Methods for treating multiple myeloma

Abstract

Embodiments of the invention relate to methods of reducing oral toxicity, such as taste impairment, in a subject receiving treatment with a targeted GPRC5D therapeutic agent.

Description

Cross Reference to Related Applications

[0001] This application claims priority to U.S. Provisional Application Serial No. 63 / 514,744, filed July 20, 2023, the entirety of which is incorporated by reference herein.

[0002] INCORPORATION BY REFERENCE OF THE SEQUENCE LISTING FILE SUBMITTED ELECTRONICALLY

[0003] This application contains a Sequence Listing submitted electronically in XML format and is hereby incorporated by reference in its entirety. The XML copy, created on June 21, 2024, is named “258199061702 (JBI6826WOPCT1) SequenceListing.xml” and is 25,460 bytes in size. TECHNICAL FIELD

[0004] Methods of treating multiple myeloma are disclosed. BACKGROUND

[0005] Multiple myeloma (MM) is a cancer of plasma cells. Mechanistically, multiple myeloma is characterized by the production of monoclonal proteins (M proteins) composed of pathologic immunoglobulins or fragments of such pathologic immunoglobulins that have lost their function. Proliferation of multiple myeloma cells leads to subsequent displacement from the normal bone marrow niche, while overproduction of M proteins causes characteristic osteolytic lesions, increased susceptibility to infection, hypercalcemia, renal dysfunction or failure, and neurological complications.

[0006] Therapeutic 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. Therapeutic options include proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), alkylating agents, monoclonal antibodies (mAbs), antibody drug conjugates, histone deacetylase inhibitors, nuclear protein export inhibitors, chimeric antigen receptor (CAR) T cell therapy, and stem cell transplantation.

[0007] Despite these therapeutic achievements, the disease recurs and is associated with additional risk factors (e.g., comorbidities or increased age), thus warranting the need for new therapeutic approaches, such as new dosages and treatment regimens. In particular, in the elderly population, stem cell transplantation is often not a viable option, and in patients with refractory disease who have been treated with several therapies, multiple myeloma remains an incurable malignancy and unmet medical need with significant morbidity and mortality. Specifically, there remains a need for treatment regimens that enable rapid, deep, and durable clinical remission, while providing manageable safety profiles. There remains a need for treatment regimens that provide improved side effect profiles and quality of life for patients. Summary of the Invention

[0008] One embodiment of the present invention provides a method for reducing oral toxicity in a subject receiving treatment with a targeted GPRC5D therapeutic agent, the method comprising administering a preventive intervention against oral toxicity to the subject prior to administration of a therapeutically effective amount of the targeted GPRC5D therapeutic agent throughout the treatment phase, wherein the preventive intervention is selected from the group consisting of dexamethasone, pregabalin, clonazepam, and combinations thereof.

[0009] In some implementations, the GPRC5D-targeting therapeutic agent is a GPRC5DxCD3 bispecific antibody, such as talquetamab.

[0010] In some embodiments, 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.

[0011] 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.

[0012] In some implementations, the GPRC5DxCD3 bispecific antibody is an IgG1, IgG2, IgG3, or IgG4 isotype.

[0013] In some implementations, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype.

[0014] In some implementations, the GPRC5DxCD3 bispecific antibody contains one or more substitutions in its Fc region.

[0015] In some implementations, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A, and L235A substitutions in its Fc region.

[0016] In some implementations, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A, L235A, F405L, and R409K substitutions in its Fc region.

[0017] In some embodiments, the Fc region of the GPRC5D-specific IgG4 antibody that derives the GPRC5D binding arm contains S228P, L234A, and L235A substitutions in its Fc region.

[0018] In some embodiments, the Fc region of the CD3-specific IgG4 antibody that derives the CD3-binding arm contains S228P, L234A, L235A, F405L, and R409K substitutions. 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.

[0019] 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.

[0020] 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.

[0021] 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.

[0022] In some implementations, the GPRC5DxCD3 bispecific antibody is taquituzumab.

[0023] In some implementations, the subject has been diagnosed with multiple myeloma.

[0024] In some implementations, the subjects had relapsed or refractory multiple myeloma (RRMM).

[0025] In some implementation schemes, the subjects have received at least three lines of prior treatment.

[0026] In some implementation schemes, the subjects have received at least four lines of prior treatment.

[0027] In some implementation schemes, subjects have received at least five lines of prior treatment (five drug exposures).

[0028] In some implementation schemes, subjects have received at least three lines of prior therapy, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0029] In some implementation schemes, subjects have received at least four lines of prior therapy, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0030] In some implementation schemes, the preventative intervention is dexamethasone.

[0031] In some implementations, the preventative intervention is dexamethasone mouthwash (an oral solution containing dexamethasone), for example, 0.5 mg dexamethasone twice daily.

[0032] In some implementations, the preventative intervention is a 0.1 mg / mL dexamethasone mouthwash (e.g., 0.5 mg dexamethasone twice daily).

[0033] In some embodiments, the method includes administering dexamethasone mouthwash in a dose of 5 mL (e.g., 0.5 mg / 5 mL) twice daily (e.g., wherein the subject rinses his mouth with the mouthwash for about 5 minutes without swallowing, and preferably does not eat or drink for about 30 minutes afterward).

[0034] In some implementations, the method includes applying dexamethasone mouthwash twice daily in a dose of 5 mL and applying 50 mg of fluconazole once daily (e.g., to prevent oral thrush).

[0035] In some implementations, the method includes increasing the dose of dexamethasone mouthwash up to a maximum of four times daily after an event of decreased taste score (≥6 points).

[0036] In some implementations, the preventive intervention is pregabalin (e.g., in capsule or tablet form, preferably 50 mg capsules).

[0037] In some implementations, the method includes administering pregabalin at a dose of 50 mg twice daily.

[0038] In some implementations, the method includes increasing the dose of pregabalin after an event of decreased taste score (≥6 points).

[0039] In some implementations, the method includes increasing the dose of pregabalin to 150 mg / day initially, and then to a maximum of 300 mg / day after one week following an event of decreased taste score (≥6 points).

[0040] In some implementation schemes, the preventative intervention is clonazepam.

[0041] In some implementations, the preventive intervention is clonazepam mouthwash (e.g., 0.5 mg clonazepam twice daily).

[0042] In some implementations, the preventative intervention is clonazepam orally disintegrating tablets (ODT) (e.g., 0.5 mg clonazepam orally disintegrating tablets (ODT), twice daily).

[0043] In some implementations, the preventative intervention is a 0.1 mg / mL clonazepam mouthwash.

[0044] In some embodiments, the method includes administering 0.1 mg / mL clonazepam mouthwash at a dose of 5 mL (e.g., 0.5 mg / 5 mL) twice daily (e.g., wherein the subject rinses his mouth with the mouthwash for about 5 minutes without swallowing, and preferably does not eat or drink for about 30 minutes afterward).

[0045] In some implementations, the method includes continuing to use clonazepam mouthwash at the same dose if the taste score (measured by taste test strips) has decreased by 6 points or more.

[0046] In some implementations, the method includes administering a prophylactic intervention, 5 to 9 days prior to the administration of a first dose (e.g., a first escalation dose) of the targeted GPRC5D therapeutic agent.

[0047] In some implementations, the method includes a preventative intervention of administering a first dose 6 to 8 days prior to administering a first dose (e.g., a first escalation dose) of the targeted GPRC5D therapeutic agent, and continuing to administer the preventative intervention daily throughout the treatment phase.

[0048] In some implementations, the method includes a preventative intervention of administering a first dose 7 days prior to administering a first dose (e.g., a first escalation dose) of the targeted GPRC5D therapeutic agent, and continuing to administer the preventative intervention daily throughout the treatment phase.

[0049] In some implementations, the method includes administering a preventative intervention daily for 5 to 9 days prior to the administration of a first dose (e.g., a first escalation dose) of the targeted GPRC5D therapeutic agent, and continuing to administer the preventative intervention daily throughout the treatment phase.

[0050] In some implementations, the method includes administering a preventative intervention for 6 to 8 days daily prior to the administration of a first dose (e.g., a first escalation dose) of the targeted GPRC5D therapeutic agent.

[0051] In some implementations, the method includes administering a preventative intervention for 7 days daily prior to the administration of a first dose (e.g., a first escalation dose) of the targeted GPRC5D therapeutic agent.

[0052] 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 therapeutic dose of the GPRC5DxCD3 bispecific antibody.

[0053] In some implementations, the method includes administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject weekly (QW).

[0054] In some implementations, the method includes administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject every two weeks (Q2W).

[0055] In some implementations, the method includes subcutaneous administration of the GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 400 μg / kg weekly (QW).

[0056] In some implementations, the method includes subcutaneous administration of the GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 800 μg / kg every two weeks (Q2W).

[0057] In some embodiments, the method includes subcutaneously administering two or three escalating doses of the GPRC5DxCD3 bispecific antibody prior to the subcutaneous administration of a therapeutic dose.

[0058] In some embodiments, the method includes subcutaneous administration of escalating doses of GPRC5DxCD3 bispecific antibody at 10 μg / kg and 60 μg / kg prior to the administration of a therapeutic dose;

[0059] In some embodiments, the method includes subcutaneously administering escalating doses of GPRC5DxCD3 bispecific antibody at doses of 10 μg / kg, 60 μg / kg, and 400 μg / kg prior to the administration of a therapeutic dose.

[0060] In some implementations, the method includes subcutaneous administration of escalating doses of the GPRC5DxCD3 bispecific antibody at intervals of 2 to 4 days.

[0061] In some embodiments, the method includes subcutaneous administration of the GPRC5DxCD3 bispecific antibody according to the following dosing schedule for the first 28-day treatment cycle: 0.01 mg / kg exothermic escalator 1 (day 1), followed by 0.06 mg / kg escalator 2 (day 4), followed by 0.4 mg / kg escalator 3 (day 8), followed by a first treatment dose of 0.8 mg / kg (day 15).

[0062] In some implementations, the escalating doses are administered at intervals of ≥2 days, and the first treatment dose is administered ≥2 days after escalating dose 3, between day 7 and day 15.

[0063] In some implementations, for subsequent 28-day treatment cycles (cycle 2+) following the first 28-day treatment cycle, the GPRC5DxCD3 bispecific antibody is administered at 0.8 mg / kg Q2W (e.g., on day 1 and day 15 of each treatment cycle) 14 ± 3 days after the previous treatment dose.

[0064] In some implementations, the subject exhibits reduced oral toxicity (e.g., reduced taste impairment) compared to subjects who did not receive the same preventative intervention, as determined, for example, by taste assessment using taste test strips.

[0065] In some implementations, the subject experiences less oral toxicity (e.g., less taste impairment) compared to subjects who do not receive the same preventative intervention, for example, as determined by taste assessment using taste test strips.

[0066] In some implementations, the subject has a reduced degree of oral toxicity (e.g., a reduced degree of taste impairment) compared to a subject who did not receive the same preventative intervention, for example, as determined by taste assessment using taste test strips.

[0067] In some implementations, the subject does not experience oral toxicity (e.g., no taste impairment) due to preventive interventions (oral toxicity, such as taste impairment, is prevented), for example, as determined by taste assessment using taste test strips.

[0068] In some implementations, the method reduces the proportion of subjects in the population who experience at least one instance of a deterioration in taste score by 6 or more points relative to baseline during the treatment phase, such as by measuring taste test strips, for example, by standard taste assessment.

[0069] In some implementations, the subject exhibits one or more of the following clinical outcomes (e.g., as determined by the total WETT test score):

[0070] 1. The incidence of taste dysfunction (hypopnea) was lower in subjects who did not receive the same preventive interventions, and / or

[0071] 2. The incidence of severe hypogesia / loss of taste was lower in subjects who did not receive the same preventive intervention, and / or

[0072] 3. Compared with subjects who did not receive the same preventive intervention, the time to first occurrence of severe taste reduction / loss was longer, and / or

[0073] 4. Compared with subjects who did not receive the same preventive intervention, the remission / improvement rate of taste reduction / loss was higher at 3 and 6 months.

[0074] However, all the methods described in this article, however expressed, can be described as having the corresponding uses, especially medical uses. Attached Figure Description

[0075] The following figures form part of this specification and are included to further illustrate certain aspects of the invention. A better understanding of the invention can be achieved by referring to one or more of these figures in conjunction with the description of specific embodiments given herein.

[0076] Figure 1The study design of a phase 2, open-label, randomized study (TALISMAN study) for evaluating preventive interventions for taquituzumab-related oral toxicity is provided.

[0077] Figure 2 A standardized WETT-SA53 percentile table is provided. Detailed Implementation

[0078] 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.

[0079] As used in this article, the singular forms “a,” “a,” and “the” include the plural forms.

[0080] 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.

[0081] 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.

[0082] "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.

[0083] 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 peptides, enzyme-catalyzed peptides, or genetically engineered peptides, including 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; camelified VH domains; and minimal recognition units consisting of amino acid residues of antibody CDRs, 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.

[0084] "Bispecific" refers to antibodies that specifically bind to two different antigens or two different epitopes within the same antigen. Bispecific antibodies may have cross-reactivity with other related antigens, for example, cross-reactivity with the same antigen from other species (homologous) (such as humans or monkeys, such as cynomolgus macaques or pantroglodytes), or they may bind to epitopes shared between two or more different antigens.

[0085] "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.

[0086] "CD3" refers to a human antigen expressed on T cells as part of a multimolecular T-cell receptor (TCR) complex and composed of homodimers or heterodimers formed by the association of two or four receptor chains: CD3ε, CD3δ, CD3ζ, and CD3γ. The human CD3ε chain contains the amino acid sequence of SEQ ID NO: 2. SEQ ID NO: 3 shows the extracellular domain of the CD3ε chain.

[0087] SEQ ID NO: 2

[0088] MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGS KPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI

[0089] SEQ ID NO: 3

[0090] DGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMD

[0091] 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] "In combination with" means administering two or more therapeutic agents together to the subject as a mixture, as a single agent to the subject simultaneously, or as a single agent to the subject in any order.

[0093] The complementarity-determining region (CDR) is the antibody region that binds to the antigen. CDRs can be defined using various descriptions, such as Kabat (Wu et al., J Exp Med 132: 211-50, 1970) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al., J Mol Biol 196: 901-17, 1987), IMGT (Lefranc et al., Dev Comp Immunol 27: 55-77, 2003), and AbM (Martin and Thornton, J Bmol Biol 263: 800-15, 1996). The correspondence between various depictions and variable region numbers is described (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 methods described above (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.

[0094] 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.”

[0095] "Reducing oral toxicity" refers to reducing the severity of oral toxicity in subjects, and / or reducing the occurrence of oral toxicity in subjects, and / or preventing the occurrence of oral toxicity in subjects.

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

[0097] "GPRC5D-targeting therapeutic agents" refer to therapeutic agents, such as antibodies, that bind to GPRC5D on multiple myeloma cells.

[0098] "GPRC5DxCD3 bispecific antibody" refers to a bispecific antibody that specifically binds to GPRC5D and CD3.

[0099] "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 germline immunoglobulin gene or rearranged immunoglobulin gene. In some cases, a "human antibody" may comprise 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.

[0100] "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.

[0101] "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.

[0102] "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.

[0103] 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.

[0104] 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.

[0105] "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.

[0106] "Pharmaceutical composition" refers to a composition containing an active ingredient and a pharmaceutically acceptable carrier.

[0107] "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.

[0108] As used herein, “preventive intervention for oral toxicity” means that the treatment using the preventive intervention is initiated before the start of the treatment phase of the GPRC5D-targeted therapeutic agent (i.e., before the subject receives the first dose of the GPRC5D-targeted therapeutic agent); preferably, the preventive intervention continues after the subject has started treatment with the GPRC5D-targeted therapeutic agent (i.e., the subject receives the preventive intervention before, and preferably during, the treatment phase of the GPRC5D-targeted therapeutic agent).

[0109] "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.

[0110] "Refractory" refers to cancers that are not suitable for surgical intervention and do not initially respond to treatment.

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

[0112] "Escalation 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), a "trigger" dosing strategy may include one or more lower escalation doses followed by a higher therapeutic dose.

[0113] "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.

[0114] "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.

[0115] "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.

[0116] "Treatment" or "management" refers to both therapeutic measures and preventative or defensive actions, with the goal of preventing or mitigating (alleviating) 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.

[0117] "Therapeutic dose" refers to the dose of an active agent administered to a subject for the treatment of a disease. Therapeutic doses may be administered repeatedly at regular dosing intervals (e.g., once a week, once every two weeks). One or more escalating doses may precede the therapeutic dose.

[0118] As used herein, a “treatment phase” refers to a period of time during which a subject receives a targeted GPRC5D therapeutic agent according to a dosing schedule, including any escalation doses and therapeutic doses, starting from the subject receiving the first dose of the targeted GPRC5D therapeutic agent (e.g., the first escalation dose) and continuing until the subject discontinues treatment with the targeted GPRC5D therapeutic agent. For example, a treatment phase may begin when the subject receives the first escalation dose and continue for weeks or months as the subject receives subsequent escalation doses and therapeutic doses.

[0119] "Category III exposure" patients are those diagnosed with multiple myeloma (MM) who have previously (at least) received treatment with proteasome inhibitors (PIs), immunomodulatory agents, and anti-CD38 monoclonal antibodies.

[0120] "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.

[0121] Unless otherwise explicitly stated, throughout this 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 ed., 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.

[0122] This article uses the standard single-letter and three-letter amino acid codes as shown in Table 1.

[0123] Table 1 .

[0124]

[0125] GPRC5DxCD3 bispecific antibodies and uses thereof

[0126] Multiple myeloma (MM) remains an incurable malignancy and an unmet medical need with significant morbidity and mortality in patients with relapsed or refractory disease who have exhausted multiple therapies. Despite treatment advances including agents such as proteasome inhibitors (PIs), immunomodulatory drugs (ImiDs), and monoclonal antibodies (mAbs), the disease remains the most frequently relapsed. In the first prospective real-world standard-of-care study of patients with relapsed or refractory multiple myeloma (RRMM) with three types of exposure, the regimen used showed no clear standard of care and resulted in poor outcomes in patients with three types of exposure who had undergone extensive pretreatment. T-cell retargeting agents targeting CD3 and epitopes such as BCMA, FcRH5, and GPRC5D, as well as anti-BCMA CAR-T cells, have broadened the range of treatment options. These new treatment regimens targeting alternative mechanisms of action can better control the disease, provide deeper and more durable responses, and better long-term outcomes, including maintaining health-related quality of life. However, the specific toxicities of these new agents should be better investigated and managed. Despite significant progress, MM remains an incurable malignant tumor and represents an unmet medical need with significant morbidity and mortality.

[0127] GPRC5D is a 7-transmembrane receptor protein whose expression has been shown to be limited to normal plasma cells and hardened keratinized tissues (such as hair follicles). The relatively limited expression of GPRC5D makes it a target with a relatively low risk of on-target / detumescent toxicity, designating it as a suitable target for T-cell (T-cell)-mediated therapies for plasma cell diseases such as multiple myeloma. Taquituzumab is a novel humanized IgG4 bispecific antibody designed to target the CD3 receptor complex on T cells and multiple myeloma cells expressing GPRC5D, leading to T-cell activation and subsequent lysis of GPRC5D-expressing cells.

[0128] Oral toxicity is one of the most frequently reported adverse events (AEs) associated with taquitumab treatment. Characterized by dry mouth, taste disturbances, and / or dysphagia, oral toxicity is of particular concern due to its potential to reduce patients' quality of life, cause weight loss, and lead to discontinuation of taquitumab treatment. In the MonumenTAL-1 clinical trial, the discontinuation rate was approximately 5%. The etiology of oral toxicity following taquitumab treatment remains to be elucidated. Targeted, detumescent effects of GPRC5D-directed T cells may be a factor; however, GPRC5D expression can only be confirmed in filiform papillae. Filiform papillae are the most numerous papillae, distributed across the anterior two-thirds of the dorsal surface of the tongue, and they are not associated with taste receptors. Drugs capable of treating or reversing oral toxicity associated with GPRC5D-targeted therapies remain to be identified, and the pathogenesis of this oral toxicity side effect requires further investigation.

[0129] The inventors have developed novel treatment regimens to reduce or prevent oral toxicity and / or mitigate its severity in subjects receiving targeted GPRC5D therapeutic agents (such as GPRC5DxCD3 bispecific antibodies). In a preferred embodiment, prophylactic use of one or more of these treatment regimens reduces oral side effects (e.g., taste impairment) of targeted GPRC5D treatment compared to no prophylaxis, thereby improving quality of life and maintaining subject adherence to the targeted GPRC5D dosing regimen.

[0130] As used herein, oral toxicity includes dry mouth and / or taste impairment (altered taste and / or loss of taste) and / or difficulty swallowing. Taste impairment may include taste disturbance and / or decreased taste and / or loss of taste.

[0131] Antibodies of the invention

[0132] In view of this disclosure, any suitable GPRC5D-targeting therapeutic agent known to those skilled in the art can be used in this invention. In a preferred embodiment, the GPRC5D-targeting therapeutic agent is a GPRC5DxCD3 bispecific antibody.

[0133] 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.

[0134] In some embodiments, the GPRC5DxCD3 bispecific antibody comprises any one of the GPRC5D binding domains described in U.S. Patent No. 10,562,968, the entire contents of which are incorporated herein by reference. In some embodiments, the GPRC5DxCD3 bispecific antibody comprises any one of the CD3 binding domains described in U.S. Patent No. 10,562,968. In some embodiments, the GPRC5DxCD3 bispecific antibody comprises any one of the bispecific antibodies described in U.S. Patent No. 10,562,968.

[0135] In some implementations, the GPRC5DxCD3 bispecific antibody is chimeric, humanized, or human.

[0136] 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.

[0137] SEQ ID NO: 34:

[0138] ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0139] 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 sequence of the antibody. Table 2 shows the selected IgG1, IgG2, and IgG4 allotypes.

[0140] Table 2 .

[0141]

[0142] 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.

[0143] 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.

[0144] The Fc substitution that can be used to reduce CDC is the K322A substitution.

[0145] The well-known S228P substitution can also be performed in IgG4 antibodies to enhance IgG4 stability.

[0146] 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.

[0147] 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.

[0148] 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 conform to the EU index.

[0149] 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.

[0150] Tables 3 and 4 provide sequences of exemplary embodiments of the GPRC5DxCD3 bispecific antibody according to the Kabat numbering system.

[0151] Table 3. Sequences of GPRC5D binding arms

[0152]

[0153] Table 4. Sequences of CD3 binding arms

[0154]

[0155] 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.

[0156] Taquetumab is a GPRC5D-directed bispecific antibody that is being developed for the treatment of patients with relapsed or refractory multiple myeloma. See, for example, Chari A et al., Blood 2022; 140 (suppl 1): 384-387, which is incorporated herein by reference. Taquetumab is a bispecific GPRC5D-directed CD3 T-cell connector that is being developed as a monotherapy for the treatment of 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.

[0157] 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.

[0158] Further embodiments of the GPRC5DxCD3 bispecific antibody that can be used according to the present invention are described below.

[0159] In some embodiments, 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.

[0160] 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.

[0161] In some implementations, the GPRC5DxCD3 bispecific antibody is an IgG1, IgG2, IgG3, or IgG4 isotype.

[0162] In some implementations, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype.

[0163] In some implementations, the GPRC5DxCD3 bispecific antibody contains one or more substitutions in its Fc region.

[0164] In some implementations, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A, and L235A substitutions in its Fc region.

[0165] In some implementations, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A, L235A, F405L, and R409K substitutions in its Fc region.

[0166] In some embodiments, the Fc region of the GPRC5D-specific IgG4 antibody that derives the GPRC5D binding arm contains S228P, L234A, and L235A substitutions in its Fc region.

[0167] In some embodiments, the Fc region of the CD3-specific IgG4 antibody that derives the CD3-binding arm contains S228P, L234A, L235A, F405L, and R409K substitutions. 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.

[0168] 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.

[0169] 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.

[0170] 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.

[0171] In some implementations, the GPRC5DxCD3 bispecific antibody is taquituzumab.

[0172] Multiple myeloma patient population

[0173] In some implementations, the GPRC5DxCD3 bispecific antibody disclosed herein is used to treat multiple myeloma in subjects (e.g., human subjects) who are relapsed or refractory to 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.

[0174] In some implementations, the subject is relapsed or refractory to treatment with agents used to treat multiple myeloma or other hematologic malignancies.

[0175] In some implementations, the subject has been treated with 1 to 11 lines of prior therapy or 1 to 10 lines of prior therapy.

[0176] In some implementations, the subject has previously undergone autologous stem cell transplantation (ASCT).

[0177] In some implementation schemes, the subjects have received at least three lines of prior treatment.

[0178] In some implementation schemes, the subjects have received at least four lines of prior treatment.

[0179] In some implementation schemes, subjects have received at least five lines of prior treatment (five drug exposures).

[0180] In some implementation schemes, subjects have received at least three lines of prior therapy, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0181] In some implementation schemes, subjects have received at least four lines of prior therapy, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

[0182] 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.

[0183] In some implementations, the subjects had received three prior anticancer therapies before receiving the GPRC5DxCD3 bispecific antibody.

[0184] 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.

[0185] 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 ixartuximab. In another embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (iMiD) is pomalidomide, and the anti-CD38 antibody is daratumumab. In another embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (iMiD) is pomalidomide, and the anti-CD38 antibody is ixartuximab. In another embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (iMiD) is thalidomide, and the anti-CD38 antibody is ixartuximab. In another embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (iMiD) is thalidomide, and the anti-CD38 antibody is ixartuximab.

[0186] 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 ixartuximab. 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 ixartuximab. In another embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (iMiD) is thalidomide, and the anti-CD38 antibody is ixartuximab. In another embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (iMiD) is thalidomide, and the anti-CD38 antibody is ixartuximab.

[0187] In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (iMiD) is lenalidomide, and the anti-CD38 antibody is daratumumab. In another embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (iMiD) is lenalidomide, and the anti-CD38 antibody is ixazomib. In another embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (iMiD) is pomalidomide, and the anti-CD38 antibody is daratumumab. In another embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (iMiD) is pomalidomide, and the anti-CD38 antibody is ixazomib. In another embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (iMiD) is thalidomide, and the anti-CD38 antibody is daratumumab. In another embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (iMiD) is thalidomide, and the anti-CD38 antibody is ixazomib.

[0188] In some implementations, the subject has relapsed or refractory history to treatment with one or more treatments or therapies, such as THALOMID. ® (Thalidomide), REVLIMID ® (Lenalidomide), POMALYST ® (Pomalidomide), Velcade ® (Bortezomib), NINLARO (Ixazomib), KYPROLIS ® (Carfizomi), FARADYK ® (elinexoratt), AREDIA ® (pamidronic acid), ZOMETA® (Zoledronic acid), DARZALEX ® (Daratumumab), Erotozumab or Melphalan, Xpovio ® (Celiniso), Venclexta ® (Veneclax), GSK 916, CAR-T therapy, or other targeted BCMA therapies.

[0189] 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.

[0190] In some implementations, multiple myeloma is relapsed or refractory to treatment with the following agents: anti-CD38 antibody, celinizol, veneclade, lenalidomide, bortezomib, pomalidomide, carfilzomib, erlotuzumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[0191] In one implementation, the anti-CD38 antibody is daratumumab.

[0192] In another implementation, the anti-CD38 antibody is exatuximab.

[0193] 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.

[0194] Cytogenetic abnormalities can be detected, for example, by fluorescence in situ hybridization (FISH). In two 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 a protein containing the multiple myeloma SET domain (MMSET) (also known as WHSC1 / NSD2), while t(14; 16)(q32; q23) involves a translocation of the MAF transcription factor C-MAF. 17p deletion (del17p) involves the loss of the p53 locus.

[0195] Chromosomal rearrangements can be identified using well-known methods, such as fluorescence in situ hybridization, chromosome karyotyping, pulsed-field gel electrophoresis, or sequencing.

[0196] Prophylactic interventions against GPRC5D-related oral toxicity

[0197] The inventors have developed novel treatment regimens to reduce or prevent oral toxicity (such as taste impairment) and / or mitigate its severity in subjects receiving GPRC5D-targeting therapeutic agents (such as GPRC5DxCD3 bispecific antibodies (e.g., taquituzumab)).

[0198] 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.

[0199] 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.

[0200] As used herein, “Q2W” (also known as “bi-weekly” or “every two weeks”) means a frequency of once every two weeks, while “QW” (also known as “once a week”) means a frequency of once a week. The once-weekly (QW) administration of treatment doses is also referred to herein as a weekly dosing schedule. The once-every-two-week (Q2W) administration of treatment doses is also referred to herein as a bi-weekly dosing schedule. As used herein, “Q4W” means a frequency of once every four weeks. Q4W is sometimes also referred to herein as “once a month,” but technically refers to once every four weeks or once every 28 days (e.g., in a 28-day cycle, the first treatment dose is administered on day 1 of cycle 1, the second treatment dose is administered on day 1 of cycle 2, and so on).

[0201] 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.

[0202] Table 7

[0203]

[0204] 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

[0205] 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.

[0206] *Explanation of the IMWG criteria used to encode CR and VGPR in subjects where the only measurable disease is expressed through 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.

[0207] The IMWG criteria for remission in the treatment of 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 consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016; 17(8):e328-346; Rajkumar SV, Harousseau JL, Durie B et al., Consensus recommendations for the uniform reporting of clinical Trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011; 117(18):4691-4695.

[0208] In some implementations, a subject's response to the preventative intervention described herein can be tested using one or more of the following procedures:

[0209] - Taste assessment using WETT, as described in this article;

[0210] - Taste assessment using taste test strips (e.g., according to the standard taste assessment described herein);

[0211] -Based on the NCI-CTCAE 5.0 classification of taste disorders;

[0212] -PRO: EORTC-QLQ-C30 / OH-15, STTA, Dry Mouth Questionnaire, and PRO-CTCAE Oral Toxicity Project;

[0213] - Measurement of stimulating and non-stimulating saliva flow;

[0214] - Tongue and / or salivary gland biopsy (optional)

[0215] According to one implementation plan, taste test strips are used to assess the subject's sense of taste according to the following procedure, referred to herein as "standard taste assessment":

[0216] Standard taste assessment :

[0217] - The taste test strip is 8cm long and 2cm² in area. 2 It is infused with taste stimulants. The lowest concentration of each taste quality should be recognizable by only half of the healthy individuals; the highest concentration should be recognizable by approximately 100% of the participants.

[0218] - Four concentrations are used for each taste quality (sweet, sour, salty, bitter, umami) (4 = minimum concentration, 1 = maximum concentration).

[0219] - Taste test strips (plus 2 blank strips without taste) are presented in ascending order of concentration (Table 11). Two sequences of 22 taste test strips in each group (4 concentrations for each taste quality plus 2 blanks) were administered in pseudo-random order.

[0220] - Prior to the procedure, subjects were instructed to avoid eating, drinking, or using tobacco products (including e-cigarettes or e-cigarette equivalents, excluding nicotine patches) for 30 minutes to 1 hour prior to the procedure.

[0221] Procedure :

[0222] 1. Select one sequence from the sequences A / C, A / D, B / C, or B / D as shown in Table 11 for evaluation. The order is changed for each evaluation.

[0223] 2. Place the taste test strip in the middle of the tongue, about 1.5 cm from the tip of the tongue.

[0224] 3. The participants were asked to close their mouths and choose one of six possible answers (sweet, sour, salty, bitter, umami, or tasteless) from a form.

[0225] 4. Before using the next taste test strip for evaluation, the subject is asked to rinse their mouth with water.

[0226] 5. After the evaluation is completed, the total score is calculated based on the highest score for each taste. The test can award a maximum of 4 points for each taste quality, with the highest (i.e., the best) total score being 20 points.

[0227] Table 11 : Taste strips sequence

[0228]

[0229] As used herein, “baseline taste score” refers to a subject’s taste score prior to receiving treatment with a targeted GPRC5D agent; for example, a subject’s baseline taste score may be obtained within 7 days prior to receiving the first dose of the targeted GPRC5D agent. In a preferred embodiment, the baseline taste score is determined by averaging two taste assessment scores: (a) 1 to 7 days prior to Day 1 of GPRC5D treatment (i.e., Day -7 to Day -1) and (b) Day 1 of GPRC5D treatment (where “Day 1 of GPRC5D treatment” refers to the day the subject receives the first dose of the targeted GPRC5D agent).

[0230] According to an alternative implementation, the subject's sense of taste is assessed according to the following procedure, referred to herein as the "Waterless Experience Taste Test (WETT)," which is commercially available.

[0231] Taste evaluation using taste strips (WETT) :

[0232] The taste assessment uses a 1cm x 6cm plastic strip with a proprietary monomeric cellulose pad embedded with sucrose (sweet), citric acid (acidic), sodium chloride (salty), caffeine (bitter), monosodium glutamate (umami), or a blank taste agent.

[0233] Each taste quality (sweet, sour, salty, bitter, umami) is tested at four concentrations (4 = lowest concentration, 1 = highest concentration). No rinsing with liquid is required. Taste test strips (plus 7 tasteless blank strips) are presented in a predetermined pseudo-random order. The test consists of two phases. In the first phase, 27 taste test strips (4 concentrations for each taste quality plus 7 blank strips) are used to present the taste stimuli in increasing concentration order. In the second phase, 26 taste test strips (4 concentrations for each taste quality plus 6 blank strips) are used to present the taste stimuli in decreasing concentration order.

[0234] Preparation prior to this procedure :

[0235] Participants were instructed to avoid eating, drinking, or using tobacco products (including e-cigarettes or e-cigarette equivalents, except nicotine patches) for 3 hours prior to the procedure.

[0236] Procedure :

[0237] 1. The taste test was conducted by the participants themselves.

[0238] 2. Each taste test strip is numbered sequentially and packaged in 4 separate packets.

[0239] 3. Participants place each test strip on their tongue and around their tongue (especially the sides) in sequence, starting with test strip #1, for 10 to 15 seconds.

[0240] 4. Using the provided answer sheet, fill in the corresponding circle under the taste (sweet, sour, salty, bitter, savory (soup-like, salty-savory) or no taste) identified on the test strip.

[0241] 5. After completion, participants submit the questionnaire to clinical staff.

[0242] 6. The duration of the test varies from person to person and depends on the participant's taste ability. For most normal subjects, the test takes 5 to 10 minutes.

[0243] Scoring :

[0244] 1. Use the scoring key provided with the kit to evaluate the test results.

[0245] 2. To score the test, use WETT ™ The scoring keys (1 of 2 and 2 of 2) are placed on top of the WETT answer sheet (WETT-SA-53), so that the red arrow on the WETT scoring key aligns with the WETT... ™ Align the red dots on the answer sheet. Add up the correct answers for each column (indicated by the fill circles shown on the scorecard) and mark the sum at the bottom of the answer sheet. These values ​​represent the number of correct answers for each test quality, as well as the number of correct answers on the blank test strip. The total score is obtained by adding the numbers in each column and entering the sum in the box on the right side of page two of the answer card (WETT-SA-53). The total score added to the WETT-SA-53 card will be used against the standardized WETT-SA53 percentile table for healthy men and women. Figure 2 Error shown! Reference source not found:

[0246] a. A score equal to or below 19-21 (10th percentile) indicates functional impairment.

[0247] b. A score of 14 or below (5th percentile) strongly suggests severe hypotaste or loss of taste.

[0248] Dosing schedule

[0249] In some implementations, the treatment phase includes subcutaneous administration of talutuzumab according to one or both of the following weight-based dosing schedules (QW and / or Q2W) shown in Tables 9 and 10, where mg / kg refers to the number of milligrams of talutuzumab per kilogram of patient body weight:

[0250] Table 9: Weekly dosing schedule

[0251]

[0252] Table 10: Biweekly dosing schedule

[0253]

[0254] Other embodiments of the invention are described below.

[0255] One embodiment of the present invention provides a method for reducing oral toxicity (e.g., taste impairment) in a subject receiving treatment with a targeted GPRC5D therapeutic agent, the method comprising administering a preventive intervention against oral toxicity to the subject prior to administration of a therapeutically effective amount of the targeted GPRC5D therapeutic agent (e.g., for the treatment of multiple myeloma) throughout the treatment phase, wherein the preventive intervention is selected from the group consisting of dexamethasone, pregabalin, clonazepam, and combinations thereof.

[0256] In some implementation schemes, the preventative intervention is dexamethasone.

[0257] In some implementations, the preventative intervention is dexamethasone mouthwash (an oral solution containing dexamethasone), for example, 0.5 mg dexamethasone twice daily.

[0258] In some implementations, the preventative intervention is a 0.1 mg / mL dexamethasone mouthwash (e.g., 0.5 mg dexamethasone twice daily).

[0259] In some embodiments, the method includes administering dexamethasone mouthwash in a dose of 5 mL (e.g., 0.5 mg / 5 mL) twice daily (e.g., wherein the subject rinses his mouth with the mouthwash for about 5 minutes without swallowing, and preferably does not eat or drink for about 30 minutes afterward).

[0260] In some implementations, the method includes applying dexamethasone mouthwash twice daily in a dose of 5 mL and applying 50 mg of fluconazole once daily (e.g., to prevent oral thrush).

[0261] In some implementations, the method includes increasing the dose of dexamethasone mouthwash up to a maximum of four times daily after an event of decreased taste score (≥6 points).

[0262] In some implementations, the preventative intervention is pregabalin (e.g., in capsule or tablet form). In one implementation, pregabalin is administered in 50 mg capsule form.

[0263] In some implementations, the method includes administering pregabalin at a dose of 50 mg twice daily.

[0264] In some implementations, the method includes increasing the dose of pregabalin after an event of decreased taste score (≥6 points).

[0265] In some implementations, the method includes increasing the dose of pregabalin to 150 mg / day initially, and then to a maximum of 300 mg / day after one week following an event of decreased taste score (≥6 points).

[0266] In some implementation schemes, the preventative intervention is clonazepam.

[0267] In some implementations, the preventive intervention is clonazepam mouthwash (e.g., 0.5 mg clonazepam twice daily).

[0268] In some implementations, the preventative intervention is clonazepam orally disintegrating tablets (ODT) (e.g., 0.5 mg clonazepam orally disintegrating tablets (ODT), twice daily).

[0269] In some implementations, the preventative intervention is a 0.1 mg / mL clonazepam mouthwash.

[0270] In some embodiments, the method includes administering 0.1 mg / mL clonazepam mouthwash in 5 mL (e.g., 0.5 mg / 5 mL) twice daily (e.g., wherein the subject rinses his mouth with the mouthwash for about 5 minutes without swallowing, and preferably does not eat or drink for about 30 minutes afterward).

[0271] In some implementations, the method includes continuing to use clonazepam mouthwash at the same dose if the taste score (measured by taste test strips) has decreased by 6 points or more.

[0272] In some embodiments, the method includes a preventative intervention of administering the first dose at least 1 day, or at least 2 days, or at least 3 days, or at least 4 days, or at least 5 days, or at least 6 days, or at least 7 days prior to administering the first dose (e.g., the first incremental dose) of the targeted GPRC5D therapeutic agent.

[0273] In some embodiments, the method includes a preventative intervention of administering a first dose 5 to 9 days prior to administering a first dose (e.g., a first incremental dose) of the targeted GPRC5D therapeutic agent, and preferably the preventative intervention is administered continuously (e.g., daily) throughout the treatment phase.

[0274] In some embodiments, the method includes a preventive intervention of administering a first dose 6 to 8 days prior to administering a first dose (e.g., a first incremental dose) of the targeted GPRC5D therapeutic agent, and preferably the preventive intervention is administered continuously (e.g., daily) throughout the treatment phase.

[0275] In some embodiments, the method includes a preventative intervention of administering a first dose 7 days prior to administering a first dose (e.g., a first incremental dose) of the targeted GPRC5D therapeutic agent, and preferably continuing the preventative intervention throughout the treatment phase (e.g., daily administration).

[0276] In some implementations, the method includes administering a preventative intervention for 5 to 9 days daily prior to the administration of a first dose (e.g., a first incremental dose) of the targeted GPRC5D therapeutic agent, and continuing to administer the preventative intervention (e.g., daily) throughout the treatment phase.

[0277] In some implementations, the method includes administering a preventative intervention for 6 to 8 days daily prior to the administration of a first dose (e.g., a first escalation dose) of the targeted GPRC5D therapeutic agent.

[0278] In some implementations, the method includes administering a preventative intervention for 7 days daily prior to the administration of a first dose (e.g., a first escalation dose) of the targeted GPRC5D therapeutic agent.

[0279] In some implementations, the treatment phase includes administering one or more escalating doses of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject prior to the administration of a therapeutic dose of the GPRC5DxCD3 bispecific antibody.

[0280] In some implementations, this treatment phase includes weekly (QW) subcutaneous administration of a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject.

[0281] In some implementations, this treatment phase includes administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject every two weeks (Q2W).

[0282] In some implementations, this treatment phase includes administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject every four weeks (Q4W).

[0283] In some implementations, the treatment phase includes administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject every two weeks (Q2W) and then every four weeks (Q4W).

[0284] In some implementations, this treatment phase involves the subcutaneous administration of the GPRC5DxCD3 bispecific antibody at a treatment dose of approximately 400 μg / kg per week (QW).

[0285] In some implementations, this treatment phase involves subcutaneous administration of the GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 800 μg / kg every two weeks (Q2W).

[0286] In some implementations, the treatment phase includes subcutaneous administration of the GPRC5DxCD3 bispecific antibody at a treatment dose of approximately 800 µg / kg every two weeks (Q2W), followed by administration of the GPRC5DxCD3 bispecific antibody at a treatment dose of approximately 800 µg / kg every four weeks (Q4W).

[0287] In some implementations, according to IMWG 2016 standards, this treatment phase includes subcutaneous administration of the GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 800 µg / kg every two weeks (Q2W), followed by administration of the GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 800 µg / kg every four weeks (Q4W) starting from C5D1 if the subject has a VGPR or better response; or administration of the GPRC5DxCD3 bispecific antibody at a therapeutic dose of approximately 800 µg / kg every four weeks (Q4W) starting from C7D1 if the subject has a PR or better response.

[0288] In some implementations, the treatment phase includes subcutaneous administration of two or three escalating doses of the GPRC5DxCD3 bispecific antibody prior to the subcutaneous administration of the therapeutic dose.

[0289] In some implementations, the treatment phase includes subcutaneous administration of 10 μg / kg and 60 μg / kg of GPRC5DxCD3 bispecific antibody prior to the subcutaneous administration of the therapeutic dose.

[0290] In some implementations, the treatment phase includes subcutaneous administration of escalating doses of GPRC5DxCD3 bispecific antibody at 10 μg / kg, 60 μg / kg, and 400 μg / kg prior to the administration of the therapeutic dose.

[0291] In some implementations, the treatment phases include subcutaneous administration of escalating doses of the GPRC5DxCD3 bispecific antibody at intervals of 2 to 4 days.

[0292] In some implementations, the treatment phase includes subcutaneous administration of the GPRC5DxCD3 bispecific antibody according to the following dosing schedule for the first 28-day treatment cycle: escalating dose 1 of 0.01 mg / kg (day 1), followed by escalating dose 2 of 0.06 mg / kg (day 4), followed by escalating dose 3 of 0.4 mg / kg (day 8), followed by the first treatment dose of 0.8 mg / kg (day 15).

[0293] In some implementations, the escalating doses are administered at intervals of ≥2 days, and the first treatment dose is administered ≥2 days after escalating dose 3, between day 7 and day 15.

[0294] In some implementations, for subsequent 28-day treatment cycles (cycle 2+) following the first 28-day treatment cycle, the GPRC5DxCD3 bispecific antibody is administered at 0.8 mg / kg Q2W (e.g., on day 1 and day 15 of each treatment cycle) 14 ± 3 days after the previous treatment dose.

[0295] In some implementations, the method includes administering talquitumab in a 28-day cycle: during cycle 1, administering escalating doses and a first treatment dose of talquitumab:

[0296] • Incremental dose 1 (e.g., day 1): 0.01 mg / kg,

[0297] • Incremental dose 2 (e.g., day 4): 0.06 mg / kg,

[0298] • Incremental dose 3 (e.g., day 8): 0.4 mg / kg,

[0299] • First therapeutic dose (e.g., day 15): 0.8 mg / kg,

[0300] The escalating doses are administered at least 2 days apart, and the first treatment dose is administered at least 2 days after escalation dose 3 (e.g., between day 8 and day 15); and during cycle 2 and all subsequent cycles, taquitumab is administered at 0.8 mg / kg Q2W (e.g., day 1 and day 15 of each cycle) 14 ± 3 days after the previous treatment dose, wherein, according to IMWG 2016 criteria, if the subject has a VGPR or better response, the dosing frequency is optionally reduced to Q4W starting from day 1 of cycle 5 (C5D1); or if the subject has a PR or better response, the dosing frequency is optionally reduced to Q4W starting from day 1 of cycle 7 (C7D1).

[0301] In some implementations, the subject exhibits reduced oral toxicity (e.g., reduced taste impairment) compared to subjects who did not receive the same preventative intervention, as determined, for example, by taste assessment using taste test strips.

[0302] In some implementations, the subject experiences less oral toxicity (e.g., less taste impairment) compared to subjects who do not receive the same preventative intervention, for example, as determined by taste assessment using taste test strips.

[0303] In some implementations, the subject has a reduced degree of oral toxicity (e.g., a reduced degree of taste impairment) compared to a subject who did not receive the same preventative intervention, for example, as determined by taste assessment using taste test strips.

[0304] In some implementations, the subject does not experience oral toxicity (e.g., no taste impairment) due to preventive interventions (oral toxicity, such as taste impairment, is prevented), for example, as determined by taste assessment using taste test strips.

[0305] In some implementations, the method reduces oral toxicity (e.g., reduces taste impairment) in a subject population compared to a subject population that did not receive the same preventative intervention, for example, as determined by taste assessment using taste test strips.

[0306] In some implementations, the method reduces the occurrence of oral toxicity (e.g., reduces the occurrence of taste impairment) in a subject population compared to a subject population that did not receive the same preventive intervention, for example, as determined by taste assessment using taste test strips.

[0307] In some implementations, the method reduces the severity of oral toxicity (e.g., the severity of taste impairment) in a subject population compared to a subject population that did not receive the same preventative intervention, for example, as determined by taste assessment using taste test strips.

[0308] In some implementations, the method prevents oral toxicity (e.g., prevents taste impairment) in the subject population due to preventive interventions (oral toxicity such as taste impairment is prevented), for example, as determined by taste assessment using taste test strips.

[0309] In some implementations, the method reduces the proportion of subjects in the population who experience at least one instance of a deterioration in taste score by 6 or more points relative to baseline during the treatment phase, such as by measuring taste test strips, for example, by standard taste assessment.

[0310] In some implementations, the subject exhibits one or more of the following clinical outcomes, for example, as determined by a Waterless Experience Taste Test (WETT) score:

[0311] 1. The incidence of taste dysfunction (hypopnea) was lower in subjects who did not receive the same preventive interventions, and / or

[0312] 2. The incidence of severe hypogesia / loss of taste was lower in subjects who did not receive the same preventive intervention, and / or

[0313] 3. Compared with subjects who did not receive the same preventive intervention, the time to first occurrence of severe taste reduction / loss was longer, and / or

[0314] 4. Compared with subjects who did not receive the same preventive intervention, the remission / improvement rate of taste reduction / loss was higher at 3 and 6 months.

[0315] Exemplary embodiments

[0316] 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.

[0317] 1. A method for reducing oral toxicity (e.g., taste impairment) in a subject receiving treatment with a targeted GPRC5D therapeutic agent, the method comprising administering a preventive intervention against oral toxicity to the subject prior to administering a therapeutically effective amount of the targeted GPRC5D therapeutic agent throughout the treatment phase, wherein the preventive intervention is selected from the group consisting of dexamethasone, pregabalin, clonazepam, and combinations thereof.

[0318] 2. The method according to embodiment 1, wherein the GPRC5D-targeting therapeutic agent is a GPRC5DxCD3 bispecific antibody.

[0319] 3. The method according to embodiment 2, 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.

[0320] 4. The method according to embodiment 2 or 3, wherein the GPRC5DxCD3 bispecific antibody comprises: a GPRC5D binding domain comprising a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11; and a CD3 binding domain comprising a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 21.

[0321] 5. The method according to any one of embodiments 2 to 4, wherein the GPRC5DxCD3 bispecific antibody is an IgG1, IgG2, IgG3 or IgG4 isotype.

[0322] 6. The method according to any one of embodiments 2 to 5, wherein the GPRC5DxCD3 bispecific antibody is an IgG4 isotype.

[0323] 7. The method according to any one of embodiments 2 to 6, wherein the GPRC5DxCD3 bispecific antibody contains one or more substitutions in its Fc region.

[0324] 8. The method according to any one of embodiments 2 to 7, wherein the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A and L235A substitutions in its Fc region.

[0325] 9. The method according to any one of embodiments 2 to 8, wherein the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A, L235A, F405L and R409K substitutions in its Fc region.

[0326] 10. The method according to any one of embodiments 2 to 9, wherein the Fc region of the GPRC5D-specific IgG4 antibody from which the GPRC5D binding arm is derived contains S228P, L234A and L235A substitutions in its Fc region.

[0327] 11. The method according to any one of embodiments 2 to 10, wherein the Fc region of the CD3-specific IgG4 antibody from which the CD3 binding arm is derived contains S228P, L234A, L235A, F405L and R409K substitutions in its Fc region.

[0328] 12. The method according to any one of embodiments 2 to 11, 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.

[0329] 13. The method according to any one of embodiments 2 to 11, 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.

[0330] 14. The method according to any one of embodiments 2 to 11, 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.

[0331] 15. The method according to any one of embodiments 2 to 11, 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.

[0332] 16. The method according to any one of embodiments 2 to 12, wherein the GPRC5DxCD3 bispecific antibody is taquituzumab.

[0333] 17. The method according to any one of embodiments 1 to 16, wherein the subject has been diagnosed with multiple myeloma.

[0334] 18. The method according to any one of embodiments 1 to 17, wherein the subject has received at least three lines of prior treatment.

[0335] 19. The method according to any one of embodiments 1 to 17, wherein the subject has received at least four lines of prior treatment.

[0336] 20. The method according to any one of embodiments 1 to 17, wherein the subject has relapsed or refractory multiple myeloma (RRMM).

[0337] 21. The method according to any one of embodiments 1 to 17, wherein the subject has received at least three lines of prior treatment, including proteasome inhibitors, immunomodulators and anti-CD38 monoclonal antibodies.

[0338] 22. The method according to any one of embodiments 1 to 17, wherein the subject has received at least four lines of prior treatment, including proteasome inhibitors, immunomodulators and anti-CD38 monoclonal antibodies.

[0339] 23. The method according to any one of embodiments 1 to 22, wherein the preventive intervention is dexamethasone.

[0340] 24. The method according to embodiment 23, wherein the preventive intervention is dexamethasone mouthwash (an oral solution containing dexamethasone), for example, 0.5 mg dexamethasone twice daily.

[0341] 25. The method according to embodiment 23 or 24, wherein the preventive intervention is 0.1 mg / mL dexamethasone mouthwash (e.g., 0.5 mg dexamethasone twice daily).

[0342] 26. The method according to embodiment 24 or 25, wherein the method comprises administering the dexamethasone mouthwash at a dose of 5 mL (e.g., 0.5 mg / 5 mL) twice daily (e.g., wherein the subject rinses his mouth with the mouthwash for about 5 minutes without swallowing, and preferably does not eat or drink for about 30 minutes thereafter).

[0343] 27. The method according to embodiment 24 or 25, wherein the method comprises administering the dexamethasone mouthwash twice daily at a dose of 5 mL and administering 50 mg of fluconazole once daily (e.g., to prevent oral thrush).

[0344] 28. The method according to any one of embodiments 24 to 27, wherein the method comprises increasing the dose of the dexamethasone mouthwash to a maximum of four times daily after an event of decreased taste score (≥6 points).

[0345] 29. The method according to any one of embodiments 1 to 22, wherein the preventive intervention is pregabalin (e.g., in capsule or tablet form, preferably 50 mg capsule).

[0346] 30. The method according to embodiment 29, wherein the method comprises administering pregabalin at a dose of 50 mg twice daily.

[0347] 31. The method according to embodiment 29 or 30, wherein the method includes increasing the dose of pregabalin after an event of decreased taste score (≥6 points).

[0348] 32. The method according to embodiment 29 or 30, wherein the method comprises, after the occurrence of a taste score decrease (≥6 points) event, initially increasing the dose of pregabalin to 150 mg / day, and then increasing it to a maximum of 300 mg / day after one week.

[0349] 33. The method according to any one of embodiments 1 to 22, wherein the preventive intervention is clonazepam.

[0350] 34. The method according to embodiment 33, wherein the preventive intervention is clonazepam mouthwash (e.g., 0.5 mg clonazepam twice daily).

[0351] 35. The method according to embodiment 33, wherein the preventive intervention is 0.1 mg / mL clonazepam mouthwash.

[0352] 36. The method according to any one of embodiments 33 to 35, the method comprising administering 0.1 mg / mL clonazepam mouthwash at a dose of 5 mL (e.g., 0.5 mg / 5 mL) twice daily (e.g., wherein the subject rinses his mouth with the mouthwash for about 5 minutes without swallowing, and preferably does not eat or drink for about 30 minutes thereafter).

[0353] 37. The method according to embodiment 36, wherein if the taste score (measured by taste test strips) has decreased by 6 points or more, the method includes continuing to use clonazepam mouthwash at the same dose.

[0354] 38. The method according to any one of embodiments 1 to 37, wherein the method includes administering the first dose of the preventive intervention 5 to 9 days prior to administering the first dose (e.g., a first incremental dose) of the targeted GPRC5D therapeutic agent.

[0355] 39. The method according to any one of embodiments 1 to 37, wherein the method comprises administering the first dose of the preventive intervention 6 to 8 days prior to administering the first dose (e.g., the first incremental dose) of the targeted GPRC5D therapeutic agent, and continuing to administer the preventive intervention daily throughout the treatment phase.

[0356] 40. The method according to any one of embodiments 1 to 37, the method comprising administering the first dose of the preventive intervention 7 days prior to administering the first dose (e.g., a first escalating dose) of the targeted GPRC5D therapeutic agent, and continuing to administer the preventive intervention daily throughout the treatment phase.

[0357] 41. The method according to any one of embodiments 1 to 30, wherein the method comprises administering the preventive intervention daily for 5 to 9 days prior to administering a first dose (e.g., a first incremental dose) of the targeted GPRC5D therapeutic agent, and continuing to administer the preventive intervention daily throughout the treatment phase.

[0358] 42. The method according to any one of embodiments 1 to 37, wherein the method comprises administering the preventive intervention daily for 6 to 8 days prior to administering a first dose (e.g., a first incremental dose) of the targeted GPRC5D therapeutic agent.

[0359] 43. The method according to any one of embodiments 1 to 37, wherein the method comprises administering the preventive intervention daily for 7 days prior to administering a first dose (e.g., a first incremental dose) of the targeted GPRC5D therapeutic agent.

[0360] 44. The method according to any one of embodiments 2 to 43, wherein the method comprises subcutaneously administering one or more escalating doses of the GPRC5DxCD3 bispecific antibody to the subject prior to administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody.

[0361] 45. The method according to any one of embodiments 2 to 44, the method comprising administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject subcutaneously weekly (QW).

[0362] 46. ​​The method according to any one of embodiments 2 to 44, in accordance with the IMWG 2016 standard, the method comprising administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject every two weeks (Q2W), and then, optionally, if the subject has a VGPR or better response, administering the GPRC5DxCD3 bispecific antibody every four weeks (Q4W) starting from C5D1; or if the subject has a PR or better response, administering it every four weeks (Q4W) starting from C7D1.

[0363] 47. The method according to any one of embodiments 2 to 44, the method comprising subcutaneously administering the GPRC5DxCD3 bispecific antibody at a therapeutic dose of about 400 μg / kg weekly (QW).

[0364] 48. The method according to any one of embodiments 2 to 44, the method comprising subcutaneously administering the GPRC5DxCD3 bispecific antibody at a therapeutic dose of about 800 μg / kg every two weeks (Q2W).

[0365] 49. The method according to any one of embodiments 2 to 48, wherein the method comprises subcutaneously administering two or three escalating doses of the GPRC5DxCD3 bispecific antibody prior to subcutaneous administration of a therapeutic dose.

[0366] 50. The method according to any one of embodiments 2 to 48, 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.

[0367] 51. The method according to any one of embodiments 2 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.

[0368] 52. The method according to any one of embodiments 44 to 51, wherein the method comprises subcutaneously administering escalating doses of the GPRC5DxCD3 bispecific antibody at intervals of 2 to 4 days.

[0369] 53. The method according to any one of embodiments 2 to 44, the method comprising subcutaneous administration of the GPRC5DxCD3 bispecific antibody according to the following dosing schedule for the first 28-day treatment cycle: 0.01 mg / kg increment dose 1 (day 1), followed by 0.06 mg / kg increment dose 2 (day 4), followed by 0.4 mg / kg increment dose 3 (day 8), followed by a first treatment dose of 0.8 mg / kg (day 15).

[0370] 54. The method according to embodiment 53, wherein the incremental doses are administered at intervals of ≥2 days, and the first treatment dose is administered ≥2 days after the incremental dose 3, between day 7 and day 15.

[0371] 55. The method according to embodiment 53 or 54, wherein for subsequent 28-day treatment cycles (cycle 2+) following the first 28-day treatment cycle, the GPRC5DxCD3 bispecific antibody is administered at 0.8 mg / kg Q2W (e.g., on day 1 and day 15 of each treatment cycle) 14±3 days after the previous treatment dose.

[0372] 56. The method according to any one of embodiments 1 to 55, wherein the oral toxicity of the subject is reduced (e.g., reduced taste impairment) compared to the subject who did not receive the same preventive intervention, for example, as determined by taste assessment using taste test strips.

[0373] 57. The method according to any one of embodiments 1 to 56, wherein the oral toxicity of the subject is reduced (e.g., taste impairment is reduced) compared with the subject who did not receive the same preventive intervention, for example, as determined by taste assessment using taste test strips.

[0374] 58. The method according to any one of embodiments 1 to 57, wherein the subject has a reduced degree of oral toxicity (e.g., a reduced degree of taste impairment) compared to a subject who did not receive the same preventive intervention, for example, as determined by taste assessment using taste test strips.

[0375] 59. The method according to any one of embodiments 1 to 58, wherein the subject does not experience oral toxicity (e.g., no taste impairment) due to the preventive intervention (oral toxicity, such as taste impairment, is prevented), for example, as determined by taste assessment using taste test strips.

[0376] 60. The method according to any one of embodiments 1 to 59, wherein the method reduces the proportion of subjects in the population whose taste score deteriorates by 6 points or more from baseline at least once during the treatment phase, such as by measuring taste test strips, for example by standard taste assessment.

[0377] 61. The method according to any one of embodiments 1 to 60, wherein the method comprises administering tarquiltuzumab in a 28-day cycle:

[0378] During cycle 1, administer the following escalation doses and initial treatment dose of taquitumab:

[0379] • Incremental dose 1 (e.g., day 1): 0.01 mg / kg,

[0380] • Incremental dose 2 (e.g., day 4): 0.06 mg / kg,

[0381] • Incremental dose 3 (e.g., day 8): 0.4 mg / kg,

[0382] • First therapeutic dose (e.g., day 15): 0.8 mg / kg,

[0383] The escalating doses are administered at least 2-day intervals, and the first treatment dose is administered at least 2 days after escalating dose 3 (e.g., between day 8 and day 15); and

[0384] During cycle 2 and all subsequent cycles, taquitumab was administered at 0.8 mg / kg every 2 weeks (e.g., on day 1 and day 15 of each cycle) 14 ± 3 days after the previous treatment dose.

[0385] In accordance with the IMWG2016 criteria, if the subject has VGPR or better efficacy, the dosing frequency may optionally be reduced to Q4W starting from day 1 of cycle 5 (C5D1); or if the subject has PR or better efficacy, the dosing frequency may optionally be reduced to Q4W starting from day 1 of cycle 7 (C7D1).

[0386] 62. The method according to any one of embodiments 1 to 61, wherein the subject exhibits one or more of the following clinical outcomes, as determined by the WETT score:

[0387] 1. The incidence of taste dysfunction (hypopnea) was lower in subjects who did not receive the same preventive interventions, and / or

[0388] 2. The incidence of severe hypogesia / loss of taste was lower in subjects who did not receive the same preventive intervention, and / or

[0389] 3. Compared with subjects who did not receive the same preventive intervention, the time to first occurrence of severe taste reduction / loss was longer, and / or

[0390] 4. Compared with subjects who did not receive the same preventive intervention, the remission / improvement rate of taste reduction / loss was higher at 3 and 6 months.

[0391] 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.

[0392] Every patent, patent application, and publication cited or described in this document is incorporated herein by reference in its entirety.

[0393] Example

[0394] 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.

[0395] Example 1 : Phase 2, open-label, randomized study (TALISMAN study) for the evaluation of prophylactic interventions against taquetamab-related oral toxicity Bispecific antibodies

[0396] The basic principle of this study is to further characterize the oral toxicity of talquitumab and to investigate the effect of preventive measures on reducing or preventing oral side effects of talquitumab.

[0397] Table A. Sequences of GPRC5D binding arms

[0398] The anti-GPRC5D / anti-CD3 antibody taquitumab (also known as Tal) (described, for example, in U.S. Patent No. 10,562,968, the entire contents of which are incorporated herein by reference) was prepared by Janssen Pharmaceuticals. It was produced by culturing recombinant Chinese hamster ovary cells, followed by isolation, chromatographic purification, and formulation. Taquitumab comprises the GPRC5D binding arm GC5B596 and the CD3 binding arm CD3B219, the amino acid sequences of which are shown in Tables A and B.

[0399] Table B. Sequences of CD3 binding arms

[0400]

[0401] Objectives

[0402]

[0403] Methods

[0404] This is an open-label, randomized study designed to evaluate the efficacy of different prophylactic measures in alleviating taquituzumab-related oral toxicity. Cohort A will serve as a control. Currently, no prophylactic measures have demonstrated proven efficacy.

[0405] The main objective of this study is, for example, through the waterless experience taste test (WETT). ® The scoring measures were used to identify preventive interventions that could maximally reduce the incidence, severity, and duration of taquitumab-related taste impairment and to better characterize the clinical manifestations of taquitumab-related taste impairment. Key secondary objectives included determining the impact of preventive measures on taste dysfunction, weight, olfactory function, and salivary changes, and using PROs (Prognostics of Taquitumab) that focus on assessing taste disturbances, oral mucositis, dysphagia, and dry mouth to evaluate health-related quality-of-life parameters.

[0406] The hypothesis of this study is that preventative measures, initiated before the first dose of taquitumab and continued daily throughout the treatment phase, can minimize the incidence, severity, or duration of taquitumab-related taste loss compared to no preventative measures.

[0407] This is an open-label, randomized, multicenter study in adult RRMM participants who have been previously exposed to at least one PI, one IMiD, and anti-CD38 mAh and are considering talutuzumab treatment. The study will include screening, treatment, and follow-up phases. Oral side effects of talutuzumab will be closely monitored in four cohorts: a standard treatment cohort, i.e., the control cohort (cohort A), and three cohorts (cohorts B, C, and D) where prophylactic measures will be added to prevent the occurrence of oral side effects or reduce their severity, with particular attention to taste changes or loss. Oral side effects of talutuzumab will be closely monitored in all four cohorts. Decisions to modify the evaluation of prophylactic interventions or to add new cohorts or interventions may be considered later based on study results.

[0408] Figure 1

[0409] Following randomization, participants in cohorts B, C, and D will begin designated prophylaxis one week prior to initiating talutuzumab treatment. Prophylaxis will continue throughout the treatment phase as long as participants continue talutuzumab treatment. Following escalation of talutuzumab treatment, participants will receive a 0.8 mg / kg SC Q2W regimen until disease progression, death, loss to follow-up, withdrawal of informed consent, discontinuation of treatment, or up to 12 months after the start of talutuzumab treatment, whichever occurs first. At the investigator's discretion, if a participant has a confirmed VGPR or better response, they will be allowed to switch to talutuzumab 0.8 mg / kg SC Q4W starting from day 1 of cycle 5 (C5D1); and if a participant has a confirmed PR or better response, they will be allowed to switch to talutuzumab 0.8 mg / kg SC Q4W starting from day 1 of cycle 7 (C7D1). Participants may receive dosing as outpatients or as inpatients for talutuzumab SC dosing monitoring.

[0410] Approximately 120 participants will be randomly assigned (1:1:1:1) to four cohorts. The study design is as follows: Dose selection rationale It is displayed in the middle.

[0411] Cohort A will serve as a control cohort to characterize oral side effects of taquitumab. Treatment of oral side effects will be determined at the discretion of the attending physician. Treatment of oral side effects may be considered using medications other than those used in this study as preventative interventions.

[0412] Participants in queues B, C, and D will receive the following precautions:

[0413] Cohort B: 0.1 mg / mL dexamethasone mouthwash, 5 mL twice daily.

[0414] Cohort C: Pregabalin 50mg oral dose, twice daily.

[0415] Cohort D: 0.5 mg clonazepam orally disintegrating tablets (ODT), twice daily.

[0416] If taste dysfunction has already occurred, researchers may consider adjusting the dosage of any preventative measures based on clinical judgment and the severity of taste reduction or loss as assessed by the WETT score.

[0417] All participants will be tested under the following key procedures:

[0418] Taste assessment using taste test strips (WETT)

[0419] ▪ Assessment of oral toxicity manifestations, including taste disturbances, oral mucositis, dry mouth, and dysphagia, according to NCI-CTCAE version 5.0 classification.

[0420] Olfactory function assessment, including odor recognition and threshold testing.

[0421] ▪PRO: EORTC-QLQ-C30, EORTC-QLQ-OH-15, Epstein Taste Scale, STTA, Brief Dry Mouth Questionnaire, and PRO-CTCAE

[0422] ▪ Tongue and / or salivary gland biopsy (performed only at selected centers)

[0423] Tongue swabs were used for microbiome analysis (participants in cohort A only).

[0424] Saliva assessment: secretion volume and characteristics

[0425] The total estimated recruitment time is approximately 18 months. The treatment period for individual participants can last up to 12 months. Therefore, the estimated duration of individual participation ranges from 12 to 30 months.

[0426] The study suggests that taquituzumab may be used for treatments longer than the planned one-year treatment schedule.

[0427] Rationale for taquetamab Q2W dosing

[0428] Rationale for taquetamab Q4W dosing

[0429] 0.8 mg / kg SC Q2W was effective, well-tolerated, and had a manageable safety profile in participants with extensive pretreatment for RRMM. Furthermore, the 0.8 mg / kg SC Q2W regimen was more convenient than more frequent regimens such as 0.4 mg / kg SC QW. The dosage and schedule for subcutaneous administration of taquitumab (0.01 mg / kg, 0.06 mg / kg, and 0.4 mg / kg escalators, followed by a 0.8 mg / kg SC Q2W treatment dose) were selected based on PK, pharmacodynamic, safety, and efficacy results from the Phase 1 portion of the MonomenTAL-1 study (taquitumab monotherapy). The third escalator dose in this study (0.4 mg / kg) was slightly higher than the dose evaluated in the Phase 1 and Phase 2 portions of MonomenTAL-1 (0.3 mg / kg), but this adjustment was supported by the safety demonstrated by weekly administration of the 0.4 mg / kg dose as a treatment dose in the MonomenTAL-1 study. The concentration-time and safety profiles of the 0.01 mg / kg, 0.06 mg / kg, and 0.3 mg / kg escalation followed by 0.8 mg / kg SC Q2W treatment regimen were similar to those of the 0.01 mg / kg, 0.06 mg / kg, and 0.4 mg / kg escalation followed by 0.8 mg / kg SC Q2W treatment regimen.

[0430] Rationale for dexamethasone mouthwash dosing

[0431] In the current study, for participants with a confirmed VGPR or better response, the investigator determined that the dosing frequency of talutumab could be reduced to Q4W starting from C5D1. For participants with a confirmed PR or better response, talutumab dosing could be changed to Q4W starting from C7D1. The median concentration-time curves estimated after Q4W dosing at C5D1 or C7D1 were higher than the EC50 determined in the ex vivo cytotoxicity assay. 90 The maximum concentration associated with the value was estimated to be sufficient to maintain efficacy under low tumor burden. Furthermore, based on preliminary safety exposure-response analysis, a dose-response relationship was observed for talutuzumab-specific AEs (skin, oral, and finger / toenail toxicities). Therefore, patients who switch to a lower dose after being a responder for some time may benefit from a lower (or non-worsening) incidence of AEs. The proposed Q4W dosing schedule for talutuzumab 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, and the reduced exposure from Q4W dosing starting in 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).

[0432] Rationale for pregabalin dosing

[0433] A 0.5 mg / 5 mL mouthwash twice daily is the usual starting dose for mild and active oral cGVHD. Once complete remission is achieved, the dose can be reduced to once daily to prevent relapse. To mimic the effect of dexamethasone mouthwash in patients with oral cGVHD, a prophylactic twice-daily dose will be used one week prior to the start of taquituzumab treatment, along with 50 mg of fluconazole once daily.

[0434] Rationale for clonazepam dosing

[0435] The normal starting dose for treating neuropathic pain is 75 mg twice daily. Since participants will receive prophylactic treatment, pregabalin will be started at 50 mg twice daily to minimize the occurrence of side effects.

[0436] Prophylactic medication

[0437] The dosage and schedule for clonazepam were selected based on a study using topical clonazepam for burning mouth syndrome, in which 1 mg tablets were taken sublingually three times daily for 14 days, as discussed in the section. In this study, 0.5 mg clonazepam orally disintegrating tablets will be provided to improve drug distribution in the oral cavity. Participants will begin taking 0.5 mg clonazepam twice daily one week prior to the start of taquituzumab treatment. Clonazepam orally disintegrating tablets (ODT) disintegrate rapidly in the mouth upon contact with saliva; therefore, additional water intake may be unnecessary or only a small amount may be required during administration.

[0438] Detailed instructions for administration are provided below.

[0439] Taquetamab treatment dosing schedule

[0440] The preventative intervention measures are summarized in the table below:

[0441]

[0442] Prescription information will include information that complies with applicable regulations.

[0443] Endpoints

[0444] The duration of each cycle of subcutaneous injection of taquitumab will be 28 days.

[0445] For cycle 1, tarquiltuzumab will be administered according to the following incremental dosing schedule:

[0446] • Incremental dose 1 (Day 1): 0.01 mg / kg

[0447] • Incremental dose 2 (day 4): 0.06 mg / kg

[0448] • Incremental dose 3 (day 8): 0.4 mg / kg

[0449] • Therapeutic dose (day 15): 0.8 mg / kg

[0450] The escalating doses will be administered at least 2 days apart. The first treatment dose will be administered at least 2 days after escalation dose 3, between day 8 and day 15.

[0451] For cycles 2+, tarquitumab must be administered at 0.8 mg / kg every 2 weeks (i.e., on days 1 and 15 of each cycle) 14 ± 3 days after the previous treatment dose. For participants with a confirmed VGPR or better response, the frequency of tarquitumab administration may be reduced to every 4 weeks starting from C5D1, at the investigator's discretion. For participants with a confirmed PR or better response, tarquitumab administration may be changed to every 4 weeks starting from C7D1, at the investigator's discretion.

[0452] Figure 2

[0453] The goals and endpoints are summarized in the table below:

[0454]

[0455]

[0456] The primary endpoint, assessed by total WETT test score during the study treatment phase,

[0457] as follows:

[0458] • The incidence of taste dysfunction (loss of taste), where taste dysfunction is defined as: according to the normative WETT-SA53 percentile table ( Figure 2 For males (sex specified at birth), the total WETT score should be ≤19, and for females (sex specified at birth), the total WETT score should be ≤21. It is worth noting that the validation test demonstrates a sex-dependent difference in test results, which has been taken into account in the WETT score matrix.

[0459] • The incidence of severe hypogesia / loss of taste, where severe hypogesia / loss of taste is defined as: according to the normative WETT-SA 53 percentile (see Inclusion criteria (Total WETT score ≤14).

[0460] • The time of first occurrence of severe hypogesia / loss of taste was defined as the time from the date of first dose of taquitumab to the date of first occurrence of severe hypogesia / loss of taste, based on the total WETT score. For participants who did not experience severe hypogesia / loss of taste, the time of first occurrence was censored.

[0461] • The rate of relief / improvement of taste loss / loss at 3 and 6 months, where relief / improvement was defined as either of the following two possible scenarios:

[0462] - Taste dysfunction is downgraded to no taste dysfunction, that is, the total WETT score of men ≤19 and women ≤21 in the visits 3 months and 6 months ago is changed to the total WETT score of men >19 and women >21 at 3 months and 6 months.

[0463] - Severe hypogesia / loss of taste is downgraded to non-severe hypogesia / loss of taste, that is, the total WETT score ≤14 before 3 months and 6 months becomes the total WETT score >14 at 3 months and 6 months.

[0464] Descriptive statistics will be provided for each primary endpoint.

[0465] Taste evaluation using taste strips (WETT)

[0466] Inclusion criteria include the following: being ≥18 years of age at the time of informed consent (or the legal age of majority in the jurisdiction where the study is conducted, whichever is greater); and:

[0467] 1. Both of the following criteria must be met:

[0468] a. Diagnosed with MM according to the IMWG diagnostic criteria.

[0469] b. A measurable disease is present at screening (assessed by a local laboratory), defined as meeting any of the following criteria:

[0470] i. Serum M protein level ≥0.5 g / dL; or

[0471] ii. Urine M protein level ≥200mg / 24h; or

[0472] iii. Light chain multiple myeloma, with no measurable M protein in serum or urine: sFLC ≥ 10 mg / dL and abnormal serum immunoglobulin κ / λ FLC ratio.

[0473] iv. For participants with no measurable disease in serum, urine, or affected FLC, plasmacytoma (≥2 cm) is present.

[0474] 2. Class III exposure (previous treatment with PI, IMiD and anti-CD38 mAb).

[0475] Note: Relapsed disease is defined as an initial response to prior treatment followed by confirmed disease progression >60 days after discontinuation of treatment, according to IMWG criteria. Refractory disease is defined as a <25% reduction in M ​​protein or confirmed disease progression, according to IMWG criteria, during prior treatment or within ≤60 days after discontinuation of treatment.

[0476] 3. Based on the investigator's assessment of efficacy according to IMWG criteria at or after the last treatment regimen, there is written evidence of disease progression.

[0477] 4. ECOG PS score of 0 or 1 at screening (Error! Citation source not found.). Participants with an ECOG PS score of 2 or 3 are eligible to participate in this study if their ECOG PS score is associated with stable physical limitations (e.g., wheelchair dependence due to a previous spinal cord injury) and is not associated with multiple myeloma or its related treatments.

[0478] The exclusion criteria include the following:

[0479] 1. Known allergy, hypersensitivity, or intolerance to any investigational drug or its excipients that is contraindicated or life-threatening.

[0480] Note: For additional exclusion criteria for specific preventative measures, please refer to the prescribing information.

[0481] 2. Stroke, transient ischemic attack or epilepsy that occurred within 6 months prior to enrollment.

[0482] 3. Any of the following must have occurred within 6 months prior to the first dose of study treatment: severe or unstable angina, myocardial infarction; major thromboembolic event (e.g., pulmonary embolism, cerebrovascular accident), clinically significant ventricular arrhythmia, or heart failure classified as New York Heart Association class III or IV.

[0483] Uncomplicated deep vein thrombosis is not considered excluded.

[0484] 4. Any one of the following:

[0485] a. Hepatitis B infection (HBsAg or HBV-DNA positive): If the infection status is unclear, a viral load test is required to determine the infection status.

[0486] b. Active hepatitis C infection, as measured by a positive HCV-RNA test. Participants with a history of positive HCV antibodies must undergo HCV-RNA testing. Participants with a history of chronic hepatitis C infection (defined as positive for both HCV antibodies and HCV-RNA) who have completed antiviral therapy and whose HCV-RNA is undetectable for at least 12 weeks after treatment completion are eligible to participate in this study.

[0487] 5. Those who have undergone major surgery or suffered significant trauma within 2 weeks prior to the start of the study treatment, or who have not yet fully recovered from surgery, or who are scheduled to undergo major surgery during the study treatment period or within 2 weeks after the final dose of the study treatment.

[0488] Note: Participants scheduled for surgery under local anesthesia may participate. Vertebroplasty or vertebroplasty is not considered a major surgery. If there is any doubt as to whether a procedure is considered a major surgery, researchers are advised to consult with the sponsor and resolve any issues before enrolling participants in the study.

[0489] 6. WETT scores indicating severe hypoesthesia or anesthesia at screening. Also included were unresolved / severe taste disturbances mentioned by participants, or findings from physical / oral examinations. Some examples included leukoplakia, a history of oral cancer, extensive caries, severe periodontitis, active oral infections, candidiasis, parotid gland removal, or dry mouth due to radiation therapy.

[0490] 7. Any medical or psychiatric condition or illness that may interfere with the research process or results, or that the researcher believes poses a risk to participation in the study, such as:

[0491] a. Uncontrolled diabetes

[0492] b. Acute diffuse infiltrative lung disease.

[0493] c. There is evidence of an active systemic viral, fungal, or bacterial infection requiring systemic antimicrobial therapy.

[0494] d. Active autoimmune diseases require systemic immunosuppressive therapy within 6 months prior to the start of study treatment. Exceptions: Participants with vitiligo, well-controlled type 1 diabetes, or a history of autoimmune thyroiditis (based on clinical symptoms and currently normal thyroid function), regardless of when these conditions were diagnosed, are eligible to participate.

[0495] e. Disabling mental illness (e.g., alcohol or drug abuse), severe dementia, or severe mental impairment that researchers believe would impair adherence to research procedures.

[0496] f. Any other circumstances that would impair a participant’s ability to receive or tolerate the planned treatment at the research center, to understand the informed consent form, or any condition that the investigator believes is not in the best interests of the participant (e.g., would impair their health) or that may hinder, limit, or confuse the assessments required by the protocol.

[0497] g. History of not following recommended medical treatment.

[0498] 8. Known active CNS involvement or clinical signs of MM meningeal involvement. If either of these is suspected, a negative whole-brain MRI and lumbar cytology are required.

[0499] 9. Plasma cell leukemia (according to IMWG criteria), Waldenström macroglobulinemia, POEMS syndrome (polyneuropathy, organ enlargement, endocrine disorders, M protein and skin changes) or primary amyloid light chain amyloidosis (at enrollment).

[0500] 10. Any one of the following:

[0501] a. A history of any other malignant tumor besides multiple myeloma, and that malignant tumor is considered to have a high risk of recurrence requiring systemic treatment.

[0502] b. Any ongoing B-cell malignancy (excluding multiple myeloma) or myelodysplastic syndrome.

[0503] c. Any active malignancy other than relapsed / refractory multiple myeloma (i.e., progressed or requiring a change of treatment within the past 24 months). The only permitted exception is malignancies that have been treated within the past 24 months and are considered cured:

[0504] 1) Non-muscle-invasive bladder cancer (isolated Ta-PUNLMP or low grade, <3cm, no CIS).

[0505] 2) Non-melanoma skin cancer that has been cured, or localized melanoma that has been cured by surgical excision alone.

[0506] 3) Non-invasive cervical cancer.

[0507] 4) Breast cancer: Well-treated lobular carcinoma in situ or ductal carcinoma in situ, or a history of localized breast cancer (with permission for anti-hormone therapy).

[0508] 5) Localized prostate cancer (MO, NO), Gleason score ≤7a, receiving only local treatment (RP / RT / local treatment).

[0509] 6) Other malignant tumors that, after consultation with the sponsor's medical monitor, are deemed to have been cured and have an extremely low risk of recurrence.

[0510] Note: If you have any questions, please consult the sponsor before including participants.

[0511] 11. Within a specified time frame prior to randomization, have been previously or concurrently exposed to any of the following:

[0512] a. Has previously received any treatment targeting GPRC5D.

[0513] b. Received T-cell redirection therapy (e.g., bispecific antibody therapy or bispecific T-cell connector) within 3 weeks.

[0514] c. Received genetically modified adoptive cell therapy (e.g., CAR-T cells, natural killer cells) within 3 months.

[0515] d. Received targeted therapy, epigenetic therapy, or investigational drug or invasive investigational medical device treatment within 21 days or more than 5 half-lives (whichever is shorter).

[0516] e. Received or planned to receive any live attenuated vaccine within 4 weeks prior to the first dose of the investigational drug. Non-live vaccines approved or authorized for emergency use by local health authorities (e.g., COVID-19 vaccines) are permitted.

[0517] f. Received monoclonal antibody treatment within 21 days.

[0518] g. Received cytotoxic therapy within 21 days.

[0519] h. Received PI treatment within 14 days.

[0520] i. Received IMiD treatment within 14 days.

[0521] j. Received radiation therapy within 14 days, or localized radiation therapy within 7 days. Any radiation therapy received in the oral cavity or front of the neck within the past 3 months.

[0522] 12. Have you received any of the following:

[0523] a. Participants who received an allogeneic SCT within 6 months prior to the first dose of study treatment. Participants receiving an allogeneic transplant must have discontinued all immunosuppressive medications within 6 weeks prior to the start of study treatment and must show no signs of graft-versus-host disease.

[0524] b. Individuals who received autologous SCT within 12 weeks prior to the start of the study treatment.

[0525] 13. During the 14-day period prior to the first dose of the study drug, the maximum cumulative dose of corticosteroids was ≥140 mg of prednisone or an equivalent dose (excluding pretreatment drugs).

[0526] 14. Any anticipated preventative interventions included in this study are being used.

[0527] Preparation prior to this procedure

[0528] The taste assessment uses a 1cm x 6cm plastic strip with a proprietary monomeric cellulose pad embedded with sucrose (sweet), citric acid (acidic), sodium chloride (salty), caffeine (bitter), monosodium glutamate (umami), or a blank taste agent.

[0529] Each taste quality (sweet, sour, salty, bitter, umami) will be tested using four concentrations (4 = lowest concentration, 1 = highest concentration). No rinsing with liquid is required. Taste test strips (plus 7 tasteless blank strips) will be presented in a predetermined pseudo-random order. The test consists of two phases. In the first phase, 27 taste test strips (4 concentrations for each taste quality plus 7 blank strips) will be used to present the taste stimuli in increasing concentration order. In the second phase, 26 taste test strips (4 concentrations for each taste quality plus 6 blank strips) will be used to present the taste stimuli in decreasing concentration order.

[0530] Procedure

[0531] Participants were instructed to avoid eating, drinking, or using tobacco products (including e-cigarettes or e-cigarette equivalents, except nicotine patches) for 3 hours prior to the procedure.

[0532] Scoring (performed by clinical staff)

[0533] 3. The taste test was conducted by the participants themselves.

[0534] 4. Each taste test strip is numbered sequentially and packaged in 4 separate packets.

[0535] 5. Participants place each test strip on their tongue and around their tongue (especially the sides) in sequence, starting with test strip #1, for 10 to 15 seconds.

[0536] 6. Using the provided answer sheet, fill in the corresponding circle under the taste (sweet, sour, salty, bitter, savory (soup-like, salty-savory) or no taste) identified on the test strip.

[0537] 7. After completion, participants submit the questionnaire to clinical staff.

[0538] 8. The test duration varies from person to person and depends on the participant's taste ability. For most normal subjects, the test duration is 5 to 10 minutes.

[0539] Figure 2

[0540] 9. Use the scoring key provided with the kit to evaluate the test results.

[0541] 10. To score the test, use WETT ™ The scoring keys (2 of 1 and 2 of 2) are placed on top of the WETT answer sheet (WETT-SA-53), so that the red arrow on the WETT scoring key aligns with the WETT... ™ Align the red dots on the answer sheet. Add up the correct answers for each column (indicated by the fill circles shown on the scorecard) and mark the sum at the bottom of the answer sheet. These values ​​represent the number of correct answers for each test quality, as well as the number of correct answers on the blank test strip. The total score is obtained by adding the numbers in each column and entering the sum in the box on the right side of page two of the answer card (WETT-SA-53). The total score added to the WETT-SA-53 card will be used against the standardized WETT-SA53 percentile table for healthy men and women. ​ Error shown! Reference source not found:

[0542] a. A score equal to or below 19-21 (10th percentile) indicates functional impairment.

[0543] b. A score of 14 or below (5th percentile) strongly suggests severe hypotaste or loss of taste.

Claims

1. A method for reducing oral toxicity in a subject receiving a targeted GPRC5D therapeutic agent, the method comprising administering a preventive intervention against oral toxicity to the subject prior to administering a therapeutically effective amount of the targeted GPRC5D therapeutic agent throughout the treatment phase, wherein the preventive intervention is selected from the group consisting of dexamethasone, pregabalin, clonazepam, and combinations thereof.

2. The method according to claim 1, wherein the GPRC5D-targeting therapeutic agent is a GPRC5DxCD3 bispecific antibody.

3. The method according to claim 2, 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.

4. The method according to claim 2 or 3, wherein the GPRC5DxCD3 bispecific antibody comprises: a GPRC5D binding domain comprising a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11; and a CD3 binding domain comprising a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO:

21.

5. The method according to any one of claims 2 to 4, wherein the GPRC5DxCD3 bispecific antibody is an IgG1, IgG2, IgG3 or IgG4 isotype.

6. The method according to any one of claims 2 to 5, wherein the GPRC5DxCD3 bispecific antibody is an IgG4 isotype.

7. The method according to any one of claims 2 to 6, wherein the GPRC5DxCD3 bispecific antibody contains one or more substitutions in its Fc region.

8. The method according to any one of claims 2 to 7, wherein the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A and L235A substitutions in its Fc region.

9. The method according to any one of claims 2 to 8, wherein the GPRC5DxCD3 bispecific antibody is an IgG4 isotype and contains S228P, F234A, L235A, F405L and R409K substitutions in its Fc region.

10. The method according to any one of claims 2 to 9, wherein the Fc region of the GPRC5D-specific IgG4 antibody from which the GPRC5D binding arm is derived contains S228P, L234A, and L235A substitutions in its Fc region.

11. The method according to any one of claims 2 to 10, wherein the Fc region of the CD3-specific IgG4 antibody from which the CD3 binding arm is derived contains S228P, L234A, L235A, F405L, and R409K substitutions in its Fc region.

12. The method according to any one of claims 2 to 11, 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.

13. The method according to any one of claims 2 to 11, 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.

14. The method according to any one of claims 2 to 11, 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.

15. The method according to any one of claims 2 to 11, 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.

16. The method according to any one of claims 2 to 12, wherein the GPRC5DxCD3 bispecific antibody is taquituzumab.

17. The method according to any one of claims 1 to 16, wherein the subject has been diagnosed with multiple myeloma.

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

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

20. The method according to any one of claims 1 to 17, wherein the subject suffers from relapsed or refractory multiple myeloma.

21. The method according to any one of claims 1 to 17, wherein the subject has received at least three lines of prior treatment, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

22. The method according to any one of claims 1 to 17, wherein the subject has received at least four lines of prior treatment, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

23. The method according to any one of claims 1 to 22, wherein the preventive intervention is dexamethasone.

24. The method of claim 23, wherein the preventive intervention is dexamethasone mouthwash (an oral solution containing dexamethasone).

25. The method according to claim 23 or 24, wherein the preventive intervention is a 0.1 mg / mL dexamethasone mouthwash.

26. The method according to claim 24 or 25, wherein the method comprises administering the dexamethasone mouthwash twice daily at a dose of 0.5 mg.

27. The method according to claim 24 or 25, wherein the method comprises administering the dexamethasone mouthwash twice daily at a dose of 0.5 mg / 5 mL and administering 50 mg of fluconazole once daily.

28. The method according to any one of claims 24 to 27, the method comprising increasing the dose of the dexamethasone mouthwash up to a maximum of four times daily after an event of decreased taste score (≥6 points).

29. The method according to any one of claims 1 to 22, wherein the preventive intervention is pregabalin.

30. The method of claim 29, wherein the method comprises administering pregabalin at a dose of 50 mg twice daily.

31. The method of claim 29 or 30, wherein the method comprises increasing the dose of pregabalin after an event of decreased taste score (≥6 points).

32. The method according to claim 29 or 30, wherein the method comprises, after the occurrence of a taste score decrease (≥6 points), initially increasing the dose of pregabalin to 150 mg / day, and then increasing it to a maximum of 300 mg / day after one week.

33. The method according to any one of claims 1 to 22, wherein the preventive intervention is clonazepam.

34. The method of claim 33, wherein the preventive intervention is clonazepam mouthwash.

35. The method of claim 33, wherein the preventive intervention is 0.1 mg / mL clonazepam mouthwash.

36. The method according to any one of claims 33 to 35, the method comprising administering clonazepam mouthwash at a dose of 0.5 mg twice daily.

37. The method of claim 36, wherein if the taste score has decreased by 6 points or more, the method comprises continuing to use clonazepam mouthwash at the same dose.

38. The method according to any one of claims 1 to 37, wherein the method comprises administering the first dose of the preventive intervention 5 to 9 days prior to administering the first dose of the targeted GPRC5D therapeutic agent.

39. The method according to any one of claims 1 to 37, the method comprising administering the first dose of the preventive intervention 6 to 8 days prior to administering the first dose of the targeted GPRC5D therapeutic agent, and continuing to administer the preventive intervention daily throughout the treatment phase.

40. The method according to any one of claims 1 to 37, the method comprising administering the first dose of the preventive intervention 7 days prior to administering the first dose of the targeted GPRC5D therapeutic agent, and continuing to administer the preventive intervention daily throughout the treatment phase.

41. The method according to any one of claims 1 to 30, wherein the method comprises administering the preventive intervention daily for 5 to 9 days prior to administering the first dose of the targeted GPRC5D therapeutic agent, and continuing to administer the preventive intervention daily throughout the treatment phase.

42. The method according to any one of claims 1 to 37, wherein the method comprises administering the preventive intervention daily for 6 to 8 days prior to administering the first dose of the targeted GPRC5D therapeutic agent.

43. The method according to any one of claims 1 to 37, wherein the method comprises administering the preventive intervention daily for 7 days prior to administering the first dose of the targeted GPRC5D therapeutic agent.

44. The method according to any one of claims 2 to 43, the method comprising subcutaneously administering one or more escalating doses of the GPRC5DxCD3 bispecific antibody to the subject prior to administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody.

45. The method according to any one of claims 2 to 44, the method comprising administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody to the subject subcutaneously weekly (QW).

46. ​​The method according to any one of claims 2 to 44, the method comprising administering a therapeutic dose of the GPRC5DxCD3 bispecific antibody subcutaneously to the subject every two weeks (Q2W).

47. The method according to any one of claims 2 to 44, the method comprising subcutaneously administering the GPRC5DxCD3 bispecific antibody weekly (QW) at a therapeutic dose of about 400 μg / kg.

48. The method according to any one of claims 2 to 44, the method comprising subcutaneously administering the GPRC5DxCD3 bispecific antibody at a therapeutic dose of about 800 μg / kg every two weeks (Q2W).

49. The method according to any one of claims 2 to 48, wherein the method comprises subcutaneously administering two or three escalating doses of the GPRC5DxCD3 bispecific antibody prior to subcutaneous administration of a therapeutic dose.

50. The method according to any one of claims 2 to 48, 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.

51. The method according to any one of claims 2 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.

52. The method according to any one of claims 44 to 51, wherein the method comprises subcutaneously administering escalating doses of the GPRC5DxCD3 bispecific antibody at intervals of 2 to 4 days.

53. The method according to any one of claims 2 to 44, the method comprising subcutaneously administering the GPRC5DxCD3 bispecific antibody according to the following dosing schedule for the first 28-day treatment cycle: an escalating dose 1 of 0.01 mg / kg (day 1), followed by an escalating dose 2 of 0.06 mg / kg (day 4), followed by an escalating dose 3 of 0.4 mg / kg (day 8), followed by a first treatment dose of 0.8 mg / kg (day 15).

54. The method of claim 53, wherein the escalating doses are administered at intervals of ≥2 days, and the first therapeutic dose is administered ≥2 days after the escalating dose 3, between day 7 and day 15.

55. The method according to claim 53 or 54, wherein for subsequent 28-day treatment cycles (cycle 2+) following the first 28-day treatment cycle, the GPRC5DxCD3 bispecific antibody is administered at 0.8 mg / kg Q2W 14±3 days after the previous treatment dose.

56. The method according to any one of claims 1 to 55, wherein the oral toxicity of the subject is reduced compared to the subject who did not receive the same preventive intervention.

57. The method according to any one of claims 1 to 56, wherein oral toxicity is reduced in the subject compared to a subject who did not receive the same preventive intervention.

58. The method according to any one of claims 1 to 57, wherein the severity of oral toxicity in the subject is reduced compared to subjects who did not receive the same preventive intervention.

59. The method according to any one of claims 1 to 58, wherein the subject did not experience oral toxicity due to the preventive intervention.

60. The method according to any one of claims 1 to 59, wherein the method reduces the proportion of subjects in the population who, during the treatment phase, experience at least one instance of a deterioration in taste score by 6 or more points relative to baseline, as measured by taste test strips.

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