Compositions Comprising Bispecific GPRC5D / CD3 Antibodies

Abstract

Provided herein are aqueous pharmaceutical compositions containing formulations of bispecific GPRC5D / CD3 antibodies or antigen-binding fragments thereof, and methods for preparing the same. Also provided herein are methods for treating cancer in a subject in need thereof by administering to the subject the aqueous pharmaceutical compositions disclosed herein. Further provided herein are kits and articles of manufacture containing the aqueous pharmaceutical compositions disclosed herein.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 487,514, filed February 28, 2023, and U.S. Provisional Patent Application No. 63 / 588,488, filed October 6, 2023, the entire contents of which are incorporated herein by reference in their entirety.

[0002] (Reference to electronically submitted sequence listing) This application contains a Sequence Listing that has been submitted electronically in XML format, which is incorporated by reference herein in its entirety. The XML copy was created on October 6, 2023, is titled "258199.061201(JBI6770USNP1)SequenceListing.xml", and is 36,888 bytes in size.

[0003] FIELD OF THE INVENTION Compositions and methods for formulating pharmaceutical compositions comprising bispecific GPRC5D / CD3 antibodies are disclosed. [Background technology]

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

[0005] Treatment options for multiple myeloma have improved over time and vary depending on the aggressiveness of the disease, underlying prognostic factors, the patient's health status, and pre-existing comorbidities. Treatment options include proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies (mAbs), and stem cell transplantation.

[0006] Despite these treatment outcomes, the disease recurs and is associated with additional risk factors (e.g., comorbidities or aging), thus justifying the need for novel treatment approaches, such as new dosages and treatment regimens. Particularly in the elderly population, where stem cell transplantation is often not a viable option, and in patients with refractory disease who have exhausted all available therapies, multiple myeloma remains an incurable malignancy and an unmet medical need with significant morbidity and mortality.

[0007] T cell redirection killing is a desired mode of action in many treatment areas. Generally, T cell redirection molecules are engineered to have at least two antigen binding sites, one site binding to a surface antigen on target cells and the other site binding to a T cell surface antigen. There remains a need in the art for pharmaceutical compositions comprising such antibodies for the treatment of patients with multiple myeloma, including compositions that are stable for long periods within a certain temperature range. Summary of the Invention

[0008] Disclosed herein are aqueous pharmaceutical compositions comprising specific formulations of G Protein-Coupled Receptor, Class C, Group 5, Member D (GPRC5D) / Cluster of Differentiation 3 (CD3) antibodies. In certain embodiments, the antibody is talquetamab (Tal), an investigational bispecific antibody that binds to G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D) and CD3.

[0009] In part, described herein is an aqueous pharmaceutical composition comprising: (a) a bispecific G protein-coupled receptor class C group 5 member D (GPRC5D) / cluster of differentiation 3 (CD3) antibody or antigen-binding fragment thereof at a concentration of about 0.5 mg / mL to about 3.5 mg / mL, wherein the bispecific GPRC5D / CD3 antibody or antigen-binding fragment thereof is (1) a first heavy chain (HC1) comprising an HC1 variable region 1 (VH1); wherein VH1 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; (2) a first light chain (LC1) comprising an LC1 variable region (VL1); wherein VL1 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively; (3) a second heavy chain (HC2) comprising an HC2 variable region 2 (VH2); and wherein VH2 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; (4) a second light chain (LC2) comprising an LC2 variable region 2 (VL2); and wherein VL2 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively; Including, (b) about 10 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt; (c) about 6% (w / v) to about 10% (w / v) sucrose; (d) about 7 μg / mL to about 33 μg / mL ethylenediaminetetraacetic acid (EDTA); (e) about 0.01% to about 0.07% polysorbate 20, and (f) a pH of about 4.6 to about 5.8; An aqueous pharmaceutical composition is provided comprising:

[0010] In some embodiments, provided herein is an aqueous pharmaceutical composition comprising: (a) a bispecific G protein-coupled receptor class C group 5 member D (GPRC5D) / cluster of differentiation 3 (CD3) antibody or antigen-binding fragment thereof at a concentration of about 25 mg / mL to about 55 mg / mL, wherein the bispecific GPRC5D / CD3 antibody or antigen-binding fragment thereof is (1) a first heavy chain (HC1) comprising an HC1 variable region 1 (VH1); wherein VH1 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; (2) a first light chain (LC1) comprising an LC1 variable region (VL1); wherein VL1 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively; (3) a second heavy chain (HC2) comprising an HC2 variable region 2 (VH2); and wherein VH2 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; (4) a second light chain (LC2) comprising an LC2 variable region 2 (VL2); and wherein VL2 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively; Including, (b) about 10 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt; (c) about 6% (w / v) to about 10% (w / v) sucrose; (d) about 7 μg / mL to about 33 μg / mL ethylenediaminetetraacetic acid (EDTA); (e) about 0.01% to about 0.07% polysorbate 20, and (f) a pH of about 4.6 to about 5.8; An aqueous pharmaceutical composition is provided comprising:

[0011] In some embodiments, the aqueous pharmaceutical composition comprises 2 mg / mL of bispecific GPRC5D / CD3 antibody, 15 mM acetate and / or a pharmaceutically acceptable acetate salt, 8% (w / v) sucrose, 20 μg / mL EDTA, 0.04% PS 20, and a pH of 5.2.

[0012] In some embodiments, the aqueous pharmaceutical composition comprises 40 mg / mL of bispecific GPRC5D / CD3 antibody, 15 mM acetate and / or a pharmaceutically acceptable acetate salt, 8% (w / v) sucrose, 20 μg / mL EDTA, 0.04% PS 20, and a pH of 5.2.

[0013] In some embodiments, methods are provided for treating cancer in a subject in need thereof, hi some embodiments, the methods comprise administering to the subject an aqueous pharmaceutical composition provided herein.

[0014] In some embodiments, methods are provided for preparing aqueous compositions of bispecific G protein-coupled receptor class C group 5 member D (GPRC5D) / cluster of differentiation 3 (CD3) antibodies or antigen-binding fragments thereof. In some embodiments, the bispecific GPRC5D / CD3 antibodies or antigen-binding fragments thereof are (1) a first heavy chain (HC1) comprising an HC1 variable region 1 (VH1); wherein VH1 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; (2) a first light chain (LC1) comprising an LC1 variable region (VL1); wherein VL1 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively; (3) a second heavy chain (HC2) comprising an HC2 variable region 2 (VH2); and wherein VH2 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; (4) a second light chain (LC2) comprising an LC2 variable region 2 (VL2); and wherein VL2 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively; Includes:

[0015] In some embodiments, the method comprises combining a composition comprising about 2 mg / mL of a bispecific GPRC5D / CD3 antibody, about 15 mM acetate and / or a pharmaceutically acceptable acetate salt, about 8% (w / v) sucrose, about 18 μg / mL EDTA, and about 0.04% polysorbate (PS) 20, wherein the stable aqueous pharmaceutical composition has a pH of about 5.2.

[0016] In some embodiments, methods are provided for preparing aqueous compositions of bispecific G protein-coupled receptor class C group 5 member D (GPRC5D) / cluster of differentiation 3 (CD3) antibodies or antigen-binding fragments thereof. In some embodiments, the bispecific GPRC5D / CD3 antibodies or antigen-binding fragments thereof are (5) a first heavy chain (HC1) comprising an HC1 variable region 1 (VH1); wherein VH1 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; (6) a first light chain (LC1) comprising an LC1 variable region (VL1); wherein VL1 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively; (7) a second heavy chain (HC2) comprising an HC2 variable region 2 (VH2); and wherein VH2 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; (8) a second light chain (LC2) comprising an LC2 variable region 2 (VL2); wherein VL2 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively; Includes:

[0017] In some embodiments, the method comprises combining a composition comprising about 40 mg / mL of a bispecific GPRC5D / CD3 antibody, about 15 mM acetate and / or a pharmaceutically acceptable acetate salt, about 8% (w / v) sucrose, about 18 μg / mL EDTA, and about 0.04% polysorbate (PS) 20, wherein the stable aqueous pharmaceutical composition has a pH of about 5.2.

[0018] In some embodiments, the aqueous pharmaceutical composition is stable, hi some embodiments, stability is defined as provided herein.

[0019] In some embodiments, the GPRC5D / CD3 antibody is talquetamab.

[0020] In some embodiments, a kit is provided that includes the aqueous pharmaceutical composition provided herein and instructions for its use.

[0021] In some embodiments, an article of manufacture is provided. In some embodiments, the article of manufacture comprises a container holding an aqueous pharmaceutical composition provided herein.

[0022] In some embodiments, there is provided a use of the aqueous pharmaceutical composition provided herein for treating cancer in a subject, hi some embodiments, the use comprises administering the aqueous pharmaceutical composition to a subject in need thereof. [Brief explanation of the drawings]

[0023] The foregoing summary, as well as the following detailed description of preferred embodiments of the present application, will be better understood when read in conjunction with the appended drawings. It should be understood, however, that the present application is not limited to the precise embodiments shown in the drawings. [Figure 1] Figure 1 shows the main effect of test formulation parameters on % monomer as measured by SEC. [Figure 2] Figure 2 shows the main effect of the formulation parameters tested on the % aggregates measured by SEC. [Figure 3] Figure 3 shows the main effect of test formulation parameters on % fragments measured by SEC. [Figure 4] FIG. 4 shows the main effect of acetate test formulation parameters on % monomer as measured by SEC. [Figure 5] FIG. 5 shows the main effect of acetate test formulation parameters on % aggregates measured by SEC. [Figure 6] FIG. 6 shows the main effect of acetate test formulation parameters on % fragments measured by SEC. DETAILED DESCRIPTION OF THE INVENTION

[0024] The compositions and methods of the present disclosure may be understood more readily by reference to the following detailed description taken in conjunction with the accompanying drawings, which form a part of this disclosure: It is to be understood that the disclosed compositions and methods are not limited to the specific compositions and methods described and / or illustrated herein, and that the terminology used herein is for the purpose of describing particular embodiments, by way of example only, and is not intended to limit the claimed compositions and methods.

[0025] Unless otherwise stated, any description of possible mechanisms or modes of operation or reasons for improvement is intended to be illustrative only, and the compositions and methods of the present disclosure are not limited by the merits or demerits of any such proposed mechanisms or modes of operation or reasons for improvement.

[0026] When a range of numerical values ​​is recited or established herein, the range includes its endpoints and all individual integers and fractions within the range, and also includes each of the narrower ranges formed by all the various possible combinations of these endpoints and internal integers and fractions, each of which forms a subgroup of the larger group of values ​​within the recited range, as if it were explicitly recited. When a range of numerical values ​​is recited herein as being higher than the recited value, the range is nevertheless finite, with its upper limit defined by a value operable within the context of the invention described herein. When a range of numerical values ​​is recited herein as being lower than the recited value, the range is nevertheless defined by a non-zero value at its lower limit. It is not intended that the scope of the invention be limited to the specific values ​​recited when defining the range. All ranges are inclusive and combinable.

[0027] When values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. Reference to a particular numerical value is intended to include at least that particular value unless the context dictates otherwise.

[0028] It is also understood that certain features of the compositions and methods of the present disclosure, which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the compositions and methods of the present disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.

[0029] As used herein, the singular forms "a," "an," and "the" are intended to include plurals.

[0030] Various terms relating to aspects of the present specification are used throughout the specification and claims. Unless otherwise indicated, such terms shall be given their ordinary meaning in the art. Other specifically defined terms shall be construed in a manner consistent with the definition provided herein.

[0031] As used herein, "about," when used in connection with a numerical range, cutoff, or specific value, indicates that the recited value may vary by up to 10% from the recited value. Because many of the numerical values ​​used herein are determined experimentally, those skilled in the art will understand that such determinations may, and often will, vary between different experiments. The values ​​used herein should not be considered unduly limited by this inherent variation. Thus, the term "about" is used to encompass a variation of ±10% or less, a variation of ±5% or less, a variation of ±1% or less, a variation of ±0.5% or less, or a variation of ±0.1% or less from the specified value.

[0032] The term "comprising" is intended to include examples encompassed by the terms "consisting essentially of" and "consisting of." Similarly, the term "consisting essentially of" is intended to include examples encompassed by the term "consisting of." Unless the context clearly dictates otherwise, throughout the specification and claims, the words "comprise," "comprising," and the like, are to be construed in an inclusive sense, i.e., "including, but not limited to," as opposed to an exclusive or exclusive sense.

[0033] The term "antibody" and similar terms are intended broadly to include immunoglobulin molecules or fragments thereof, including monoclonal antibodies (such as murine, human, human-adapted, humanized, and chimeric monoclonal antibodies), antibody fragments, bispecific or multispecific antibodies, dimeric, tetrameric, or multimeric antibodies, and single-chain antibodies.

[0034] Immunoglobulins can be assigned to five major classes, namely, IgA, IgD, IgE, IgG, and IgM, depending on the amino acid sequence of the heavy chain constant domain. IgA and IgG are further subdivided into isotypes, IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. Antibody light chains of any vertebrate species can be assigned to one of two clearly distinct types, namely, kappa (κ) and lambda (λ), based on the amino acid sequence of their constant domain.

[0035] "Antibody fragment" refers to a portion of an immunoglobulin molecule that retains the antigen-binding properties of the parent full-length antibody. Exemplary antibody fragments are heavy chain complementarity-determining regions (HCDRs) 1, 2, and 3, light chain complementarity-determining regions (LCDRs) 1, 2, and 3, a heavy chain variable region (VH), or a light chain variable region (VL). Antibody fragments include Fab fragments, which are monovalent fragments consisting of the VL, VH, constant light chain (CL), and constant heavy chain 1 (CH1) domains; F(ab)2 fragments, which are bivalent fragments comprising two Fab fragments linked by a disulfide bridge at the hinge region; Fd fragments consisting of the VH and CH1 domains; Fv fragments consisting of the VL and VH domains of a single antibody arm; and domain antibody (dAb) fragments consisting of the VH domain. Although VH and VL domains can be engineered and linked together via synthetic linkers to form a variety of single-chain antibody designs, the VH / VL domains pair intramolecularly, or, when the VH and VL domains are expressed as separate single-chain antibody constructs, pair intermolecularly to form a monovalent antigen-binding site, such as a single-chain Fv (scFv) or diabody, as described, for example, in WO 1998 / 44001, WO 1988 / 01649, WO 1994 / 13804, and WO 1992 / 01047. These antibody fragments are obtained using techniques known to those skilled in the art, and the fragments are screened for utility in the same manner as full-length antibodies.

[0036] Antibody variable regions consist of a "framework" region interrupted by three "antigen-binding sites," which are defined using various terms: (i) the complementarity-determining regions (CDRs), three in the VH (HCDR1, HCDR2, HCDR3) and three in the VL (LCDR1, LCDR2, LCDR3), are based on sequence diversity (Wu and Kabat 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), and (ii) the "hypervariable regions" ("HVRs" or "HVs"), three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3), are based on sequence diversity (CDRs), which ... "IMGT-CDR" refers to the region of an antibody variable domain that is hypervariable in structure, as defined by the International Association for the Advancement of Science (IAAS) of Antibody Var. 196:901-17, 1987. Other terms include "IMGT-CDR" (Lefranc et al., Dev Comparat Immunol 27:55-77, 2003) and "Specificity Determining Residue Usage" (SDRU) (Almagro Mol Recognit 17:132-43, 2004). The International ImMunoGeneTics (IMGT) database (www_imgt_org) provides standard numbering and definitions for antigen-binding sites. The correspondence between CDR, HV, and IMGT descriptive outlines is provided in Lefranc et al., Dev Comparat Immunol 27:55-77, 2003.

[0037] "Monoclonal antibody" refers to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition exhibits a single binding specificity and affinity for a particular epitope, or, in the case of bispecific monoclonal antibodies, dual binding specificities for two distinct epitopes. Thus, a monoclonal antibody refers to an antibody population in which each heavy and each light chain has a single amino acid composition, except for possible, well-known modifications such as removal of the C-terminal lysine from the antibody heavy chain. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibodies may be monospecific or multispecific, and monovalent, bivalent, or multivalent. Bispecific antibodies are encompassed within the term monoclonal antibody.

[0038] "Bispecific" refers to an antibody that specifically binds to two different antigens or two different epitopes on the same antigen. Bispecific antibodies may be cross-reactive to other related antigens, e.g., the same antigen (homologues) from other species such as humans or monkeys, e.g., cynomolgus monkeys (Macaca cynomolgus, cyno) or chimpanzees (Pan troglodytes), or may bind to an epitope shared between two or more different antigens.

[0039] A "human antibody" refers to an antibody optimized to elicit a minimal immune response when administered to a human subject. The variable regions of a human antibody are derived from human immunoglobulin sequences. If a human antibody contains a constant region or a portion of a constant region, the constant region is also derived from human immunoglobulin sequences. A human antibody contains heavy and light chain variable regions "derived" from sequences of human origin when the variable regions of the human antibody are obtained from a system using human germline immunoglobulins or rearranged immunoglobulin genes. Exemplary such systems are phage-displayed human immunoglobulin gene libraries and transgenic non-human animals, such as mice or rats, carrying human immunoglobulin loci. A "human antibody" typically contains amino acid differences compared to immunoglobulins expressed in humans due to differences in the systems used to obtain human antibodies and human immunoglobulin loci, the introduction of somatic mutations or intentional substitutions into frameworks or CDRs, or both. Typically, a "human antibody" is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical in amino acid sequence to the amino acid sequence encoded by a human germline immunoglobulin or rearranged immunoglobulin gene. Optionally, a "human antibody" can comprise a consensus framework sequence obtained from human framework sequence analysis, e.g., as described in Knappik et al., (2000) J Mol Biol 296:57-86, or a synthetic HCDR3 incorporated into a phage-displayed human immunoglobulin gene library, e.g., as described in Shi et al., (2010) J Mol Biol 397:385-96 and WO 2009 / 085462. Antibodies in which at least one CDR is derived from a non-human species are not included in the definition of "human antibody."

[0040] A "humanized antibody" refers to an antibody in which at least one CDR is derived from a non-human species and at least one framework is derived from a human immunoglobulin sequence. Humanized antibodies can contain substitutions in the framework, so that the framework may not be an exact copy of an expressed human immunoglobulin or human immunoglobulin germline gene sequence.

[0041] "Isolated" refers to a protein that has been subjected to at least one purification or isolation step, as well as to a homogenous population of molecules (e.g., a protein such as a synthetic polynucleotide or antibody) that have been substantially separated and / or purified from other components associated with the system in which the molecule is produced, such as a recombinant cell. An "isolated antibody" refers to an antibody that is substantially free of other cellular material and / or chemicals, and includes antibodies isolated to greater degrees of purity, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% purity.

[0042] "GPRC5DxCD3 bispecific antibody" refers to a molecule containing two or more binding regions, one of which specifically binds to the cell surface antigen G protein-coupled receptor class C group 5 member D antigen (GPRC5D) on a target cell or tissue, and a second binding region of the molecule specifically binds to the T cell antigen CD3. This dual / multiple target binding ability recruits T cells to the target cell or tissue, resulting in eradication of the target cell or tissue. GPRC5D / CD3 bispecific antibodies are described in U.S. Pat. No. 10,562,968, which is incorporated herein by reference in its entirety.

[0043] "GPRC5D" refers to the human G protein-coupled receptor family C group 5 member D, having the amino acid sequence set forth in SEQ ID NO:21. MYKDCIESTGDYFLLCDAEGPWGIILESLAILGIVVTILLLLAFLFLMRKIQDCSQWNVLPTQLLFLLSVLGLFGLAFAFIIELNQQTAPVRYFLFGVLFALCFSCLLAHASNLVKLVRGCVSFSWTTILCIAIGCSLLQIIIATEYVTLIMTRGMMFVNMTPCQLNVDFVVLLVYVLFLMALTFFVSKATFCGPCENWKQHGRLIFITVLFSIIIWVVWISMLLRGNPQFQRQPQWDDPVVCIALVTNAWVFLLLYIVPELCILYRSCRQECPLQGNACPVTAYQHSFQVENQELSRARDSDGAEEDVALTSYGTPIQPQTVDPTQECFIPQAKLSPQQDAGGV (SEQ ID NO: 21)

[0044] "CD3" refers to a human antigen expressed on T cells as part of the multimolecular T cell receptor (TCR) complex and consisting of a homodimer or heterodimer formed from the association of two or four receptor chains: CD3 epsilon, CD3 delta, CD3 zeta, and CD3 gamma. Human CD3 epsilon comprises the amino acid sequence of SEQ ID NO: 22. SEQ ID NO: 23 shows the extracellular domain of CD3 epsilon. MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI (SEQ ID NO: 22) DGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMD (SEQ ID NO: 23)

[0045] "Epitope" refers to the portion of an antigen to which an antibody specifically binds. Epitopes usually consist of chemically active (e.g., polar, nonpolar, or hydrophobic) surface groups of moieties such as amino acids or polysaccharide side chains and may have specific charge characteristics as well as specific three-dimensional structural characteristics. Epitopes can be composed of contiguous and / or discontinuous amino acids that form a conformational spatial unit. In discontinuous epitopes, amino acids in different parts of the linear sequence of the antigen are brought into close proximity in three-dimensional space due to folding of the protein molecule.

[0046] "Variant" refers to a polypeptide or polynucleotide that differs from a reference polypeptide or polynucleotide by one or more modifications, such as, for example, a substitution, insertion, or deletion.

[0047] By "in combination with" it is meant that two or more therapeutic agents can be administered to a subject together in a mixture, simultaneously as single agents, or sequentially as single agents in any order.

[0048] "Treat," "treatment," and like terms refer to both therapeutic and prophylactic or preventative measures, and include reducing the severity and / or frequency of symptoms, eliminating symptoms and / or the underlying cause of symptoms, reducing the frequency or likelihood of symptoms and / or the underlying cause of symptoms, and ameliorating or repairing damage caused directly or indirectly by malignancy. Treatment also includes prolonging survival as compared to expected survival of a subject not receiving treatment. Subjects to be treated include those suffering from a condition or disease as well as those susceptible to a condition or disease, or those in whom the condition or disease is to be prevented.

[0049] A "therapeutically effective amount" refers to an amount of the disclosed composition effective to achieve the desired treatment at the required dosage and for the required period of time. A therapeutically effective amount may vary depending on factors such as the subject's condition, age, sex, and weight, as well as the ability of the combined therapy to elicit a desired response in the subject. Exemplary indicators of a therapeutically effective amount include, for example, an improvement in the patient's health, a decrease in tumor burden, a halt or delay in tumor growth, and / or the absence of metastasis of cancer cells to other locations in the body.

[0050] A "pharmaceutical composition" refers to a composition comprising an active ingredient and a pharmaceutically acceptable carrier. As used herein, "pharmaceutical product" or "DP" is synonymous with "pharmaceutical composition" or "aqueous pharmaceutical composition" unless expressly stated otherwise. Accordingly, embodiments that refer to a "pharmaceutical composition" or "aqueous pharmaceutical composition" or a described feature thereof are understood to encompass and apply to a "pharmaceutical product" or "DP." Similarly, embodiments or features of a "pharmaceutical product" or "DP" are understood to encompass and apply to a "pharmaceutical composition" or "aqueous pharmaceutical composition."

[0051] A pharmaceutical composition, aqueous pharmaceutical composition, medicament, or DP of the present disclosure may be "stable." As used herein, a pharmaceutical composition, aqueous pharmaceutical composition, medicament, or DP (which are all synonymous) is considered stable if it complies with the criteria provided herein. For example, a pharmaceutical composition, aqueous pharmaceutical composition, medicament, or DP is considered stable if it meets certain predetermined thresholds for solution color, pH, turbidity, number of subvisible particles, percentage of purity (by cSDS), percentage of new peaks (by cSDS), percentage of major components (by SE-HPLC), percentage of low molecular weight species (by SE-HPLC), percentage of high molecular weight species (by SE-HPLC), percentage of main peak (by IEX), percentage of sum of acidic peaks (by IEX), percentage of sum of basic peaks (by IEX), protein concentration, percentage of T cell activation, percentage of PS20 (w / v), or any combination thereof. The stability of a pharmaceutical composition, aqueous pharmaceutical composition, drug product, or DP may depend on any one of the above criteria, or any combination thereof. Therefore, a pharmaceutical composition, aqueous pharmaceutical composition, drug product, or DP that meets certain criteria may be considered stable even if other criteria are not met. Furthermore, it should be understood that cSDS, SE-HPLC, and IEX techniques are merely exemplary. The percentage of purity, percentage of new peaks, percentage of major components, percentage of low molecular weight species, percentage of high molecular weight species, percentage of main peak, percentage of total acidic peaks, and percentage of total basic peaks may be determined by any method known in the art. Such methods are within the scope of the present disclosure.

[0052] A "pharmaceutically acceptable carrier" or "excipient" refers to an ingredient in a pharmaceutical composition, other than an active ingredient, that is not toxic to a subject.

[0053] The term "cancer," as used herein, is defined as a disease characterized by the rapid and uncontrolled growth of abnormal cells. Cancer cells can spread locally or to other parts of the body via the bloodstream and lymphatic system. In certain embodiments, the cancer is a hematological malignancy or a solid tumor. In some embodiments, the hematological malignancy is selected from the group consisting of multiple myeloma, smoldering multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), follicular lymphoma (FL), mantle-cell lymphoma (MCL), Waldenstrom's hypergammaglobulinemia, plasma cell leukemia, light-chain amyloidosis (AL), precursor B-cell lymphoblastic leukemia, precursor B-cell lymphoblastic leukemia, acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and / or myelodysplastic syndromes (MSS). syndrome (MDS), chronic lymphocytic leukemia (CLL), B-cell malignancies, chronic myeloid leukemia (CML), hairy cell leukemia (HCL), blastic plasmacytoid dendritic cell neoplasm, Hodgkin's lymphoma, non-Hodgkin's lymphoma, marginal zone B-cell lymphoma (MZL), mucosa-associated lymphatic tissue (MALT), plasma cell leukemia, anaplastic large-cell lymphoma (ALCL), leukemia, or lymphoma.

[0054] "Tumor cells" or "cancer cells" refer to cancerous, precancerous, or transformed cells that have undergone spontaneous or induced phenotypic changes, either in vivo, ex vivo, or in tissue culture. These changes do not necessarily involve the incorporation of new genetic material. Transformation can occur through infection with a transforming virus and the incorporation of new genomic nucleic acid, through the incorporation of exogenous nucleic acid, or can occur spontaneously or after exposure to a carcinogen, thereby mutating endogenous genes. Transformation / cancer is exemplified by morphological changes, cellular immortalization, aberrant growth control, formation of foci, proliferation, malignant lesions, modulation of tumor-specific marker levels, invasiveness, and tumor growth in suitable animal hosts, such as nude mice, in vitro, in vivo, and ex vivo.

[0055] A "T cell redirecting therapeutic agent" refers to a molecule containing two or more binding regions, where one of the binding regions specifically binds to a cell surface antigen on a target cell or tissue, and where 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 BCMA or GPRC5D. Examples of T cell antigens include, for example, CD3. This dual / multiple target binding ability recruits T cells to the target cell or tissue, resulting in eradication of the target cell or tissue.

[0056] A "subject" includes any human or non-human animal. A "non-human animal" includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. The terms "subject" and "patient" may be used interchangeably herein.

[0057] explanation Throughout this specification, the numbering of amino acid residues in antibody constant regions is according to the EU index as set forth in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991), unless otherwise expressly stated herein. The numbering of antibody constant chains can be found, for example, in the IMGT Web Resources, IMGT Scientific chart, on the ImMunoGeneTics website.

[0058] Conventional one-letter and three-letter amino acid codes are used herein as shown in Table 1.

[0059] [Table 1]

[0060] GPRC5D / CD3 bispecific antibodies and uses thereof Disclosed herein are aqueous pharmaceutical compositions comprising bispecific GPRC5D / CD3 antibodies and methods of using same for the treatment of multiple myeloma, including the treatment of human subjects who have relapsed or are refractory to treatment with one or more prior therapies.

[0061] In some embodiments, provided herein is an aqueous pharmaceutical composition comprising: (a) a bispecific G protein-coupled receptor, class C, group 5, member D (GPRC5D) / cluster of differentiation 3 (CD3) antibody or antigen-binding fragment thereof at a concentration of about 0.5 mg / mL to about 100 mg / mL, wherein the bispecific GPRC5D / CD3 antibody or antigen-binding fragment thereof is (1) a first heavy chain (HC1) comprising an HC1 variable region 1 (VH1); wherein VH1 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; (2) a first light chain (LC1) comprising an LC1 variable region (VL1); wherein VL1 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively; (3) a second heavy chain (HC2) comprising an HC2 variable region 2 (VH2); and wherein VH2 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; (4) a second light chain (LC2) comprising an LC2 variable region 2 (VL2); and wherein VL2 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively; Including, (b) about 10 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt; (c) about 6% (w / v) to about 10% (w / v) sucrose; (d) about 7 μg / mL to about 33 μg / mL ethylenediaminetetraacetic acid (EDTA); (e) about 0.01% to about 0.07% polysorbate 20, and (f) a pH of about 4.7 to about 5.7; An aqueous pharmaceutical composition is provided comprising:

[0062] In some embodiments, provided herein is an aqueous pharmaceutical composition comprising: (a) a bispecific G protein-coupled receptor, class C, group 5, member D (GPRC5D) / cluster of differentiation 3 (CD3) antibody or antigen-binding fragment thereof at a concentration of about 0.5 mg / mL to about 3.5 mg / mL, wherein the bispecific GPRC5D / CD3 antibody or antigen-binding fragment thereof is (5) a first heavy chain (HC1) comprising an HC1 variable region 1 (VH1); wherein VH1 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; (6) a first light chain (LC1) comprising an LC1 variable region (VL1); wherein VL1 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively; (7) a second heavy chain (HC2) comprising an HC2 variable region 2 (VH2); and wherein VH2 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; (8) a second light chain (LC2) comprising an LC2 variable region 2 (VL2); wherein VL2 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively; Including, (f) about 10 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt; (g) about 6% (w / v) to about 10% (w / v) sucrose; (h) about 7 μg / mL to about 33 μg / mL ethylenediaminetetraacetic acid (EDTA); (i) about 0.01% to about 0.07% polysorbate 20, and (j) a pH of about 4.7 to about 5.7; An aqueous pharmaceutical composition is provided comprising:

[0063] In some embodiments, provided herein is an aqueous pharmaceutical composition comprising: (a) a bispecific G protein-coupled receptor, class C, group 5, member D (GPRC5D) / cluster of differentiation 3 (CD3) antibody or antigen-binding fragment thereof at a concentration of about 25 mg / mL to about 55 mg / mL, wherein the bispecific GPRC5D / CD3 antibody or antigen-binding fragment thereof is (1) a first heavy chain (HC1) comprising an HC1 variable region 1 (VH1); wherein VH1 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; (2) a first light chain (LC1) comprising an LC1 variable region (VL1); wherein VL1 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively; (3) a second heavy chain (HC2) comprising an HC2 variable region 2 (VH2); and wherein VH2 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; (4) a second light chain (LC2) comprising an LC2 variable region 2 (VL2); and wherein VL2 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively; Including, (b) about 10 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt; (c) about 6% (w / v) to about 10% (w / v) sucrose; (d) about 7 μg / mL to about 33 μg / mL ethylenediaminetetraacetic acid (EDTA); (e) about 0.01% to about 0.07% polysorbate 20, and (f) a pH of about 4.7 to about 5.7; An aqueous pharmaceutical composition is provided comprising:

[0064] In some embodiments, the GPRC5D / CD3 bispecific antibody comprises a GPRC5D binding domain comprising a VH having an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, and an HCDR3 of SEQ ID NO: 3, and a VL having an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6, and a CD3 binding domain comprising a VH having an HCDR1 of SEQ ID NO: 11, an HCDR2 of SEQ ID NO: 12, and an HCDR3 of SEQ ID NO: 13, and a VL having an LCDR1 of SEQ ID NO: 14, an LCDR2 of SEQ ID NO: 15, and an LCDR3 of SEQ ID NO: 16. The HCDRs and LCDRs of the GPRC5D / CD3 bispecific antibodies are listed in Table 2 below.

[0065] [Table 2]

[0066] The CDRs listed in the above table are in the Kabat numbering system. However, as provided herein, the CDRs of the present disclosure may be provided by any suitable numbering system, such as the Kabat, Chothia, IMGT, or AbM numbering systems. Tables 3-5 below provide exemplary CDRs utilizing the Chothia, AbM, and IMGT numbering systems:

[0067] [Table 3]

[0068] [Table 4]

[0069] [Table 5]

[0070] In some embodiments, the GPRC5D / CD3 bispecific antibody comprises a GPRC5D binding domain comprising a VH having an HCDR1 of SEQ ID NO: 1, an HCDR2 of SEQ ID NO: 2, and an HCDR3 of SEQ ID NO: 3, and a VL having an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6, and a CD3 binding domain comprising a VH having an HCDR1 of SEQ ID NO: 11, an HCDR2 of SEQ ID NO: 12, and an HCDR3 of SEQ ID NO: 13, and a VL having an LCDR1 of SEQ ID NO: 14, an LCDR2 of SEQ ID NO: 15, and an LCDR3 of SEQ ID NO: 16.

[0071] In some embodiments, the GPRC5D / CD3 bispecific antibody comprises a GPRC5D binding domain comprising a VH having an HCDR1 of SEQ ID NO: 24, an HCDR2 of SEQ ID NO: 25, and an HCDR3 of SEQ ID NO: 3, and a VL having an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6, and a CD3 binding domain comprising a VH having an HCDR1 of SEQ ID NO: 26, an HCDR2 of SEQ ID NO: 27, and an HCDR3 of SEQ ID NO: 13, and a VL having an LCDR1 of SEQ ID NO: 14, an LCDR2 of SEQ ID NO: 15, and an LCDR3 of SEQ ID NO: 16.

[0072] In some embodiments, the GPRC5D / CD3 bispecific antibody comprises a GPRC5D binding domain comprising a VH having an HCDR1 of SEQ ID NO: 28, an HCDR2 of SEQ ID NO: 29, and an HCDR3 of SEQ ID NO: 3, and a VL having an LCDR1 of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and an LCDR3 of SEQ ID NO: 6, and a CD3 binding domain comprising a VH having an HCDR1 of SEQ ID NO: 30, an HCDR2 of SEQ ID NO: 31, and an HCDR3 of SEQ ID NO: 13, and a VL having an LCDR1 of SEQ ID NO: 14, an LCDR2 of SEQ ID NO: 15, and an LCDR3 of SEQ ID NO: 16.

[0073] In some embodiments, the GPRC5D / CD3 bispecific antibody comprises a GPRC5D binding domain comprising a VH having an HCDR1 of SEQ ID NO: 32, an HCDR2 of SEQ ID NO: 33, an HCDR3 of SEQ ID NO: 34, an LCDR1 of SEQ ID NO: 35, an LCDR2 having the amino acid sequence SAS, and a VL having an LCDR3 of SEQ ID NO: 6, and a CD3 binding domain comprising a VH having an HCDR1 of SEQ ID NO: 36, an HCDR2 of SEQ ID NO: 37, an HCDR3 of SEQ ID NO: 38, an LCDR1 of SEQ ID NO: 39, an LCDR2 having the amino acid sequence GTN, and a VL having an LCDR3 of SEQ ID NO: 16.

[0074] In certain embodiments, a bispecific GPRC5D / CD3 antibody comprises a VH1 having the amino acid sequence of SEQ ID NO: 7 and a VL1 having the amino acid sequence of SEQ ID NO: 8. In certain embodiments, a bispecific GPRC5D / CD3 antibody comprises an HC1 having the amino acid sequence of SEQ ID NO: 9 and an LC1 having the amino acid sequence of SEQ ID NO: 10. In certain embodiments, a bispecific GPRC5D / CD3 antibody comprises a VH2 having the amino acid sequence of SEQ ID NO: 17 and a VL2 having the amino acid sequence of SEQ ID NO: 18. In certain embodiments, a bispecific GPRC5D / CD3 antibody comprises an HC2 having the amino acid sequence of SEQ ID NO: 19 and an LC2 having the amino acid sequence of SEQ ID NO: 20.

[0075] In some embodiments, the GPRC5D binding arm of the GPRC5D / CD3 bispecific antibody and the CD3 binding arm of the GPRC5D / CD3 bispecific antibody comprise the amino acid sequences provided in Tables 6a and 6b.

[0076] [Table 6]

[0077] [Table 7]

[0078] In some embodiments, the bispecific GPRC5D / CD3 antibody may be, for example, talquetamab. In some embodiments, talquetamab comprises a first heavy chain (HC1), a first light chain (LC1), a second heavy chain (HC2), and a second light chain (LC2), wherein HC1 is associated with LC1 and HC2 is associated with LC2, and wherein HC1 and LC1 form a first antigen-binding site that immunospecifically binds to GPRC5D, and HC2 and LC2 form a second antigen-binding site that immunospecifically binds to CD3. In some embodiments, talquetamab comprises an HC1 of SEQ ID NO: 9, an LC1 of SEQ ID NO: 10, an HC2 of SEQ ID NO: 19, and an LC2 of SEQ ID NO: 20. In some embodiments, the GPRC5D arm and the CD3 arm of talquetamab form a functional bispecific antibody through interaction between their respective Fc domains.

[0079] In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 0.5 mg / mL to about 100 mg / mL, about 30.0 mg / mL to about 90.0 mg / mL, about 40 mg / mL to about 90.0 mg / mL, about 50 mg / mL to about 90.0 mg / mL, or about 60.0 mg / mL to about 90.0 mg / mL, or any value or range therebetween. In some embodiments, the bispecific GPRC5D / CD3 antibody can have a concentration of, for example, about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, or about 90 mg / mL, or any value therebetween. In some embodiments, the bispecific GPRC5D / CD3 antibody may have a concentration of, for example, about 2 mg / mL, about 30 mg / mL, about 40 mg / mL, about 60 mg / mL, or about 90 mg / mL.

[0080] In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 0.5 mg / mL to about 3.5 mg / mL, about 1.0 mg / mL to about 3.0 mg / mL, or about 1.5 mg / mL to about 2.5 mg / mL, or any value or range therebetween.

[0081] In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 0.5 mg / mL to about 3.5 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 1.0 mg / mL to about 3.5 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 1.5 mg / mL to about 3.5 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 2.0 mg / mL to about 3.5 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 2.5 mg / mL to about 3.5 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 3.0 mg / mL to about 3.5 mg / mL.

[0082] In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 0.5 mg / mL to about 3.5 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 0.5 mg / mL to about 3.0 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 0.5 mg / mL to about 2.5 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 0.5 mg / mL to about 2.0 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 0.5 mg / mL to about 1.5 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 0.5 mg / mL to about 1.0 mg / mL.

[0083] In some embodiments, the bispecific GPRC5D / CD3 antibody can have a concentration of, for example, about 0.5 mg / mL, about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, or about 3.5 mg / mL, or any value therebetween. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 0.5 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 1.0 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 1.5 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 2 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 2.5 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 3 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 3.5 mg / mL.

[0084] In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 25 mg / mL to about 55 mg / mL, about 30 mg / mL to about 50 mg / mL, about 35 mg / mL to about 45 mg / mL, or about 38 mg / mL to about 42 mg / mL, or any value or range therebetween.

[0085] In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 25 mg / mL to about 55 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 30 mg / mL to about 55 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 35 mg / mL to about 55 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 40 mg / mL to about 55 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 45 mg / mL to about 55 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 50 mg / mL to about 55 mg / mL.

[0086] In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 25 mg / mL to about 55 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 25 mg / mL to about 50 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 25 mg / mL to about 45 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 25 mg / mL to about 40 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 25 mg / mL to about 35 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 25 mg / mL to about 30 mg / mL.

[0087] In some embodiments, the bispecific GPRC5D / CD3 antibody can have a concentration of, for example, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 36 mg / mL, about 37 mg / mL, about 38 mg / mL, about 39 mg / mL, about 40 mg / mL, about 41 mg / mL, about 42 mg / mL, about 43 mg / mL, about 44 mg / mL, about 45 mg / mL, about 50 mg / mL, or about 55 mg / mL, or any value therebetween. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 25 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 30 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 35 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 36 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 37 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 38 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 39 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 40 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 41 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 42 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 43 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 44 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 45 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 50 mg / mL. In some embodiments, the bispecific GPRC5D / CD3 antibody has a concentration of about 55 mg / mL.

[0088] In some embodiments, the GPRC5D / CD3 antibody can be, for example, talquetamab. In some embodiments, talquetamab is present at a concentration of about 0.5 mg / mL to about 3.5 mg / mL, about 1.0 mg / mL to about 3.0 mg / mL, or about 1.5 mg / mL to about 2.5 mg / mL, or any value or range therebetween.

[0089] In some embodiments, talquetamab is present at a concentration of about 0.5 mg / mL to about 3.5 mg / mL. In some embodiments, talquetamab is present at a concentration of about 1.0 mg / mL to about 3.5 mg / mL. In some embodiments, talquetamab is present at a concentration of about 1.5 mg / mL to about 3.5 mg / mL. In some embodiments, talquetamab is present at a concentration of about 2.0 mg / mL to about 3.5 mg / mL. In some embodiments, talquetamab is present at a concentration of about 2.5 mg / mL to about 3.5 mg / mL. In some embodiments, talquetamab is present at a concentration of about 3.0 mg / mL to about 3.5 mg / mL.

[0090] In some embodiments, talquetamab is present at a concentration of about 0.5 mg / mL to about 3.5 mg / mL. In some embodiments, talquetamab is present at a concentration of about 0.5 mg / mL to about 3.0 mg / mL. In some embodiments, talquetamab is present at a concentration of about 0.5 mg / mL to about 2.5 mg / mL. In some embodiments, talquetamab is present at a concentration of about 0.5 mg / mL to about 2.0 mg / mL. In some embodiments, talquetamab is present at a concentration of about 0.5 mg / mL to about 1.5 mg / mL. In some embodiments, talquetamab is present at a concentration of about 0.5 mg / mL to about 1.0 mg / mL.

[0091] In some embodiments, talquetamab is present at a concentration of, for example, about 0.5 mg / mL, about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, or about 3.5 mg / mL, or any value therebetween. In some embodiments, talquetamab is present at a concentration of about 0.5 mg / mL. In some embodiments, talquetamab is present at a concentration of about 1.0 mg / mL. In some embodiments, talquetamab is present at a concentration of about 1.5 mg / mL. In some embodiments, talquetamab is present at a concentration of about 2 mg / mL. In some embodiments, talquetamab is present at a concentration of about 2.5 mg / mL. In some embodiments, talquetamab is present at a concentration of about 3 mg / mL. In some embodiments, talquetamab is present at a concentration of about 3.5 mg / mL.

[0092] In some embodiments, talquetamab is present at a concentration of about 25 mg / mL to about 55 mg / mL, about 30 mg / mL to about 50 mg / mL, about 35 mg / mL to about 45 mg / mL, or about 38 mg / mL to about 42 mg / mL, or any value or range therebetween.

[0093] In some embodiments, talquetamab is present at a concentration of about 25 mg / mL to about 55 mg / mL. In some embodiments, talquetamab is present at a concentration of about 30 mg / mL to about 55 mg / mL. In some embodiments, talquetamab is present at a concentration of about 35 mg / mL to about 55 mg / mL. In some embodiments, talquetamab is present at a concentration of about 40 mg / mL to about 55 mg / mL. In some embodiments, talquetamab is present at a concentration of about 45 mg / mL to about 55 mg / mL. In some embodiments, talquetamab is present at a concentration of about 50 mg / mL to about 55 mg / mL.

[0094] In some embodiments, talquetamab is present at a concentration of about 25 mg / mL to about 55 mg / mL. In some embodiments, talquetamab is present at a concentration of about 25 mg / mL to about 50 mg / mL. In some embodiments, talquetamab is present at a concentration of about 25 mg / mL to about 45 mg / mL. In some embodiments, talquetamab is present at a concentration of about 25 mg / mL to about 40 mg / mL. In some embodiments, talquetamab is present at a concentration of about 25 mg / mL to about 35 mg / mL. In some embodiments, talquetamab is present at a concentration of about 25 mg / mL to about 30 mg / mL.

[0095] In some embodiments, talquetamab is present at a concentration of, for example, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 36 mg / mL, about 37 mg / mL, about 38 mg / mL, about 39 mg / mL, about 40 mg / mL, about 41 mg / mL, about 42 mg / mL, about 43 mg / mL, about 44 mg / mL, about 45 mg / mL, about 50 mg / mL, or about 55 mg / mL, or any value therebetween. In some embodiments, talquetamab is present at a concentration of about 25 mg / mL. In some embodiments, talquetamab is present at a concentration of about 30 mg / mL. In some embodiments, talquetamab is present at a concentration of about 35 mg / mL. In some embodiments, talquetamab is present at a concentration of about 36 mg / mL. In some embodiments, talquetamab is present at a concentration of about 37 mg / mL. In some embodiments, talquetamab is present at a concentration of about 38 mg / mL. In some embodiments, talquetamab is present at a concentration of about 39 mg / mL. In some embodiments, talquetamab is present at a concentration of about 40 mg / mL. In some embodiments, talquetamab is present at a concentration of about 41 mg / mL. In some embodiments, talquetamab is present at a concentration of about 42 mg / mL. In some embodiments, talquetamab is present at a concentration of about 43 mg / mL. In some embodiments, talquetamab is present at a concentration of about 44 mg / mL. In some embodiments, talquetamab is present at a concentration of about 45 mg / mL. In some embodiments, talquetamab is present at a concentration of about 50 mg / mL. In some embodiments, talquetamab is present at a concentration of about 55 mg / mL.

[0096] In some embodiments, the composition comprises about 10 mM to about 20 mM, about 12 mM to about 18 mM, or about 14 mM to about 16 mM acetate and / or a pharmaceutically acceptable acetate salt, or any value or range therebetween.

[0097] In some embodiments, the composition comprises about 10 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 11 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 12 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 13 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 14 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 15 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 16 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 17 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 18 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 19 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt.

[0098] In some embodiments, the composition comprises about 10 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 10 mM to about 19 mM acetate and / or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 10 mM to about 18 mM acetate and / or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 10 mM to about 17 mM acetate and / or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 10 mM to about 16 mM acetate and / or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 10 mM to about 15 mM acetate and / or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 10 mM to about 14 mM acetate and / or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 10 mM to about 13 mM acetate and / or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 10 mM to about 12 mM acetate and / or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 10 mM to about 11 mM acetate and / or a pharmaceutically acceptable acetate salt.

[0099] In some embodiments, the composition can contain, for example, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, or about 20 mM acetate and / or a pharmaceutically acceptable acetate salt, or any value therebetween. In some embodiments, the composition contains about 10 mM acetate or a pharmaceutically acceptable acetate salt. In some embodiments, the composition contains about 11 mM acetate or a pharmaceutically acceptable acetate salt. In some embodiments, the composition contains about 12 mM acetate or a pharmaceutically acceptable acetate salt. In some embodiments, the composition contains about 13 mM acetate or a pharmaceutically acceptable acetate salt. In some embodiments, the composition contains about 14 mM acetate or a pharmaceutically acceptable acetate salt. In some embodiments, the composition contains about 15 mM acetate or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 16 mM acetate or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 17 mM acetate or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 18 mM acetate or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 19 mM acetate or a pharmaceutically acceptable acetate salt. In some embodiments, the composition comprises about 20 mM acetate or a pharmaceutically acceptable acetate salt.

[0100] In some embodiments, the composition comprises about 6% (w / v) to about 10% (w / v) or about 7% (w / v) to about 9% (w / v) sucrose, or any value or range therebetween.

[0101] In some embodiments, the composition comprises about 6% (w / v) to about 10% (w / v) sucrose. In some embodiments, the composition comprises about 7% (w / v) to about 10% (w / v) sucrose. In some embodiments, the composition comprises about 8% (w / v) to about 10% (w / v) sucrose. In some embodiments, the composition comprises about 9% (w / v) to about 10% (w / v) sucrose.

[0102] In some embodiments, the composition comprises about 6% (w / v) to about 10% (w / v) sucrose. In some embodiments, the composition comprises about 6% (w / v) to about 9% (w / v) sucrose. In some embodiments, the composition comprises about 6% (w / v) to about 8% (w / v) sucrose. In some embodiments, the composition comprises about 6% (w / v) to about 7% (w / v) sucrose.

[0103] In some embodiments, the composition may comprise, for example, about 6% (w / v), about 7% (w / v), about 8% (w / v), about 9% (w / v), or about 10% (w / v) sucrose, or any value therebetween. In some embodiments, the composition comprises about 6% (w / v) sucrose. In some embodiments, the composition comprises about 7% (w / v) sucrose. In some embodiments, the composition comprises about 8% (w / v) sucrose. In some embodiments, the composition comprises about 9% (w / v) sucrose. In some embodiments, the composition comprises about 10% (w / v) sucrose.

[0104] In some embodiments, the composition comprises EDTA from about 7 μg / mL to about 33 μg / mL, 12 μg / mL to about 28 μg / mL, or about 15 μg / mL to about 21 μg / mL, or any value or range therebetween.

[0105] In some embodiments, the composition comprises from about 7 μg / mL to about 33 μg / mL of EDTA. In some embodiments, the composition comprises from about 12 μg / mL to about 33 μg / mL of EDTA. In some embodiments, the composition comprises from about 15 μg / mL to about 33 μg / mL of EDTA. In some embodiments, the composition comprises from about 16 μg / mL to about 33 μg / mL of EDTA. In some embodiments, the composition comprises from about 17 μg / mL to about 33 μg / mL of EDTA. In some embodiments, the composition comprises from about 18 μg / mL to about 33 μg / mL of EDTA. In some embodiments, the composition comprises from about 19 μg / mL to about 33 μg / mL of EDTA. In some embodiments, the composition comprises from about 20 μg / mL to about 33 μg / mL of EDTA. In some embodiments, the composition comprises from about 21 μg / mL to about 33 μg / mL of EDTA. In some embodiments, the composition comprises about 24 μg / mL to about 33 μg / mL of EDTA, hi some embodiments, the composition comprises about 28 μg / mL to about 33 μg / mL of EDTA.

[0106] In some embodiments, the composition comprises from about 7 μg / mL to about 33 μg / mL of EDTA. In some embodiments, the composition comprises from about 7 μg / mL to about 28 μg / mL of EDTA. In some embodiments, the composition comprises from about 7 μg / mL to about 24 μg / mL of EDTA. In some embodiments, the composition comprises from about 7 μg / mL to about 21 μg / mL of EDTA. In some embodiments, the composition comprises from about 7 μg / mL to about 20 μg / mL of EDTA. In some embodiments, the composition comprises from about 7 μg / mL to about 19 μg / mL of EDTA. In some embodiments, the composition comprises from about 7 μg / mL to about 18 μg / mL of EDTA. In some embodiments, the composition comprises from about 7 μg / mL to about 17 μg / mL of EDTA. In some embodiments, the composition comprises from about 7 μg / mL to about 16 μg / mL of EDTA. In some embodiments, the composition comprises from about 7 μg / mL to about 15 μg / mL of EDTA. In some embodiments, the composition comprises about 7 μg / mL to about 12 μg / mL of EDTA.

[0107] In some embodiments, the composition can contain, for example, about 7 μg / mL, 12 μg / mL, 15 μg / mL, 16 μg / mL, about 17 μg / mL, about 18 μg / mL, about 19 μg / mL, about 20 μg / mL, about 21 μg / mL, about 22 μg / mL, about 23 μg / mL, about 24 μg / mL, about 28 μg / mL, or about 33 μg / mL of EDTA, or any value therebetween. In some embodiments, the composition contains about 7 μg / mL of EDTA. In some embodiments, the composition contains about 12 μg / mL of EDTA. In some embodiments, the composition contains about 15 μg / mL of EDTA. In some embodiments, the composition contains about 16 μg / mL of EDTA. In some embodiments, the composition contains about 17 μg / mL of EDTA. In some embodiments, the composition contains about 18 μg / mL of EDTA. In some embodiments, the composition contains about 19 μg / mL of EDTA. In some embodiments, the composition comprises about 20 μg / mL EDTA. In some embodiments, the composition comprises about 21 μg / mL EDTA. In some embodiments, the composition comprises about 22 μg / mL EDTA. In some embodiments, the composition comprises about 23 μg / mL EDTA. In some embodiments, the composition comprises about 24 μg / mL EDTA. In some embodiments, the composition comprises about 28 μg / mL EDTA. In some embodiments, the composition comprises about 33 μg / mL EDTA.

[0108] In some embodiments, the composition comprises about 0.01% to about 0.07%, about 0.02% to about 0.06%, or about 0.03% to about 0.05% polysorbate 20 (PS20), or any value or range therebetween.

[0109] In some embodiments, the composition comprises about 0.01% to about 0.07% PS20. In some embodiments, the composition comprises about 0.02% to about 0.07% PS20. In some embodiments, the composition comprises about 0.03% to about 0.07% PS20. In some embodiments, the composition comprises about 0.04% to about 0.07% PS20. In some embodiments, the composition comprises about 0.05% to about 0.07% PS20. In some embodiments, the composition comprises about 0.06% to about 0.07% PS20.

[0110] In some embodiments, the composition comprises about 0.01% to about 0.07% PS20. In some embodiments, the composition comprises about 0.01% to about 0.06% PS20. In some embodiments, the composition comprises about 0.01% to about 0.05% PS20. In some embodiments, the composition comprises about 0.01% to about 0.04% PS20. In some embodiments, the composition comprises about 0.01% to about 0.03% PS20. In some embodiments, the composition comprises about 0.01% to about 0.02% PS20.

[0111] In some embodiments, the composition may include, for example, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, or about 0.07% PS20, or any value therebetween. In some embodiments, the composition includes about 0.01% PS20. In some embodiments, the composition includes about 0.02% PS20. In some embodiments, the composition includes about 0.03% PS20. In some embodiments, the composition includes about 0.04% PS20. In some embodiments, the composition includes about 0.05% PS20. In some embodiments, the composition includes about 0.06% PS20. In some embodiments, the composition includes about 0.07% PS20.

[0112] In some embodiments, the pH of the composition is from about 4.7 to about 5.7, from about 4.8 to about 5.6, from about 4.9 to about 5.5, or any value or range therebetween.

[0113] In some embodiments, the pH of the composition is about 4.7 to about 5.7. In some embodiments, the pH of the composition is about 4.8 to about 5.7. In some embodiments, the pH of the composition is about 4.9 to about 5.7. In some embodiments, the pH of the composition is about 5.0 to about 5.7. In some embodiments, the pH of the composition is about 5.1 to about 5.7. In some embodiments, the pH of the composition is about 5.2 to about 5.7. In some embodiments, the pH of the composition is about 5.3 to about 5.7. In some embodiments, the pH of the composition is about 5.4 to about 5.7. In some embodiments, the pH of the composition is about 5.5 to about 5.7. In some embodiments, the pH of the composition is about 5.6 to about 5.7.

[0114] In some embodiments, the pH of the composition is about 4.7 to about 5.7. In some embodiments, the pH of the composition is about 4.7 to about 5.6. In some embodiments, the pH of the composition is about 4.7 to about 5.5. In some embodiments, the pH of the composition is about 4.7 to about 5.4. In some embodiments, the pH of the composition is about 4.7 to about 5.3. In some embodiments, the pH of the composition is about 4.7 to about 5.2. In some embodiments, the pH of the composition is about 4.7 to about 5.1. In some embodiments, the pH of the composition is about 4.7 to about 5.0. In some embodiments, the pH of the composition is about 4.7 to about 4.9. In some embodiments, the pH of the composition is about 4.7 to about 4.8.

[0115] In some embodiments, the pH of the composition can be, for example, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, or about 5.7, or any value therebetween. In some embodiments, the pH of the composition is about 4.7. In some embodiments, the pH of the composition is about 4.8. In some embodiments, the pH of the composition is about 4.9. In some embodiments, the pH of the composition is about 5.0. In some embodiments, the pH of the composition is about 5.1. In some embodiments, the pH of the composition is about 5.2. In some embodiments, the pH of the composition is about 5.3. In some embodiments, the pH of the composition is about 5.4. In some embodiments, the pH of the composition is about 5.5. In some embodiments, the pH of the composition is about 5.6. In some embodiments, the pH of the composition is about 5.7.

[0116] The stability of the aqueous pharmaceutical compositions of the present disclosure, also referred to as drug products (DPs), is determined based on the specific amounts or proportions of GPRC5D / CD3 antibodies and other components of the DPs provided herein (such as, but not limited to, acetate and / or pharmaceutically acceptable acetate salts, sucrose, PS20, and EDTA), as well as an evaluation of various factors, including, but not limited to, solution color, pH, turbidity, percentage of purity, number of subvisible particles, percentage of new peaks, percentage of major components, percentage of high molecular weight species (HMWS), percentage of low molecular weight species (LMWS), percentage of total acidic peaks, percentage of total basic peaks, protein concentration, percentage of T cell activation, and / or percentage of PS20.

[0117] A stable DP disclosed herein should not be construed as requiring all of the factors listed herein, but rather as requiring at least one, at least two, or at least three or more of those factors. In some embodiments, a stable disclosed DP exhibits the following results for at least one, at least two, at least three, or more of the factors listed in detail herein below. In some embodiments, a stable DP exhibits the following results for most of the factors listed in detail herein below. In some embodiments, a stable DP exhibits the following results for all of the factors listed in detail herein below.

[0118] Solution color The color of the DP solution can be monitored and evaluated to verify that the appearance of the solution is consistent with previous batches upon release and over its shelf life. The color of the DP solution can reflect stability. In some embodiments, a stable DP is defined as having a solution color ranging from colorless to about BY2 or less, about BY4 or less, about B2 or less, about B4 or less, about Y2 or less, or about Y4 or less, as described in European Pharmacopoeia 2.2.2, Degree of Coloration of Liquids European Pharmacopoeia (Ph.Eur.) 10th Edition Monograph No. 20202, July 2019.

[0119] In some embodiments, a stable DP is defined as having a solution color of colorless to about BY2 or less, about B2 or less, or about Y2 or less after storage at a temperature of about 5° C. for about 12 months or more, after storage at a temperature of about 25° C. for about 12 months or more, and / or after storage at a temperature of about 2 years or more at about 5° C. In some embodiments, a stable DP is defined as having a solution color of colorless to about BY4 or less, about B4 or less, or about Y4 or less after storage at a temperature of about 5° C. for about 12 months or more, after storage at a temperature of about 25° C. for about 12 months or more, and / or after storage at a temperature of about 5° C. for about 2 years or more. In some embodiments, a stable DP is defined as having a solution color of colorless to about BY5 or less, about B5 or less, or about Y5 or less after storage at a temperature of about 5° C. for about 12 months or more, after storage at a temperature of about 25° C. for about 12 months or more, and / or after storage at a temperature of about 5° C. for about 2 years or more.

[0120] pH Measuring the pH of a DP solution can confirm that the pH is consistent with previous DP batches at the time of release and over the shelf life. The pH of the solution can reflect stability. In some embodiments, a stable DP is defined as having a pH of about 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0. In some embodiments, the pH of the DP is about 5.2 after storage at a temperature of about 5° C. for about 12 months or more, after storage at a temperature of about 25° C. for about 12 months or more, and / or after storage at a temperature of about 5° C. for about 2 years or more. In some embodiments, the pH ranges from about 4.7 to about 5.7 after storage at a temperature of about 5° C. for about 12 months or more, after storage at a temperature of about 25° C. for about 12 months or more, and / or after storage at a temperature of about 5° C. for about 2 years or more. In some embodiments, a stable DP is defined as having a pH range of about 4.8 to about 5.6 after storage at a temperature of about 5° C. for about 12 months or more, after storage at a temperature of about 25° C. for about 12 months or more, and / or after storage at a temperature of about 5° C. for about 2 years or more. In some embodiments, a stable DP is defined as having a pH range of about 4.9 to about 5.5 after storage at a temperature of about 5° C. for about 12 months or more, after storage at a temperature of about 25° C. for about 12 months or more, and / or after storage at a temperature of about 5° C. for about 2 years or more.

[0121] Turbidity Turbidity allows for the measurement of the presence of particles in a DP solution to ensure consistency with previous DP batches and allows for applicable compendial guidance at the time of release and throughout shelf life. Solution turbidity can reflect stability. In some embodiments, a stable DP is defined as having a turbidity value of about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nephelometric turbidity units (NTU) after storage at a temperature of about 5° C. for about 12 months or more, after storage at a temperature of about 25° C. for about 12 months or more, and / or after storage at a temperature of about 5° C. for about 2 years or more. In some embodiments, a stable DP is defined as having a turbidity value of about 18 NTU or less after storage at a temperature of about 5° C. for about 12 months or more, after storage at a temperature of about 25° C. for about 12 months or more, and / or after storage at a temperature of about 5° C. for about 2 years or more. In some embodiments, a stable DP is defined as having a turbidity value of about 13 NTU or less after storage at a temperature of about 5° C. for about 12 months or more, after storage at a temperature of about 25° C. for about 12 months or more, and / or after storage at a temperature of about 5° C. for about 2 years or more. In some embodiments, a stable DP is defined as having a turbidity value of about 8 NTU or less after storage at a temperature of about 5° C. for about 12 months or more, after storage at a temperature of about 25° C. for about 12 months or more, and / or after storage at a temperature of about 5° C. for about 2 years or more.

[0122] particle analysis The stability of a DP is set to a certain threshold of particle contamination based on the average number of particles invisible to the naked eye. In some embodiments, the average number of particles present in a tested DP unit should not exceed 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, or 6000 per container for particle sizes of 10 μm or greater. In some embodiments, the average number of particles present in a tested DP unit should not exceed 6000 per container for particle sizes of 10 μm or greater. In some embodiments, the average number of particles present in a tested DP unit should not exceed 100, 200, 300, 400, 500, or 600 per container for particle sizes of 25 μm or greater. In some embodiments, the average number of particles present in a tested DP unit should not exceed 600 per container for particle sizes of 25 μm or greater.

[0123] cSDS conditions Capillary SDS-PAGE (cSDS) is a method that separates denatured proteins based on molecular weight, similar to gel-based SDS-PAGE. This process allows for quantifying DP purity and monitoring its stability upon release and over its shelf life.

[0124] In some embodiments, DP stability is defined based on the results of various cSDS variables (e.g., percent purity or the presence of new peaks) when the cSDS is subjected to reducing or non-reducing conditions after storage at a temperature of about 5° C. for about 12 months or more, after storage at a temperature of about 25° C. for about 12 months or more, and / or after storage at a temperature of about 5° C. for about 2 years or more.

[0125] In some embodiments, a stable DP is defined as having a percent purity under reducing conditions of about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or about or equal to 100%, or any value or range therebetween, after storage of the DP at a temperature of about 5° C. for about 12 months or more, after storage of the DP at a temperature of about 25° C. for about 12 months or more, and / or after storage of the DP at a temperature of about 5° C. for about 2 years or more.

[0126] In some embodiments, a stable DP is defined as one that does not exhibit more than 0.5%, more than 0.8%, more than 0.9%, more than 1.0%, more than 1.2%, more than 1.3%, more than 1.4%, more than 1.5%, more than 1.6%, more than 1.7%, more than 1.8%, more than 1.9%, or more than 2% new peaks in the reduced cSDS result when compared to an untreated reference material after storing the DP at a temperature of about 5°C for about 12 months or more, after storing the DP at a temperature of about 25°C for about 12 months or more, and / or after storing the DP at a temperature of about 5°C for about 2 years or more.

[0127] In some embodiments, a stable DP is defined as having a percent purity under reducing conditions of about 90% or greater and no new peaks greater than 1.5% when compared to a reference material after storage of the DP at a temperature of about 5° C. for about 12 months or more, after storage of the DP at a temperature of about 25° C. for about 12 months or more, and / or after storage of the DP at a temperature of about 5° C. for about 2 years or more. In some embodiments, a stable DP is defined as having a percent purity of about 95% or greater and no new peaks greater than 1.2% when compared to a reference material after storage of the DP at a temperature of about 5° C. for about 12 months or more, after storage of the DP at a temperature of about 25° C. for about 12 months or more, and / or after storage of the DP at a temperature of about 5° C. for about 2 years or more. In some embodiments, a stable DP is defined as having a percent purity of about 97% or greater and no new peaks greater than 1.0% when compared to a reference material after storage of the DP at a temperature of about 5° C. for about 12 months or more, after storage of the DP at a temperature of about 25° C. for about 12 months or more, and / or after storage of the DP at a temperature of about 5° C. for about 2 years or more.

[0128] In some embodiments, a stable DP is defined as having a percent purity under non-reducing conditions of about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%, or any range therebetween, after storage of the DP at a temperature of about 5° C. for about 12 months or more, after storage of the DP at a temperature of about 25° C. for about 12 months or more, and / or after storage of the DP at a temperature of about 5° C. for about 2 years or more.

[0129] In some embodiments, a stable DP is defined as one that does not exhibit more than 0.5%, more than 0.8%, more than 0.9%, more than 1.0%, more than 1.2%, more than 1.3%, more than 1.4%, more than 1.5%, more than 1.6%, more than 1.7%, more than 1.8%, more than 1.9%, or more than 2% new peaks in the non-reduced cSDS result when compared to an untreated reference material after storing the DP at a temperature of about 5°C for about 12 months or more, after storing the DP at a temperature of about 25°C for about 12 months or more, and / or after storing the DP at a temperature of about 5°C for about 2 years or more.

[0130] In some embodiments, a stable DP is defined as having a percent purity under non-reducing conditions of about 90% or greater and no new peaks greater than 1.5% when compared to a reference material after storage of the DP at a temperature of about 5° C. for about 12 months or more, after storage of the DP at a temperature of about 25° C. for about 12 months or more, and / or after storage of the DP at a temperature of about 5° C. for about 2 years or more. In some embodiments, a stable DP is defined as having a percent purity of about 94% or greater and no new peaks greater than 1.2% when compared to a reference material after storage of the DP at a temperature of about 5° C. for about 12 months or more, after storage of the DP at a temperature of about 25° C. for about 12 months or more, and / or after storage of the DP at a temperature of about 5° C. for about 2 years or more. In some embodiments, a stable DP is defined as having a percent purity of about 96% or greater and no new peaks greater than 1.0% when compared to a reference material after storage of the DP at a temperature of about 5° C. for about 12 months or more, after storage of the DP at a temperature of about 25° C. for about 12 months or more, and / or after storage of the DP at a temperature of about 5° C. for about 2 years or more.

[0131] Size-exclusion HPLC (SE-HPLC) results consistent with stability The SE-HPLC procedure allows one to assess the purity of the DP and monitor its stability under non-denaturing conditions upon release and over its shelf life.

[0132] In some embodiments, DP stability is defined based on the results of various SE-HPLC variables, such as major components (MC), high molecular weight species (HMWS), or low molecular weight species (LMWS), after storage of the DP at a temperature of about 5° C. for about 12 months or more, after storage at a temperature of about 25° C. for about 12 months or more, and / or after storage at a temperature of about 5° C. for about 2 years or more.

[0133] In some embodiments, a stable DP is defined as having an MC of about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or equal to or about 100%, or any value or range therebetween, after storage of the DP at a temperature of about 5° C. for about 12 months or more, after storage of the DP at a temperature of about 25° C. for about 12 months or more, and / or after storage of the DP at a temperature of about 5° C. for about 2 years or more. In some embodiments, a stable DP is defined as having an MC of about 90% or greater after storage of the DP at a temperature of about 5° C. for about 12 months or more, after storage of the DP at a temperature of about 25° C. for about 12 months or more, and / or after storage of the DP at a temperature of about 5° C. for about 2 years or more. In some embodiments, a stable DP is defined as having an MC of about 95% or greater after storage of the DP at a temperature of about 5° C. for about 12 months or more, after storage of the DP at a temperature of about 25° C. for about 12 months or more, and / or after storage of the DP at a temperature of about 5° C. for about 2 years or more. In some embodiments, a stable DP is defined as having an MC of about 97% or greater after storage of the DP at a temperature of about 5° C. for about 12 months or more, after storage of the DP at a temperature of about 25° C. for about 12 months or more, and / or after storage of the DP at a temperature of about 5° C. for about 2 years or more.

[0134] In some embodiments, a stable DP is defined as having an HMWS of about 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or any value or range therebetween after storage of the DP at a temperature of about 5° C. for about 12 months or more, after storage of the DP at a temperature of about 25° C. for about 12 months or more, and / or after storage of the DP at a temperature of about 5° C. for about 2 years or more. In some embodiments, a stable DP is defined as having an HMWS of about 10% or less after storage of the DP at a temperature of about 5° C. for about 12 months or more, after storage of the DP at a temperature of about 25° C. for about 12 months or more, and / or after storage of the DP at a temperature of about 5° C. for about 2 years or more. In some embodiments, a stable DP is defined as having an HMWS of about 5% or less after storage of the DP for about 12 months or more at a temperature of about 5° C., after storage of the DP for about 12 months or more at a temperature of about 25° C., and / or after storage of the DP for about 2 years or more at a temperature of about 5° C. In some embodiments, a stable DP is defined as having an HMWS of about 3% or less after storage of the DP for about 12 months or more at a temperature of about 5° C., after storage of the DP for about 12 months or more at a temperature of about 25° C., and / or after storage of the DP for about 2 years or more at a temperature of about 5° C.

[0135] In some embodiments, a stable DP is defined as having an LMWS of about 0.1%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10%, or any value or range therebetween, after storage of the DP at a temperature of about 5° C. for about 12 months or more, after storage of the DP at a temperature of about 25° C. for about 12 months or more, and / or after storage of the DP at a temperature of about 5° C. for about 2 years or more. In some embodiments, a stable DP is defined as having an LMWS of about 5% or less after storage of the DP at a temperature of about 5° C. for about 12 months or more, after storage of the DP at a temperature of about 25° C. for about 12 months or more, and / or after storage of the DP at a temperature of about 5° C. for about 2 years or more. In some embodiments, a stable DP is defined as having an LMWS of about 2% or less after storage of the DP at a temperature of about 5° C. for about 12 months or more, after storage of the DP at a temperature of about 25° C. for about 12 months or more, and / or after storage of the DP at a temperature of about 5° C. for about 2 years or more. In some embodiments, a stable DP is defined as having an LMWS of about 1% or less after storage of the DP at a temperature of about 5° C. for about 12 months or more, after storage of the DP at a temperature of about 25° C. for about 12 months or more, and / or after storage of the DP at a temperature of about 5° C. for about 2 years or more.

[0136] Ion Exchange Chromatography (IEX) The IEX method separates proteins based on their overall charge. This procedure allows for monitoring the charge-based isoform distribution of a pharmaceutical product upon release and over its shelf life. In some embodiments, DP stability is defined based on the results of various IEX variables, such as main peak (MP), sum of acidic peaks, or sum of basic peaks, after DP storage at a temperature of about 25° C. for about 12 months or more, and / or after storage at a temperature of about 5° C. for about 2 years or more.

[0137] In some embodiments, a stable DP is defined as having an IEX with an MP of about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or any value or range therebetween, after about 12 months or more of DP storage at a temperature of about 25° C. and / or after about 2 years or more of storage at a temperature of about 5° C. In some embodiments, a stable DP is defined as having an IEX with an MP of 50% or more after about 12 months or more of DP storage at a temperature of about 25° C. and / or after about 2 years or more of storage at a temperature of about 5° C. In some embodiments, a stable DP is defined as having an IEX with an MP of 55% or more after about 12 months or more of DP storage at a temperature of about 25° C. and / or after about 2 years or more of storage at a temperature of about 5° C. In some embodiments, a stable DP is defined as having an IEX with 60% or greater MP after about 12 months or greater of DP storage at a temperature of about 25°C and / or after about 2 years or greater of storage at a temperature of about 5°C.

[0138] In some embodiments, a stable DP is defined as having an IEX with a total of about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or any value or range therebetween, after about 12 months or more of DP storage at a temperature of about 25° C. and / or after about 2 years or more of storage at a temperature of about 5° C. In some embodiments, a stable DP is defined as having an IEX with a total of about 50% or less of acidic peaks, after about 12 months or more of DP storage at a temperature of about 25° C. and / or after about 2 years or more of storage at a temperature of about 5° C. In some embodiments, a stable DP is defined as having an IEX with a total of about 40% or less of acidic peaks, after about 12 months or more of DP storage at a temperature of about 25° C. and / or after about 2 years or more of storage at a temperature of about 5° C. In some embodiments, a stable DP is defined as having an IEX with a total of about 30% or less of the total acidic peaks after about 12 months or more of DP storage at a temperature of about 25°C and / or after about 2 years or more of storage at a temperature of about 5°C.

[0139] In some embodiments, a stable DP is defined as having an IEX with a sum of basic peaks of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35%, or any value or range therebetween, after about 12 months or more of DP storage at a temperature of about 25°C, and / or after about 2 years or more of storage at a temperature of about 5°C. In some embodiments, a stable DP is defined as having an IEX with a total of about 25% or less of the sum of basic peaks after about 12 months or more of DP storage at a temperature of about 25° C. and / or after about 2 years or more of storage at a temperature of about 5° C. In some embodiments, a stable DP is defined as having an IEX with a total of less than or about 15% of the sum of basic peaks after about 12 months or more of DP storage at a temperature of about 25° C. and / or after about 2 years or more of storage at a temperature of about 5° C. In some embodiments, a stable DP is defined as having an IEX with a total of less than or about 10% of the sum of basic peaks after about 12 months or more of DP storage at a temperature of about 25° C. and / or after about 2 years or more of storage at a temperature of about 5° C.

[0140] Protein concentration The protein concentration of a DP can be verified to be consistent with previous DP batches at the time of shipment and over its shelf life. Protein concentration can be quantified by measuring the UV light absorbance of the pharmaceutical solution at 280 nm (A280).

[0141] 2 mg / mL DP formulation In some embodiments, a stable DP is defined as having a protein concentration of about 1 mg / mL, 1.2 mg / mL, 1.4 mg / mL, 1.6 mg / mL, 1.8 mg / mL, 2 mg / mL, 2.2 mg / mL, 2.4 mg / mL, 2.6 mg / mL, 2.8 mg / mL, 3 mg / mL, or any value or range therebetween, after about 12 months or more of DP storage at a temperature of about 25° C. and / or after about 2 years or more of storage at a temperature of about 5° C. In some embodiments, a stable DP is defined as having a protein concentration of about 1.8 mg / mL to about 2.2 mg / mL after about 12 months or more of DP storage at a temperature of about 25° C. and / or after about 2 years or more of storage at a temperature of about 5° C. In some embodiments, a stable DP is defined as having a protein concentration of about 1.85 mg / mL to about 2.15 mg / mL after about 12 months or more of DP storage at a temperature of about 25° C. and / or after about 2 years or more of storage at a temperature of about 5° C. In some embodiments, a stable DP is defined as having a protein concentration of about 1.9 mg / mL to about 2.1 mg / mL after about 12 months or more of DP storage at a temperature of about 25° C. and / or after about 2 years or more of storage at a temperature of about 5° C.

[0142] 40 mg / mL DP formulation In some embodiments, a stable DP is defined as having a protein concentration of about 30 mg / mL, 31 mg / mL, 32 mg / mL, 33 mg / mL, 34 mg / mL, 35 mg / mL, 36 mg / mL, 37 mg / mL, 38 mg / mL, 39 mg / mL, 40 mg / mL, 41 mg / mL, 42 mg / mL, 43 mg / mL, 44 mg / mL, 45 mg / mL, 46 mg / mL, 47 mg / mL, 48 mg / mL, 49 mg / mL, or 50 mg / mL, or any value or range therebetween, after about 12 months or more of DP storage at a temperature of about 25° C. and / or after about 2 years or more of storage at a temperature of about 5° C. In some embodiments, a stable DP is defined as having a protein concentration of about 34 mg / mL to about 44 mg / mL after about 12 months or more of DP storage at a temperature of about 25° C. and / or after about 2 years or more of storage at a temperature of about 5° C. In some embodiments, a stable DP is defined as having a protein concentration of about 37 mg / mL to about 43 mg / mL after about 12 months or more of DP storage at a temperature of about 25° C. and / or after about 2 years or more of storage at a temperature of about 5° C. In some embodiments, a stable DP is defined as having a protein concentration of about 38 mg / mL to about 42 mg / mL after about 12 months or more of DP storage at a temperature of about 25° C. and / or after about 2 years or more of storage at a temperature of about 5° C.

[0143] Peptide mapping Post-translational modifications (PTMs), such as oxidation, deamidation, and isomerization, are enzymatic modifications that can be detected within the structure of an antibody. In some embodiments, DP stability is assessed based on the level of PTMs in the antibody. The test sample is enzymatically digested to obtain peptide segments. These peptides are then evaluated, for example, by mass spectrometry (MS), tandem mass spectrometry (MS-MS), or ultra-high-performance liquid chromatography mass spectroscopy (UPLC-MS). Each analyzed peptide sequence is identified relative to its known location within the overall antibody structure. Post-translational modifications are measured by comparing the measured mass of the identified peptide sequence with its expected mass.

[0144] Drug efficacy In vitro T cell activation assays allow for the assessment of the level of DP stability. This activation can be assessed by, but is not limited to, using the nuclear factor of activated T cells response element (NFAT-RE)-mediated luminescence assay.

[0145] GPRC5D / CD3-mediated T cell activation In some embodiments, a stable DP is defined as having about 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, or 160% of the GPRC5D / CD3-mediated T cell activation activity relative to a reference, or any value or range therebetween, after about 12 months or more of DP storage at a temperature of about 5° C., after about 12 months or more of storage at a temperature of about 25° C., and / or after about 2 years or more of storage at a temperature of about 5° C. In some embodiments, a stable DP is defined as having about 50% to about 150% of the GPRC5D / CD3-mediated T cell activation activity relative to a reference, after about 12 months or more of DP storage at a temperature of about 25° C., and / or after about 2 years or more of storage at a temperature of about 5° C. In some embodiments, a stable DP is defined as having GPRC5D / CD3-mediated T cell activation activity in the range of about 60% to about 140% relative to a reference after about 12 months or more of DP storage at a temperature of about 25° C. and / or after about 2 years or more of storage at a temperature of about 5° C. In some embodiments, stable DP stability is defined as having GPRC5D / CD3-mediated T cell activation activity in the range of about 80% to about 120% relative to a reference after about 12 months or more of DP storage at a temperature of about 25° C. and / or after about 2 years or more of storage at a temperature of about 5° C. In some embodiments, the GPRC5D / CD3-mediated T cell activation activity is talquetamab-mediated T cell activation activity.

[0146] Polysorbate 20 (PS20) In some embodiments, a stable DP is defined as having a PS20 concentration of about 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, or any value or range therebetween, weight to volume percentage, after about 12 months or more of DP storage at a temperature of about 5° C., after about 12 months or more of storage at a temperature of about 25° C., and / or after about 2 years or more of storage at a temperature of about 5° C. In some embodiments, a stable DP is defined as having a PS20 concentration of about 0.02% (w / v) to about 0.1% (w / v) after about 12 months or more of DP storage at a temperature of about 25° C. and / or after about 2 years or more of storage at a temperature of about 5° C. In one embodiment, a stable DP is defined as having a PS20 concentration of about 0.01% (w / v) to about 0.07% (w / v) after about 12 months or more of DP storage at a temperature of about 5° C., after about 12 months or more of storage at a temperature of about 25° C., and / or after about 2 years or more of storage at a temperature of about 5° C. In some embodiments, a stable DP is defined as having a PS20 concentration of about 0.02% (w / v) to about 0.06% (w / v) after about 12 months or more of DP storage at a temperature of about 25° C. and / or after about 2 years or more of storage at a temperature of about 5° C. In some embodiments, a stable DP is defined as having a PS20 concentration of about 0.03% (w / v) to about 0.05% (w / v) after about 12 months or more of DP storage at a temperature of about 25° C. and / or after about 2 years or more of storage at a temperature of about 5° C.

[0147] Total volume of aqueous pharmaceutical composition 2 mg / mL formulation In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) ranges from about 5 mL to about 10 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is from about 0.5 mL to about 20 mL, from about 1 mL to about 15 mL, from about 5 mL to about 10 mL, or from about 6 mL to about 8 mL, or any value or range therebetween.

[0148] In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.6 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.7 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.8 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.9 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 1 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 2 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 3 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 4 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 5 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 6 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 7 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 8 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 9 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 10 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 11 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 12 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 13 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 14 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 15 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 16 mL to about 30 mL.In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 17 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 18 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 19 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 20 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 25 mL to about 30 mL.

[0149] In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 25 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 20 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 19 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 18 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 17 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 16 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 15 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 14 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 13 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 12 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 11 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 10 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 9 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 8 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 7 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 6 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 5 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 4 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 3 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 2 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 1 mL.In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 0.9 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 0.8 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 0.7 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 0.6 mL.

[0150] In some embodiments, the total volume of the aqueous pharmaceutical composition is about 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 11 mL, 12 mL, 13 mL, 14 mL, 15 mL, 16 mL, 18 mL, 19 mL, 20 mL, 25 mL, or 30 mL, or any value or range therebetween. In some embodiments, the total volume of the aqueous pharmaceutical composition is 0.5 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 0.6 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 0.7 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 0.8 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 0.9 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 1 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 2 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 3 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 4 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 5 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 6 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 7 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 8 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 9 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 10 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 11 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 12 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 13 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 14 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 15 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 16 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 17 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 18 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 19 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 20 mL.In some embodiments, the total volume of the aqueous pharmaceutical composition is 25 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 30 mL. In some embodiments, the aqueous pharmaceutical composition is a stable aqueous pharmaceutical composition. In some embodiments, the stability of the aqueous pharmaceutical composition is as defined and provided herein.

[0151] 40 mg / mL formulation In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) ranges from about 5 mL to about 10 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is from about 0.5 mL to about 20 mL, from about 1 mL to about 15 mL, from about 5 mL to about 10 mL, or from about 6 mL to about 8 mL, or any value or range therebetween.

[0152] In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.6 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.7 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.8 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.9 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 1 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 2 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 3 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 4 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 5 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 6 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 7 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 8 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 9 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 10 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 11 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 12 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 13 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 14 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 15 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 16 mL to about 30 mL.In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 17 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 18 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 19 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 20 mL to about 30 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 25 mL to about 30 mL.

[0153] In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 25 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 20 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 19 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 18 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 17 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 16 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 15 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 14 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 13 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 12 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 11 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 10 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 9 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 8 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 7 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 6 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 5 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 4 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 3 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 2 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 1 mL.In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 0.9 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 0.8 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 0.7 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition (or DP) is about 0.5 mL to about 0.6 mL.

[0154] In some embodiments, the total volume of the aqueous pharmaceutical composition is about 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1 mL, 1.1 mL, 1.2 mL, 1.3 mL, 1.4 mL, 1.5 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 8 mL, 9 mL, 10 mL, 11 mL, 12 mL, 13 mL, 14 mL, 15 mL, 16 mL, 18 mL, 19 mL, 20 mL, 25 mL, or 30 mL, or any value or range therebetween. In some embodiments, the total volume of the aqueous pharmaceutical composition is 0.5 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 0.6 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 0.7 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 0.8 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 0.9 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 1 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 1.1 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 1.2 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 1.3 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 1.4 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 1.5 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 2 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 3 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 4 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 5 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 6 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 7 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 8 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 9 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 10 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 11 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 12 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 13 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 14 mL.In some embodiments, the total volume of the aqueous pharmaceutical composition is 15 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 16 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 17 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 18 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 19 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 20 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 25 mL. In some embodiments, the total volume of the aqueous pharmaceutical composition is 30 mL. In some embodiments, the aqueous pharmaceutical composition is a stable aqueous pharmaceutical composition. In some embodiments, the stability of the aqueous pharmaceutical composition is as defined and provided herein.

[0155] method In some embodiments, a method of treating cancer in a subject in need thereof is provided. In some embodiments, the method comprises administering to the subject an aqueous pharmaceutical composition disclosed herein. In some embodiments, the aqueous pharmaceutical composition is a stable aqueous pharmaceutical composition. In some embodiments, the stable aqueous pharmaceutical composition is as defined and provided herein. In some embodiments, the administration is subcutaneous.

[0156] cancer In some embodiments, the cancer is a hematological malignancy.

[0157] In some embodiments, the hematological malignancy is multiple myeloma. In some embodiments, the subject has newly diagnosed multiple myeloma. In some embodiments, the subject is relapsed or refractory to treatment with a previous anti-cancer treatment, such as a therapeutic agent used to treat multiple myeloma or other hematological malignancies.

[0158] In some embodiments, the subject is refractory or relapsed to treatment with one or more treatments or therapies, such as THALOMID® (thalidomide), REVLIMID® (lenalidomide), POMALYST® (pomalidomide), VELCADE® (bortezomib), NINLARO (ixazomib), KYPROLIS® (carfilzomib), FARADYK® (panobinostat), AREDIA® (pamidronate), ZOMETA® (zoledronic acid), DARZALEX® (daratumumab), elotozumab or melphalan, Xpovio® (selinexor), Venclexta® (venetoclax), GSK916, CAR-T therapy, BCMA-directed therapy, other GPRC5D-related therapy, etc.

[0159] Various qualitative and / or quantitative methods can be used to determine disease recurrence or refractory status. Possible associated symptoms include, for example, a decline or plateau in the patient's health, recurrence or worsening of various symptoms associated with solid tumors, and / or the metastasis of cancerous cells from one location to other organs, tissues, or cells within the body.

[0160] In some embodiments, the multiple myeloma is relapsed or refractory to treatment with at least four prior therapies including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody selected from, for example, daratumumab, selinexor, lenalinomide, bortezomib, pomalidomide, carfilzomib, or thalidomide, or any combination thereof. In some embodiments, the multiple myeloma is relapsed or refractory to treatment with at least three prior therapies including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody selected from, for example, daratumumab, selinexor, lenalinomide, bortezomib, pomalidomide, carfilzomib, or thalidomide, or any combination thereof, and the patient has exhibited disease progression or failed to respond to the last therapy.

[0161] In some embodiments, the multiple myeloma is relapsed or refractory to treatment with selinexor, venetoclax, anti-CD38 antibody, lenalinomide, bortezomib, pomalidomide, carfilzomib, elotozumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[0162] In some embodiments, the multiple myeloma is high-risk multiple myeloma. Subjects with high-risk multiple myeloma are known to relapse early and have poor prognosis and outcome. Subjects that can be classified as having high-risk multiple myeloma have one or more of the following cytogenetic abnormalities: t(4;14)(p16;q32), t(14;16)(q32;q23), del17p, 1qAmp, t(4;14)(p16;q32) and t(14;16)(q32;q23), t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23), and del17p. In some embodiments, subjects with high-risk multiple myeloma may have 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.

[0163] Cytogenetic abnormalities can be detected, for example, by fluorescent in situ hybridization (FISH). In chromosomal translocations, oncogenes are translocated to the IgH region on chromosome 14q32, resulting in dysregulation of these genes. The t(4;14)(p16;q32) involves a translocation of fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain-containing protein (MMSET) (also known as WHSC1 / NSD2), while the t(14;16)(q32;q23) involves a translocation of the MAF transcription factor C-MAF. The 17p deletion (del17p) involves loss of the p53 locus.

[0164] Chromosomal rearrangements can be identified using well-known methods, such as fluorescent in situ hybridization, karyotyping, pulsed-field gel electrophoresis, or sequencing.

[0165] Methods for treating multiple myeloma using GPRC5DxCD3 bispecific antibodies, such as talquetamab, are described in WO 2022 / 058445, which is incorporated herein by reference. A phase 1 clinical trial evaluating talquetamab is described in Chari et al., "Talquetamab, a T-Cell-Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma," N Engl J Med 2022;387:2232-2244, which is incorporated herein by reference.

[0166] According to one embodiment, a method for treating a human subject with relapsed or refractory multiple myeloma comprises administering a stable aqueous pharmaceutical composition of the present invention in a dosing schedule according to the subject's body weight, the dosing schedule comprising subcutaneously administering the aqueous pharmaceutical composition to the subject at escalating doses of 0.01 mg / kg, 0.06 mg / kg, 0.4 mg / kg, and 0.8 mg / kg on days 1, 3, 5, and 7, respectively, followed by subcutaneously administering the aqueous pharmaceutical composition to the subject once every two weeks at a treatment dose of 0.8 mg / kg, wherein an aqueous pharmaceutical composition comprising 2 mg / mL of talquetamab is administered at doses of 0.01 mg / kg and 0.06 mg / kg, and an aqueous pharmaceutical composition comprising 40 mg / mL of talquetamab is administered at doses of 0.4 mg / kg and 0.8 mg / kg. As used herein with respect to the dosing schedule, mg / kg refers to mg of antibody, such as talquetamab, per kg of the subject's body weight.

[0167] According to an alternative embodiment, a method of treating a human subject with relapsed or refractory multiple myeloma comprises administering a stable aqueous pharmaceutical composition of the present invention in a dosing schedule according to the subject's body weight, the dosing schedule comprising subcutaneously administering the aqueous pharmaceutical composition to the subject at escalating doses of 0.01 mg / kg, 0.06 mg / kg, 0.3 mg / kg, and 0.8 mg / kg on days 1, 3, 5, and 7, respectively, followed by subcutaneously administering the aqueous pharmaceutical composition to the subject once every two weeks at a treatment dose of 0.8 mg / kg, wherein the aqueous pharmaceutical composition comprising 2 mg / mL of talquetamab is administered at doses of 0.01 mg / kg and 0.06 mg / kg, and the aqueous pharmaceutical composition comprising 40 mg / mL of talquetamab is administered at doses of 0.3 mg / kg and 0.8 mg / kg.

[0168] According to an alternative embodiment, a method of treating a human subject with relapsed or refractory multiple myeloma comprises administering a stable aqueous pharmaceutical composition of the present invention in a dosing schedule according to the subject's body weight, the dosing schedule comprising subcutaneously administering the aqueous pharmaceutical composition to the subject at escalating doses of 0.01 mg / kg, 0.06 mg / kg, and 0.4 mg / kg on days 1, 3, and 5, respectively, followed by subcutaneously administering the aqueous pharmaceutical composition to the subject once a week at a treatment dose of 0.4 mg / kg, wherein the aqueous pharmaceutical composition comprising 2 mg / mL of talquetamab is administered at doses of 0.01 mg / kg and 0.06 mg / kg, and the aqueous pharmaceutical composition comprising 40 mg / mL of talquetamab is administered at each dose of 0.4 mg / kg.

[0169] In a preferred embodiment, the pharmaceutical composition is therapeutically effective in treating relapsed or refractory multiple myeloma in a human subject, and in particular, the composition is effective in inducing a partial response, a very good partial response, a complete response, or a stringent complete response as determined by the International Myeloma Working Group (IMWG) response criteria. As used herein, overall response rate (ORR) refers to the percentage of patients in a population who achieve a partial response (PR) or better, i.e., a partial response, a very good partial response, a complete response, or a stringent complete response. The IMWG criteria for response to multiple myeloma treatment are provided in Table A below.

[0170] [Table 8] CR = complete response; FLC = free light chain; IMWG = International Myeloma Working Group; M protein = monoclonal paraprotein; MR = minimal response; PC = plasma cell; PD = progressive disease; PR = partial response; sCR = stringent complete response; SD = stable disease; VGPR = very good partial response a The presence / absence of clonal cells is based on the kappa / lambda ratio. An abnormal kappa / lambda ratio by immunohistochemistry or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting the presence of an abnormal clone is a kappa / lambda greater than 4:1 or less than 1:2. * Clarification of the IMWG criteria for coding CR and VGPR in subjects whose only measurable disease is due to serum FLC levels: CR in such subjects exhibits the CR criteria listed above plus a normal FLC ratio of 0.26 to 1.65. VGPR in such subjects requires a greater than 90% reduction in the difference between involved and uninvolved FLC levels.

[0171] The IMWG criteria for response to multiple myeloma treatment are also described, for example, in Durie et al., Kumar et al., and Rajkumar et al.: Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006; 20(9): 1467-1473; Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016; 17(8): e328-346; Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011; 117(18): 4691-4695, which are incorporated herein by reference.

[0172] In certain embodiments, the pharmaceutical compositions of the invention, when administered subcutaneously to each subject according to the dosing schedule shown in Table B, C, or D, induce an overall response rate (ORR) of at least 70% in a population of patients as defined by the IMWG criteria.

[0173] [Table 9] a Based on actual weight. b The dose may be administered 2 to 4 days after the previous dose, and may be given up to 7 days after the previous dose to allow for resolution of adverse reactions. c Maintain a minimum of 6 days between weekly doses and 12 days between biweekly (every 2 weeks) doses.

[0174] [Table 10] a Based on actual weight. b The dose may be administered 2 to 4 days after the previous dose, and may be given up to 7 days after the previous dose to allow for resolution of adverse reactions. c Maintain a minimum of 6 days between weekly doses and 12 days between biweekly (every 2 weeks) doses.

[0175] [Table 11] a Based on actual weight. b The dose may be administered 2 to 4 days after the previous dose, and may be given up to 7 days after the previous dose to allow for resolution of adverse reactions. c Maintain a minimum of 6 days between weekly doses and 12 days between biweekly (every 2 weeks) doses.

[0176] In certain embodiments, aqueous pharmaceutical compositions comprising 2 mg / mL of talquetamab (administered at doses of 0.01 mg / kg and 0.06 mg / kg in Tables B-D) have the compositions shown in Table 26 or Table 27, and aqueous pharmaceutical compositions comprising 40 mg / mL of talquetamab (administered at doses of 0.3 mg / kg, 0.4 mg / kg, and 0.8 mg / kg in Tables B-D) have the compositions shown in Table 22 or Table 23.

[0177] In certain embodiments, an aqueous pharmaceutical composition containing 2 mg / mL of talquetamab used for doses of 0.01 mg / kg and 0.06 mg / kg has the following composition per 1.5 mL: 3 mg of talquetamab, edetate disodium (0.027 mg), glacial acetic acid (0.36 mg), polysorbate 20 (0.6 mg), sodium acetate (1.39 mg), sucrose (120 mg), and water for injection, USP.

[0178] In certain embodiments, an aqueous pharmaceutical composition containing 40 mg / mL of talquetamab used for doses of 0.3 mg / kg, 0.4 mg / kg, and 0.8 mg / kg has the following composition per mL: 40 mg of talquetamab, edetate disodium (0.018 mg), glacial acetic acid (0.24 mg), polysorbate 20 (0.4 mg), sodium acetate (0.90 mg), sucrose (80 mg), and water for injection, USP.

[0179] According to certain embodiments, the treatment method further comprises administering a pretreatment medication 1-3 hours before each escalating dose, the pretreatment medication comprising a corticosteroid (oral or intravenous dexamethasone, 16 mg or equivalent); an antihistamine (oral or intravenous diphenhydramine, 50 mg or equivalent); and an antipyretic (oral or intravenous acetaminophen, 650 mg to 1000 mg or equivalent).

[0180] According to certain embodiments, the treatment methods described herein are effective to induce a clinical response in a subject according to the International Myeloma Working Group (IMWG) diagnostic criteria. In certain embodiments, the methods result in an overall response rate (ORR) of at least 50%, at least 55%, at least 60%, at least 65%, or at least 66%, or at least 67%, or at least 68%, or at least 69%, or at least 70%, or at least 71%, or at least 72%, or at least 73%, or at least 74% in a population of human subjects according to the IMWG criteria, e.g., as described in Example 14.

[0181] Also provided herein is a method for preparing an aqueous pharmaceutical composition comprising a bispecific G protein-coupled receptor, class C, group 5, member D (GPRC5D) antibody or antigen-binding fragment thereof, wherein the bispecific GPRC5D / CD3 antibody or antigen-binding fragment thereof comprises a first heavy chain (HC1) comprising an HC1 variable region 1 (VH1), and a first light chain (LC1) comprising an LC1 variable region (VL1) comprising heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; a second heavy chain (HC2) comprising an HC2 variable region 2 (VH2) comprising light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; and a second light chain (LC2) comprising an LC2 variable region 2 (VL2), wherein VH2 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; and and a composition comprising about 2 mg / mL of a bispecific GPRC5D / CD3 antibody, about 15 mM acetate and / or a pharmaceutically acceptable acetate salt, about 8% (w / v) sucrose, about 18 μg / mL EDTA, and about 0.04% polysorbate (PS) 20, wherein the stable aqueous pharmaceutical composition has a pH of about 5.2. In some embodiments, the aqueous pharmaceutical composition is a stable aqueous pharmaceutical composition, and the stability of the aqueous pharmaceutical composition is as defined and provided herein.

[0182] In some embodiments, the bispecific GPRC5D / CD3 antibody comprises a VH1 having the amino acid sequence of SEQ ID NO: 7 and a VL1 having the amino acid sequence of SEQ ID NO: 8. In some embodiments, the bispecific GPRC5D / CD3 antibody comprises an HC1 having the amino acid sequence of SEQ ID NO: 9 and an LC1 having the amino acid sequence of SEQ ID NO: 10. In some embodiments, the bispecific GPRC5D / CD3 antibody comprises a VH2 having the amino acid sequence of SEQ ID NO: 17 and a VL2 having the amino acid sequence of SEQ ID NO: 18. In certain embodiments, the bispecific GPRC5D / CD3 antibody comprises an HC2 having the amino acid sequence of SEQ ID NO: 19 and an LC2 having the amino acid sequence of SEQ ID NO: 20.

[0183] In some embodiments, the bispecific GPRC5D / CD3 antibody may be, for example, talquetamab. In some embodiments, talquetamab comprises a first heavy chain (HC1), a first light chain (LC1), a second heavy chain (HC2), and a second light chain (LC2), wherein HC1 associates with LC1 and HC2 associates with LC2, and wherein HC1 and LC1 form a first antigen-binding site that immunospecifically binds to GPRC5D, and HC2 and LC2 form a second antigen-binding site that immunospecifically binds to CD3. In some embodiments, talquetamab comprises an HC1 of SEQ ID NO: 9, an LC1 of SEQ ID NO: 10, an HC2 of SEQ ID NO: 19, and an LC2 of SEQ ID NO: 20. In some embodiments, the GPRC5D arm of talquetamab and the CD3 arm of talquetamab form a functional bispecific antibody through interaction between their respective Fc domains.

[0184] Also provided herein is a method for preparing a stable aqueous pharmaceutical composition comprising a bispecific G protein-coupled receptor, class C, group 5, member D (GPRC5D) antibody or antigen-binding fragment thereof, wherein the bispecific GPRC5D / CD3 antibody or antigen-binding fragment thereof comprises a first heavy chain (HC1) comprising an HC1 variable region 1 (VH1), wherein VH1 comprises a first light chain (LC1) comprising an LC1 variable region (VL1) comprising heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; a second heavy chain (HC2) comprising an HC2 variable region 2 (VH2) comprising light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; wherein VH2 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; and a second light chain (LC2) comprising an LC2 variable region 2 (VL2), wherein VL2 comprises light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively; and a composition comprising about 40 mg / mL of a bispecific GPRC5D / CD3 antibody, about 15 mM acetate and / or a pharmaceutically acceptable acetate salt, about 8% (w / v) sucrose, about 18 μg / mL EDTA, and about 0.04% polysorbate (PS) 20, wherein the stable aqueous pharmaceutical composition has a pH of about 5.2. In some embodiments, the stability of the aqueous pharmaceutical composition is as defined and provided herein.

[0185] In some embodiments, the bispecific GPRC5D / CD3 antibody comprises a VH1 having the amino acid sequence of SEQ ID NO: 7 and a VL1 having the amino acid sequence of SEQ ID NO: 8. In some embodiments, the bispecific GPRC5D / CD3 antibody comprises an HC1 having the amino acid sequence of SEQ ID NO: 9 and an LC1 having the amino acid sequence of SEQ ID NO: 10. In some embodiments, the bispecific GPRC5D / CD3 antibody comprises a VH2 having the amino acid sequence of SEQ ID NO: 17 and a VL2 having the amino acid sequence of SEQ ID NO: 18. In certain embodiments, the bispecific GPRC5D / CD3 antibody comprises an HC2 having the amino acid sequence of SEQ ID NO: 19 and an LC2 having the amino acid sequence of SEQ ID NO: 20.

[0186] In some embodiments, the bispecific GPRC5D / CD3 antibody may be, for example, talquetamab. In some embodiments, talquetamab comprises a first heavy chain (HC1), a first light chain (LC1), a second heavy chain (HC2), and a second light chain (LC2), wherein HC1 associates with LC1 and HC2 associates with LC2, and wherein HC1 and LC1 form a first antigen-binding site that immunospecifically binds to GPRC5D, and HC2 and LC2 form a second antigen-binding site that immunospecifically binds to CD3. In some embodiments, talquetamab comprises an HC1 of SEQ ID NO: 9, an LC1 of SEQ ID NO: 10, an HC2 of SEQ ID NO: 19, and an LC2 of SEQ ID NO: 20. In some embodiments, the GPRC5D arm of talquetamab and the CD3 arm of talquetamab form a functional bispecific antibody through interaction between their respective Fc domains.

[0187] The aqueous pharmaceutical compositions disclosed herein can be packaged in a kit, container, pack, dispenser, or vial. In some embodiments, the aqueous pharmaceutical composition is a stable aqueous pharmaceutical composition. In some embodiments, the stability of the aqueous pharmaceutical composition is as defined and provided herein.

[0188] Provided herein is a kit comprising the aqueous pharmaceutical composition of the present disclosure and instructions for use thereof. In some embodiments, the aqueous pharmaceutical composition is a stable aqueous pharmaceutical composition. In some embodiments, the stability of the aqueous pharmaceutical composition is as defined and provided herein.

[0189] Also provided herein is an article of manufacture comprising a container holding an aqueous pharmaceutical composition of the present disclosure. In some embodiments, the aqueous pharmaceutical composition is a stable aqueous pharmaceutical composition. In some embodiments, the stability of the aqueous pharmaceutical composition is as defined and provided herein. In some embodiments, the container is a vial having a stopper that can be punctured by a syringe.

[0190] Embodiment Exemplary embodiments of the disclosed technology are provided herein for illustrative purposes only and are not intended to limit the scope of the disclosure or the claims appended hereto.

[0191] In some embodiments, the following embodiments are provided: 1a. An aqueous pharmaceutical composition comprising: a) a bispecific G protein-coupled receptor, class C, group 5, member D (GPRC5D) / cluster of differentiation 3 (CD3) antibody or antigen-binding fragment thereof at a concentration of about 0.5 mg / mL to about 100 mg / mL, wherein the bispecific GPRC5D / CD3 antibody or antigen-binding fragment thereof is (1) a first heavy chain (HC1) comprising an HC1 variable region 1 (VH1); wherein VH1 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; (2) a first light chain (LC1) comprising an LC1 variable region (VL1); wherein VL1 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively; (3) a second heavy chain (HC2) comprising an HC2 variable region 2 (VH2); and wherein VH2 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; (4) a second light chain (LC2) comprising an LC2 variable region 2 (VL2); and wherein VL2 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively; Including, b) about 10 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt; c) about 6% (w / v) to about 10% (w / v) sucrose; d) about 7 μg / mL to about 33 μg / mL ethylenediaminetetraacetic acid (EDTA); e) about 0.01% to about 0.07% polysorbate 20, and f) pH of about 4.6 to about 5.8 1. An aqueous pharmaceutical composition comprising:

[0192] 1b. An aqueous pharmaceutical composition comprising: a) a bispecific G protein-coupled receptor, class C, group 5, member D (GPRC5D) / cluster of differentiation 3 (CD3) antibody or antigen-binding fragment thereof at a concentration of about 0.5 mg / mL to about 3.5 mg / mL, wherein the bispecific GPRC5D / CD3 antibody or antigen-binding fragment thereof is (1) a first heavy chain (HC1) comprising an HC1 variable region 1 (VH1); wherein VH1 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; (2) a first light chain (LC1) comprising an LC1 variable region (VL1); wherein VL1 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively; (3) a second heavy chain (HC2) comprising an HC2 variable region 2 (VH2); and wherein VH2 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; (4) a second light chain (LC2) comprising an LC2 variable region 2 (VL2); and wherein VL2 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively; Including, b) about 10 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt; c) about 6% (w / v) to about 10% (w / v) sucrose; d) about 7 μg / mL to about 33 μg / mL ethylenediaminetetraacetic acid (EDTA); e) about 0.01% to about 0.07% polysorbate 20, and f) pH of about 4.6 to about 5.8 1. An aqueous pharmaceutical composition comprising: 2. An aqueous pharmaceutical composition comprising: a) a bispecific G protein-coupled receptor, class C, group 5, member D (GPRC5D) / cluster of differentiation 3 (CD3) antibody or antigen-binding fragment thereof at a concentration of about 25 mg / mL to about 55 mg / mL, wherein the bispecific GPRC5D / CD3 antibody or antigen-binding fragment thereof is (1) a first heavy chain (HC1) comprising an HC1 variable region 1 (VH1); wherein VH1 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; (2) a first light chain (LC1) comprising an LC1 variable region (VL1); wherein VL1 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively; (3) a second heavy chain (HC2) comprising an HC2 variable region 2 (VH2); and wherein VH2 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; (4) a second light chain (LC2) comprising an LC2 variable region 2 (VL2); and wherein VL2 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively; Including, b) about 10 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt; c) about 6% (w / v) to about 10% (w / v) sucrose; d) about 7 μg / mL to about 33 μg / mL ethylenediaminetetraacetic acid (EDTA); e) about 0.01% to about 0.07% polysorbate 20, and f) pH of about 4.6 to about 5.8 1. An aqueous pharmaceutical composition comprising: 3. The aqueous pharmaceutical composition of embodiment 1a, 1b or 2, wherein the bispecific GPRC5D / CD3 antibody comprises a VH1 having the amino acid sequence of SEQ ID NO: 7 and a VL1 having the amino acid sequence of SEQ ID NO: 8. 4. The aqueous pharmaceutical composition of embodiment 1a, 1b or 2, wherein the bispecific GPRC5D / CD3 antibody comprises an HC1 having the amino acid sequence of SEQ ID NO: 9 and an LC1 having the amino acid sequence of SEQ ID NO: 10. 5. The aqueous pharmaceutical composition of embodiment 1a, 1b or 2, wherein the bispecific GPRC5D / CD3 antibody comprises a VH2 having the amino acid sequence of SEQ ID NO: 17 and a VL2 having the amino acid sequence of SEQ ID NO: 18. 6. The aqueous pharmaceutical composition of embodiment 1a, 1b or 2, wherein the bispecific GPRC5D / CD3 antibody comprises an HC2 having the amino acid sequence of SEQ ID NO: 19 and an LC2 having the amino acid sequence of SEQ ID NO: 20. 7. The aqueous pharmaceutical composition of embodiment 1a, 1b, or 2, wherein the bispecific GPRC5D / CD3 antibody is talquetamab. 8. The aqueous pharmaceutical composition of embodiment 1b, wherein the bispecific GPRC5D / CD3 antibody has a concentration of about 1 mg / mL to about 3 mg / mL. 9. The aqueous pharmaceutical composition of embodiment 8, wherein the bispecific GPRC5D / CD3 antibody has a concentration of about 1.5 mg / mL to about 2.5 mg / mL. 10. The aqueous pharmaceutical composition of embodiment 9, wherein the bispecific GPRC5D / CD3 antibody has a concentration of about 2 mg / mL. 11. The aqueous pharmaceutical composition of embodiment 2, wherein the bispecific GPRC5D / CD3 antibody has a concentration of about 30 mg / mL to about 50 mg / mL. 12. The aqueous pharmaceutical composition of embodiment 11, wherein the bispecific GPRC5D / CD3 antibody has a concentration of about 35 mg / mL to about 45 mg / mL. 13. The aqueous pharmaceutical composition of embodiment 12, wherein the bispecific GPRC5D / CD3 antibody has a concentration of about 40 mg / mL. 14. The aqueous pharmaceutical composition of embodiment 1a, 1b, or 2, comprising about 12 mM to about 18 mM acetate and / or a pharmaceutically acceptable acetate salt. 15. The aqueous pharmaceutical composition of embodiment 1a, 1b, or 2, comprising about 14 mM to about 16 mM acetate and / or a pharmaceutically acceptable acetate salt. 16. The aqueous pharmaceutical composition of embodiment 1a, 1b, or 2, comprising about 15 mM acetate and / or a pharmaceutically acceptable acetate salt. 17. The aqueous pharmaceutical composition of embodiment 1a, 1b, or 2, comprising about 7% (w / v) to about 9% (w / v) sucrose. 18. The aqueous pharmaceutical composition of embodiment 17, comprising about 8% (w / v) sucrose. 19. The aqueous pharmaceutical composition of embodiment 1a, 1b, or 2, comprising about 15 μg / mL to about 21 μg / mL of EDTA. 20. The aqueous pharmaceutical composition of embodiment 1a, 1b, or 2, comprising about 18 μg / mL EDTA. 21. The aqueous pharmaceutical composition of embodiment 1a, 1b, or 2, comprising about 0.02% to about 0.06% PS-20. 22. The aqueous pharmaceutical composition of embodiment 21, comprising about 0.03% to about 0.05% PS-20. 23. The aqueous pharmaceutical composition of embodiment 22, comprising about 0.04% PS-20. 24. The aqueous pharmaceutical composition of embodiment 1a, 1b, or 2, having a pH of about 4.8 to about 5.6. 25. The aqueous pharmaceutical composition of embodiment 24, having a pH of about 4.9 to about 5.5. 26. The aqueous pharmaceutical composition of embodiment 25, having a pH of about 5.2. 1. The aqueous pharmaceutical composition of embodiment 1b, comprising 27.2 mg / mL of bispecific GPRC5D / CD3 antibody, 15 mM acetate and / or a pharmaceutically acceptable acetate salt, 8% (w / v) sucrose, 18 μg / mL EDTA, 0.04% PS20, and a pH of 5.2. 3. The aqueous pharmaceutical composition of embodiment 2, comprising 28.40 mg / mL of the bispecific GPRC5D / CD3 antibody, 15 mM acetate and / or a pharmaceutically acceptable acetate salt, 8% (w / v) sucrose, 18 μg / mL EDTA, 0.04% PS20, and a pH of 5.2. 29. The aqueous pharmaceutical composition of any one of embodiments 1a, 1b, or 2-28, which is stable. 30. The aqueous pharmaceutical composition of embodiment 29, wherein the stability is defined based on solution color, pH, turbidity, percentage of purity, percentage of new peaks, percentage of major components, percentage of high molecular weight species (HWMS), percentage of low molecular weight species (LMWS), percentage of sum of acidic peaks, percentage of sum of basic peaks, protein concentration, percentage of T cell activation, percentage of PS20 (w / v), or any combination thereof. 31.About 2~8 ℃ 31. The aqueous pharmaceutical composition of embodiment 29 or 30, which is stable at a temperature of 32. A method of treating cancer in a human subject in need thereof, comprising administering to the subject an aqueous pharmaceutical composition of any one of embodiments 1a, 1b, or 2-31. 33. The method of embodiment 32, wherein administering is subcutaneous administration. 34. A method for preparing a stable aqueous pharmaceutical composition of a bispecific G protein-coupled receptor, class C, group 5, member D (GPRC5D) / cluster of differentiation 3 (CD3) antibody or antigen-binding fragment thereof, wherein the bispecific GPRC5D / CD3 antibody or antigen-binding fragment thereof comprises: (1) a first heavy chain (HC1) comprising an HC1 variable region 1 (VH1); wherein VH1 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; (2) a first light chain (LC1) comprising an LC1 variable region (VL1); wherein VL1 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively; (3) a second heavy chain (HC2) comprising an HC2 variable region 2 (VH2); and wherein VH2 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; (4) a second light chain (LC2) comprising an LC2 variable region 2 (VL2); and wherein VL2 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively; Including, 1. A method comprising combining a composition comprising about 2 mg / mL of a bispecific GPRC5D / CD3 antibody, about 15 mM acetate and / or a pharmaceutically acceptable acetate salt, about 8% (w / v) sucrose, about 18 μg / mL EDTA, and about 0.04% polysorbate (PS) 20, wherein the stable aqueous pharmaceutical composition has a pH of about 5.2. 35. A method for preparing a stable aqueous pharmaceutical composition of a bispecific G protein-coupled receptor, class C, group 5, member D (GPRC5D) / cluster of differentiation 3 (CD3) antibody or antigen-binding fragment thereof, wherein the bispecific GPRC5D / CD3 antibody or antigen-binding fragment thereof comprises: (1) a first heavy chain (HC1) comprising an HC1 variable region 1 (VH1); wherein VH1 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; (2) a first light chain (LC1) comprising an LC1 variable region (VL1); wherein VL1 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively; (3) a second heavy chain (HC2) comprising an HC2 variable region 2 (VH2); and wherein VH2 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; (4) a second light chain (LC2) comprising an LC2 variable region 2 (VL2); and wherein VL2 comprises a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively; Including, 1. A method comprising combining a composition comprising about 40 mg / mL of a bispecific GPRC5D / CD3 antibody, about 15 mM acetate and / or a pharmaceutically acceptable acetate salt, about 8% (w / v) sucrose, about 18 μg / mL EDTA, and about 0.04% polysorbate (PS) 20, wherein the stable aqueous pharmaceutical composition has a pH of about 5.2. 36. The method of embodiment 34 or 35, wherein the bispecific GPRC5D / CD3 antibody comprises a VH1 having the amino acid sequence of SEQ ID NO: 7 and a VL1 having the amino acid sequence of SEQ ID NO: 8. 37. The method of embodiment 34 or 35, wherein the bispecific GPRC5D / CD3 antibody comprises HC1 having the amino acid sequence of SEQ ID NO: 9 and LC1 having the amino acid sequence of SEQ ID NO: 10. 38. The method of embodiment 34 or 35, wherein the bispecific GPRC5D / CD3 antibody comprises a VH2 having the amino acid sequence of SEQ ID NO: 17 and a VL2 having the amino acid sequence of SEQ ID NO: 18. 39. The method of embodiment 34 or 35, wherein the bispecific GPRC5D / CD3 antibody comprises an HC2 having the amino acid sequence of SEQ ID NO: 19 and an LC2 having the amino acid sequence of SEQ ID NO: 20. 40. The method of embodiment 34 or 35, wherein the bispecific GPRC5D / CD3 antibody is talquetamab. 41. The method of any one of embodiments 34-40, wherein the aqueous pharmaceutical composition is stable. 42. The method of embodiment 41, wherein the stability is defined based on solution color, pH, turbidity, percentage of purity, percentage of new peaks, percentage of major components, percentage of high molecular weight species (HWMS), percentage of low molecular weight species (LMWS), percentage of sum of acidic peaks, percentage of sum of basic peaks, protein concentration, percentage of T cell activation, percentage of PS20 (w / v), or any combination thereof. 43. A kit comprising the aqueous pharmaceutical composition of any one of embodiments 1a, 1b, or 2-31 and instructions for its use. 44. An article of manufacture comprising a container holding the aqueous pharmaceutical composition of any one of embodiments 1a, 1b, or 2-31. 45. The article of manufacture of embodiment 44, wherein the container is a vial having a stopper pierceable by a syringe. 46. ​​The aqueous pharmaceutical composition of any one of embodiments 1a, 1b, or 2-31, for use in the treatment of cancer. 47. The aqueous pharmaceutical composition of any one of embodiments 1a, 1b, or 2-31, for use in preparing a medicament for the treatment of cancer. 48. Use of the aqueous pharmaceutical composition of any one of embodiments 1a, 1b, or 2-31 for treating cancer in a subject in need thereof, comprising administering the aqueous pharmaceutical composition to the subject in need thereof. 49. The use according to embodiment 48, wherein the administration is subcutaneous. 50. The method of embodiment 32 or 33, wherein the human subject is an adult with relapsed or refractory multiple myeloma and has received at least four prior therapies including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. 51. The method of embodiment 32 or 33, wherein the human subject is an adult with relapsed and refractory multiple myeloma, has received at least three prior therapies including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody, and has shown disease progression or failed to respond to the last therapy. 52a. Administering the aqueous pharmaceutical composition according to a dosing schedule based on the subject's weight, wherein the dosing schedule is: administering the aqueous pharmaceutical composition subcutaneously to the subject at escalating doses of 0.01 mg / kg, 0.06 mg / kg, 0.4 mg / kg, and 0.8 mg / kg on days 1, 3, 5, and 7, respectively, and thereafter administering the aqueous pharmaceutical composition subcutaneously to the subject once every two weeks at a treatment dose of 0.8 mg / kg; 52. The method of embodiment 50 or 51, wherein the aqueous pharmaceutical composition comprising 2 mg / mL of talquetamab is administered at doses of 0.01 mg / kg and 0.06 mg / kg, and the aqueous pharmaceutical composition comprising 40 mg / mL of talquetamab is administered at doses of 0.4 mg / kg and 0.8 mg / kg, respectively. 52b. Administering the aqueous pharmaceutical composition according to a dosing schedule based on the subject's body weight, wherein the dosing schedule is: administering the aqueous pharmaceutical composition subcutaneously to the subject at escalating doses of 0.01 mg / kg, 0.06 mg / kg, 0.3 mg / kg, and 0.8 mg / kg on days 1, 3, 5, and 7, respectively, and thereafter administering the aqueous pharmaceutical composition subcutaneously to the subject once every two weeks at a treatment dose of 0.8 mg / kg; 52. The method of embodiment 50 or 51, wherein the aqueous pharmaceutical composition comprising 2 mg / mL of talquetamab is administered at doses of 0.01 mg / kg and 0.06 mg / kg, and the aqueous pharmaceutical composition comprising 40 mg / mL of talquetamab is administered at doses of 0.3 mg / kg and 0.8 mg / kg, respectively. 53. Administering the aqueous pharmaceutical composition according to a dosing schedule based on the subject's body weight, wherein the dosing schedule is administering the aqueous pharmaceutical composition subcutaneously to the subject at escalating doses of 0.01 mg / kg, 0.06 mg / kg, and 0.4 mg / kg on days 1, 3, and 5, respectively, and thereafter administering the aqueous pharmaceutical composition subcutaneously to the subject once weekly at a treatment dose of 0.4 mg / kg; 52. The method of embodiment 50 or 51, wherein the aqueous pharmaceutical composition comprising 2 mg / mL of talquetamab is administered at doses of 0.01 mg / kg and 0.06 mg / kg, and the aqueous pharmaceutical composition comprising 40 mg / mL of talquetamab is administered at each dose of 0.4 mg / kg. The method of embodiment 52a, 52b, or 53, wherein the aqueous pharmaceutical composition comprising 54.2 mg / mL of talquetamab has the following composition per 1.5 mL: 3 mg of talquetamab, edetate disodium (0.027 mg), glacial acetic acid (0.36 mg), polysorbate 20 (0.6 mg), sodium acetate (1.39 mg), sucrose (120 mg), and water for injection, USP. The method of any of embodiments 52a, 52b, 53, or 54, wherein the aqueous pharmaceutical composition comprising 55.40 mg / mL of talquetamab has the following composition per mL: 40 mg of talquetamab, edetate disodium (0.018 mg), glacial acetic acid (0.24 mg), polysorbate 20 (0.4 mg), sodium acetate (0.90 mg), sucrose (80 mg), and water for injection, USP. 56. The method of any of embodiments 50, 51, 52a, 52b, or 53-55, further comprising administering a pretreatment medication 1 to 3 hours before each escalating dose, the pretreatment medication comprising a corticosteroid (oral or intravenous dexamethasone, 16 mg or equivalent); an antihistamine (oral or intravenous diphenhydramine, 50 mg or equivalent); and an antipyretic (oral or intravenous acetaminophen, 650 mg to 1000 mg or equivalent). 57. The method of any of embodiments 50, 51, 52a, 52b, or 53-55, which is effective to induce a partial response, a very good partial response, a complete response, or a stringent complete response in the subject according to IMWG criteria. 58. The method of any of embodiments 50, 51, 52a, 52b, or 53-55, which results in an overall response rate (ORR) of at least 70% in a population of human subjects according to IMWG criteria. 59. Contains talquetamab, subcutaneous administration of the composition to a population of patients diagnosed with relapsed or refractory multiple myeloma induces an overall response rate (ORR) of at least 70% in the population (according to IMWG criteria) following a dosing schedule comprising subcutaneous administration of the composition at doses of 0.01 mg / kg, 0.06 mg / kg, and 0.4 mg / kg on days 1, 3, and 5, respectively, followed by subcutaneous administration of the composition to the subjects at a dose of 0.4 mg / kg once weekly, administered based on each patient's body weight; a composition containing 2 mg / mL of talquetamab is administered at doses of 0.01 mg / kg and 0.06 mg / kg, and an aqueous pharmaceutical composition containing 40 mg / mL of talquetamab is administered at doses of 0.4 mg / kg; The aqueous pharmaceutical composition of any one of embodiments 1a, 1b, or 2-31, wherein each patient in the population has received at least three or four prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. 60. Contains talquetamab, subcutaneous administration of the composition to a population of patients diagnosed with relapsed or refractory multiple myeloma induces an overall response rate (ORR) of at least 70% in the population (according to IMWG criteria) following a dosing schedule comprising subcutaneous administration of the composition at doses of 0.01 mg / kg, 0.06 mg / kg, 0.3 mg / kg, and 0.8 mg / kg on days 1, 3, 5, and 7, respectively, followed by subcutaneous administration of the composition to the subjects at a dose of 0.8 mg / kg once every two weeks, administered based on each patient's body weight; a composition containing 2 mg / mL of talquetamab is administered at doses of 0.01 mg / kg and 0.06 mg / kg, and an aqueous pharmaceutical composition containing 40 mg / mL of talquetamab is administered at doses of 0.3 mg / kg and 0.8 mg / kg; The aqueous pharmaceutical composition of any one of embodiments 1a, 1b, or 2-31, wherein each patient in the population has received at least three or four prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. 61. Contains talquetamab, subcutaneous administration of the composition to a population of patients diagnosed with relapsed or refractory multiple myeloma induces an overall response rate (ORR) of at least 70% in the population (according to IMWG criteria) following a dosing schedule comprising subcutaneous administration of the composition at doses of 0.01 mg / kg, 0.06 mg / kg, 0.4 mg / kg, and 0.8 mg / kg on days 1, 3, 5, and 7, respectively, followed by subcutaneous administration of the composition to the subjects at a dose of 0.8 mg / kg once every two weeks, administered based on each patient's body weight; a composition containing 2 mg / mL of talquetamab is administered at doses of 0.01 mg / kg and 0.06 mg / kg, and an aqueous pharmaceutical composition containing 40 mg / mL of talquetamab is administered at doses of 0.4 mg / kg and 0.8 mg / kg; The aqueous pharmaceutical composition of any one of embodiments 1a, 1b, or 2-31, wherein each patient in the population has received at least three or four prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. [Example]

[0193] The following examples are provided to further illustrate some of the embodiments disclosed herein and are intended to illustrate, but not limit, embodiments of the present disclosure.

[0194] Description of analytical tests used herein Analytical Tests - General Characterization Solution color Solution color is monitored for drug products to assess appearance and ensure consistency with previous batches upon release and over shelf life. Solution color can also be an indicator of product stability. To determine solution color, test samples are visually compared to a set of defined reference solutions.

[0195] A defined amount of the liquid contents is transferred to a pre-scored ampoule of the same dimensions as the reference solution. The contents of the ampoule are then visually compared to the European Pharmacopoeia color reference solution. The color intensity is determined in diffuse daylight viewed against a white background.

[0196] Solution material color and method Materials and methods are described in European Pharmacopoeia 2.2.2, Degree of Coloration of Liquids European Pharmacopoeia (Ph.Eur.) 10th Edition Monograph No. 20202, July 2019. Briefly, test articles are compared to a set of B (brown), BY (brownish yellow), and Y (yellow) color reference solutions. The stability of the aqueous pharmaceutical composition, as determined by the color of the solution, is defined as provided herein.

[0197] pH pH Materials and Methods - The pH of the test articles is measured using a daily calibrated electronic pH meter with a standardized pH electrode. All calibration solutions, reference buffers, and test articles are equilibrated to 25°C prior to testing and maintained at 25°C throughout the test. The stability of aqueous pharmaceutical compositions as determined by pH is defined as provided herein.

[0198] Turbidity Turbidity Materials and Methods - Materials and methods are based on European Pharmacopoeia 2.2.1, Clarity and Degree of Opalescence of Liquids. Stability of aqueous pharmaceutical compositions as determined by turbidity is defined as provided herein.

[0199] Analytical Testing - Particulate Matter Particulate matter (not visible to the naked eye) Materials and Methods - All materials and methods conform to the United States Pharmacopoeia <788> Compliant with Particulate Matter. A compendial liquid particle counter equipped with a compendial volumetric sampler device is used. Test articles are equilibrated to room temperature for at least 60 minutes but not more than 10 hours prior to testing. Test article vials are measured in accordance with the U.S. Pharmacopoeia <788> Pool in a manner that complies with Particulate Matter, United States Pharmacopoeia <788> Remove four portions of appropriate volume from each pooled test article as directed by the Particulate Matter and count the number of particles 10 μm and 25 μm or larger for each portion. Disregard the result obtained for the first portion and use the results of the remaining three to calculate the average particle count for the preparation tested.

[0200] Particle Analysis (Invisible to the Naked Eye) Compendial Results - Test results comply with the United States Pharmacopoeia <788> Particulate Matter, European Pharmacopoeia 2.9.19, and Japanese Pharmacopoeia XVII / 6.07 Particulate contamination: particles invisible to the naked eye. Therefore, the average number of particles present in the tested unit should not exceed 6000 particles per container for particles of 10 μm or greater, and 600 particles per container for particles of 25 μm or greater.

[0201] Analytical Testing - Purity Capillary electrophoresis sodium dodecyl sulfate (cSDS)-reduced Reduced cSDS Materials and Methods—The analysis uses a commercially available capillary electrophoresis system with a bare fused-silica capillary, 50 μm inner diameter x 30.2 cm long, in a temperature-controlled cartridge. The capillary is equipped with a detection window transparent to UV light. The capillary is electrokinetically rinsed before each injection. Prior to each sample analysis, the capillary is filled with a sieving matrix consisting of an entangled polymer solution. The method utilizes SDS-MW gel running buffer and protein molecular weight authentication standards ranging from approximately 10 to 148 kDa. The UV absorption spectrophotometer detector of the instrument is set to a wavelength of 220 nm, and the capillary temperature is set to 25°C. To achieve reduced sample processing conditions, the test article (in duplicate) is mixed with SDS and 2-mercaptoethanol and then heated for a specified time and temperature to completely denature and reduce the protein. The reduced sample is electrokinetically injected by applying a voltage of 5 kV to the capillary for approximately 20 seconds, and then analyzed by applying a larger electric field for approximately 35 minutes. Detection is achieved by absorbance in the far-UV region of the spectrum at 220 nm. Percentage of total signal data is collected for the light chain, heavy chain, and aglycosylated heavy chain (AG HC). The stability of the aqueous pharmaceutical composition as determined by cSDS is defined as provided herein.

[0202] Capillary electrophoresis sodium dodecyl sulfate (cSDS) - non-reducing Non-reduced cSDS Materials and Methods: The analysis uses a commercially available capillary electrophoresis system with a bare fused-silica capillary, 50 μm inner diameter x 30.2 cm length, in a temperature-controlled cartridge. The capillary is equipped with a detection window transparent to UV light. The capillary is electrokinetically rinsed before each injection. Before each sample analysis, the capillary is filled with a sieving matrix consisting of an entangled polymer solution. The method utilizes SDS-MW gel running buffer, protein molecular weight authentication standards ranging from approximately 10 to 148 kDa, and a validated talquetamab reference material sample. The instrument's UV absorption spectrophotometer detector is set to a wavelength of 220 nm, and the capillary temperature is set to 25°C. For non-reduced sample processing conditions, the test article (in duplicate) is mixed with SDS and an alkylating reagent (N-ethylmaleimide, to prevent shuffling or reformation of disulfide bonds). It is then heated for a specified time and temperature to completely denature the protein and minimize the formation of fragments and artifact bands. The non-reduced sample is electrokinetically injected into the capillary by applying a voltage of 5 kV for approximately 20 seconds, followed by analysis by applying a larger electric field for approximately 35 minutes. Detection is achieved by absorbance in the far-UV region of the spectrum at 220 nm. Percent total signal data is collected. Data is also analyzed for the presence of new peaks compared to the talquetamab reference material. Percent purity is defined as percent heavy chain + percent light chain. The stability of the aqueous pharmaceutical composition as determined by cSDS is defined as provided herein.

[0203] Size-exclusion high-performance liquid chromatography (SE-HPLC) SE-HPLC Materials and Methods—Reference materials and test articles were diluted to the target protein concentration. A 20 μL volume of the analyte was injected onto a 7.8 mm x 30 cm exclusion column with a 5 μm particle size silica base and a cutoff range of 10 to 500 kDa. Aqueous phosphate buffer was used as the mobile phase at a flow rate of 0.7 mL / min, and the absorbance of the eluate was continuously monitored at 280 nm. Monomers (major components or peaks), aggregates (high molecular weight species, or HMWS), and fragments (low molecular weight species, or LMWS) were separated on the column and eluted at different retention times. The amounts of these species were measured by monitoring the peak absorbance at 280 nm. The stability of aqueous pharmaceutical compositions determined by SE-HPLC is defined as provided herein. The stability of aqueous pharmaceutical compositions determined by SE-HPLC main component (MC) is defined as provided herein. The stability of aqueous pharmaceutical compositions determined by SE-HPLC HMWS is defined as provided herein. The stability of an aqueous pharmaceutical composition as determined by LMWS of SE-HPLC is defined as provided herein.

[0204] Ion Exchange Chromatography (IEX) IEX Materials and Methods The analytical procedure was performed using an HPLC system equipped with a diode array or UV detector, column heating capability, and a temperature-controlled HPLC autoinjector. The stationary phase was a MAbPac SCX-10, 4 x 250 mm, 10 μm particle size, cation exchange column maintained at 35°C ± 2°C. Mobile phase A was ThermoFisher CX-1 pH gradient buffer A (pH 5.6) diluted 1:10 with DI water. Mobile phase B was ThermoFisher CX-1 pH gradient buffer B (pH 10.2) diluted 1:10 with DI water. Reference and test substances were diluted to target protein concentrations. Aliquots of 10–100 μl were transferred to sample vials and placed in a temperature-controlled HPLC autoinjector set at 5°C ± 2°C. The run time per sample was 16 minutes at a flow rate of 0.75 mL / min. A gradient mediated by mobile phases A and B was applied, which incrementally increased the pH of the mobile phase during the run. As the pH increased, the isoforms became neutral and eluted from the column. The eluate was continuously monitored at 280 nm, and the relative amounts of each isoform were determined by comparing peak area counts. The largest peak observed was designated the main peak. All peaks / groups eluted before the main peak as designated acidic species, and all peaks / groups eluted after the main peak as designated basic species. The stability of the aqueous pharmaceutical composition as determined by IEX is defined as provided herein. The stability of the aqueous pharmaceutical composition as determined by IEX main peak (MP) is defined as provided herein. The stability of the aqueous pharmaceutical composition as determined by IEX sum of acidic peaks is defined as provided herein. The stability of the aqueous pharmaceutical composition as determined by IEX sum of basic peaks is defined as provided herein.

[0205] Analytical Test - Quantity Protein concentration by A280 The protein concentration of the drug product is determined by quantitation of absorbance at 280 nm (A280).

[0206] Protein Concentration by A280 Materials and Methods Protein concentration is measured using a qualified and calibrated double-beam UV-Vis spectrophotometer. A 40 mg / mL talquetamab test article is diluted 1:80 using 0.9% (w / v) NaCl. A 2 mg / mL talquetamab test article is diluted 1:6.7 using 0.9% (w / v) NaCl. Samples are measured using quartz semi-microcuvettes (1.4 mL) with a 1 cm path length and black or matte surfaces. The spectrophotometer is set to a wavelength of 280 nm, a 1 nm slit width, and a 1 second response. 0.9% (w / v) NaCl is used as a blank control. Protein concentration (mg / mL) is determined by multiplying the absorbance of the test article by the dilution factor, the extinction constant of the antibody, and the path length of the instrument (for example, but not limited to, an extinction constant of 1.49 mg / mL for talquetamab). -1 cm -1 and the pathlength of the instrument (1 cm). The stability of an aqueous pharmaceutical composition, as determined by A280 protein concentration, is defined as provided herein. The stability of a 2 mg / mL aqueous pharmaceutical composition, as determined by A280 protein concentration, is defined as provided herein. The stability of a 40 mg / mL aqueous pharmaceutical composition, as determined by A280 protein concentration, is defined as provided herein.

[0207] Analytical Testing - Potency Efficacy (T cell activation by GPRC5D / CD3) In vitro T cell activation by the GPRC5D / CD3 bispecific antibodies provided herein is demonstrated using a nuclear factor of activated T cells-response element (NFAT-RE)-mediated luminescence assay.

[0208] This reporter assay uses luminescence induced by activation of the NFAT (nuclear factor of activated T cells) pathway in engineered effector cells expressing CD3 as a readout for target cell / effector cell co-engagement and is a surrogate measure of target cell killing. MM.1R B lymphoblastoid cells expressing GPRC5D on their cell surface are used as target cells. Both engagement of the anti-GPRC5D Fab region with GPRC5D-expressing target cells and engagement of the anti-CD3 Fab region with engineered CD3+ T cells are required for T cell activation and subsequent NFAT-RE-mediated luminescence.

[0209] Materials and Methods for GPRC5D / CD3 T Cell Activation. Qualified talquetamab was used as the reference material and control. 1.3 x 10 cells per mL of culture medium (4% heat-inactivated fetal bovine serum in RPMI) were used. 6 1.75 x 10 viable cells per mL of Jurkat TCR / CD3 effector cell solution and culture medium 5 A solution of MM.1R B lymphoblast target cells is prepared at 1000 viable cells. Equal amounts of effector and target cells are aliquoted into individual wells on a 96-well cell culture plate. The plate is then incubated for 16-24 hours at 37°C (±2°C) with 5% (±2%) CO2. After incubation, Bio-Glo™ luciferase substrate is added to each well and gently agitated on a plate shaker for at least 5 minutes. Luminescence (relative light units (RLU) values) is measured using a microtiter luminescence plate reader within 30 minutes of substrate addition. Data are reported as percent bioactivity relative to the reference material. The stability of the aqueous pharmaceutical composition, as determined by GPRC5D / CD3 T cell activation activity, is defined as provided herein.

[0210] Analytical Tests - Surfactants Quantitative determination of polysorbate 20 Polysorbate 20 is quantitatively determined by mixed-mode ion-exchange / hydrophobic HPLC.

[0211] PS20 Materials and Methods. Analysis is performed on a gradient HPLC equipped with a 2.1 x 20 mm online column containing 30 μm water-wettable mixed-mode polymeric spherical adsorbent particles, an ELSD, and a temperature-controlled column section at 30°C. The flow rate is set at 1 mL / min, and the ELSD nebulizer and evaporator temperatures are both set at 50°C. Mobile phase A is 2% v / v formic acid in water, and mobile phase B is 2% v / v formic acid in isopropyl alcohol. Undiluted polysorbate 20 is used to prepare calibration and check standards. Test article samples are injected undiluted. Stability of aqueous pharmaceutical compositions, as determined by polysorbate 20 quantification, is defined as provided herein.

[0212] Analytical Testing - Routine Characterization Peptide Map The purpose of this test is to measure the level of post-translational modifications, such as oxidation, deamidation, and isomerization, that may be present in the antibody structure. The test article is subjected to enzymatic digestion to obtain peptide segments. These peptides are then evaluated by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Each analyzed peptide sequence is identified relative to its known location within the overall antibody structure. Post-translational modifications are measured by comparing the measured mass of the identified peptide sequence with its expected mass.

[0213] Peptide Mapping Materials and Methods. Samples are denatured with 6 M guanidine, 50 mM Tris pH 8.0, 5 mM EDTA, and filtered using a 30 kDa centrifugal filter device (flow-through discarded). The denatured sample is reduced with 1 M dithiothreitol (DTT), followed by alkylation with 1 M sodium iodoacetate and further treatment with DTT to quench the reaction. The reaction mixture is exchanged into digestion buffer (50 mM Tris pH 7.0 with 1 mM CaCl2) through a Sephadex G-25 column, with separate columns used for blanks, reference materials, and test articles. An aliquot of a 1 mg / mL trypsin stock solution is added to the sample in digestion buffer to obtain a trypsin concentration of 20 μL / mL. The solution is incubated at 37°C for 2 hours ± 30 minutes. The trypsin-treated solution is cooled to room temperature, and the enzyme is inactivated with trifluoroacetic acid. The processed samples were evaluated by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) using a Waters Acquity BEH (ethylene bridged hybrid) C18, 2.1 x 100 mm, 1.7 µm, 130 Å column and an attached autosampler. Mobile phase A was 0.1% formic acid in water, and mobile phase B was 0.1% FA in acetonitrile (mobile phase B). The autosampler was set to 2-8 °C, the column was set to 40 °C, and the flow rate was set to 500 µL / min. Eluted peptides were subjected to electrospray ionization and detected using a calibrated online mass spectrometer.

[0214] Example 1: Early Formulation Development High-throughput (HTP) multifactorial screening test A high-throughput (HTP) multifactorial screening study was conducted to select combinations of formulation buffer type and concentration, excipient type, and pH. This was accomplished by generating multiple test formulations consisting of various combinations of buffer type and concentration, excipients, and pH values. The target antibody concentration used in all test formulations was 2 mg / mL. Sucrose was evaluated at 8.5% (w / v) and sorbitol at 5.0% (w / v).

[0215] In this study, approximately 200 μL of each test formulation was aliquoted into a 96-well plate, sealed to prevent evaporation, and held under stressed (40° C.) stability conditions for 3 weeks. The test formulations were then analyzed by SEC. The compositions of the test formulations and their corresponding SEC results are listed below in Tables 7, 8, and 9 for each buffer. Main effect plots calculated from all test formulation data were generated using Minitab 19.0 statistical software (Figures 1, 2, and 3).

[0216] [Table 12]

[0217] [Table 13]

[0218] [Table 14]

[0219] As seen in Figure 1, pH appears to have a strong, nonlinear, biphasic effect on the % monomer response, with a pH value of approximately 5.4 at the apex of the curve. Test formulations above 5.4 appear to lose monomer primarily to aggregation, while test formulations below pH 5.4 appear to lose monomer to fragmentation, as reflected in Figures 2 and 3, respectively. Monomer values ​​at pH 5.1 and 5.6 are slightly lower than those at 5.4. However, monomer loss above 5.6 and below pH 5.1 appears to occur in a steeply nonlinear manner, inferring a finite pH range over which the formulation remains stable. Based on the pH profiles for the buffer species, histidine and phosphate were excluded as buffers.

[0220] To further evaluate the acetate buffer, a second set of main effects plots was generated using data from the acetate test formulations alone (Figures 4, 5, 6).

[0221] Figures 5 and 6 again show a strong linear effect of pH on aggregation and fragmentation, respectively, while Figure 4 again shows a nonlinear effect of pH on the monomer, although the curves appear to begin to plateau at pH 5.1.

[0222] Figures 4 and 6 show that decreasing acetate buffer concentration correlates with increased stability, while Figure 5 shows acetate buffer concentrations that have no significant effect on aggregation. Figures 4 and 5 show sucrose showing a slight increase in stability relative to sorbitol, while Figure 6 shows sorbitol showing a similarly slight increase in stability relative to sucrose.

[0223] Taken together, these initial screening studies identified an optimal formulation consisting of acetate buffer at low concentrations and a pH of 5.1–5.4. Based on practical considerations, sucrose was selected as the excipient.

[0224] Oxidative Stress Screening Test A preliminary oxidative stress screening study was conducted to evaluate the susceptibility (or lack thereof) of DP to oxidation. Oxidative stress was mediated by the addition of trace metals to DP test formulations, which were stored under stress (40°C) stability conditions for one month. As a mitigation strategy, EDTA was also added to the test formulations to evaluate its ability to mitigate oxidation.

[0225] This study included three experimental formulations: 1) without metals, 2) with metals, and 3) with metals and EDTA. The metal-free test formulation consisted of 1 mg / mL DP in 10 mM acetate, 8% (w / v) sucrose, 0.04% (w / v) PS20, pH 5.2. The metal-containing test formulation consisted of the metal-free test formulation supplemented with trace (low ppb) metals. The metal species selected for this study were based on the composition of metal alloy components potentially present in the manufacturing process. The concentrations of trace metals used in this study were 2- to 20-fold higher than the trace metals historically reported in the literature during the DP manufacturing process. The metal- and EDTA-containing test formulation was consistent with the metal-containing test formulation supplemented with 20 μg / mL EDTA.

[0226] The test formulations were aliquoted into 8R vials with a fill volume of 3.3 mL. All vials were stoppered, capped, and crimp sealed. The vials were stored under stress (40°C) stability conditions for one month. Samples were then removed and assayed.

[0227] After one month under stressed (40°C) stability conditions, the metal-free test formulation showed an increase in HMWS as measured by SE-HPLC and a decrease in purity as measured by both non-reduced and reduced cSDS (Table 10). These results are consistent with monoclonal antibodies stored under stressed (40°C) stability conditions for one month. The metal-containing test formulation showed a dramatic increase in HMWS and a decrease in purity compared to the metal-free formulation at the same time point. This data suggests that the species and concentrations of trace metals used in this study contributed to increased degradation relative to similar test formulations without metals under stressed (40°C) stability conditions for one month. However, the metal-containing and EDTA test formulations showed assay values ​​consistent with those without metals. These data suggest that the addition of EDTA to the test formulation mitigated the apparent increased diffusion effect seen with trace metals in the metal-containing test formulations under stressed (40°C) stability conditions for one month.

[0228] [Table 15]

[0229] Based on the results of this preliminary oxidative stress screening study, EDTA was added to the DP formulation.

[0230] Example 2: Shaking a range of polysorbate concentrations A shaking stress test was conducted to evaluate the range of polysorbate concentrations capable of maintaining mAb stability against mechanical stress. This test evaluated formulations containing PS20 concentrations ranging from 0.01 to 0.08% (w / v). PS20 was added to formulations containing 2 mg / mL and 40 mg / mL talquetamab in 15 mM acetate, 8% (w / v) sucrose, 0.02 mg / mL EDTA, pH 5.2, to achieve PS20 concentrations of 0.01, 0.02%, 0.04%, 0.06%, and 0.08% (w / v). The 2 mg / mL formulation was filled into 6 mL type I glass vials with a fill volume of 2.0 mL, and the 40 mg / mL formulation was filled into 2 mL type I glass vials with a fill volume of 1.4 mL. The vials were placed on an orbital platform shaker and agitated at 250 rpm at ambient temperature for 24 hours. The samples were analyzed and the results are shown in Tables 11 and 12.

[0231] For formulations varying in PS20 concentration from 0.02 to 0.08% (w / v), no significant changes were observed between formulations stirred for at least 24 hours. Sub-Vis results for all PS20 concentrations and conditions can be considered essentially the same when viewed within the context of the magnitude of the compendial acceptance criteria and the overall methodology. For formulations containing 0.01% PS20, there was a slight increase in HMWS (%) and loss of major components (%) (aggregates and monomers, respectively). However, these values ​​are consistent with the definition of a stable aqueous pharmaceutical composition provided herein.

[0232] This study demonstrated that talquetamab formulations containing 0.01–0.08% (w / v) PS20 remained stable under mechanical stress conditions.

[0233] [Table 16] a)The formulation composition is 2 mg / mL or 40 mg / mL talquetamab in 15 mM acetate, 8% (w / v) sucrose, 0.02 mg / mL EDTA, pH 5.2, in addition to the levels of PS20 indicated in the table.

[0234] [Table 17] a) The formulation composition is 2 mg / mL or 40 mg / mL talquetamab in 15 mM acetate, 8% (w / v) sucrose, 0.02 mg / mL EDTA, pH 5.2, in addition to the levels of PS20 indicated in the table.

[0235] Example 3: Freeze-thaw stress test Tests were conducted to demonstrate the robustness of the formulation to the physicochemical stress induced by repeated freeze-thaw cycles.

[0236] In this study, 2 mg / mL and 40 mg / mL formulations (15 mM acetate, 8% (w / v) sucrose, 20 μg / mL EDTA, 0.04% (w / v) PS20, pH 5.2) were filled into 5 mL polycarbonate containers and placed upright in a -70°C freezer. After freezing was complete, the vials were removed from the freezer and placed at ambient temperature for thawing. Once fully thawed, the containers were gently swirled to ensure solution homogeneity, and then repeatedly frozen and thawed (F / T) until a total of five cycles were completed. The control sample did not undergo any freeze-thaw cycles. Both the control and the frozen and thawed samples were analyzed.

[0237] As shown in Table 13, the quality attributes of the samples that underwent five F / T cycles were nearly identical to the control samples stored at 2-8°C and not subjected to freeze-thaw conditions. Furthermore, no significant changes in protein concentration, solution color, pH, or turbidity were observed.

[0238] [Table 18]

[0239] The results of this study demonstrate the robustness of the 2 mg / mL and 40 mg / mL formulations to freeze-thaw induced stress.

[0240] Example 4: Metal spiking test Studies were conducted to further evaluate the impact of metal ions potentially present in or introduced into the drug product during the manufacturing process of the 2 mg / mL and 40 mg / mL talquetamab DP formulations.

[0241] The test formulation consisted of 2 mg / mL or 40 mg / mL talquetamab, 15 mM acetate, 8% sucrose, 20 μg / mL EDTA, and 0.04% PS 20 (pH 5.2), with iron (Fe 3+ ), chromium (Cr3 + ), copper (Cu 2+ ), Nickel (Ni 2+ ), and molybdenum (Mo 5+ The metals were tested with or without the addition of ZnO. The metal selection was based on the composition of metal alloying elements potentially present in the manufacturing process. To demonstrate robustness, exaggerated stress conditions were created by utilizing metal concentrations 5-13 times greater than trace metal values ​​historically reported in the literature during the DP manufacturing process.

[0242] The 2 mg / mL test formulation was aliquoted into 6R vials with a fill volume of 3.5 mL, and the 40 mg / mL test formulation was aliquoted into 2 mL vials with a fill volume of 2.0 mL. All vials were stoppered, capped, and crimp-sealed. The vials were stable for up to 6 months at recommended (5°C) and accelerated (25°C) conditions. Samples were taken and assayed at the designated time points.

[0243] As shown in Table 14, the quality attributes of the metal ion-stressed 2 mg / mL and 40 mg / mL formulations after 6 months of storage at 2-8°C were nearly identical to the respective control formulations. Furthermore, for all test formulations stored at 2-8°C, there was little or no change in the quality attribute values ​​at 6 months compared to the T=0 values. Finally, the quality attribute values ​​of all metal-loaded formulations stored at 2-8°C for 6 months were consistent with the definition of a stable aqueous pharmaceutical composition provided herein.

[0244] As shown in Table 15, the quality attributes of the metal ion-stressed 2 mg / mL and 40 mg / mL formulations after 6 months of storage at 25°C were nearly identical to their respective control formulations. For all test formulations, slight to minimal changes in several quality attribute values ​​were observed at 6 months compared to T=0 values. The extent of change was consistent with the expected degradation of these monoclonal antibody quality attributes upon 6 months of storage at 25°C. Finally, the quality attribute values ​​of all metal-loaded formulations stored at 25°C for 6 months were consistent with the definition of a stable aqueous pharmaceutical composition provided herein.

[0245] Taken together, the data demonstrate the robustness of the formulations at 2 mg / mL and 40 mg / mL against potential oxidative stress experienced during normal and / or exaggerated pharmaceutical manufacturing processes and storage conditions.

[0246] [Table 19]

[0247] [Table 20]

[0248] Example 5: Development of formulation robustness Test Design A stable monoclonal antibody formulation is the result of the net effect of complex interactions between the formulation's components. To evaluate these interactions, we used Design of Experiments (DOE) methodology to create a multifactorial stability study in which a statistically determined number of experimental test formulations are generated that simultaneously vary the parameters of the formulation components. Statistical analysis of the test results provides a quantitative understanding of how formulation parameters interact to affect stability attributes, thereby demonstrating the robustness of the formulation.

[0249] Experimental test formulations of GPRC5D / CD3 drug product were held at recommended conditions (5°C) for up to 12 months and at accelerated conditions (25°C) for up to 6 months. Formulation components evaluated were protein concentration, acetate concentration, sucrose concentration, polysorbate 20 concentration, EDTA concentration, and pH. Concentration ranges for the factors tested are listed in Table 16 (target formulation values ​​are included in the table for context). The study encompassed both 2 mg / mL and 40 mg / mL DP formulations. The typical protein concentration range for evaluation is + / - 12% of the target value. Therefore, the upper protein concentration value selected for testing corresponds to 112% of the 40 mg / mL formulation. For convenience, 1 mg / mL was used at the lower protein concentration (50% of the 2 mg / mL formulation).

[0250] [Table 21]

[0251] Based on this criteria, a six-factor IV, fractional factorial design was constructed using JMP® statistical software (Table 17).

[0252] [Table 22]

[0253] The vials were stoppered, capped, and crimp sealed. The vials were placed on stability at recommended conditions (5°C) and accelerated conditions (25°C). At designated time points, samples were taken and assayed.

[0254] Test results The test results for each attribute of the 16 formulations at the start of the study (time 0), after 6 months at accelerated temperature (25°C), and after 6 and 12 months at recommended storage conditions (5°C) are shown in Table 18. Data are reported as the range, mean, and standard deviation of the 16 formulations for each attribute.

[0255] Analytical results for all formulations held at 5°C for 12 months demonstrated little change in assay test values, indicating stability. The ability of all formulations with a multivariate range of excipient concentrations to produce a narrow range of assay test result values ​​demonstrated the robustness of the formulations within the boundaries and storage conditions tested. Furthermore, the full range of values ​​observed in this study was consistent with the definition of a stable aqueous pharmaceutical composition provided herein when held at 5°C for 12 months.

[0256] Analytical results for all formulations held at accelerated storage conditions (25° C.) for 6 months showed degradation effects consistent with the stability profile of the GPRC5DxCD3 antibody exposed to long-term accelerated storage conditions, as demonstrated by the increased magnitude of the range of result values ​​when compared to both the start of the study (time 0) and 12 months at 5° C. However, the calculated mean values ​​and overall range of values ​​observed for all nine assay results were consistent with the definition of a stable aqueous pharmaceutical composition provided herein when held at accelerated (25° C.) storage conditions for 6 months.

[0257] [Table 23]

[0258] Statistical analysis of research results A statistical analysis of the 12M 2-8°C data was performed using a factorial regression model to determine which factors had statistically significant effects on a given response. Table 19 lists the calculated p-values ​​for each factor for a given response and the corresponding adjusted R-squared values ​​generated by the model. A p-value of less than 0.05 is considered statistically significant.

[0259] [Table 24]

[0260] API concentration While API concentration showed a statistically significant negative correlation with %monomer, it also showed a corresponding statistically significant positive correlation with %aggregates. These trends indicate that increasing API concentration correlates with decreased stability as measured by SEC. However, within the concentration range evaluated in this study (1-90 mg / mL), the range of %monomer and %aggregates assay results observed was consistent with the definition of a stable aqueous pharmaceutical composition provided herein.

[0261] API concentration also showed a statistically significant positive correlation with % Main Peak. However, as shown in Table 19, the range of resulting values ​​for % Main Peak appears to be very narrow for these attributes. Therefore, although calculated to be statistically significant, API concentrations between 1 and 90 mg / mL are not expected to have a practical impact on % Main Peak.

[0262] pH of the formulation Formulation pH showed a statistically significant negative correlation with % monomer, while also showing a corresponding statistically significant positive correlation with % aggregate. These trends indicate that increasing pH correlates with decreased stability as measured by SEC. However, within the pH range evaluated in this study (4.7-5.7), the range of % monomer and % aggregate assay results observed was consistent with the definition of a stable aqueous pharmaceutical composition provided herein.

[0263] pH also showed a statistically significant negative correlation with % Main Peak, while showing a statistically significant positive correlation with % Acid Peak. However, similar to API concentration, the range of resulting values ​​for % Acid Peak and % Main Peak appears to be very narrow for these three attributes, as shown in Table 19. Therefore, although calculated to be statistically significant, a pH between 4.7 and 5.7 is not expected to have a practical effect on % Acid Peak and % Main Peak.

[0264] Example 6: Bulk production of formulated drug Process Description Processing Solution

[0265] [Table 25]

[0266] Ultrafiltration / Diafiltration (UF / DF) Ultrafiltration / diafiltration (UF / DF) was performed to reformulate the talquetamab planova filtrate intermediate manufacturing solution into a pre-formulated bulk (pFB) solution consisting of 90 mg / mL talquetamab, 10 mM acetate, 8% (w / v) sucrose, pH 5.2.

[0267] Preparation of talquetamab bulk formulation (FB) Polysorbate 20 (4.0% w / v) and EDTA (2 mg / mL) stock solutions were added to the pFB at a 1:100 dilution to obtain a final concentration of 0.04% (w / v) polysorbate 20 and 20 μg / mL EDTA, resulting in a formulated bulk (FB) consisting of 90 mg / mL talquetamab in 15 mM acetate, 8% (w / v) sucrose, 0.04% polysorbate 20, 20 μg / mL EDTA, pH 5.2. The FB solution was then mixed homogeneously. Final filtration of the formulated bulk was achieved using a sterile 0.45 / 0.22 μm filter followed immediately by an in-line 0.22 μm filter.

[0268] Final Bulk Fill After the final filtration, the FB was filled into polycarbonate biotainers, with a filling volume ranging from 20% to 90% of the biotainer's stated volume.

[0269] Final bulk storage and transportation The storage and transportation conditions for the formulated bulk prior to drug manufacturing were 5°C ± 3°C, protected from light, if the FB was stored for approximately one week or less, or -40°C ± 10°C, protected from light, if the FB was stored for more than one week.

[0270] Example 7: Preparation of a 40 mg / mL DP solution Dilution of talquetamab formulated bulk (FB) The bulk intermediate manufacturing solution formulated with talquetamab was diluted to reformulate it into a drug product solution consisting of 40 mg / mL talquetamab, 15 mM acetate, 8% (w / v) sucrose, 20 μg / mL EDTA, pH 5.2.

[0271] Dilution Buffer Provided herein is a tabular summary of the composition of the dilution buffer in Table 21. Final filtration of the dilution buffer was achieved using a sterile 0.22 μm filter.

[0272] [Table 26]

[0273] Preparation of talquetamab 40 mg / mL drug solution Dilution buffer was added to 90 mg / mL FB to obtain a 40 mg / mL drug product solution consisting of 40 mg / mL talquetamab in 15 mM acetate, 8% (w / v) sucrose, 0.04% polysorbate 20, 20 μg / mL EDTA, pH 5.2.

[0274] Example 8: 40 mg / mL Pharmaceutical Formulation: Composition and Components of Primary Packaging A summary of the composition of the 40 mg / mL talquetamab pharmaceutical formulation is provided herein in Tables 22 and 23.

[0275] [Table 27]

[0276] [Table 28]

[0277] The primary packaging for the 40 mg / mL talquetamab drug product (DP) consists of a glass vial, a polymeric vial stopper, and an aluminum seal. Table 24 provides the specific components of the primary packaging material for the 40 mg / mL DP presentation.

[0278] [Table 29]

[0279] Example 9: Preparation of 2 mg / mL DP solution Dilution of talquetamab formulated bulk (FB) The bulk intermediate manufacturing solution formulated with talquetamab was diluted to reformulate it into a drug product solution consisting of 2 mg / mL talquetamab, 15 mM acetate, 8% (w / v) sucrose, 20 μg / mL EDTA, pH 5.2.

[0280] Dilution Buffer Provided herein is a tabular summary of the composition of the dilution buffer in Table 25. Final filtration of the dilution buffer was achieved using a sterile 0.22 μm filter.

[0281] [Table 30]

[0282] Preparation of talquetamab 2 mg / mL drug solution Dilution buffer was added to 90 mg / mL FB to obtain a 2 mg / mL drug product solution consisting of 2 mg / mL talquetamab in 15 mM acetate, 8% (w / v) sucrose, 0.04% polysorbate 20, 20 μg / mL EDTA, pH 5.2.

[0283] Example 10: 2 mg / mL Pharmaceutical Formulation: Composition and Components of Primary Packaging A summary of the composition of the 2 mg / mL talquetamab pharmaceutical formulation is provided herein in Tables 26 and 27.

[0284] [Table 31]

[0285] [Table 32]

[0286] The primary packaging for the 2 mg / mL talquetamab drug product (DP) consists of a glass vial, a polymeric vial stopper, and an aluminum seal. Table 28 lists the specific components of the primary packaging material for the 2 mg / mL DP presentation.

[0287] [Table 33]

[0288] Example 11: Stability Study Description at 40 mg / mL This study was conducted to monitor the drug product characteristics of stable talquetamab 40 mg / mL under various environmental conditions and time lengths. Investigational test articles were prepared by aliquoting the formulated bulk into 2 mL vials with a fill volume of 1.4 mL. The vials were stoppered, capped, and crimp sealed.

[0289] All tests were performed with the vials inverted.

[0290] [Table 34]

[0291] Stability test results Stability results for the talquetamab DP held under recommended, accelerated, and stress conditions are listed below. At all time points for the DP held under recommended storage conditions (after storage at a temperature of about 5° C. for about 12 months or more and / or after storage at a temperature of about 5° C. for about 2 years or more), all test parameter result values ​​observed per assay test exceeded criteria consistent with the definition of a stable aqueous pharmaceutical composition provided herein. Similarly, peptide map results showed little or no consequential change over time in the measured rates of post-translational modifications.

[0292] Results for the talquetamab DP held at accelerated and stressed conditions demonstrated the expected degradation rates for drug products exposed to long-term accelerated and stressed storage conditions. Of particular note, all test parameter result values ​​observed per assay test for the DP held at accelerated conditions (25° C.) for 12 months demonstrated results consistent with the definition of a stable aqueous pharmaceutical composition provided herein. 5℃ data

[0293] [Table 35]

[0294] [Table 36]

[0295] [Table 37]

[0296] [Table 38]

[0297] Data at 25℃

[0298] [Table 39]

[0299] [Table 40]

[0300] [Table 41]

[0301] [Table 42]

[0302] 40℃ data

[0303] [Table 43]

[0304] [Table 44]

[0305] [Table 45]

[0306] [Table 46]

[0307] Example 12: Stability Study Description at 2 mg / mL This study was conducted to monitor the drug product characteristics of stable talquetamab 2 mg / mL under various environmental conditions and time lengths. Investigational test articles were prepared by aliquoting the formulated bulk into 6R vials with a fill volume of 2.0 mL. The vials were stoppered, capped, and crimp sealed.

[0308] All tests were performed with the vials inverted.

[0309] [Table 47]

[0310] Stability test results Stability results for the talquetamab DP held under recommended, accelerated, and stress conditions are listed below. At all time points for the DP held under recommended storage conditions (after storage at a temperature of about 5° C. for about 12 months or more and / or after storage at a temperature of about 5° C. for about 2 years or more), all test parameter result values ​​observed per assay test exceeded criteria consistent with the definition of a stable aqueous pharmaceutical composition provided herein. Similarly, peptide map results showed little or no consequential change over time in the measured rates of post-translational modifications.

[0311] The results for the talquetamab DP held at accelerated and stressed conditions demonstrated the expected degradation rates for a drug product exposed to long-term accelerated and stressed storage conditions. Of particular note, the majority of test parameter result values ​​observed per assay test for the DP held at accelerated conditions (25°C) for 12 months demonstrated results consistent with the definition of a stable aqueous pharmaceutical composition provided herein, with all but one of the results falling within the defined stability parameters. Interestingly, the only outlier was at the 6-month time point, with the 9-month data indicating that the DP was stable at accelerated conditions for up to 9 months. This may indicate that the 6-month data for T cell activation represents an outlier, and therefore, the DP may be considered consistent with the definition of a stable aqueous pharmaceutical composition provided herein for all test parameter results. 5℃ data

[0312] [Table 48]

[0313] [Table 49]

[0314] [Table 50]

[0315] [Table 51]

[0316] Data at 25℃

[0317] [Table 52]

[0318] [Table 53]

[0319] [Table 54]

[0320] [Table 55]

[0321] 40℃ data

[0322] [Table 56]

[0323] [Table 57]

[0324] [Table 58]

[0325] [Table 59]

[0326] Example 13: Stability of formulations containing 30 mg / mL, 60 mg / mL, and 90 mg / mL talquetamab To investigate the stability of formulations with higher talquetamab concentrations, three formulations containing 30 mg / mL, 60 mg / mL, and 90 mg / mL talquetamab, respectively, were placed in stability chambers at 2-8°C and 25°C for up to 18 months. The target composition for all three formulations was 15 mM acetate, 8% (w / v) sucrose, 20 μg / mL disodium EDTA, 0.04% (w / v) PS 20, pH 5.2. The formulations were analyzed for major component, aggregate, and fragment content by SE-HPLC, purity by cSDS (reduced and nonreduced), charge heterogeneity by cIEF, and subvisible particulate matter by light obscuration (LO).

[0327] No substantial changes were observed for the cIEF and cSDS (reduced and non-reduced) data and subvisible particle counts (data not shown).

[0328] The SE-HPLC data for all three formulations (Table 55) show nearly identical stability profiles over 18 months at 2-8°C, with all reported values ​​consistent with the most favorable mode of stability.

[0329] Comparison of the stability profiles of all three formulations over 3 months at 25° C. shows a slight but present correlation between increasing protein concentration and decrease in major component. However, the magnitude of the decrease occurred over a narrow range, and all protein concentrations showed major component values ​​consistent with the most favorable embodiment for stability.

[0330] [Table 60] a The 30 mg / mL formulation sample was generated at the 6 month time point. NA = Not applicable

[0331] Example 14: Phase 1 study of talquetamab administered as monotherapy in relapsed or refractory multiple myeloma The efficacy of talquetamab monotherapy was evaluated in patients with relapsed or refractory multiple myeloma in the single-arm, open-label, multicenter study, MMY1001 (MonumenTAL-1) (NCT03399799, NCT04634552). This study included patients who had previously received at least three prior therapies, including a proteasome inhibitor, an immunomodulator, and an anti-CD38 monoclonal antibody. This study also included patients who had previously received T cell redirected therapy (N=34). Patients received either talquetamab 0.4 mg / kg subcutaneously every week after two escalating doses (0.01 and 0.06 mg / kg) during the first week of treatment, or talquetamab 0.8 mg / kg subcutaneously every 2 weeks after three escalating doses (0.01, 0.06, and 0.3 mg / kg) until disease progression or unacceptable toxicity. Patients were hospitalized for monitoring for at least 48 hours after each talquetamab dose during the titration phase.

[0332] A significant number of patients in the subcutaneous cohort received the formulations shown in Table 27 for talquetamab at a 2 mg / mL concentration (for escalating doses of 0.01 mg / kg and 0.06 mg / kg) and the formulations shown in Table 23 for talquetamab at a 40 mg / mL concentration (for doses of 0.4 mg / kg and 0.8 mg / kg).

[0333] Among 122 patients treated with 0.4 mg / kg weekly talquetamab who had not previously been exposed to T cell redirected therapy, the median age was 67 years (range: 47-86), 53% were male, 92% were white, and 7% were black or African American. Patients had received a median of 5 prior therapies (range: 3-13), and 77% had received prior autologous stem cell transplantation (ASCT). 93% of patients were refractory to their last therapy, and 75% were refractory to proteasome inhibitors, immunomodulators, and anti-CD38 antibodies. Among 113 patients for whom baseline cytogenetic data were available, high-risk cytogenetic factors (presence of t(4:14), t(14:16), and / or del(17p)) were present in 35% of patients.

[0334] Among 109 patients treated with talquetamab 0.8 mg / kg every 2 weeks (every 2 weeks) who had not previously been exposed to T cell-redirected therapy, the median age was 67 years (range: 38-82), 61% were male, 87% were white, and 6% were black or African American. Patients had received a median of 5 prior therapies (range: 3-12), and 79% had received prior autologous stem cell transplantation (ASCT). 95% of patients were refractory to their last therapy, and 69% were refractory to proteasome inhibitors (PIs), immunomodulators, and anti-CD38 antibodies. Among the 94 patients for whom baseline cytogenetic data were available, high-risk cytogenetic factors (presence of t(4:14), t(14:16), and / or del(17p)) were present in 33% of patients.

[0335] Efficacy outcomes were based on overall response rate (ORR) assessed by an independent review committee using IMWG criteria.

[0336] [Table 61] CI = confidence interval; MRD = minimal residual disease; NE = not estimable The median follow-up period was 14.7 months. a MRD-negativity rate was determined by the MRD-negative status (10%) at any time after the first dose and before progressive disease (PD) or subsequent anti-myeloma therapy. -5 ) is defined as the percentage of participants who achieve b Only MRD assessment within 3 months of achieving CR / sCR until death / progression / subsequent treatment (exclusion) (10 -5 Consider the test threshold.

[0337] [Table 62] CI = confidence interval; MRD = minimal residual disease; NE = not estimable Median follow-up = 8.1 months. a MRD-negativity rate was determined by the MRD-negative status (10%) at any time after the first dose and before progressive disease (PD) or subsequent anti-myeloma therapy. -5 ) is defined as the percentage of participants who achieve b Only MRD assessment within 3 months of achieving CR / sCR until death / progression / subsequent treatment (exclusion) (10 -5 Consider the test threshold.

[0338] The median time to first response was 1.2 (range: 0.2-10.9) months and 1.3 (range: 0.2-9.2) months for the 0.4 mg / kg weekly and 0.8 mg / kg once every 2 weeks (every 2 weeks) doses, respectively. ORR results were consistent across prespecified subgroups, including number of lines of prior therapy, refractoriness to prior therapy, and baseline cytogenetic risk.

[0339] MMY1001 also included 34 patients who had previously been exposed to T-cell redirection therapy and had received at least three prior therapies, including a protease inhibitor, an immunomodulator, and an anti-CD38 monoclonal antibody. Patients received talquetamab 0.4 mg / kg subcutaneously once weekly, followed by two escalating doses (0.01 and 0.06 mg / kg) until disease progression or unacceptable toxicity. The median age was 60 years (range: 38-78 years), 59% were male, 97% were white, and 3% were black or African American. Patients had received a median of six prior therapies (range: 3-15). Prior T-cell redirection therapy was CAR-T cell therapy for 82% of patients and bispecific antibody treatment for 24%. The median follow-up period was 9.9 months, and the ORR per IRC assessment was 71%.

[0340] Talquetamab exposure was comparable across the two dosing schedules. No clinically significant effects of anti-talquetamab antibodies on PK, efficacy, or AEs were observed. PD changes were comparable across both dosing schedules and consistent with talquetamab activity, including T cell activation, redistribution, and cytokine induction. In conclusion, talquetamab demonstrated robust efficacy and manageable safety in patients with heavily pretreated relapsed or refractory multiple myeloma.

Claims

1. 1. An aqueous pharmaceutical composition comprising: a) a bispecific G protein-coupled receptor, class C, group 5, member D (GPRC5D) / cluster of differentiation 3 (CD3) antibody or antigen-binding fragment thereof at a concentration of about 0.5 mg / mL to about 3.5 mg / mL, wherein the bispecific GPRC5D / CD3 antibody or antigen-binding fragment thereof is (1) a first heavy chain (HC1) comprising an HC1 variable region 1 (VH1); wherein the VH1 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; (2) a first light chain (LC1) comprising an LC1 variable region (VL1); and wherein the VL1 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (3) a second heavy chain (HC2) comprising an HC2 variable region 2 (VH2); and wherein the VH2 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; (4) a second light chain (LC2) comprising an LC2 variable region 2 (VL2); and wherein the VL2 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively; Including, b) about 10 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt; c) about 6% (w / v) to about 10% (w / v) sucrose; d) about 7 μg / mL to about 33 μg / mL ethylenediaminetetraacetic acid (EDTA); e) about 0.01% to about 0.07% polysorbate 20, and f) a pH of about 4.6 to about 5.8 1. An aqueous pharmaceutical composition comprising:

2. 1. An aqueous pharmaceutical composition comprising: a) a bispecific G protein-coupled receptor, class C, group 5, member D (GPRC5D) / cluster of differentiation 3 (CD3) antibody or antigen-binding fragment thereof at a concentration of about 25 mg / mL to about 55 mg / mL, wherein the bispecific GPRC5D / CD3 antibody or antigen-binding fragment thereof is (1) a first heavy chain (HC1) comprising an HC1 variable region 1 (VH1); wherein the VH1 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; (2) a first light chain (LC1) comprising an LC1 variable region (VL1); and wherein the VL1 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (3) a second heavy chain (HC2) comprising an HC2 variable region 2 (VH2); and wherein the VH2 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; (4) a second light chain (LC2) comprising an LC2 variable region 2 (VL2); and wherein the VL2 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively; Including, b) about 10 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt; c) about 6% (w / v) to about 10% (w / v) sucrose; d) about 7 μg / mL to about 33 μg / mL ethylenediaminetetraacetic acid (EDTA); e) about 0.01% to about 0.07% polysorbate 20, and f) a pH of about 4.6 to about 5.8 1. An aqueous pharmaceutical composition comprising:

3. 3. The aqueous pharmaceutical composition of claim 1 or 2, wherein the bispecific GPRC5D / CD3 antibody comprises a VH1 having the amino acid sequence of SEQ ID NO: 7 and a VL1 having the amino acid sequence of SEQ ID NO:

8.

4. 3. The aqueous pharmaceutical composition of claim 1 or 2, wherein the bispecific GPRC5D / CD3 antibody comprises an HC1 having the amino acid sequence of SEQ ID NO: 9 and an LC1 having the amino acid sequence of SEQ ID NO:

10.

5. 3. The aqueous pharmaceutical composition of claim 1, wherein the bispecific GPRC5D / CD3 antibody comprises a VH2 having the amino acid sequence of SEQ ID NO: 17 and a VL2 having the amino acid sequence of SEQ ID NO:

18.

6. 3. The aqueous pharmaceutical composition of claim 1 or 2, wherein the bispecific GPRC5D / CD3 antibody comprises an HC2 having the amino acid sequence of SEQ ID NO: 19 and an LC2 having the amino acid sequence of SEQ ID NO:

20.

7. 3. The aqueous pharmaceutical composition of claim 1 or 2, wherein the bispecific GPRC5D / CD3 antibody is talquetamab.

8. 2. The aqueous pharmaceutical composition of claim 1, wherein the bispecific GPRC5D / CD3 antibody has a concentration of about 1 mg / mL to about 3 mg / mL.

9. 9. The aqueous pharmaceutical composition of claim 8, wherein the bispecific GPRC5D / CD3 antibody has a concentration of about 1.5 mg / mL to about 2.5 mg / mL.

10. 10. The aqueous pharmaceutical composition of claim 9, wherein the bispecific GPRC5D / CD3 antibody has a concentration of about 2 mg / mL.

11. 3. The aqueous pharmaceutical composition of claim 2, wherein the bispecific GPRC5D / CD3 antibody has a concentration of about 30 mg / mL to about 50 mg / mL.

12. 12. The aqueous pharmaceutical composition of claim 11, wherein the bispecific GPRC5D / CD3 antibody has a concentration of about 35 mg / mL to about 45 mg / mL.

13. 13. The aqueous pharmaceutical composition of claim 12, wherein the bispecific GPRC5D / CD3 antibody has a concentration of about 40 mg / mL.

14. 3. The aqueous pharmaceutical composition of claim 1, comprising about 12 mM to about 18 mM acetate and / or a pharmaceutically acceptable acetate salt.

15. 3. The aqueous pharmaceutical composition of claim 1 or 2, comprising about 14 mM to about 16 mM acetate and / or a pharmaceutically acceptable acetate salt.

16. 3. The aqueous pharmaceutical composition of claim 1 or 2, comprising about 15 mM acetate and / or a pharmaceutically acceptable acetate salt.

17. 3. The aqueous pharmaceutical composition according to claim 1, comprising about 7% (w / v) to about 9% (w / v) sucrose.

18. 18. The aqueous pharmaceutical composition of claim 17, comprising about 8% (w / v) sucrose.

19. 3. The aqueous pharmaceutical composition of claim 1, comprising about 15 μg / mL to about 21 μg / mL of EDTA.

20. 3. The aqueous pharmaceutical composition of claim 1 or 2, comprising about 18 μg / mL of EDTA.

21. 3. The aqueous pharmaceutical composition according to claim 1, comprising about 0.02% to about 0.06% PS-20.

22. 22. The aqueous pharmaceutical composition of claim 21, comprising about 0.03 to about 0.05% PS-20.

23. 23. The aqueous pharmaceutical composition of claim 22, comprising about 0.04% PS-20.

24. 3. The aqueous pharmaceutical composition according to claim 1, wherein the pH is from about 4.8 to about 5.

6.

25. 25. The aqueous pharmaceutical composition of claim 24, wherein the pH is from about 4.9 to about 5.

5.

26. 26. The aqueous pharmaceutical composition of claim 25, wherein the pH is about 5.

2.

27. 2. The aqueous pharmaceutical composition of claim 1, comprising 2 mg / mL of the bispecific GPRC5D / CD3 antibody, 15 mM acetate and / or a pharmaceutically acceptable acetate salt, 8% (w / v) sucrose, 18 μg / mL EDTA, 0.04% PS20, and a pH of 5.

2.

28. 3. The aqueous pharmaceutical composition of claim 2, comprising 40 mg / mL of the bispecific GPRC5D / CD3 antibody, 15 mM acetate and / or a pharmaceutically acceptable acetate salt, 8% (w / v) sucrose, 18 μg / mL EDTA, 0.04% PS20, and a pH of 5.

2.

29. The aqueous pharmaceutical composition according to any one of claims 1 to 28, which is stable.

30. 30. The aqueous pharmaceutical composition of claim 29, wherein stability is defined based on solution color, pH, turbidity, percentage of purity, percentage of new peaks, percentage of major components, percentage of high molecular weight species (HWMS), percentage of low molecular weight species (LMWS), percentage of sum of acidic peaks, percentage of sum of basic peaks, protein concentration, percentage of T cell activation, percentage of PS20 (w / v), or any combination thereof.

31. 31. The aqueous pharmaceutical composition according to claim 29 or 30, which is stable at a temperature of about 2 to 8°C for at least 2 years.

32. 32. A method of treating cancer in a subject in need thereof, comprising administering to the subject the aqueous pharmaceutical composition of any one of claims 1 to 31.

33. 33. The method of claim 32, wherein the administration is subcutaneous.

34. 1. A method for preparing an aqueous pharmaceutical composition of a bispecific G protein-coupled receptor, class C, group 5, member D (GPRC5D) / cluster of differentiation 3 (CD3) antibody or antigen-binding fragment thereof, comprising: (1) a first heavy chain (HC1) comprising an HC1 variable region 1 (VH1); wherein the VH1 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; (2) a first light chain (LC1) comprising an LC1 variable region (VL1); and wherein the VL1 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (3) a second heavy chain (HC2) comprising an HC2 variable region 2 (VH2); and wherein the VH2 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; (4) a second light chain (LC2) comprising an LC2 variable region 2 (VL2); and wherein the VL2 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively; Including, 10. A method comprising combining a composition comprising about 2 mg / mL of said bispecific GPRC5D / CD3 antibody, about 15 mM acetate and / or a pharmaceutically acceptable acetate salt, about 8% (w / v) sucrose, about 18 μg / mL EDTA, and about 0.04% polysorbate (PS) 20, wherein the stable aqueous pharmaceutical composition has a pH of about 5.

2.

35. 1. A method for preparing an aqueous pharmaceutical composition of a bispecific G protein-coupled receptor, class C, group 5, member D (GPRC5D) / cluster of differentiation 3 (CD3) antibody or antigen-binding fragment thereof, comprising: (1) a first heavy chain (HC1) comprising an HC1 variable region 1 (VH1); wherein the VH1 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; (2) a first light chain (LC1) comprising an LC1 variable region (VL1); and wherein the VL1 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (3) a second heavy chain (HC2) comprising an HC2 variable region 2 (VH2); and wherein the VH2 comprises heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; (4) a second light chain (LC2) comprising an LC2 variable region 2 (VL2); and wherein the VL2 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively; Including, 10. A method comprising combining a composition comprising about 40 mg / mL of said bispecific GPRC5D / CD3 antibody, about 15 mM acetate and / or a pharmaceutically acceptable acetate salt, about 8% (w / v) sucrose, about 18 μg / mL EDTA, and about 0.04% polysorbate (PS) 20, wherein the stable aqueous pharmaceutical composition has a pH of about 5.

2.

36. The method of claim 34 or 35, wherein the bispecific GPRC5D / CD3 antibody comprises a VH1 having the amino acid sequence of SEQ ID NO: 7 and a VL1 having the amino acid sequence of SEQ ID NO:

8.

37. 36. The method of claim 34 or 35, wherein the bispecific GPRC5D / CD3 antibody comprises HC1 having the amino acid sequence of SEQ ID NO: 9 and LC1 having the amino acid sequence of SEQ ID NO:

10.

38. The method of claim 34 or 35, wherein the bispecific GPRC5D / CD3 antibody comprises a VH2 having the amino acid sequence of SEQ ID NO: 17 and a VL2 having the amino acid sequence of SEQ ID NO:

18.

39. 36. The method of claim 34 or 35, wherein the bispecific GPRC5D / CD3 antibody comprises an HC2 having the amino acid sequence of SEQ ID NO: 19 and an LC2 having the amino acid sequence of SEQ ID NO:

20.

40. 36. The method of claim 34 or 35, wherein the bispecific GPRC5D / CD3 antibody is talquetamab.

41. The method of any one of claims 34 to 40, wherein the aqueous pharmaceutical composition is stable.

42. 42. The method of claim 41, wherein stability is defined based on solution color, pH, turbidity, percentage of purity, percentage of new peaks, percentage of major components, percentage of high molecular weight species (HWMS), percentage of low molecular weight species (LMWS), percentage of sum of acidic peaks, percentage of sum of basic peaks, protein concentration, percentage of T cell activation, percentage of PS20 (w / v), or any combination thereof.

43. A kit comprising the aqueous pharmaceutical composition of any one of claims 1 to 31 and instructions for use.

44. An article of manufacture comprising a container holding the aqueous pharmaceutical composition of any one of claims 1 to 31.

45. 45. The article of manufacture of claim 44, wherein the container is a vial having a stopper pierceable by a syringe.

46. The aqueous pharmaceutical composition according to any one of claims 1 to 31, which is used for the treatment of cancer.

47. 32. The aqueous pharmaceutical composition according to any one of claims 1 to 31, for use in preparing a medicament for the treatment of cancer.

48. 32. Use of the aqueous pharmaceutical composition of any one of claims 1 to 31 for treating cancer in a subject in need thereof, comprising administering the aqueous pharmaceutical composition to the subject in need thereof.

49. 49. The use of claim 48, wherein the administration is subcutaneous.

Images