condition or disorder, or those seeking to prevent a condition or disorder.

[0115] "Therapeutic dose" refers to the dose of an active agent administered to a subject to treat a disease. Therapeutic doses may be administered on a repeated basis at regular dosing intervals (e.g., weekly, bi-weekly, monthly). One or more escalating doses may precede the therapeutic dose.

[0116] "Three categories of exposure" refers to patients diagnosed with multiple myeloma (MM) who have previously been treated with (at least) a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

[0117] "Tumor cells" or "cancer cells" refer to cancerous, precancerous, or transformed cells in vivo, in vitro, or in tissue cultures that exhibit spontaneous or induced phenotypic changes. These changes do not necessarily involve the uptake of new genetic material. Although transformation can be triggered by infection with transforming viruses and the incorporation of new genomic nucleic acids, the uptake of exogenous nucleic acids or their exogenous forms can also be initiated spontaneously or after exposure to carcinogens, leading to mutations in endogenous genes. Examples of transformation / cancer include morphological changes in vitro, in vivo, and in vitro in suitable animal hosts (such as nude mice), cell immortalization, abnormal growth control, lesion formation, proliferation, malignancy, regulation of tumor-specific marker levels, invasion, and tumor growth.

[0118] Unless otherwise explicitly stated, throughout the specification, the amino acid residues in the antibody constant region are numbered according to the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD. (1991). Antibody constant chain numbers can be found, for example, on the ImMunoGeneTics website, IMGT Web Resources, and IMGT Scientific Charts.

[0119] This article uses the standard single-letter and three-letter amino acid codes as shown in Table 1.

[0120] Table 1. amino acids Three-letter code Single-letter codes alanine Ala A Arginine Arg R Asparagine Asn N Aspartic acid Asp D Cysteine Cys C glutamic acid Gln E glutamine Glu Q glycine Gly G Histidine His H Isoleucine Ile I Leucine Leu L Lysine Lys K Methionine Met M Phenylalanine Phe F proline Pro P Serine Ser S threonine Thr T Tryptophan Trp W Tyrosine Tyr Y Valine Val V GPRC5DxCD3 Bispecific Antibody and Its Uses It is well known in the art that drug development is an unpredictable field. This lack of predictability is evidenced by the requirements of health authorities (such as the Food and Drug Administration) to establish safe and effective dosing regimens for each individual drug candidate in clinical trials. In the past decade (2011–2020), only 7.9% of all drug candidates in development received FDA approval from Phase I clinical trials. See Clinical Development Success Rates and Influencing Factors 2011–2020. Success rates are even lower in oncology, resulting in only 5.3% success rate for oncology drug candidates.

[0121] In oncology, even for drugs with established dosages for specific indications, the Food and Drug Administration (FDA) recommends further clinical studies to determine the optimal dosage for new indications; otherwise, patients may be exposed to unreasonable and significant risks, as well as other potential drawbacks. (See example...) Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases; Draft Guidance for Industry; January 2023).

[0122] Multiple myeloma remains an incurable malignancy with significant morbidity and mortality in patients with relapsed or refractory disease who have undergone several therapies, representing an unmet medical need. The inventors have developed a novel dosing regimen for the GPRC5DxCD3 bispecific antibody that provides an improved safety profile compared to currently approved regimens while maintaining deep and durable efficacy.

[0123] The inventors have discovered that adverse events (AEs) associated with the GPRC5D target, such as oral toxicities (e.g., loss of taste, taste disturbance, dry mouth and / or dysphagia), nail toxicities (e.g., nail diseases), and skin toxicities (e.g., dry skin, skin peeling, and / or pruritus), can be mitigated by certain dosing schedules that include less frequent administration of taquiltuzumab, while still achieving effective remission. It has also been found that, according to the dosing schedules described herein, adequate exposure to taquiltuzumab and the shortest time to achieve optimal remission can be achieved after approximately four 28-day treatment cycles, allowing patients to experience reduced AEs while still having deep and durable remission and minimal time to clinical response.

[0124] Monthly (Q4W) dosing of taquiltuzumab was selected based on pharmacokinetic (PK), pharmacodynamic, safety, and efficacy findings from a subset of the pivotal RP2D population in the MonumtanTAL-1 clinical study (e.g., as described in the Examples section of this document), the Phase 1b TriMM-2 clinical study (combination therapy in the relapsed / refractory population), and early data from MonumtanTAL-2 (combination therapy in the relapsed / refractory population). In these studies, TEAEs were tolerable and manageable; CRS was generally low-grade, and neurotoxic events were rare. Additionally, data from MonumtanTAL-1 (e.g., as described in the Examples section of this document) demonstrated that participants who switched to less frequent dosing after achieving remission with taquiltuzumab monotherapy had improved progression-free survival (PFS) compared to the overall pivotal population, experienced fewer study drug-related TEAEs and grade 3 or 4 TEAEs after switching, and experienced improved resolution of target-related toxicities (e.g., oral, skin, and rash AEs). Overall, data from participants who received MonumanTAL-1 in Q4W demonstrated maintenance of remission after switching, with a trend toward improved resolution of GPRC5D-related oral, skin (rash and non-rash) and nail toxicities.

[0125] PK simulations showed that the maximum EC50 was determined in the trough level of taquitumab and in the in vitro cytotoxicity assay after the first administration of 0.8 mg / kg SC. 90 The values ​​were equivalent to or higher. This assay evaluated the ability of taquituzumab to induce killing using monocytes co-cultured with T cells from healthy donors using bone marrow samples from multiple myeloma patients. The steady-state trough concentration was also correlated with the maximum EC50. 90 Equivalent to or higher. It is believed that the implementation of the Q4W dosing schedule disclosed herein will maintain the efficacy of taquitumab by balancing the maximum reduction in disease burden with participant convenience through dosing every two weeks during the first 6 cycles of treatment with reduced exposure to Q4W dosing starting from cycle 7 for participants with a confirmed PR or better response (or as early as cycle 5 for participants with a confirmed VGPR or better response).

[0126] The antibody of the present invention According to this disclosure, any suitable GPRC5DxCD3 bispecific antibody known to those skilled in the art can be used in this invention.

[0127] Various forms of bispecific antibodies include the forms described herein and recombinant IgG-like bitargeting molecules, wherein each flanking element contains Fab fragments or portions of Fab fragments of at least two different antibodies; IgG fusion molecules, wherein a full-length IgG antibody is fused with an additional Fab fragment or a portion of a Fab fragment; Fc fusion molecules, wherein a single-chain Fv molecule or a stable bivalent antibody is fused with a heavy chain constant domain, Fc region, or a portion thereof; Fab fusion molecules, wherein different Fab fragments are fused together; and heavy chain antibodies based on ScFv and bivalent antibodies (e.g., domain antibodies, nanobodies), wherein different single-chain Fv molecules or different bivalent antibodies or different heavy chain antibodies (e.g., domain antibodies, nanobodies) are fused with each other or with another protein or carrier molecule or a bispecific antibody generated via arm exchange. Exemplary bispecific forms include dual-targeting molecules, including dual-targeting (DT)-Ig (GSK / Domantis), a combination antibody (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 fusion (AcademicInstitution), and SCORPION (Emergent). BioSolutions / Trubion, Zymogenetics / BMS) and dual-parental heavy-chain domain-only antibodies (Fc-DART) (MacroGenics), F(ab)2 (Medarex / AMGEN), bifunctional or Bis-Fab (Genentech), docking lock (DNL) (ImmunoMedics), bivalent bispecific antibodies (Biotecnol) and Fab-Fv (UCB-Celltech), bispecific T-cell connector (BITE) (Micromet), tandem bivalent antibody (Tandab) (Affimed), dual-parental heavy-chain domain-only antibodies (DART) (MacroGenics), single-chain bivalent antibodies (Academic), TCR-like antibodies (AIT, ReceptorLogics), human serum albumin ScFv fusion (Merrimack) and COMBODY (Epigen Biotech), dual-targeting nanobodies (Ablynx), and dual-targeting heavy-chain domain-only antibodies.Various forms of bispecific antibodies have been described, for example, in Chames and Baty (2009) Curr Opin Drug Disc Dev 12: 276 and Nunz-Prado et al. (2015) Drug Discovery Today 20(5):588-594.

[0128] In some embodiments, the GPRC5DxCD3 bispecific antibody comprises any 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 GPRC5DxCD3 bispecific antibody comprises any of the CD3 binding domains described in U.S. Patent No. 10,562,968. In some embodiments, the GPRC5DxCD3 bispecific antibody comprises any of the GPRC5DxCD3 bispecific antibodies described in U.S. Patent No. 10,562,968.

[0129] In some implementations, the GPRC5DxCD3 bispecific antibody is chimeric, humanized, or human.

[0130] In some embodiments, the bispecific antibody is an isotype of IgG1, IgG2, IgG3, or IgG4. In a preferred embodiment, the bispecific antibody is an isotype of IgG4. An exemplary wild-type IgG4 comprises the amino acid sequence of SEQ ID NO: 34.

[0131] SEQ ID NO: 34 : Bispecific antibodies can possess any allotype. It is expected that allotypes will not affect the properties of bispecific antibodies, such as binding or Fc-mediated effector function. The immunogenicity of therapeutic antibodies is associated with an increased risk of infusion reactions and a reduced duration of therapeutic response (Baert et al., (2003)). N Engl J Med 348:602-08). The extent to which therapeutic antibodies induce an immune response in the host can be partially determined by antibody allotypes (Stickler et al., (2011)). Genes and Immunity 12:213-21). Antibody allotypes are associated with amino acid sequence variations at specific positions in the constant region of the antibody. Table 2 shows the selected IgG1, IgG2, and IgG4 allotypes.

[0132] Table 2. In some embodiments, the bispecific antibody comprises 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 phagocytosis (ADCP). Specific substitutions can be compared to wild-type IgG4 of SEQ ID NO: 34.

[0133] The following Fc sites can be substituted to reduce the binding of Fc to activated FcγR and subsequently reduce effector function: 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, and K214T / E233P / L234V / L235A / G236 deletion / A327G / P331 on IgG1. The residues A / 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, wherein the residue numbers conform to the EU index.

[0134] The Fc substitution that can be used to reduce CDC is the K322A substitution.

[0135] The well-known S228P substitution can also be performed in IgG4 antibodies to enhance IgG4 stability.

[0136] 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 CH3 domain and the second CH3 domain.

[0137] In some embodiments, one or more asymmetric substitutions are selected from the group consisting of: F405L / K409R, wild-type / F405L_R409K, T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V, L351Y_F405A_Y407 V / 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.

[0138] In some embodiments, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and contains phenylalanine at position 405 and arginine at position 409 in the first heavy chain (HC1), and leucine at position 405 and lysine at position 409 in the second heavy chain (HC2), wherein the residue numbers are based on the EU index.

[0139] In some implementations, the GPRC5DxCD3 bispecific antibody also contains proline at position 228, alanine at position 234, and alanine at position 235 of both HC1 and HC2.

[0140] Tables 3 and 4 provide sequences of exemplary embodiments of the GPRC5DxCD3 bispecific antibody according to the Kabat numbering system.

[0141] Table 3. Sequence of GPRC5D Connecting Arms Table 4. Sequences of CD3 binding arms In some implementations, the GPRC5DxCD3 bispecific antibody is JNJ-64407564 or taquituzumab (also referred to herein as Tal), which has the sequences described in Tables 3 and 4.

[0142] Taquituzumab is a GPRC5D-directed bispecific antibody that is under development for the treatment of patients with relapsed or refractory multiple myeloma. See, for example, Chari A et al. Blood2022; 140 (suppl 1): 384-387, which is incorporated herein by reference. Taquitumab is a bispecific GPRC5D-directed CD3 T-cell connective that is being developed as a monotherapy for adult patients with relapsed or refractory multiple myeloma who have received at least three or four prior therapies, including proteasome inhibitors, immunomodulatory agents, and anti-CD38 monoclonal antibodies.

[0143] Taquitumab and its methods of use are described, for example, in WO 2018 / 017786 and WO 2022 / 058445, which are incorporated herein by reference. According to a specific embodiment, the GPRC5DxCD3 bispecific monoclonal antibody has an amino acid sequence identity of at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% with respect to taquitumab.

[0144] Further embodiments of the GPRC5DxCD3 bispecific antibody that can be used according to the present invention are described below.

[0145] In some embodiments, the GPRC5DxCD3 bispecific antibody comprises: a GPRC5D binding domain of HCDR1 (SEQ ID NO: 4), HCDR2 (SEQ ID NO: 5), HCDR3 (SEQ ID NO: 6), LCDR1 (SEQ ID NO: 7), LCDR2 (SEQ ID NO: 8), and LCDR3 (SEQ ID NO: 9), and a CD3 binding domain of HCDR1 (SEQ ID NO: 14), HCDR2 (SEQ ID NO: 15), HCDR3 (SEQ ID NO: 16), LCDR1 (SEQ ID NO: 17), LCDR2 (SEQ ID NO: 18), and LCDR3 (SEQ ID NO: 19).

[0146] In some embodiments, the GPRC5D binding domain comprises 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 comprises 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.

[0147] In some implementations, the GPRC5DxCD3 bispecific antibody is an IgG1, IgG2, IgG3, or IgG4 isotype.

[0148] In some implementations, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype.

[0149] In some implementations, the GPRC5DxCD3 bispecific antibody contains one or more substitutions in its Fc region.

[0150] In some implementations, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A, and L235A substitutions in its Fc region.

[0151] In some implementations, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A, L235A, F405L, and R409K substitutions in its Fc region.

[0152] In some implementations, the GPRC5D bonding arm includes S228P, F234A and L235A replacements (according to EU index numbers) in its Fc region.

[0153] In some implementations, the Fc region of the CD3 binding arm contains S228P, F234A, L235A, F405L, and R409K replacements (according to EU index numbers) in its Fc region.

[0154] In some embodiments, the GPRC5DxCD3 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.

[0155] In some embodiments, the GPRC5DxCD3 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.

[0156] In some embodiments, the GPRC5DxCD3 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.

[0157] In some embodiments, the GPRC5DxCD3 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.

[0158] In some implementations, the GPRC5DxCD3 bispecific antibody is taquituzumab.

[0159] Multiple myeloma patient group The GPRC5DxCD3 bispecific antibody disclosed herein is intended for the treatment of multiple myeloma in subjects (e.g., human subjects). In some embodiments, the subject is relapsed or refractory to treatment with one or more prior anticancer therapies. Relapsed disease means the cancer has recurred. Refractory disease means the cancer has not improved with treatment or is no longer responsive to treatment.

[0160] In some implementations, the subject is relapsed or refractory to treatment with agents used to treat multiple myeloma or other hematologic malignancies.

[0161] In some implementations, the subject has been treated with 1 to 11 lines of prior therapy or 1 to 10 lines of prior therapy.

[0162] In some implementations, the subject has previously undergone autologous stem cell transplantation (ASCT).

[0163] In some implementations, the subject has received at least three lines of prior treatment.

[0164] In some implementations, the subject has received at least four lines of prior treatment.

[0165] In some implementation schemes, the subject has received at least five lines of prior treatment (five drug exposures).

[0166] In some implementations, the subject has received at least three lines of prior treatment, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0167] In some implementations, the subject has received at least four lines of prior treatment, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0168] In the specific implementation plan, the patient is relapsed or refractory or intolerant to last-line treatment (LOT); exposed to proteasome inhibitors, immunomodulatory drugs and anti-CD38 therapy; and has measurable disease.

[0169] In some implementations, the subjects had received three prior anticancer therapies before receiving the GPRC5DxCD3 bispecific antibody.

[0170] In one implementation, the three prior anticancer therapies are a proteasome inhibitor (PI), an immunomodulatory drug (ImiD), and an anti-CD38 antibody. In some such implementations, 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 ixazomib.

[0171] In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (ImiD) is lenalidomide, and the anti-CD38 antibody is daratumumab. In another embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (ImiD) is lenalidomide, and the anti-CD38 antibody is isatuximab. In another embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (ImiD) is pomalidomide, and the anti-CD38 antibody is daratumumab. In yet another embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (ImiD) is pomalidomide, and the anti-CD38 antibody is isatuximab. In yet another embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (ImiD) is thalidomide, and the anti-CD38 antibody is daratumumab. In one implementation, the proteasome inhibitor is bortezomib, the immunomodulatory drug (ImiD) is thalidomide, and the anti-CD38 antibody is exatuximab.

[0172] In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (ImiD) is lenalidomide, and the anti-CD38 antibody is daratumumab. In another embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (ImiD) is lenalidomide, and the anti-CD38 antibody is esartanuximab. In another embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (ImiD) is pomalidomide, and the anti-CD38 antibody is daratumumab. In another embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (ImiD) is pomalidomide, and the anti-CD38 antibody is esartanuximab. In another embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (ImiD) is thalidomide, and the anti-CD38 antibody is daratumumab. In another embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (ImiD) is thalidomide, and the anti-CD38 antibody is esartanuximab.

[0173] In one embodiment, the proteasome inhibitor is esazolidinyl, the immunomodulatory drug (ImiD) is lenalidomide, and the anti-CD38 antibody is daratumumab. In another embodiment, the proteasome inhibitor is esazolidinyl, the immunomodulatory drug (ImiD) is lenalidomide, and the anti-CD38 antibody is esazolidinium. In another embodiment, the proteasome inhibitor is esazolidinyl, the immunomodulatory drug (ImiD) is pomalidomide, and the anti-CD38 antibody is daratumumab. In another embodiment, the proteasome inhibitor is esazolidinyl, the immunomodulatory drug (ImiD) is pomalidomide, and the anti-CD38 antibody is esazolidinium. In another embodiment, the proteasome inhibitor is esazolidinyl, the immunomodulatory drug (ImiD) is thalidomide, and the anti-CD38 antibody is daratumumab. In another embodiment, the proteasome inhibitor is esazolidinyl, the immunomodulatory drug (ImiD) is thalidomide, and the anti-CD38 antibody is esazolidinium.

[0174] In some implementations, the subject has relapsed or refractory history of treatment with one or more treatments or therapies, such as THALOMID. ® (Thalidomide), REVLIMID ® (Lenalidomide), POMALYST ® (Pomalidomide), Velcade ® (Bortezomib), NINLARO (Aisazomib), KYPROLIS ® (Carfizomi), FARADYK ®(panobinostat), AREDIA ® (Disodium aminohydroxybisphosphate), ZOMETA ® (Zoledronic acid), DARZALEX ® (Daralimumab), Elotozumab, Melphalan, Xpovio ® (Selinexor), Venclexta ® (Venetoclax), GSK 916, CAR-T therapy or other BCMA-targeted therapies.

[0175] Various qualitative and / or quantitative methods can be used to determine the relapsed or refractory nature of the disease. Possible associated symptoms include, for example, a decline or stabilization of the patient's health, or the recurrence or worsening of various symptoms associated with solid tumors, and / or the spread of cancer cells from one site to other organs, tissues, or cells.

[0176] In some implementations, multiple myeloma is relapsed or refractory to treatment with anti-CD38 antibody, celinizol, venetoclax, lenalidomide, bortezomib, pomalidomide, carfilzomib, erlotuzumab, esazozomib, melphalan, or thalidomide, or any combination thereof.

[0177] In one implementation, the anti-CD38 antibody is daratumumab.

[0178] In another implementation, the anti-CD38 antibody is exatuximab.

[0179] In some implementations, multiple myeloma is high-risk multiple myeloma. Subjects with high-risk multiple myeloma are known to have early relapse and poor prognosis and outcomes. 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 implementations, the subject with high-risk multiple myeloma has one or more chromosomal abnormalities, including: 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.

[0180] Cytogenetic abnormalities can be detected, for example, by fluorescence in situ hybridization (FISH). In chromosomal translocations, oncogenes translocate to the IgH region on chromosome 14q32, leading to 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), and t(14; 16)(q32; q23) involves translocation of the MAF transcription factor C-MAF. 17p deletion (del17p) involves the loss of the p53 locus.

[0181] Chromosomal rearrangements can be identified using well-known methods, such as fluorescence in situ hybridization, chromosome karyotyping, pulsed-field gel electrophoresis, or sequencing.

[0182] Monthly administration of GPRC5DxCD3 bispecific antibody The inventors have developed novel dosing regimens for the GPRC5DxCD3 bispecific antibody that provide improved safety profiles compared to currently approved regimens while maintaining deep and durable clinical remission over time. These regimens provide reduced or less frequent dosing, which reduces the rate and / or severity of adverse events while maintaining clinical remission.

[0183] As used herein, “weight-based” means dosage administered based on the subject’s specific body weight; for example, 3 mg / kg means a dose of 3 mg of antibody per kilogram of subject body weight. Unless otherwise stated herein, when the dose is described in “mg / kg” or “μg / kg”, weight-based administration is used.

[0184] Unless otherwise stated herein, GPRC5DxCD3 bispecific antibodies (such as taquitumab) are administered according to 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, and then cycle 2 begins on day 1 of cycle 2 the day after day 28 of cycle 1 and ends on day 28 of cycle 2, and then cycle 3 begins on day 1 of cycle 2 the day after day 28 of cycle 2 and ends on day 28 of cycle 3, and so on. In some embodiments, one or more escalating doses are administered before the first treatment cycle, i.e., before day 1 of cycle 1. Therefore, 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). A cycle number with a "+" sign refers to that cycle and all subsequent cycles. For example, "C5+" means starting from the 5th cycle and all subsequent cycles (i.e., C5, C6, C7, C8, C9, etc.).

[0185] As used herein, “Q4W” means once every four weeks, “Q2W” (also referred to as “bi-weekly” or “biweekly”) means once every two weeks, and “QW” (also referred to as “weekly”) means once a week. “Q4W” may be referred to herein as “monthly”, but technically refers to once every four weeks or once every 28 days (e.g., in a 28-day cycle, the first treatment dose occurs on day 1 of cycle 1, the second treatment dose occurs on day 1 of cycle 2, and so on). Once-weekly (QW) administration of treatment doses is also referred to herein as a weekly dosing schedule; for example, a 28-day treatment cycle may have a weekly dosing schedule which includes four doses spaced one week apart (e.g., on days 1, 8, 15, and 22), or three doses spaced one week apart (e.g., on days 8, 15, and 22), or two doses spaced one week apart (e.g., on days 8 and 15). Once-bi-weekly (Q2W) administration of treatment doses is also referred to herein as a bi-weekly dosing schedule. The treatment dose is administered once every four weeks (Q4W), 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” means administering 0.4 mg / kg once a week during the first cycle of an effective treatment regimen, “C3-6: 0.8 mg / kg Q2W” means administering 0.8 mg / kg once every two weeks from the third to the sixth cycle, “C7+: 0.8 mg / kg Q4W” means administering 0.8 mg / kg once every four weeks starting from the seventh cycle, and so on.

[0186] As used herein, a “GPRC5DxCD3 treatment cycle” refers to each treatment cycle in a treatment-effective regimen in which at least one therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered to the subject. In a preferred embodiment, an escalation phase precedes the first GPRC5DxCD3 treatment cycle in a treatment-effective regimen.

[0187] According to embodiments of the present invention, the method for treating multiple myeloma is effective in inducing clinical remission in subjects, as determined by the International Myeloma Working Group (IMWG) remission criteria. Depending on the specific embodiment, the treatment method is effective in inducing partial remission, very good partial remission, complete remission, or rigorous complete remission as determined by the IMWG remission criteria. As used herein, the overall response rate (ORR) refers to the percentage of patients in the population who achieve a partial remission (PR) or better (i.e., partial remission, very good partial remission, complete remission, or rigorous complete remission). The IMWG criteria for remission in the treatment of multiple myeloma are provided in Table 7 below.

[0188] Table 7 CR = Complete Remission; FLC = Free Light Chain; IMWG = International Myeloma Working Group; M protein = Monoclonal Paraprotein; MR = Minimal Remission; PC = Plasma Cell; PD = Disease Progression; PR = Partial Remission; sCR = Strict Complete Remission; SD = Stable Disease; VGPR = Very Good Partial Remission a The presence / absence of clonal cells is based on the κ / λ ratio. Abnormal κ / λ ratios, determined by immunohistochemistry or immunofluorescence, require a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting the presence of abnormal clones is κ / λ > 4:1 or < 1:2. * Explanation of the IMWG criteria used to encode CR and VGPR in subjects where the only measurable disease is serum FLC levels: In addition to the CR criteria listed above, CR in such subjects indicates a normal FLC ratio of 0.26 to 1.65. VGPR in such subjects requires a reduction of >90% in the difference between affected and unaffected FLC levels.

[0189] The IMWG criteria for treatment response in multiple myeloma are also described in, for example, Durie et al., Kumar et al., and Rajkumar et al., which are incorporated herein by reference: 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 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 WorkshopConsensus Panel 1. Blood .2011; 117(18):4691-4695.

[0190] In some implementations, talquitumab 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 before switching to a therapeutic dose of 0.8 mg / kg subcutaneously per month (Q4W) for treatment. Where mg / kg refers to mg talquitumab per kg of patient weight: Table 9 Table 10 Depending on certain implementation schemes, the dosing frequency of the GPRC5DxCD3 bispecific antibody can be reduced from every two weeks to monthly. For example, if a subject achieves clinical remission, the dosing frequency of the GPRC5DxCD3 bispecific antibody can be reduced from every two weeks to monthly.

[0191] According to one implementation plan, if a patient achieves partial remission, the dosing frequency of the GPRC5DxCD3 bispecific antibody can be reduced from weekly to every other week after 4 treatment cycles, and if they achieve a very good partial remission, it can be further reduced from every other week to monthly after 8 cycles.

[0192] According to another implementation, the dosing regimen of the GPRC5DxCD3 bispecific antibody may consist of a treatment dose of 0.8 mg / kg every two weeks, followed by a monthly dose of 0.8 mg / kg at the 7th treatment cycle, or a monthly dose of 0.8 mg / kg at the 5th treatment cycle if the subject achieves complete remission.

[0193] According to another implementation, the dosing regimen of the GPRC5DxCD3 bispecific antibody may include subcutaneous administration of a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject every two weeks (Q2W), and subsequently (i) if the subject has achieved very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, a therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject at the beginning of the 5th treatment cycle at a monthly dosing schedule (Q4W); or (ii) regardless of the subject's clinical remission, a therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject at the beginning of the 7th treatment cycle at a monthly dosing schedule (Q4W).

[0194] According to another implementation, the dosing regimen of the GPRC5DxCD3 bispecific antibody may include subcutaneous administration of a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject every two weeks (Q2W), and subsequently (i) if the subject has achieved very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, a therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject at the start of the 5th or 6th treatment cycle at a monthly dosing schedule (Q4W); or (ii) regardless of the subject's clinical remission, a therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject at the start of the 7th treatment cycle at a monthly dosing schedule (Q4W).

[0195] According to another implementation, the dosing regimen of the GPRC5DxCD3 bispecific antibody may include subcutaneous administration of a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W), and subsequently (i) if the subject has achieved a very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, a therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject on a monthly dosing schedule (Q4W) starting at the 5th or 6th treatment cycle; or (ii) if the subject has achieved a partial remission, very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, a therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject on a monthly dosing schedule (Q4W) starting at the 7th treatment cycle or later.

[0196] Other embodiments of the invention are described below.

[0197] In some implementations, the method of treating multiple myeloma in subjects in need includes administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0198] In some implementations, the method includes subcutaneous administration of a therapeutic dose of the GPRC5DxCD3 bispecific antibody according to a monthly dosing schedule (Q4W).

[0199] In some embodiments, the method includes subcutaneously administering one or more escalating doses of the GPRC5DxCD3 bispecific antibody to the subject prior to administering a first therapeutic dose of the GPRC5DxCD3 bispecific antibody.

[0200] In some implementations, the method includes subcutaneous administration of the GPRC5DxCD3 bispecific antibody at a therapeutic dose of about 400 μg / kg to about 800 μg / kg according to a monthly dosing schedule (Q4W).

[0201] In some implementations, the method includes subcutaneous administration of the GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 400 μg / kg according to a monthly dosing schedule (Q4W).

[0202] In some implementations, the method includes subcutaneous administration of the GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 800 μg / kg according to a monthly dosing schedule (Q4W).

[0203] In some implementations, the method includes subcutaneously administering at least one therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W) and subsequently administering the therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0204] In some embodiments, the method includes administering at least one therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a weekly dosing schedule (QW), followed by administering at least one therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a bi-weekly dosing schedule (Q2W), followed by administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0205] In some implementations, the method includes administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a two-week dosing schedule (Q2W) for six treatment cycles, and, starting in the seventh treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0206] In some implementations, the method includes administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a bi-weekly dosing schedule (Q2W), and administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W) if the subject has achieved PR, VGPR, CR, or sCR as determined by the IMWG remission criteria.

[0207] In some implementations, the method includes administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a two-week dosing schedule (Q2W), and if the subject has achieved PR, VGPR, CR, or sCR as determined by the IMWG remission criteria, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W) starting at the third, fourth, or fifth treatment cycle.

[0208] In some implementations, the method includes administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a two-week dosing schedule (Q2W) for six treatment cycles, and if the patient has achieved VGPR, CR, or sCR as determined by the IMWG remission criteria, then, starting in the seventh treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0209] In some implementations, the method includes administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a two-week dosing schedule (Q2W) for seven treatment cycles, and, starting in the eighth treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0210] In some implementations, the method includes administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a bi-weekly dosing schedule (Q2W) for seven treatment cycles, and if the patient has achieved VGPR, CR, or sCR as determined by the IMWG remission criteria, then, starting in the eighth treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0211] In some implementations, the method includes administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a two-week dosing schedule (Q2W) for eight treatment cycles, and, starting in the ninth treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0212] In some implementations, the method includes administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a bi-weekly dosing schedule (Q2W) for eight treatment cycles, and if the patient has achieved VGPR, CR, or sCR as determined by the IMWG remission criteria, then, starting in the ninth treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a monthly dosing schedule (Q4W).

[0213] In some embodiments, the method includes subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a two-week dosing schedule (Q2W), and subsequently administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a monthly dosing schedule (Q4W) during the 7th or 8th treatment cycle.

[0214] In some implementations, the method includes subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W), and subsequently, if the subject has achieved complete or strict complete remission as determined by the IMWG remission criteria, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a monthly dosing schedule (Q4W) during the fifth treatment cycle.

[0215] In some implementations, the method includes subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W), and subsequently (i) if the subject has achieved a very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, at the start of the fifth treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a monthly dosing schedule (Q4W); or (ii) regardless of the subject's clinical remission, at the start of the seventh treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a monthly dosing schedule (Q4W).

[0216] In some implementations, the method includes subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W), and subsequently (i) if the subject has achieved a very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, at the start of the 5th or 6th treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a monthly dosing schedule (Q4W); or (ii) regardless of the subject's clinical remission, at the start of the 7th treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a monthly dosing schedule (Q4W).

[0217] In some implementations, the method includes subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W), and subsequently (i) if the subject has achieved a very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, then at the start of the 5th or 6th treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a monthly dosing schedule (Q4W); or (ii) if the subject has achieved a partial remission, very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, then at the start of the 7th treatment cycle or later, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a monthly dosing schedule (Q4W).

[0218] In some implementations, the amount of each therapeutic dose of the GPRC5DxCD3 bispecific antibody administered according to a weekly dosing schedule (QW), a bi-weekly dosing schedule (Q2W), or a monthly dosing schedule (Q4W) is the same.

[0219] In some implementations, the GPRC5DxCD3 bispecific antibody is administered at a therapeutic dose of 800 μg / kg according to a bi-weekly dosing schedule (Q2W) and a monthly dosing schedule (Q4W).

[0220] In some implementations, the method includes subcutaneously administering two or three escalating doses of the GPRC5DxCD3 bispecific antibody prior to the first therapeutic dose.

[0221] In some embodiments, the method includes subcutaneously administering escalating doses of GPRC5DxCD3 bispecific antibody at 10 μg / kg and 60 μg / kg prior to the administration of a therapeutic dose.

[0222] In some embodiments, the method includes subcutaneously administering escalating doses of GPRC5DxCD3 bispecific antibody at 10 μg / kg, 60 μg / kg, and 400 μg / kg prior to the administration of a therapeutic dose.

[0223] In some implementations, the method includes subcutaneous administration of escalating doses of the GPRC5DxCD3 bispecific antibody at intervals of 2 to 4 days.

[0224] In some implementations, the subject achieves a clinical response of PR, VGPR, CR, or sCR.

[0225] In some implementations, the subject achieves clinical remission as CR or sCR.

[0226] In some implementations, the method includes subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W), and subsequently (i) if the subject has achieved a very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, at the start of the fifth treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a monthly dosing schedule (Q4W); or (ii) regardless of the subject's clinical remission, at the start of the seventh treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a monthly dosing schedule (Q4W).

[0227] In some implementations, the method includes subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W), and subsequently (i) if the subject has achieved a very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, at the start of the 5th or 6th treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a monthly dosing schedule (Q4W); or (ii) regardless of the subject's clinical remission, at the start of the 7th treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject on a monthly dosing schedule (Q4W).

[0228] In some embodiments, the method includes subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject on a bi-weekly dosing schedule (Q2W), and subsequently (i) if the subject has achieved a very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, then at the start of the 5th or 6th treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously on a monthly dosing schedule (Q4W); or (ii) if the subject has achieved a partial remission, very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, then at the start of the 7th treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously on a monthly dosing schedule (Q4W). In some embodiments, the method includes subcutaneously administering two or three escalating doses of the GPRC5DxCD3 bispecific antibody before administering the first therapeutic dose.

[0229] In some embodiments, the method includes subcutaneously administering escalating doses of GPRC5DxCD3 bispecific antibody at 10 μg / kg and 60 μg / kg prior to the administration of a therapeutic dose.

[0230] In some embodiments, the method includes subcutaneously administering escalating doses of GPRC5DxCD3 bispecific antibody at 10 μg / kg, 60 μg / kg, and 400 μg / kg prior to the administration of a therapeutic dose.

[0231] In some implementations, the method includes subcutaneous administration of escalating doses of the GPRC5DxCD3 bispecific antibody at intervals of 2 to 4 days.

[0232] In some embodiments, the method includes treating a subject according to a treatment-effective regimen comprising consecutive 28-day GPRC5DxCD3 treatment cycles, wherein: during the escalation phase, one or more escalating doses of the GPRC5DxCD3 bispecific antibody are administered subcutaneously to the subject, and after the escalation phase, starting from the first GPRC5DxCD3 treatment cycle, a therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject on a bi-weekly dosing schedule (Q2W), and subsequently on a monthly dosing schedule (Q4W).

[0233] In some embodiments, the method includes treating a subject according to a treatment-effective regimen comprising consecutive 28-day GPRC5DxCD3 treatment cycles, wherein: during the escalation phase, one or more escalating doses of the GPRC5DxCD3 bispecific antibody are administered subcutaneously to the subject, and after the escalation phase, starting from the first GPRC5DxCD3 treatment cycle, a therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject on a bi-weekly dosing schedule (Q2W), and subsequently on a monthly dosing schedule (Q4W): (i) if the subject has achieved a very good partial remission, complete remission, or strictly complete remission as determined by the IMWG remission criteria, then starting at the 5th treatment cycle; or (ii) regardless of the subject's clinical remission, starting at the 7th treatment cycle.

[0234] In some embodiments, the method includes treating a subject according to a treatment-effective regimen comprising consecutive 28-day GPRC5DxCD3 treatment cycles, wherein: during the escalation phase, the subject is subcutaneously administered one or more escalating doses of the GPRC5DxCD3 bispecific antibody, and after the escalation phase, starting from the first GPRC5DxCD3 treatment cycle, the subject is subcutaneously administered a therapeutic dose of the GPRC5DxCD3 bispecific antibody on a bi-weekly dosing schedule (Q2W), and subsequently on a monthly dosing schedule (Q4W): (i) if the subject has achieved a very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, then starting at the 5th treatment cycle; or (ii) if the subject has achieved a partial remission, a very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, then starting at the 7th treatment cycle.

[0235] In some implementations, each treatment dose of the GPRC5DxCD3 bispecific antibody, administered according to a bi-weekly dosing schedule (Q2W) and a monthly dosing schedule (Q4W), is 800 μg / kg.

[0236] In some implementations, the first cycle of the regimen includes an escalation period, and starting from the second cycle, a therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject on a two-week dosing schedule (Q2W), and subsequently on a monthly dosing schedule (Q4W).

[0237] In some embodiments, the dosing regimen includes an escalation period, and then, starting from the treatment cycle immediately following the escalation period, a therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject according to a monthly dosing schedule (Q4W) (regardless of whether the subject achieves clinical remission or lacks clinical remission). In some embodiments, cycle 1 of the regimen includes an escalation period, and starting from cycle 2, a therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject according to a monthly dosing schedule (Q4W) (e.g., 0.8 mg / kg on day 1 of each cycle starting from cycle 2). In some embodiments, the escalation period includes two or three escalation doses, preferably spaced 2 to 4 days apart, followed by at least one therapeutic dose of 0.8 mg / kg (e.g., a therapeutic dose on day 15 of cycle 1). In some implementations, the escalation period includes three escalation doses (0.01 mg / kg, 0.06 mg / kg, and 0.4 mg / kg), for example, on days 2, 4, and 8 of cycle 1, followed by a treatment dose of 0.8 mg / kg, for example, on day 15 of cycle 1.

[0238] In some implementations, the first cycle of the regimen includes an escalation period, and starting from the second cycle, a therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject on a two-week dosing schedule (Q2W), and subsequently on a monthly dosing schedule (Q4W): (i) if the subject has achieved a very good partial response, complete response, or strict complete response as determined by the IMWG response criteria, then the fifth treatment cycle is initiated; or (ii) regardless of the subject's clinical response, the seventh treatment cycle is initiated.

[0239] In some implementations, subjects are administered one to three incremental doses of the GPRC5DxCD3 bispecific antibody during the escalation period.

[0240] In some implementations, two incremental doses of the GPRC5DxCD3 bispecific antibody are administered to the subject during the escalation period.

[0241] In some implementations, subjects are administered three incremental doses of the GPRC5DxCD3 bispecific antibody during the escalation period.

[0242] In some implementations, the escalation period includes a first escalation dose of 0.01 mg / kg, a second escalation dose of 0.06 mg / kg, and a third escalation dose of 0.4 mg / kg.

[0243] In some implementations, in addition to one or more escalation doses, one or more therapeutic doses of the GPRC5DxCD3 bispecific antibody are administered subcutaneously to the subject during the escalation period (e.g., according to a weekly dosing schedule).

[0244] In some implementations, in addition to one or more escalation doses, one or two therapeutic doses of the GPRC5DxCD3 bispecific antibody are administered subcutaneously to the subject during the escalation period (e.g., according to a weekly dosing schedule).

[0245] In some implementations, the first cycle of the regimen includes a first escalation dose of 0.01 mg / kg, a second escalation dose of 0.06 mg / kg, a third escalation dose of 0.4 mg / kg, and a treatment dose of 0.8 mg / kg.

[0246] In some implementations, the first cycle of the regimen includes a first escalation dose of 0.01 mg / kg, a second escalation dose of 0.06 mg / kg for 2 to 4 days after the first escalation dose, a third escalation dose of 0.4 mg / kg for 4 to 7 days after the second escalation dose, and a treatment dose of 0.8 mg / kg for 5 to 9 days after the third escalation dose.

[0247] In some implementations, the first cycle of the regimen includes a first escalation dose of 0.01 mg / kg on day 1, a second escalation dose of 0.06 mg / kg on day 3, a third escalation dose of 0.4 mg / kg on day 8, and a treatment dose of 0.8 mg / kg on day 15.

[0248] In some implementations, each of cycles 2 through 6 of the regimen comprises a Q2W treatment dose of 0.8 mg / kg on days 1 and 15, and each of cycles 7+ comprises a Q4W treatment dose of 0.8 mg / kg on day 1.

[0249] In some implementations, (i) each of cycles 2 through 6 of the regimen comprises a Q2W treatment dose of 0.8 mg / kg on days 1 and 15, and each of cycles 7+ comprises a Q4W treatment dose of 0.8 mg / kg on day 1, or (ii) each of cycles 2 through 4 of the regimen comprises a Q2W treatment dose of 0.8 mg / kg on days 1 and 15, and each of cycles 5+ comprises a Q4W treatment dose of 0.8 mg / kg on day 1 if the subject has achieved a very good partial response, complete response, or strict complete response as determined by the IMWG response criteria.

[0250] In some implementations, cycle 1 of the regimen comprises a first escalation dose of 0.01 mg / kg on day 1, a second escalation dose of 0.06 mg / kg on day 3, a third escalation dose of 0.4 mg / kg on day 8, and a treatment dose of 0.8 mg / kg on day 15; and each of cycles 2 through 6 comprises a Q2W treatment dose of 0.8 mg / kg on days 1 and 15; and each of cycles 7+ comprises a Q4W treatment dose of 0.8 mg / kg on day 1.

[0251] In some implementations, cycle 1 of the regimen comprises a first escalation dose of 0.01 mg / kg on day 1, a second escalation dose of 0.06 mg / kg on day 3, a third escalation dose of 0.4 mg / kg on day 8, and a treatment dose of 0.8 mg / kg on day 15; and any of the following: (i) each of cycles 2 through 6 of the regimen comprises a Q2W treatment dose of 0.8 mg / kg on days 1 and 15, and each of cycles 7+ comprises a Q4W treatment dose of 0.8 mg / kg on day 1, or (ii) each of cycles 2 through 4 of the regimen comprises a Q2W treatment dose of 0.8 mg / kg on days 1 and 15, and each of cycles 5+ comprises a Q4W treatment dose of 0.8 mg / kg on day 1 if the subject has achieved a very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria.

[0252] Non-limiting examples of exemplary dosing regimens of the present invention are provided in Table 11.

[0253] Table 11 Table 12 provides another non-limiting example of an exemplary dosing regimen of the present invention.

[0254] Table 12 The following provides another non-limiting example of an exemplary dosing regimen of the present invention, wherein talquituzumab is administered over a 28-day treatment cycle: - During cycle 1, administer the following doses of taquitumab subcutaneously: ○ Taquitumab escalation dose 1 (SU1): 0.01 mg / kg, administered on day 1; ○ Taquitumab escalation dose 2 (SU2): 0.06 mg / kg, administered ≥2 days after SU1; ○ Taquitumab treatment dose (sometimes referred to as escalation dose 3): 0.4 mg / kg, administered ≥2 days after SU2; ○ Taquitumab treatment dose: 0.8 mg / kg, administered ≥2 days after the first treatment dose of 0.4 mg / kg (incremental dose 3), i.e., from day 7 to day 15; - In subsequent treatment cycles following cycle 1, administer taquitumab subcutaneously at the following therapeutic dose: 0.8 mg / kg ○ Cycles 2-4 (C2-C4): Taquitumab is administered every two weeks (Q2W) SC, i.e., 14 days (±3 days) after the previous treatment dose. ○ Starting 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), where the change to Q4W occurs on day 1 of cycle 5 or cycle 6 (±3 days). ○ If a PR or better is confirmed on day 1 (±3 days) of cycle 7, the schedule must be changed to Q4W dosing; ○ If a PR or better is not confirmed on day 1 (±3 days) of cycle 7, continue dosing every 2 weeks until a confirmed PR or better is achieved.

[0255] Table 13 provides another non-limiting example of an exemplary dosing regimen of the present invention.

[0256] Table 13 In some implementations, dosing regimens including administration of GPRC5DxCD3 bispecific antibodies on a weekly (QW) and / or bi-weekly (Q2W) dosing schedule instead of a monthly (Q4W) dosing schedule improve (i) clinical response rates (e.g., ORR and / or PFS) and / or (ii) the rate and / or severity of adverse events in a reference subject population compared to a reference subject population receiving the GPRC5DxCD3 bispecific antibody on a monthly (Q4W) dosing schedule.

[0257] In some implementations, dosing regimens that include a monthly (Q4W) dosing schedule achieve a lower rate of adverse events and / or a shorter duration of adverse events than dosing regimens that include a weekly (QW) and / or bi-weekly (Q2W) dosing schedule instead of a monthly (Q4W) dosing schedule.

[0258] In some implementations, adverse events include one or more of the following: oral toxicity (e.g., loss of taste, taste disturbance, dry mouth and / or difficulty swallowing) and / or nail toxicity (e.g., nail disease) and / or skin toxicity (e.g., dry skin, skin peeling and / or itching). In some implementations, dosing regimens that include a monthly (Q4W) dosing schedule achieve stronger clinical responses and / or longer durations of clinical response than dosing regimens that include a weekly (QW) and / or bi-weekly (Q2W) dosing schedule instead of a monthly (Q4W) dosing schedule.

[0259] Exemplary Implementation The following provides enumerated embodiments of the invention. These embodiments are merely exemplary and do not limit the scope of this disclosure or the appended claims.

[0260] 1. A method for treating multiple myeloma in a subject in need, the method comprising administering a therapeutically effective amount of a GPRC5DxCD3 bispecific antibody to the subject according to a monthly (Q4W) dosing schedule.

[0261] 2. The method according to embodiment 1, wherein the GPRC5DxCD3 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.

[0262] 3. The method according to embodiment 1 or 2, wherein the GPRC5DxCD3 bispecific antibody comprises: a GPRC5D binding domain containing 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 containing 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.

[0263] 4. The method according to any one of embodiments 1 to 3, wherein the GPRC5DxCD3 bispecific antibody is an IgG1, IgG2, IgG3 or IgG4 isotype.

[0264] 5. The method according to any one of embodiments 1 to 4, wherein the GPRC5DxCD3 bispecific antibody is an IgG4 isotype.

[0265] 6. The method according to any one of embodiments 1 to 5, wherein the GPRC5DxCD3 bispecific antibody contains one or more substitutions in its Fc region.

[0266] 7. The method according to any one of embodiments 1 to 6, wherein the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A and L235A substitutions (according to EU designations) in its Fc region.

[0267] 8. The method according to any one of embodiments 1 to 7, wherein the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A, L235A, F405L and R409K substitutions (according to EU number) in its Fc region.

[0268] 9. The method according to any one of embodiments 1 to 8, wherein the Fc region of the GPRC5D bonding arm contains S228P, F234A and L235A replacements (according to EU designations) in its Fc region.

[0269] 10. The method according to any one of embodiments 1 to 9, wherein the Fc region of the CD3 binding arm contains S228P, F234A, L235A, F405L and R409K substitutions (according to EU designations) in its Fc region.

[0270] 11. The method according to any one of embodiments 1 to 10, wherein the GPRC5DxCD3 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.

[0271] 12. The method according to any one of embodiments 1 to 10, wherein the GPRC5DxCD3 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.

[0272] 13. The method according to any one of embodiments 1 to 10, wherein the GPRC5DxCD3 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.

[0273] 14. The method according to any one of embodiments 1 to 10, wherein the GPRC5DxCD3 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.

[0274] 15. The method according to any one of embodiments 1 to 10, wherein the GPRC5DxCD3 bispecific antibody is taquituzumab.

[0275] 16. The method according to any one of embodiments 1 to 15, wherein the subject suffers from relapsed or refractory multiple myeloma.

[0276] 17. The method according to any one of embodiments 1 to 16, wherein the subject has received at least three lines of prior treatment.

[0277] 18. The method according to any one of embodiments 1 to 16, wherein the subject has received at least four lines of prior treatment.

[0278] 19. The method according to any one of embodiments 1 to 16, wherein the subject has received at least five lines of prior treatment (five drug exposures).

[0279] 20. The method according to any one of embodiments 1 to 16, wherein the subject has received at least three lines of prior treatment, including proteasome inhibitors, immunomodulators and anti-CD38 monoclonal antibodies.

[0280] 21. The method according to any one of embodiments 1 to 16, wherein the subject has received at least four lines of prior treatment, including proteasome inhibitors, immunomodulators and anti-CD38 monoclonal antibodies.

[0281] 22. The method according to any one of embodiments 1 to 21, wherein the method comprises subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody according to a monthly dosing schedule (Q4W).

[0282] 23. The method according to any one of embodiments 1 to 22, wherein the method comprises subcutaneously administering one or more escalating doses of the GPRC5DxCD3 bispecific antibody to the subject prior to administering a first therapeutic dose of the GPRC5DxCD3 bispecific antibody.

[0283] 24. The method according to any one of embodiments 1 to 23, the method comprising subcutaneously administering the GPRC5DxCD3 bispecific antibody at a therapeutic dose of about 400 μg / kg to about 800 μg / kg according to the monthly dosing schedule (Q4W).

[0284] 25. The method according to any one of embodiments 1 to 23, wherein the method comprises subcutaneously administering the GPRC5DxCD3 bispecific antibody at a therapeutic dose of about 400 μg / kg according to the monthly dosing schedule (Q4W).

[0285] 26. The method according to any one of embodiments 1 to 23, wherein the method comprises subcutaneously administering the GPRC5DxCD3 bispecific antibody at a therapeutic dose of about 800 μg / kg according to the monthly dosing schedule (Q4W).

[0286] 27. The method according to any one of embodiments 1 to 26, the method comprising subcutaneously administering at least one therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to a bi-weekly dosing schedule (Q2W), and subsequently administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to the monthly dosing schedule (Q4W).

[0287] 28. The method according to any one of embodiments 1 to 27, the method comprising subcutaneously administering at least one therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to a weekly dosing schedule (QW), and subsequently administering at least one therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to a bi-weekly dosing schedule (Q2W), and subsequently administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to the monthly dosing schedule (Q4W).

[0288] 29. The method according to any one of embodiments 1 to 28, the method comprising administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject according to a bi-weekly dosing schedule (Q2W) for 6 treatment cycles, and, starting in the 7th treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to the monthly dosing schedule (Q4W).

[0289] 30. The method according to any one of embodiments 1 to 28, the method comprising administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject according to a bi-weekly dosing schedule (Q2W) for 6 treatment cycles, and if the patient has achieved VGPR, CR or sCR as determined by the IMWG remission criteria, then, starting in the 7th treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to the monthly dosing schedule (Q4W).

[0290] 31. The method according to any one of embodiments 1 to 28, the method comprising administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject according to a two-week dosing schedule (Q2W) for 7 treatment cycles, and, starting in the 8th treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to the monthly dosing schedule (Q4W).

[0291] 32. The method according to any one of embodiments 1 to 28, the method comprising administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject according to a bi-weekly dosing schedule (Q2W) for 7 treatment cycles, and if the patient has achieved VGPR, CR or sCR as determined by the IMWG remission criteria, then, starting in the 8th treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to the monthly dosing schedule (Q4W).

[0292] 33. The method according to any one of embodiments 1 to 28, the method comprising administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject according to a two-week dosing schedule (Q2W) for eight treatment cycles, and, starting in the ninth treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to the monthly dosing schedule (Q4W).

[0293] 34. The method according to any one of embodiments 1 to 28, the method comprising administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject according to a bi-weekly dosing schedule (Q2W) for 8 treatment cycles, and if the patient has achieved VGPR, CR or sCR as determined by the IMWG remission criteria, then, starting in the 9th treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to the monthly dosing schedule (Q4W).

[0294] 35. The method according to any one of embodiments 1 to 27, the method comprising subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to a bi-weekly dosing schedule (Q2W), and subsequently administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject subcutaneously according to the monthly dosing schedule (Q4W) in the 7th or 8th treatment cycle.

[0295] 36. The method according to any one of embodiments 1 to 27, the method comprising subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to a bi-weekly dosing schedule (Q2W), and subsequently, if the subject has achieved complete or strict complete remission as determined by the IMWG remission criteria, subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to the monthly dosing schedule (Q4W) in the fifth treatment cycle.

[0296] 37. The method according to any one of embodiments 27 to 36, wherein each therapeutic dose of the GPRC5DxCD3 bispecific antibody administered according to a weekly dosing schedule (QW), a bi-weekly dosing schedule (Q2W), or the monthly dosing schedule (Q4W) is the same.

[0297] 38. The method according to any one of embodiments 27 to 36, wherein the GPRC5DxCD3 bispecific antibody is administered at a therapeutic dose of 800 μg / kg according to the bi-weekly dosing schedule (Q2W) and the monthly dosing schedule (Q4W).

[0298] 39. The method according to any one of embodiments 1 to 38, wherein the method comprises subcutaneously administering two or three escalating doses of the GPRC5DxCD3 bispecific antibody prior to subcutaneous administration of the first therapeutic dose.

[0299] 40. The method according to any one of embodiments 1 to 38, wherein the method comprises subcutaneously administering escalating doses of the GPRC5DxCD3 bispecific antibody at 10 μg / kg and 60 μg / kg prior to subcutaneous administration of a therapeutic dose.

[0300] 41. The method according to any one of embodiments 1 to 38, wherein the method comprises subcutaneously administering escalating doses of the GPRC5DxCD3 bispecific antibody at doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg prior to subcutaneous administration of a therapeutic dose.

[0301] 42. The method according to any one of embodiments 1 to 41, wherein the method comprises subcutaneously administering escalating doses of the GPRC5DxCD3 bispecific antibody at intervals of 2 to 4 days.

[0302] 43. The method according to any one of embodiments 1 to 42, wherein the subject achieves a clinical remission of PR or VGPR or CR or sCR.

[0303] 44. The method according to any one of embodiments 1 to 42, wherein the subject achieves clinical remission as CR or sCR.

[0304] 45. The method according to any one of embodiments 1 to 27, the method comprising administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject according to a bi-weekly dosing schedule (Q2W), and subsequently (i) if the subject has achieved very good partial remission, complete remission, or strictly complete remission as determined by the IMWG remission criteria, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject according to the monthly dosing schedule (Q4W) at the beginning of the 5th treatment cycle; or (ii) regardless of the clinical remission of the subject, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject according to the monthly dosing schedule (Q4W) at the beginning of the 7th treatment cycle.

[0305] 46. ​​The method according to embodiment 45, wherein the GPRC5DxCD3 bispecific antibody is administered at a therapeutic dose of 800 μg / kg according to the bi-weekly dosing schedule (Q2W) and the monthly dosing schedule (Q4W).

[0306] 47. The method according to any one of embodiments 45 to 46, wherein the method comprises subcutaneously administering two or three escalating doses of the GPRC5DxCD3 bispecific antibody prior to subcutaneous administration of the first therapeutic dose.

[0307] 48. The method according to any one of embodiments 45 to 47, wherein the method comprises subcutaneously administering escalating doses of the GPRC5DxCD3 bispecific antibody at 10 μg / kg and 60 μg / kg prior to subcutaneous administration of a therapeutic dose.

[0308] 49. The method according to any one of embodiments 45 to 48, wherein the method comprises subcutaneously administering escalating doses of the GPRC5DxCD3 bispecific antibody at doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg prior to subcutaneous administration of a therapeutic dose.

[0309] 50. The method according to any one of embodiments 45 to 49, wherein the method comprises subcutaneously administering escalating doses of the GPRC5DxCD3 bispecific antibody at intervals of 2 to 4 days.

[0310] 51. The method according to any one of embodiments 45 to 50, wherein the subject achieves a clinical remission of PR or VGPR or CR or sCR.

[0311] 52. The method according to any one of embodiments 45 to 51, wherein the subject achieves clinical remission as CR or sCR.

[0312] 53. The method according to any one of embodiments 1 to 52, said method comprising treating the subject according to a treatment-effective regimen comprising a continuous 28-day GPRC5DxCD3 treatment cycle, wherein: During the escalation phase, one or more escalating doses of the GPRC5DxCD3 bispecific antibody were administered subcutaneously to the subject, and Following the escalation period, starting from the first GPRC5DxCD3 treatment cycle, the subject is given a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously according to a dosing schedule of every two weeks (Q2W), and subsequently, the subject is given a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously according to the dosing schedule of every month (Q4W).

[0313] 54. The method according to any one of embodiments 1 to 53, said method comprising treating the subject according to a treatment efficacy regimen comprising a continuous 28-day GPRC5DxCD3 treatment cycle, wherein: During the escalation phase, one or more escalating doses of the GPRC5DxCD3 bispecific antibody were administered subcutaneously to the subject, and Following the escalation period, starting from the first GPRC5DxCD3 treatment cycle, the subject is given a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously according to a two-week dosing schedule (Q2W), and subsequently, the subject is given a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously according to the monthly dosing schedule (Q4W): (i) if the subject has achieved a very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, then starting in the 5th treatment cycle; or (ii) regardless of the subject's clinical remission, starting in the 7th treatment cycle.

[0314] 55. The method according to embodiment 53 or 54, wherein each treatment dose of the GPRC5DxCD3 bispecific antibody administered according to the said bi-weekly dosing schedule (Q2W) and the said monthly dosing schedule (Q4W) is 800 μg / kg.

[0315] 56. The method according to any one of embodiments 53 to 55, wherein the first cycle of the regimen includes the escalation period, and starting from the second cycle, the therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject according to the bi-weekly dosing schedule (Q2W), and subsequently the therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject according to the monthly dosing schedule (Q4W).

[0316] 57. The method according to any one of embodiments 53 to 56, wherein the first cycle of the regimen includes the escalation period, and starting from the second cycle, the subject is subcutaneously administered the therapeutic dose of the GPRC5DxCD3 bispecific antibody according to the bi-weekly dosing schedule (Q2W), and subsequently the subject is subcutaneously administered the therapeutic dose of the GPRC5DxCD3 bispecific antibody according to the monthly dosing schedule (Q4W): (i) if the subject has achieved very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, then starting in the fifth treatment cycle; or (ii) regardless of the subject's clinical remission, starting in the seventh treatment cycle.

[0317] 58. The method according to any one of embodiments 53 to 57, wherein the subject is administered one to three incremental doses of the GPRC5DxCD3 bispecific antibody during the incremental period.

[0318] 59. The method according to any one of embodiments 53 to 58, wherein the subject is administered two incremental doses of the GPRC5DxCD3 bispecific antibody during the incremental period.

[0319] 60. The method according to any one of embodiments 53 to 58, wherein the subject is administered three incremental doses of the GPRC5DxCD3 bispecific antibody during the incremental period.

[0320] 61. The method according to any one of embodiments 53 to 60, wherein the escalation period comprises a first escalation dose of 0.01 mg / kg, a second escalation dose of 0.06 mg / kg, and a third escalation dose of 0.4 mg / kg.

[0321] 62. The method according to any one of embodiments 53 to 61, wherein, in addition to the one or more escalating doses, one or more therapeutic doses of the GPRC5DxCD3 bispecific antibody are administered subcutaneously to the subject during the escalation period (e.g., according to a weekly dosing schedule).

[0322] 63. The method according to any one of embodiments 53 to 61, wherein, in addition to the one or more escalating doses, one or two therapeutic doses of the GPRC5DxCD3 bispecific antibody are administered subcutaneously to the subject during the escalation period (e.g., according to a weekly dosing schedule).

[0323] 64. The method according to any one of embodiments 53 to 63, wherein the first cycle of the embodiment 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.

[0324] 65. The method according to any one of embodiments 53 to 64, wherein the first cycle of the embodiment 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.

[0325] 66. The method according to any one of embodiments 53 to 65, wherein the first cycle of the embodiment comprises a first escalation dose of 0.01 mg / kg on day 1, a second escalation dose of 0.06 mg / kg on day 3, a third escalation dose of 0.4 mg / kg on day 8, and a treatment dose of 0.8 mg / kg on day 15.

[0326] 67. The method according to any one of embodiments 53 to 66, wherein each of the second to sixth cycles of the embodiment comprises a Q2W treatment dose of 0.8 mg / kg on day 1 and day 15, and each of the seventh+ cycles comprises a Q4W treatment dose of 0.8 mg / kg on day 1.

[0327] 68. The method according to any one of embodiments 53 to 66, wherein: (i) each of the second to sixth cycles of the regimen comprises a Q2W treatment dose of 0.8 mg / kg on days 1 and 15, and each of the seventh+ cycles comprises a Q4W treatment dose of 0.8 mg / kg on day 1, or (ii) each of the second to fourth cycles of the regimen comprises a Q2W treatment dose of 0.8 mg / kg on days 1 and 15, and each of the fifth+ cycles comprises a Q4W treatment dose of 0.8 mg / kg on day 1 if the subject has achieved very good partial remission, complete remission or strict complete remission as determined by the IMWG remission criteria.

[0328] 69. The method according to any one of embodiments 53 to 68, wherein the first cycle of the embodiment 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 treatment dose of 0.8 mg / kg on day 15; and each of the second to sixth cycles of the embodiment comprises a Q2W treatment dose of 0.8 mg / kg on days 1 and 15; and each of the seventh+ cycles comprises a Q4W treatment dose of 0.8 mg / kg on day 1.

[0329] 70. The method according to any one of embodiments 53 to 68, wherein the first cycle of said embodiment comprises a first escalation dose of 0.01 mg / kg on day 1, a second escalation dose of 0.06 mg / kg on day 3, a third escalation dose of 0.4 mg / kg on day 8, and a treatment dose of 0.8 mg / kg on day 15; and any one of the following: (i) Each of cycles 2 through 6 of the regimen comprises a Q2W treatment dose of 0.8 mg / kg on days 1 and 15, and each of cycles 7+ comprises a Q4W treatment dose of 0.8 mg / kg on day 1, or (ii) Each of the second to fourth cycles of the regimen comprises a Q2W treatment dose of 0.8 mg / kg on day 1 and day 15, and each of the fifth+ cycles comprises a Q4W treatment dose of 0.8 mg / kg on day 1 if the subject has achieved very good partial remission, complete remission or strict complete remission as determined by the IMWG remission criteria.

[0330] 71. The method according to any one of embodiments 1 to 53, said method comprising treating the subject according to a treatment-effective regimen comprising a continuous 28-day GPRC5DxCD3 treatment cycle, wherein: During the escalation phase, one or more escalating doses of the GPRC5DxCD3 bispecific antibody (e.g., taquituzumab) are administered subcutaneously to the subject, and Following the escalation period, starting from the first GPRC5DxCD3 treatment cycle, the subject is given a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously according to a two-week dosing schedule (Q2W), and subsequently, the subject is given a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously according to the monthly dosing schedule (Q4W): (i) if the subject has achieved a very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, then starting in the 5th or 6th treatment cycle; or (ii) if the subject has achieved a partial remission, a very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, then starting in the 7th treatment cycle or later. Each treatment dose of the GPRC5DxCD3 bispecific antibody administered according to the stated bi-weekly dosing schedule (Q2W) and the stated monthly dosing schedule (Q4W) is 0.8 mg / kg.

[0331] 72. The method according to embodiment 71, wherein the escalation period comprises administering two or three escalation doses of the GPRC5DxCD3 bispecific antibody, preferably spaced 2 to 4 days apart.

[0332] 73. The method according to embodiment 71, wherein the escalation period comprises administering two or three escalation doses of the GPRC5DxCD3 bispecific antibody and a therapeutic dose of 0.8 mg / kg.

[0333] 74. The method according to embodiment 71, wherein the escalation period comprises administering three escalating doses of the GPRC5DxCD3 bispecific antibody (e.g., 0.01 mg / kg, 0.06 mg / kg, and 0.4 mg / kg) and a therapeutic dose of 0.8 mg / kg.

[0334] 75. The method according to any one of embodiments 71 to 74, wherein the first cycle of the embodiment includes the incremental period, and the bi-weekly dosing schedule (Q2W) begins in the second cycle.

[0335] 76. The method according to any one of embodiments 1 to 53, comprising treating the subject according to a treatment-effective regimen comprising consecutive 28-day GPRC5DxCD3 treatment cycles, wherein: during the escalation phase, one or more escalating doses of the GPRC5DxCD3 bispecific antibody (e.g., taquituzumab) are subcutaneously administered to the subject, and subsequently, starting from the treatment cycle immediately following the escalation phase, a therapeutic dose of the GPRC5DxCD3 bispecific antibody is subcutaneously administered to the subject according to a monthly dosing schedule (Q4W) (regardless of whether the subject has a clinical response or lacks a clinical response). Each treatment dose of the GPRC5DxCD3 bispecific antibody administered according to the stated bi-weekly dosing schedule (Q2W) and the stated monthly dosing schedule (Q4W) is 0.8 mg / kg.

[0336] 77. The method according to embodiment 76, wherein the escalation period comprises administering two or three escalation doses of the GPRC5DxCD3 bispecific antibody, preferably spaced two to four days apart.

[0337] 78. The method according to embodiment 76, wherein the escalation period comprises administering two or three escalation doses of the GPRC5DxCD3 bispecific antibody and a therapeutic dose of 0.8 mg / kg.

[0338] 79. The method according to embodiment 76, wherein the escalation period comprises administering three escalating doses of the GPRC5DxCD3 bispecific antibody (e.g., 0.01 mg / kg, 0.06 mg / kg, and 0.4 mg / kg) and a therapeutic dose of 0.8 mg / kg.

[0339] 80. The method according to any one of embodiments 76 to 79, wherein the first cycle of the embodiment includes the incremental period, and the monthly dosing schedule (Q4W) begins in the second cycle.

[0340] 81. The method according to any one of embodiments 1 to 80, wherein the GPRC5DxCD3 bispecific antibody (tartuzumab) is administered as a monotherapy.

[0341] 82. The method according to any one of embodiments 1 to 80, wherein the GPRC5DxCD3 bispecific antibody (e.g., taquituzumab) is administered as part of a combination therapy with one or more other antimyeloma agents.

[0342] 83. The method according to any one of embodiments 1 to 82, wherein the dosing regimen comprising the monthly (Q4W) dosing schedule achieves a lower incidence of adverse events and / or a shorter duration of adverse events than a dosing regimen comprising a weekly (QW) and / or bi-weekly (Q2W) dosing schedule instead of a monthly (Q4W) dosing schedule.

[0343] 84. The method according to embodiment 83, wherein the adverse event includes one or more of the following: oral toxicity (e.g., loss of taste, taste disturbance, dry mouth and / or difficulty swallowing) and / or nail toxicity (e.g., nail disease) and / or skin toxicity (e.g., dry skin, skin peeling and / or itching). 85. The method according to any one of embodiments 1 to 84, wherein the dosing regimen comprising the monthly (Q4W) dosing schedule achieves a stronger clinical response and / or a longer duration of clinical response than a dosing regimen comprising a weekly (QW) and / or bi-weekly (Q2W) dosing schedule instead of a monthly (Q4W) dosing schedule.

[0344] 86. The method according to any one of embodiments 1 to 85, wherein the dosing regimen comprising the monthly (Q4W) dosing schedule achieves a higher overall response rate (ORR) than a dosing regimen comprising a weekly (QW) and / or bi-weekly (Q2W) dosing schedule instead of a monthly (Q4W) dosing schedule.

[0345] 87. The method according to any one of embodiments 1 to 86, wherein the dosing regimen comprising the monthly (Q4W) dosing schedule achieves a longer progression-free survival (PFS) than a dosing regimen comprising a weekly (QW) and / or bi-weekly (Q2W) dosing schedule instead of a monthly (Q4W) dosing schedule.

[0346] Those skilled in the art will recognize that many changes and modifications can be made to the preferred embodiments of the invention, and that such changes and modifications can be made without departing from the spirit of the invention. Therefore, the appended claims are intended to cover all such equivalent variations that fall within the true spirit and scope of the invention.

[0347] Every patent, patent application, and publication cited or described in this document is incorporated herein by reference in its entirety. Example

[0348] The following examples are provided to further describe some embodiments of the implementations disclosed herein. These examples are intended to illustrate, and not limit, the disclosed implementations.

[0349] Example 1: Lower frequency of taquitumab in patients with relapsed / refractory multiple myeloma Efficacy and safety of lower-intensity dosing: Results from the Phase 1 / 2 MonumenTAL-1 study Antibody The anti-GPRC5D / anti-CD3 antibody taquitumab (also known as Tal) is manufactured by Janssen Pharmaceuticals. Taquitumab contains a GPRC5D binding arm and a CD3 binding arm, the amino acid sequences of which are shown in Tables 5 and 6, respectively.

[0350] Table 5. Sequence of GPRC5D Connecting Arms Table 6. Sequences of CD3 binding arms background Taquituzumab (tal) is an off-the-shelf bispecific antibody that targets G protein-coupled receptor family C5 member D (GPRC5D) and CD3. Results from the phase ½ MonomentalTAL-1 (NCT03399799 / NCT04634552) trial showed an overall response rate (ORR) >71% with a manageable safety profile in patients with relapsed / refractory multiple myeloma (RRMM) using the recommended phase 2 dose (RP2D) of subcutaneous tal (0.4 mg / kg weekly [QW] or 0.8 mg / kg every other week [Q2W]). The impact of reducing dosing intensity with bispecificity on safety and efficacy is an area of ​​clinical interest. This report describes the safety and efficacy of switching to less frequent or reduced tal dosing from MonomentalTAL-1.

[0351] method In Phase 1, patients were intolerant to or had progressed on established therapies and had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1. In Phase 2, patients had received ≥3 lines of prior therapy, including ≥1 proteasome inhibitor, ≥1 immunomodulatory agent, and ≥1 anti-CD38 monoclonal antibody, and had an ECOG PS of 0–2. Phase 1 included two planned cohorts: (A) a reduced-dosing cohort, in which patients treated with tal 0.8 mg / kg Q2W were allowed to switch to 0.4 mg / kg Q2W in the next cycle after confirmation of partial or better response (≥PR), and (B) a lower-frequency dosing cohort, in which patients treated with tal 0.8 mg / kg Q2W were allowed to switch to monthly (Q4W) 0.8 mg / kg in the next cycle after confirmation of ≥PR. Results from these planned Phase 1 cohorts were combined. Supportive analyses were also conducted on patients in phase ½ who received RP2D and switched to reduced dosing based on meeting the response criteria or reducing treatment-induced adverse events (TEAEs). Dosage reduction could be achieved by reducing dosing frequency or by reducing the dose. ORR was assessed according to IMWG criteria. TEAEs were graded according to CTCAE v4.03.

[0352] result A total of 45 patients were switched to a reduced-intensity dosing regimen. As of June 20, 2023, 24 patients were included in the expected cohort, with a median follow-up of 9.7 months. Overall, 9 / 12 patients achieved ≥PR by switching from 0.8 mg / kg Q2W to 0.4 mg / kg Q2W, and 10 / 12 patients achieved ≥PR by switching from Q2W to 0.8 mg / kg Q4W. Typically, patients were switched to a reduced-intensity dosing regimen during cycles 3 through 5. Following the dosing change, remission deepened in 11 / 19 patients, and remission was maintained in 5 / 19 patients; disease progression occurred in 3 / 19 patients. At 6 months post-switching, an estimated 88.9% of responders maintained remission. Oral-related TEAEs reported in 16 / 19 (84.2%) patients improved or disappeared in 4 patients between 1 and 6 months post-switching to a reduced-intensity dosing regimen. After 3 to 4 months, nail-related TEAEs reported in 7 / 19 (36.8%) patients improved or resolved in 2 patients. Skin-related TEAEs reported in 8 / 19 (42.1%) patients resolved in 3 patients after 1 to 3 months. Overall, improvements or resolution of oral, nail, and skin-related TEAEs were observed over time in some patients in the anticipated reduction and lower frequency dosing groups. No patients discontinued TAL due to these TEAEs. As of January 17, 2023, the supportive Phase 1 / 2 analysis included 20 patients who switched from TAL 0.4 mg / kg QW to a reduced dose (TEAE reduction, n=16; remission, n=3; both n=1), and 6 patients who switched from TAL 0.8 mg / kg Q2W to a reduced dose (TEAE reduction, n=4; remission, n=2). In patients switching from tal 0.4 mg / kg to a reduced dose, an estimated 84.2% and 78.9% of responders maintained remission at 9 months and 12 months, respectively. In patients switching from tal 0.8 mg / kg Q2W to a reduced dose, an estimated 100% and 80.0% of responders maintained remission at 9 months and 12 months, respectively.

[0353] Update results : As of September 17, 2023, 17 participants in the pivotal RP2D cohort of taquiltuzumab in MonomenTAL-1 reduced their taquiltuzumab dosing frequency from 0.8 mg / kg Q2W to 0.8 mg / kg Q4W due to the relief 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 a median PFS of 14.2 months for all participants in MonomenTAL-1 (0.8 mg / kg Q2W). Prior to the switch to Q4W dosing, all 17 participants (100%) experienced one or more study drug-related treatment-associated adverse events (TEAEs), while 12 participants (70.6%) experienced study drug-related TEAEs after the switch. Prior to the switch, 16 participants (94.1%) experienced Grade 3 or 4 events, and after the switch to Q4W dosing, 6 participants (35.3%) experienced Grade 3 or 4 events. To further address the less frequent dosing of talquitumab, a Phase 1 anticipated dose-reduction cohort was established in MonomenTAL-1, in which participants received talquitumab at 0.8 mg / kg SC Q2W until a confirmed PR or better response, followed by a reduction in talquitumab dosing frequency to Q4W. As of October 11, 2023, this cohort showed a median time to first response of 1.2 months and a median time to optimal response of 2.2 months for participants treated with talquitumab 0.8 mg / kg SC Q2W. Of the 12 participants enrolled in this cohort, 10 achieved a PR or better response and subsequently had their dosing frequency changed to 0.8 mg / kg SC Q4W, and 2 participants achieved optimal PD response. The dose-frequency change for the 10 participants with a PR or better response occurred on day 1 of cycles 3 through 5. Eight of the 10 participants maintained or deepened their response after switching to Q4W dosing. The proposed Q4W dosing schedule for talquitumab will maintain efficacy by balancing the maximum reduction in disease burden with participant convenience through dosing every two weeks during the first 6 cycles of treatment with reduced exposure to Q4W dosing starting from cycle 7 for participants with a confirmed PR or better response (or as early as cycle 5 for participants with a confirmed VGPR or better response).

[0354] in conclusion : Most patients who switched to a reduced-intensity dosing in MonomenTAL-1 experienced a deeper or maintained response to Tal. In the intended design cohort, GPRC5D-related TEAEs typically improved over time. Overall, reduced or less frequent Tal dosing may help alleviate these TEAEs while maintaining remission.

Claims

1. A method for treating multiple myeloma in a subject in need, the method comprising administering a therapeutically effective amount of a GPRC5DxCD3 bispecific antibody to the subject according to a monthly (Q4W) dosing schedule.

2. The method according to claim 1, wherein the GPRC5DxCD3 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 claim 1 or 2, wherein the GPRC5DxCD3 bispecific antibody comprises: a GPRC5D binding domain containing 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 containing 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 GPRC5DxCD3 bispecific antibody is an IgG1, IgG2, IgG3 or IgG4 isotype.

5. The method according to any one of claims 1 to 4, wherein the GPRC5DxCD3 bispecific antibody is an IgG4 isotype.

6. The method according to any one of claims 1 to 5, wherein the GPRC5DxCD3 bispecific antibody contains one or more substitutions in its Fc region.

7. The method according to any one of claims 1 to 6, wherein the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A and L235A substitutions (according to EU designations) in its Fc region.

8. The method according to any one of claims 1 to 7, wherein the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A, L235A, F405L and R409K substitutions (according to EU designations) in its Fc region.

9. The method according to any one of claims 1 to 8, wherein the Fc region of the GPRC5D bonding arm contains S228P, F234A and L235A replacements (according to EU designation) in its Fc region.

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

11. The method according to any one of claims 1 to 10, wherein the GPRC5DxCD3 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 GPRC5DxCD3 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 GPRC5DxCD3 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 GPRC5DxCD3 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 GPRC5DxCD3 bispecific antibody is taquituzumab.

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

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

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

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

20. The method according to any one of claims 1 to 16, wherein the subject has received at least three lines of prior treatment, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

21. The method according to any one of claims 1 to 16, wherein the subject has received at least four lines of prior treatment, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

22. The method according to any one of claims 1 to 21, wherein the method comprises subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody according to a monthly dosing schedule (Q4W).

23. The method according to any one of claims 1 to 22, the method comprising subcutaneously administering one or more escalating doses of the GPRC5DxCD3 bispecific antibody to the subject prior to administering a first therapeutic dose of the GPRC5DxCD3 bispecific antibody.

24. The method according to any one of claims 1 to 23, the method comprising subcutaneously administering the GPRC5DxCD3 bispecific antibody at a therapeutic dose of about 400 μg / kg to about 800 μg / kg according to the monthly dosing schedule (Q4W).

25. The method according to any one of claims 1 to 23, the method comprising subcutaneously administering the GPRC5DxCD3 bispecific antibody at a therapeutic dose of about 400 μg / kg according to the monthly dosing schedule (Q4W).

26. The method according to any one of claims 1 to 23, the method comprising subcutaneously administering the GPRC5DxCD3 bispecific antibody at a therapeutic dose of about 800 μg / kg according to the monthly dosing schedule (Q4W).

27. The method according to any one of claims 1 to 26, the method comprising subcutaneously administering at least one therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to a bi-weekly dosing schedule (Q2W), and subsequently administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to the monthly dosing schedule (Q4W).

28. The method according to any one of claims 1 to 27, the method comprising subcutaneously administering at least one therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to a weekly dosing schedule (QW), and subsequently administering at least one therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to a bi-weekly dosing schedule (Q2W), and subsequently administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to the monthly dosing schedule (Q4W).

29. The method according to any one of claims 1 to 28, the method comprising administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject according to a two-week dosing schedule (Q2W) for six treatment cycles, and, starting in the seventh treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to the monthly dosing schedule (Q4W).

30. The method according to any one of claims 1 to 28, the method comprising subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to a bi-weekly dosing schedule (Q2W) for 6 treatment cycles, and if the patient has achieved VGPR, CR or sCR as determined by the IMWG remission criteria, then, starting in the 7th treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to the monthly dosing schedule (Q4W).

31. The method according to any one of claims 1 to 28, the method comprising administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject according to a bi-weekly dosing schedule (Q2W) for 7 treatment cycles, and, starting in the 8th treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to the monthly dosing schedule (Q4W).

32. The method according to any one of claims 1 to 28, the method comprising subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to a bi-weekly dosing schedule (Q2W) for 7 treatment cycles, and if the patient has achieved VGPR, CR or sCR as determined by the IMWG remission criteria, then, starting in the 8th treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to the monthly dosing schedule (Q4W).

33. The method according to any one of claims 1 to 28, the method comprising administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject according to a two-week dosing schedule (Q2W) for eight treatment cycles, and, starting in the ninth treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to the monthly dosing schedule (Q4W).

34. The method according to any one of claims 1 to 28, the method comprising subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to a bi-weekly dosing schedule (Q2W) for eight treatment cycles, and if the patient has achieved VGPR, CR or sCR as determined by the IMWG remission criteria, then, starting in the ninth treatment cycle, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to the monthly dosing schedule (Q4W).

35. The method according to any one of claims 1 to 27, the method comprising subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to a bi-weekly dosing schedule (Q2W), and subsequently administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject subcutaneously according to the monthly dosing schedule (Q4W) during the 7th or 8th treatment cycle.

36. The method according to any one of claims 1 to 27, the method comprising subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to a bi-weekly dosing schedule (Q2W), and subsequently, if the subject has achieved complete or strict complete remission as determined by the IMWG remission criteria, subcutaneously administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject according to the monthly dosing schedule (Q4W) in the fifth treatment cycle.

37. The method according to any one of claims 27 to 36, wherein each therapeutic dose of the GPRC5DxCD3 bispecific antibody administered according to a weekly dosing schedule (QW), a bi-weekly dosing schedule (Q2W), or the monthly dosing schedule (Q4W) is the same.

38. The method according to any one of claims 27 to 36, wherein the GPRC5DxCD3 bispecific antibody is administered at a therapeutic dose of 800 μg / kg according to the bi-weekly dosing schedule (Q2W) and the monthly dosing schedule (Q4W).

39. The method according to any one of claims 1 to 38, wherein the method comprises subcutaneously administering two or three escalating doses of the GPRC5DxCD3 bispecific antibody prior to subcutaneous administration of the first therapeutic dose.

40. The method according to any one of claims 1 to 38, wherein the method comprises subcutaneously administering escalating doses of the GPRC5DxCD3 bispecific antibody at 10 μg / kg and 60 μg / kg prior to subcutaneous administration of a therapeutic dose.

41. The method according to any one of claims 1 to 38, wherein the method comprises subcutaneously administering escalating doses of the GPRC5DxCD3 bispecific antibody at doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg prior to the subcutaneous administration of a therapeutic dose.

42. The method according to any one of claims 1 to 41, wherein the method comprises subcutaneously administering escalating doses of the GPRC5DxCD3 bispecific antibody at intervals of 2 to 4 days.

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

44. The method according to any one of claims 1 to 42, wherein the subject achieves clinical remission as CR or sCR.

45. The method according to any one of claims 1 to 27, the method comprising administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject according to a bi-weekly dosing schedule (Q2W), and subsequently (i) if the subject has achieved very good partial remission, complete remission, or strictly complete remission as determined by the IMWG remission criteria, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject according to the monthly dosing schedule (Q4W) at the beginning of the 5th treatment cycle; or (ii) regardless of the clinical remission of the subject, administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject according to the monthly dosing schedule (Q4W) at the beginning of the 7th treatment cycle.

46. ​​The method of claim 45, wherein the GPRC5DxCD3 bispecific antibody is administered at a therapeutic dose of 800 μg / kg according to the bi-weekly dosing schedule (Q2W) and the monthly dosing schedule (Q4W).

47. The method according to any one of claims 45 to 46, wherein the method comprises subcutaneously administering two or three escalating doses of the GPRC5DxCD3 bispecific antibody prior to subcutaneous administration of the first therapeutic dose.

48. The method according to any one of claims 45 to 47, wherein the method comprises subcutaneously administering escalating doses of the GPRC5DxCD3 bispecific antibody at doses of 10 μg / kg and 60 μg / kg prior to subcutaneous administration of a therapeutic dose.

49. The method according to any one of claims 45 to 48, the method comprising subcutaneously administering escalating doses of the GPRC5DxCD3 bispecific antibody at 10 μg / kg, 60 μg / kg, and 400 μg / kg prior to subcutaneous administration of a therapeutic dose.

50. The method according to any one of claims 45 to 49, wherein the method comprises subcutaneously administering escalating doses of the GPRC5DxCD3 bispecific antibody at intervals of 2 to 4 days.

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

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

53. The method according to any one of claims 1 to 52, the method comprising treating the subject according to a treatment-effective regimen comprising consecutive 28-day GPRC5DxCD3 treatment cycles, wherein: During the escalation phase, one or more escalating doses of the GPRC5DxCD3 bispecific antibody were administered subcutaneously to the subject, and Following the escalation period, starting from the first GPRC5DxCD3 treatment cycle, the subject is given a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously according to a dosing schedule of every two weeks (Q2W), and subsequently, the subject is given a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously according to the dosing schedule of every month (Q4W).

54. The method according to any one of claims 1 to 53, the method comprising treating the subject according to a treatment-effective regimen comprising consecutive 28-day GPRC5DxCD3 treatment cycles, wherein: During the escalation phase, one or more escalating doses of the GPRC5DxCD3 bispecific antibody were administered subcutaneously to the subject, and Following the escalation period, starting from the first GPRC5DxCD3 treatment cycle, the subject is given a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously according to a two-week dosing schedule (Q2W), and subsequently, the subject is given a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously according to the monthly dosing schedule (Q4W): (i) if the subject has achieved a very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, then starting in the 5th treatment cycle; or (ii) regardless of the subject's clinical remission, starting in the 7th treatment cycle.

55. The method according to claim 53 or 54, wherein each treatment dose of the GPRC5DxCD3 bispecific antibody administered according to the bi-weekly dosing schedule (Q2W) and the monthly dosing schedule (Q4W) is 800 μg / kg.

56. The method according to any one of claims 53 to 55, wherein the first cycle of the regimen includes the escalation period, and starting from the second cycle, the therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject according to the bi-weekly dosing schedule (Q2W), and subsequently the therapeutic dose of the GPRC5DxCD3 bispecific antibody is administered subcutaneously to the subject according to the monthly dosing schedule (Q4W).

57. The method according to any one of claims 53 to 56, wherein the first cycle of the regimen includes the escalation period, and starting from the second cycle, the subject is subcutaneously administered the therapeutic dose of the GPRC5DxCD3 bispecific antibody according to the bi-weekly dosing schedule (Q2W), and subsequently the subject is subcutaneously administered the therapeutic dose of the GPRC5DxCD3 bispecific antibody according to the monthly dosing schedule (Q4W): (i) if the subject has achieved very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, then starting the fifth treatment cycle; or (ii) regardless of the subject's clinical remission, starting the seventh treatment cycle.

58. The method according to any one of claims 53 to 57, wherein one to three incremental doses of the GPRC5DxCD3 bispecific antibody are administered to the subject during the incremental period.

59. The method according to any one of claims 53 to 58, wherein the subject is administered two incremental doses of the GPRC5DxCD3 bispecific antibody during the incremental period.

60. The method according to any one of claims 53 to 58, wherein the subject is administered three incremental doses of the GPRC5DxCD3 bispecific antibody during the incremental period.

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

62. The method according to any one of claims 53 to 61, wherein, in addition to the one or more escalating doses, one or more therapeutic doses of the GPRC5DxCD3 bispecific antibody are also administered subcutaneously to the subject during the escalation period (e.g., according to a weekly dosing schedule).

63. The method according to any one of claims 53 to 61, wherein, in addition to the one or more escalating doses, one or two therapeutic doses of the GPRC5DxCD3 bispecific antibody are administered subcutaneously to the subject during the escalation period (e.g., according to a weekly dosing schedule).

64. The method according to any one of claims 53 to 63, wherein the first cycle of the regimen comprises a first incremental dose of 0.01 mg / kg, a second incremental dose of 0.06 mg / kg, a third incremental 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 the first cycle 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 claims 53 to 65, wherein the first cycle of the regimen comprises a first incremental dose of 0.01 mg / kg on day 1, a second incremental dose of 0.06 mg / kg on day 3, a third incremental 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 the second to sixth cycles of the said scheme comprises a Q2W treatment dose of 0.8 mg / kg on day 1 and day 15, and each of the seventh+ cycles comprises a Q4W treatment dose of 0.8 mg / kg on day 1.

68. The method according to any one of claims 53 to 66, wherein: (i) Each of cycles 2 through 6 of the regimen comprises a Q2W treatment dose of 0.8 mg / kg on days 1 and 15, and each of cycles 7+ comprises a Q4W treatment dose of 0.8 mg / kg on day 1, or (ii) Each of cycles 2 through 4 of the regimen comprises a Q2W treatment dose of 0.8 mg / kg on days 1 and 15, and if the subject has achieved very good partial remission, complete remission, or strict complete remission as determined by the IMWG remission criteria, each of cycles 5+ comprises a Q4W treatment dose of 0.8 mg / kg on day 1.

69. The method according to any one of claims 53 to 68, wherein the first cycle 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 treatment dose of 0.8 mg / kg on day 15; and each of the second to sixth cycles of the regimen comprises a Q2W treatment dose of 0.8 mg / kg on days 1 and 15; and each of the seventh+ cycles comprises a Q4W treatment dose of 0.8 mg / kg on day 1.

70. The method according to any one of claims 53 to 68, wherein the first cycle of said regimen comprises a first escalation dose of 0.01 mg / kg on day 1, a second escalation dose of 0.06 mg / kg on day 3, a third escalation dose of 0.4 mg / kg on day 8, and a treatment dose of 0.8 mg / kg on day 15; and any one of the following: (i) Each of cycles 2 through 6 of the regimen comprises a Q2W treatment dose of 0.8 mg / kg on days 1 and 15, and each of cycles 7+ comprises a Q4W treatment dose of 0.8 mg / kg on day 1, or (ii) Each of the second to fourth cycles of the regimen comprises a Q2W treatment dose of 0.8 mg / kg on day 1 and day 15, and each of the fifth+ cycles comprises a Q4W treatment dose of 0.8 mg / kg on day 1 if the subject has achieved very good partial remission, complete remission or strict complete remission as determined by the IMWG remission criteria.

71. The method according to any one of claims 1 to 70, wherein the dosing regimen comprising the monthly (Q4W) dosing schedule achieves a lower incidence of adverse events and / or a shorter duration of adverse events than a dosing regimen comprising a weekly (QW) and / or bi-weekly (Q2W) dosing schedule instead of a monthly (Q4W) dosing schedule.

72. The method of claim 71, wherein the adverse events include one or more of the following: oral toxicity (e.g., loss of taste, taste disorder, dry mouth and / or difficulty swallowing) and / or nail toxicity (e.g., nail disease) and / or skin toxicity (e.g., dry skin, skin peeling and / or itching).

73. The method according to any one of claims 1 to 72, wherein the dosing regimen comprising the monthly (Q4W) dosing schedule achieves a stronger clinical response and / or a longer duration of clinical response than a dosing regimen comprising a weekly (QW) and / or bi-weekly (Q2W) dosing schedule instead of a monthly (Q4W) dosing schedule.

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