Compositions comprising bispecific GPRC5d / CD3 antibodies

Abstract

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

Description

[0001] Cross Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Application Serial No. 63 / 487,514, filed February 28, 2023, and U.S. Provisional Application Serial No. 63 / 588,488, filed October 6, 2023, the disclosure of which is incorporated herein by reference in its entirety.

[0003] Reference to a Sequence Listing on File Electronically

[0004] This application contains a sequence list electronically filed in XML format, the entire contents of which are incorporated herein by reference. The XML copy was created on October 6, 2023, named "258199.061201(JBI6770USNP1)SequenceListing.xml", and has a size of 36,888 bytes. Technical Field

[0005] Compositions and methods for formulating pharmaceutical compositions comprising bispecific GPRC5D / CD3 antibodies are disclosed. Background Technology

[0006] Multiple myeloma (MM) is a cancer of plasma cells. Mechanistically, MM is characterized by the production of a monoclonal protein (M protein) composed of pathological immunoglobulins or fragments of such pathological immunoglobulins that have lost their function. The proliferation of MM cells leads to subsequent migration from the normal bone marrow niche, while the overproduction of M protein causes characteristic osteolytic lesions, increased susceptibility to infection, hypercalcemia, renal insufficiency or failure, and neurological complications.

[0007] Treatment options for multiple myeloma have improved over time and vary depending on the aggressiveness of the disease, potential prognostic factors, the patient's physical condition, and existing comorbidities. Treatment options include proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies (mAbs), and stem cell transplantation.

[0008] Despite these therapeutic gains, the disease relapses and is associated with additional risk factors (e.g., comorbidities or increasing age), thus ensuring the need for novel treatments, such as new dosages and regimens. Especially in older populations, stem cell transplantation is often not a viable option, and in patients with refractory disease who have exhausted all available therapies, multiple myeloma remains an incurable malignancy and an unmet medical need, with significant morbidity and mortality.

[0009] T cell redirected killing is an ideal mode of action in many therapeutic areas. Generally, T cell redirecting molecules are engineered to have at least two antigen binding sites, one of which binds to a surface antigen on a target cell and the other of which binds to a T cell surface antigen. There remains a need in the art for pharmaceutical compositions comprising such antibodies for treating multiple myeloma patients, including compositions that are stable over a range of temperatures for an extended period of time. SUMMARY

[0010] Disclosed herein are aqueous pharmaceutical compositions comprising a particular formulation of a G protein-coupled receptor family C group 5 member D (GPRC5D) / cluster of differentiation 3 (CD3) antibody. In certain embodiments, the antibody is talquetamab (Tal), an investigational bispecific antibody that binds to G protein-coupled receptor family C group 5 member D (GPRC5D) and CD3.

[0011] In some embodiments, provided herein are aqueous pharmaceutical compositions comprising:

[0012] (a) a bispecific G protein-coupled receptor family 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, the bispecific GPRC5D / CD3 antibody or antigen-binding fragment thereof comprising:

[0013] (1) a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1),

[0014] wherein VH1 comprises a heavy chain complementarity determining region 1 (HCDR1), an HCDR2, and an HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively;

[0015] (2) a first light chain (LC1) comprising a LC1 variable region (VL1),

[0016] wherein VL1 comprises a light chain complementarity determining region 1 (LCDR1), an LCDR2, and an LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively;

[0017] (3) a second heavy chain (HC2) comprising a HC2 variable region 2 (VH2),

[0018] wherein VH2 comprises a heavy chain complementarity determining region 1 (HCDR1), an HCDR2, and an HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; and

[0019] (4) a second light chain (LC2) comprising a LC2 variable region 2 (VL2),

[0020] VL2 comprises light chain complementarity-determining regions 1 (LCDR1), LCDR2, and LCDR3 having amino acid sequences of SEQ ID NO:14, 15, and 16, respectively; (b) about 10 mM to about 20 mM of acetate and / or pharmaceutically acceptable acetate;

[0021] (c) Sucrose of about 6% (w / v) to about 10% (w / v);

[0022] (d) Ethylenediaminetetraacetic acid (EDTA) of approximately 7 μg / mL to approximately 33 μg / mL;

[0023] (e) about 0.01% to about 0.07% of polysorbate 20; and

[0024] (f) pH from about 4.6 to about 5.8.

[0025] In some embodiments, this document provides an aqueous pharmaceutical composition comprising:

[0026] (a) Bispecific G protein-coupled receptor C family at concentrations of approximately 25 mg / mL to approximately 55 mg / mL

[0027] Group 5 member D (GPRC5D) / differentiation cluster 3 (CD3) antibody or its antigen-binding fragment, the bispecific GPRC5D / CD3 antibody or its antigen-binding fragment comprising:

[0028] (1) The first heavy chain (HC1) containing the HC1 variable region 1 (VH1),

[0029] VH1 contains heavy chain complementarity-determining regions 1 (HCDR1), HCDR2, and HCDR3, which have amino acid sequences of SEQ ID NO:1, 2, and 3, respectively.

[0030] (2) The first light chain (LC1) containing the LC1 variable region (VL1),

[0031] VL1 contains light chain complementarity-determining regions 1 (LCDR1), LCDR2, and LCDR3, which have amino acid sequences of SEQ ID NO:4, 5, and 6, respectively.

[0032] (3) The second heavy chain (HC2) containing the HC2 variable region 2 (VH2),

[0033] VH2 contains heavy chain complementarity-determining regions 1 (HCDR1), HCDR2, and HCDR3, respectively, having amino acid sequences of SEQ ID NO: 11, 12, and 13; and

[0034] (4) A second light chain (LC2) containing the LC2 variable region 2 (VL2),

[0035] wherein VL2 comprises light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively;

[0036] (b) about 10 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt;

[0037] (c) about 6% (w / v) to about 10% (w / v) sucrose;

[0038] (d) about 7 pg / mL to about 33 pg / mL ethylenediaminetetraacetic acid (EDTA);

[0039] (e) about 0.01% to about 0.07% polysorbate 20; and

[0040] (f) a pH of about 4.6 to about 5.8.

[0041] In some embodiments, the aqueous pharmaceutical composition comprises 2 mg / mL of the bispecific GPRC5D / CD3 antibody, 15 mM acetate and / or a pharmaceutically acceptable acetate salt, 8% (w / v) sucrose, 20 pg / mL EDTA, 0.04% PS20, and has a pH of 5.2.

[0042] In some embodiments, the aqueous pharmaceutical composition comprises 40 mg / mL of the bispecific GPRC5D / CD3 antibody, 15 mM acetate and / or a pharmaceutically acceptable acetate salt, 8% (w / v) sucrose, 20 pg / mL EDTA, 0.04% PS20, and has a pH of 5.2.

[0043] In some embodiments, methods of treating cancer in a subject in need thereof are provided. In some embodiments, the methods comprise administering to the subject an aqueous pharmaceutical composition as provided herein.

[0044] In some embodiments, methods for preparing an aqueous composition of a bispecific G Protein-Coupled Receptor Family with 5th Member C (GPRC5D) / Cluster of Differentiation 3 (CD3) antibody or antigen binding fragment thereof are provided. In some embodiments, the bispecific GPRC5D / CD3 antibody or antigen binding fragment thereof comprises:

[0045] (1) a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1),

[0046] wherein VH1 comprises heavy chain complementarity determining regions 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively;

[0047] (2) a first light chain (LC1) comprising a LC1 variable region (VL1),

[0048] wherein VL1 comprises light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively;

[0049] (3) a second heavy chain (HC2) comprising a HC2 variable region 2 (VH2),

[0050] wherein VH2 comprises heavy chain complementarity determining regions 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; and

[0051] (4) a second light chain (LC2) comprising a LC2 variable region 2 (VL2), wherein VL2 comprises light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively;

[0052] In some embodiments, the method comprises mixing a composition comprising about 2 mg / mL of a bispecific G Protein-Coupled Receptor Family with 5 Members, 5th Group (GPRC5D) / Cluster of Differentiation 3 (CD3) antibody, about 15 mM acetate and / or a pharmaceutically acceptable acetate salt, about 8% (w / v) sucrose, about 18 pg / mL EDTA, and about 0.04% polysorbate (PS) 20, wherein the stable aqueous pharmaceutical composition has a pH of about 5.2.

[0053] In some embodiments, a method for preparing an aqueous composition of a bispecific G Protein-Coupled Receptor Family with 5 Members, 5th Group (GPRC5D) / Cluster of Differentiation 3 (CD3) antibody or antigen binding fragment thereof is provided. In some embodiments, the bispecific GPRC5D / CD3 antibody or antigen binding fragment thereof comprises:

[0054] (5) a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1),

[0055] wherein VH1 comprises heavy chain complementarity determining regions 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively;

[0056] (6) a first light chain (LC1) comprising a LC1 variable region (VL1),

[0057] wherein VL1 comprises light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively;

[0058] (7) a second heavy chain (HC2) comprising an HC2 variable region 2 (VH2),

[0059] wherein VH2 comprises heavy chain complementarity determining regions 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; and

[0060] (8) a second light chain (LC2) comprising an LC2 variable region 2 (VL2), wherein VL2 comprises light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively;

[0061] In some embodiments, the method comprises admixing 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 pg / mL EDTA, and about 0.04% polysorbate (PS) 20, wherein the stable aqueous pharmaceutical composition has a pH of about 5.2.

[0062] In some embodiments, the aqueous pharmaceutical composition is stable. In some embodiments, stability is defined as provided herein.

[0063] In some embodiments, the GPRC5D / CD3 antibody is talquetamab.

[0064] In some embodiments, a kit is provided comprising a pharmaceutical aqueous composition as provided herein and instructions for use thereof.

[0065] In some embodiments, an article of manufacture is provided. In some embodiments, the article of manufacture comprises a container holding an aqueous pharmaceutical composition as provided herein.

[0066] In some embodiments, use of an aqueous pharmaceutical composition as provided herein for treating cancer in a subject is provided. In some embodiments, the use comprises administering the aqueous pharmaceutical composition to a subject in need thereof. BRIEF DESCRIPTION OF DRAWINGS

[0067] The foregoing summary, as well as the following detailed description of preferred embodiments of the present patent application, will be better understood when read in conjunction with the accompanying drawings, in which:

[0068] Figure 1 The primary effect of test formulation parameters on % monomer measured by SEC is shown.

[0069] Figure 2Main effects of test formulation parameters on % aggregate measured by SEC are shown.

[0070] Figure 3 Main effects of test formulation parameters on % fragment measured by SEC are shown.

[0071] Figure 4 Main effects of acetate test formulation parameters on % monomer measured by SEC are shown.

[0072] Figure 5 Main effects of acetate test formulation parameters on % aggregate measured by SEC are shown.

[0073] Figure 6 Main effects of acetate test formulation parameters on % fragment measured by SEC are shown. DETAILED DESCRIPTION

[0074] The disclosed compositions and methods can be more readily understood with reference to the following detailed description taken in conjunction with the accompanying drawings, in which:

[0075] Unless specifically stated otherwise, any description herein of possible mechanisms or modes of action or reasons for improvement are intended for illustrative purposes only and the disclosed compositions and methods are not bound by the correctness or incorrectness of any such suggested mechanisms or modes of action or reasons for improvement.

[0076] When a range of values is recited or established herein, the range includes its end values and all individual integers and fractions within that range, and also includes each of the narrower ranges formed by the combination of the end values and the individual integers and fractions within the range, to the same extent as if each of the narrower ranges was individually recited herein, to the same extent as if each of the narrower ranges was individually recited herein. When a range of values is recited as being greater than a specified value, the range is however finite and its upper limit is defined by a value that is operable in the context of the application as described herein. When a range of values is recited as being less than a specified value, the lower limit of the range is however defined by a non-zero value. It is not intended to limit the scope of the application to the specific values recited when defining a range. All ranges include the end values and are combinable.

[0077] Where a value is expressed as an approximation using “about” before the value, it is understood that the specific value constitutes another embodiment. Reference to a specific numerical value includes at least that specific value, unless the context clearly dictates otherwise.

[0078] It is to be understood that certain features of the disclosed compositions and methods are set forth in

[0079] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0080] Various terms related to aspects of the description are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unless otherwise specifically stated. Other specifically defined terms are to be construed in a manner consistent with the definition provided herein.

[0081] As used herein, when used in reference to a numerical range, cutoff, or specific value, "about" is used to indicate that an amount that can differ by as much as 10% of the stated amount. Since many of the numerical values used herein are determined experimentally, it will be understood by those skilled in the art that such determinations can vary from experiment to experiment and generally vary from experiment to experiment. Due to this inherent variability, values used herein are not to be taken as being overly limiting. Thus, the term "about" is used to encompass variations of ±10% or less, ±5% or less, ±1% or less, ±0.5% or less, or ±0.1% or less from a specified value.

[0082] The term "comprising" is intended to include examples of the terms "consisting essentially of" and "consisting of"; similarly, the term "consisting essentially of is intended to include examples of the term "consisting of". Unless the context clearly dictates otherwise, the words "comprising," "comprises," and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to."

[0083] The term "antibody" and like terms are broad and 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.

[0084] Depending on the amino acid sequence of the constant domain of the heavy chains, immunoglobulins can be assigned to five major classes, namely IgA, IgD, IgE, IgG, and IgM. Depending on their isotype, IgA and IgG can be further divided into subclasses, i.e., IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. Based on the amino acid sequences of their constant domains, the light chains of any vertebrate species can be assigned to one of two clearly distinct types, namely kappa and lambda.

[0085] An "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 (HCDR) 1, 2, and 3; light chain complementarity determining regions (LCDR) 1, 2, and 3; a heavy chain variable region (VH); or a light chain variable region (VL). Antibody fragments include: a Fab fragment, which is a monovalent fragment consisting of the VL, VH, constant light (CL), and constant heavy 1 (CH1) domains; a F(ab)2 fragment, which is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the VH and CH1 domains; a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; and a domain antibody (dAb) fragment, which consists of a VH domain. The VH and VL domains can be engineered and linked together via synthetic linkers to form various types of single-chain antibody designs, where the VH / VL domains can pair intramolecularly or intermolecularly to form a monovalent antigen-binding site in cases where the VH and VL domains are expressed from separate single-chain antibody constructs, such as single-chain Fv (scFv) or diabodies; described, for example, in International Patent Publications WO 1998 / 44001, WO 1988 / 01649, WO 1994 / 13804, and WO 1992 / 01047. These antibody fragments are obtained using techniques well known in the art and screened for the same functional properties as full-length antibodies.

[0086] Antibody variable regions are composed of "framework" regions interrupted by three "antigen binding sites." Different terminology is used to define the antigen binding sites: (i) the complementarity determining regions (CDRs), three in VH (HCDR1, HCDR2, HCDR3) and three in VL (LCDR1, LCDR2, LCDR3), are based on sequence variability (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" ("HVR" or "HV"), three in VH (H1, H2, H3) and three in VL (L1, L2, L3), refer to the regions of antibody variable domains that are structurally hypervariable, as defined by Chothia and Lesk (Chothia and Lesk, Mol Biol 196:901-17, 1987). Other terms include "IMGT-CDRs" (Lefranc et al., Dev Comparat Immunol 27:55-77, 2003) and "specificity-determining residues usage" (SDRU) (Almagro, Mol Recognit 17:132-43, 2004). The International Immunogenetics (IMGT) database (www_imgt_org) provides standardized numbering and definition of antigen binding sites. The correspondence between CDR, HV, and IMGT descriptions is described in Lefranc et al., Dev Comparat Immunol 27:55-77, 2003.

[0087] A "monoclonal antibody" refers to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope, or, in the case of a bispecific monoclonal antibody, a dual binding specificity for two different epitopes. Thus, a monoclonal antibody refers to a population of antibody molecules that have a single amino acid composition in each of the heavy and light chains, except for possible well- known alterations such as the removal of a C-terminal lysine from the antibody heavy chain. Monoclonal antibodies can have heterogeneous glycosylation within the antibody population. Monoclonal antibodies can be monospecific or multispecific, or monovalent, divalent, or multivalent. The term "monoclonal antibody" includes bispecific antibodies.

[0088] “Bispecific” refers to an antibody that specifically binds to two different antigens or two different epitopes within the same antigen. Bispecific antibodies can have cross-reactivity to other related antigens, for example, to the same antigen from other species (homologous), such as human or monkey, e.g., cynomolgus (cyno) or Pan troglodytes, or can bind to an epitope shared between two or more different antigens.

[0089] “Human antibody” refers to an antibody that is optimized to have 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 comprises a constant region or a portion of a constant region, the constant region is also derived from human immunoglobulin sequences. If the variable regions of a human antibody are obtained from a system that uses human germline immunoglobulin or rearranged immunoglobulin genes, the human antibody comprises heavy and light chain variable regions that are “derived” from human germline sequences. Such exemplary systems are human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals, such as mice or rats that carry human immunoglobulin loci. Because of differences between the systems used to obtain human antibodies and human immunoglobulin loci, the introduction of somatic mutations or intentional introduction of substitutions into the framework or CDRs, or both, “human antibodies” typically comprise amino acid differences compared to immunoglobulins expressed in humans. Typically, the amino acid sequence of a “human antibody” has at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence encoded by a human germline immunoglobulin gene or rearranged immunoglobulin gene. In some cases, a “human antibody” can comprise a consensus framework sequence derived from human framework sequence analysis (e.g., as described in Knappik et al. (2000) J Mol Biol 296:57-86) or synthetic HCDR3s incorporated into human immunoglobulin gene libraries displayed on phage (e.g., as described in Shi et al. (2010) J Mol Biol 397:385-96 and International Patent Publication 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.”

[0090] “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 comprise substitutions in the framework such that the frameworks can not be exact copies of expressed human immunoglobulin or human immunoglobulin germline gene sequences.

[0091] “Isolated” refers to a homogeneous group of molecules (such as a synthetic polynucleotide or protein, such as an antibody) that have been substantially separated from other components of the system in which the molecule was produced (e.g., recombinant cells), and / or purified from, as well as proteins that have been subjected to at least one purification or isolation step. An “isolated antibody” is an antibody that is substantially free of other cellular material and / or chemicals, and encompasses an antibody that has been separated to a higher purity, such as 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% purity.

[0092] “GPRC5DxCD3 bispecific antibody” refers to a molecule containing two or more binding regions, wherein one of these binding regions specifically binds the cell surface antigen G Protein-Coupled Receptor Family 5 Member D antigen (GPRC5D) on a target cell or tissue, and wherein a second binding region of the molecule specifically binds the T cell antigen CD3. This dual / multi-target binding capability recruits T cells to the target cell or tissue, thereby eradicating the target cell or tissue. GPRC5D / CD3 bispecific antibodies are described in U.S. Patent 10,562,968, which is incorporated by reference in its entirety.

[0093] “GPRC5D” refers to the human G Protein-Coupled Receptor Family 5 Member D having the amino acid sequence set forth in SEQ ID NO: 21.

[0094] MYKDCIESTGDYFLLCDAEGPWGIILESLAILGIVVTILLLLAFLFLMRKIQDCSQWNVLPTQLLFLLSVLGLFGLAFAFIIELNQQTAPVRYFLFGVLFALCFSCLLAHASNLVKLVRGCVSFSWTTILCIAIGCSLLQIIIATEYVTLIMTRGMMFVNMTPCQLNVDFVVLLVYVLFLMALTFFVSKATFCGPCENWKQHGRLIFITVLFSIIIWVVWISMLLRGNPQFQRQPQWDDPVVCIALVTNAWVFLLLYIVPELCILYRSCRQECPLQGNACPVTAYQHSFQVENQELSRARDSDGAEEDVALTSYGTPIQPQTVDPTQECFIPQAKLSPQQDAGGV (SEQ ID NO: 21)

[0095] “CD3” refers to a human antigen expressed on T cells as part of a multi-molecular T cell receptor (TCR) complex and consisting of a homodimer or heterodimer of two or four receptor chains: CD3 epsilon, CD3 delta, CD3 zeta, and CD3 gamma, formed by the association of. Human CD3 epsilon comprises the amino acid sequence of SEQ ID NO: 22. SEQ ID NO: 23 shows the extracellular domain of CD3 epsilon.

[0096] MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI (SEQ ID NO: 22)

[0097] MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI (SEQ ID NO: 22)

[0098] “Epitope” refers to the part of an antigen to which an antibody specifically binds. Epitopes usually consist of chemically active (such as, e.g., polar, nonpolar, or charged) surface groups of molecules such as amino acids or polysaccharide side chains and can have specific three-dimensional structural characteristics, as well as specific charge characteristics. Epitopes can be formed both by contiguous and / or noncontiguous amino acids. For discontinuous epitopes, amino acids from different parts of the linear sequence come close to one another in 3-dimensional space as a result of protein folding.

[0099] “Variant” refers to a polypeptide or polynucleotide that differs from a reference polypeptide or reference polynucleotide by one or more modifications (e.g., substitutions, insertions, or deletions).

[0100] “Used in conjunction with” means 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.

[0101] “Treatment” and like terms refer to therapeutic treatment and prophylactic or preventative measures, and include reducing the severity and / or frequency of symptoms, eliminating symptoms and / or their underlying cause, reducing the frequency or likelihood of symptoms and / or their underlying cause, ameliorating or remedying damage caused by a malignancy either directly or indirectly. Treatment also includes prolonging survival as compared to expected survival of a subject who does not receive treatment. Subjects to be treated include those who have a condition or disorder as well as those who are predisposed to a condition or disorder or are to be prevented from having a condition or disorder.

[0102] “Therapeutically effective amount” refers to the amount of a disclosed composition that is required, in the dosages and period of time needed, to achieve the desired therapeutic result. The therapeutically effective amount can vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the combination therapy to elicit a desired remission in the subject. Exemplary indicators of a therapeutically effective amount include, for example: improvement in the patient’s health, reduction in tumor burden, tumor growth is arrested or slowed, and / or cancer cells do not metastasize to other parts of the body.

[0103] “Pharmaceutical composition” refers to a composition comprising an active ingredient and a pharmaceutically acceptable carrier. As used herein, “drug product” or “DP” is synonymous with “pharmaceutical composition” or “aqueous pharmaceutical composition” unless explicitly stated otherwise. Thus, embodiments directed to or describing features of “pharmaceutical composition” or “aqueous pharmaceutical composition” are understood to encompass and apply to “drug product” or “DP”. Likewise, embodiments or features of “drug product” or “DP” are understood to encompass and apply to “pharmaceutical composition” or “aqueous pharmaceutical composition”.

[0104] The pharmaceutical composition, aqueous pharmaceutical composition, drug product, or DP of the present disclosure can be“stable.” As used herein, a pharmaceutical composition, aqueous pharmaceutical composition, drug product, or DP (all synonymous) is considered stable if it meets the criteria provided herein. For example, a pharmaceutical composition, aqueous pharmaceutical composition, drug product, or DP is considered stable if it meets certain predetermined thresholds for solution color, pH, turbidity, number of sub-visible particles, percent purity by cSDS, percent new peaks by cSDS, percent major components by SE-HPLC, percent low molecular weight species by SE-HPLC, percent high molecular weight species by SE-HPLC, percent main peak by IEX, percent sum of acidic peaks by IEX, percent sum of basic peaks by IEX, protein concentration, percent T cell activation, percent PS20 (w / v), or any combination thereof. The stability of the pharmaceutical composition, aqueous pharmaceutical composition, drug product, or DP can depend on any one or any combination of the above criteria. Thus, a pharmaceutical composition, aqueous pharmaceutical composition, drug product, or DP that meets certain criteria can be considered stable even if other criteria are not met. Further, it is understood that the techniques of cSDS, SE-HPLC, and IEX are merely exemplary. The percent purity, percent new peaks, percent major components, percent low molecular weight species, percent high molecular weight species, percent main peak, percent sum of acidic peaks, and percent sum of basic peaks can be determined by any method known in the art. Such methods are all within the scope of the present disclosure.

[0105] “Pharmaceutically acceptable carrier” or“excipient” refers to a component of a pharmaceutical composition other than the active ingredient that is not toxic to a subject.

[0106] As used herein, the term “cancer” is defined as a disease characterized by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. In certain embodiments, the cancer is a hematological malignancy or a solid tumor. In some embodiments, the hematological malignancy is 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 macroglobulinemia, plasma cell leukemia, amyloid light chain (AL), precursor B-cell lymphoblastic leukemia, precursor B-cell lymphoblastic leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), B-cell malignancy, 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 lymphoid tissue lymphoma (MALT), plasma cell leukemia, anaplastic large cell lymphoma (ALCL), leukemia or lymphoma.

[0107] “Tumor cell” or “cancer cell” refers to a cancerous, precancerous, or transformed cell in vivo, ex vivo, or in tissue culture, which has spontaneous or induced phenotypic changes. These changes do not necessarily involve the uptake of new genetic material. Although transformation can be initiated by infection with a transforming virus and incorporation of new genomic nucleic acids, exogenous nucleic acids or their uptake can also spontaneously initiate or initiate following exposure to a carcinogen, thereby mutating endogenous genes. Transformations / cancer examples are morphological changes, cell immortalization, abnormal growth control, lesion formation, proliferation, malignancy, modulation of tumor-specific marker levels, invasion, tumor growth in vitro, in vivo, and ex vivo in suitable animal hosts, such as nude mice, and the like.

[0108] “T cell redirecting therapeutic” refers to a molecule comprising two or more binding regions, wherein one of the binding regions specifically binds a cell surface antigen on a target cell or tissue, and wherein a second binding region of the molecule specifically binds 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 target / multi-target binding capability recruits T cells to the target cell or tissue, thereby eradicating the target cell or tissue.

[0109] A “subject” includes any human or non-human animal. “Non-human animals” include 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” can be used interchangeably herein.

[0110] Description

[0111] Unless specifically indicated otherwise, throughout the specification, numbering of amino acid residues in antibody constant regions is in accordance with the EU index as set out by Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991). Antibody constant chain numbering can be found, e.g., on the ImMunoGeneTics website, IMGT Web resource, IMGT Scientific Charts.

[0112] The conventional one-letter and three-letter amino acid codes as shown in Table 1 are used herein.

[0113] Table 1.

[0114] Amino Acids Three-Letter Code One-Letter Code Alanine Ala A Arginine Arg R Asparagine Asn N Aspartic Acid Asp D Cysteine Cys C Glutamic Acid Gln E Glutamine Glu Q Glycine Gly G Histidine His H Isoleucine Ile I Leucine Leu L Lysine Lys K Methionine Met M Phenylalanine Phe F Proline Pro P Serine Ser S Threonine Thr T Tryptophan Trp W Tyrosine Tyr Y Valine Val V

[0115] GPRC5D / CD3 bispecific antibodies and uses thereof

[0116] Disclosed herein are aqueous pharmaceutical compositions comprising bispecific GPRC5D / CD3 antibodies, and methods of using the same to treat multiple myeloma, including human subjects who have relapsed or are refractory to treatment with one or more prior therapies.

[0117] In some embodiments, provided herein are aqueous pharmaceutical compositions comprising:

[0118] (a) a bispecific G Protein-Coupled Receptor Family 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, the bispecific GPRC5D / CD3 antibody, or antigen-binding fragment thereof, comprising:

[0119] (1) a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1),

[0120] 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;

[0121] (2) a first light chain (LC1) comprising a LC1 variable region (VL1),

[0122] wherein VL1 comprises light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively;

[0123] (3) a second heavy chain (HC2) comprising a HC2 variable region 2 (VH2),

[0124] wherein VH2 comprises heavy chain complementarity determining regions 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; and

[0125] (4) a second light chain (LC2) comprising a LC2 variable region 2 (VL2),

[0126] wherein VL2 comprises light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively; (b) about 10 mM to about 20 mM acetate and / or a pharmaceutically acceptable salt of acetate;

[0127] (c) about 6% (w / v) to about 10% (w / v) sucrose;

[0128] (d) about 7 pg / mL to about 33 pg / mL ethylenediaminetetraacetic acid (EDTA);

[0129] (e) about 0.01% to about 0.07% polysorbate 20; and

[0130] (f) a pH of about 4.7 to about 5.7.

[0131] In some embodiments, provided herein are aqueous pharmaceutical compositions comprising:

[0132] (a) a bispecific G protein-coupled receptor family 5 member C (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, the bispecific GPRC5D / CD3 antibody, or antigen binding fragment thereof, comprising:

[0133] (5) a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1),

[0134] wherein VH1 comprises heavy chain complementarity determining regions 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively;

[0135] (6) a first light chain (LC1) comprising an LC1 variable region (VL1),

[0136] wherein VL1 comprises light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively;

[0137] (7) a second heavy chain (HC2) comprising an HC2 variable region 2 (VH2),

[0138] wherein VH2 comprises heavy chain complementarity determining regions 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; and

[0139] (8) a second light chain (LC2) comprising an LC2 variable region 2 (VL2),

[0140] wherein VL2 comprises light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively;

[0141] (f) about 10 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt;

[0142] (g) about 6% (w / v) to about 10% (w / v) sucrose;

[0143] (h) about 7 pg / mL to about 33 pg / mL ethylenediaminetetraacetic acid (EDTA);

[0144] (i) about 0.01% to about 0.07% polysorbate 20; and

[0145] (j) a pH of about 4.7 to about 5.7.

[0146] In some embodiments, provided herein are aqueous pharmaceutical compositions comprising:

[0147] (a) a bispecific G protein-coupled receptor family 5 member C (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, the bispecific GPRC5D / CD3 antibody, or antigen binding fragment thereof, comprising:

[0148] (1) a first heavy chain (HC1) comprising an HC1 variable region 1 (VH1),

[0149] wherein VH1 comprises heavy chain complementarity determining regions 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively;

[0150] (2) a first light chain (LC1) comprising a VL1 variable region (VL1),

[0151] wherein VL1 comprises light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively;

[0152] (3) a second heavy chain (HC2) comprising a VH2 variable region (VH2),

[0153] wherein VH2 comprises heavy chain complementarity determining regions 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; and

[0154] (4) a second light chain (LC2) comprising a VL2 variable region (VL2),

[0155] wherein VL2 comprises light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively;

[0156] (b) about 10 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt;

[0157] (c) about 6% (w / v) to about 10% (w / v) sucrose;

[0158] (d) about 7 pg / mL to about 33 pg / mL ethylenediaminetetraacetic acid (EDTA);

[0159] (e) about 0.01% to about 0.07% polysorbate 20; and

[0160] (f) a pH of about 4.7 to about 5.7.

[0161] In some embodiments, the GPRC5D / CD3 bispecific antibody comprises: a GPRC5D binding domain comprising a VH having HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, and a VL having LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6; and a CD3 binding domain comprising a VH having HCDR1 of SEQ ID NO: 11, HCDR2 of SEQ ID NO: 12, HCDR3 of SEQ ID NO: 13, and a VL having LCDR1 of SEQ ID NO: 14, LCDR2 of SEQ ID NO: 15, and LCDR3 of SEQ ID NO: 16. The HCDRs and LCDRs of the GPRC5D / CD3 bispecific antibodies are set forth in Table 2 below:

[0162] Table 2: Exemplary CDRs of GPRC5D / CD3 bispecific antibodies

[0163]

[0164] The CDRs described in the above table are in the Kabat numbering system. However, as provided herein, the CDRs of the present disclosure can be provided by any suitable numbering system, such as any of the Kabat, Chothia, IMGT, or AbM numbering systems. Tables 3-5 below provide exemplary CDRs utilizing the Chothia, AbM, and IMGT numbering systems:

[0165] Table 3: Exemplary CDRs of GPRC5D / CD3 bispecific antibodies - Chothia numbering system:

[0166]

[0167] Table 4: Exemplary CDRs of GPRC5D / CD3 bispecific antibodies - AbM numbering system:

[0168]

[0169] Table 5: Exemplary CDRs of GPRC5D / CD3 bispecific antibodies - IMGT numbering system:

[0170]

[0171] In some embodiments, the GPRC5D / CD3 bispecific antibody comprises: a GPRC5D binding domain comprising a VH having HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, and a VL having LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6; and a CD3 binding domain comprising a VH having HCDR1 of SEQ ID NO: 11, HCDR2 of SEQ ID NO: 12, HCDR3 of SEQ ID NO: 13, and a VL having LCDR1 of SEQ ID NO: 14, LCDR2 of SEQ ID NO: 15, and LCDR3 of SEQ ID NO: 16.

[0172] In some embodiments, the GPRC5D / CD3 bispecific antibody comprises: a GPRC5D binding domain comprising a VH having HCDR1 of SEQ ID NO: 24, HCDR2 of SEQ ID NO: 25, HCDR3 of SEQ ID NO: 3, and a VL having LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6; and a CD3 binding domain comprising a VH having HCDR1 of SEQ ID NO: 26, HCDR2 of SEQ ID NO: 27, HCDR3 of SEQ ID NO: 13, and a VL having LCDR1 of SEQ ID NO: 14, LCDR2 of SEQ ID NO: 15, and LCDR3 of SEQ ID NO: 16.

[0173] In some embodiments, the GPRC5D / CD3 bispecific antibody comprises: a GPRC5D binding domain comprising a VH having HCDR1 of SEQ ID NO: 28, HCDR2 of SEQ ID NO: 29, HCDR3 of SEQ ID NO: 3, and a VL having LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6; and a CD3 binding domain comprising a VH having HCDR1 of SEQ ID NO: 30, HCDR2 of SEQ ID NO: 31, HCDR3 of SEQ ID NO: 13, and a VL having LCDR1 of SEQ ID NO: 14, LCDR2 of SEQ ID NO: 15, and LCDR3 of SEQ ID NO: 16.

[0174] In some embodiments, the GPRC5D / CD3 bispecific antibody comprises: a GPRC5D binding domain comprising a VH having HCDR1 of SEQ ID NO: 32, HCDR2 of SEQ ID NO: 33, HCDR3 of SEQ ID NO: 34, and a VL having LCDR1 of SEQ ID NO: 35, LCDR2 of the amino acid sequence SAS, and LCDR3 of SEQ ID NO: 6; and a CD3 binding domain comprising a VH having HCDR1 of SEQ ID NO: 36, HCDR2 of SEQ ID NO: 37, HCDR3 of SEQ ID NO: 38, and a VL having LCDR1 of SEQ ID NO: 39, LCDR2 of the amino acid sequence GTN, and LCDR3 of SEQ ID NO: 16.

[0175] In certain 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 certain embodiments, the bispecific GPRC5D / CD3 antibody comprises a HC1 having the amino acid sequence of SEQ ID NO: 9 and a LC1 having the amino acid sequence of SEQ ID NO: 10. In certain 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 a HC2 having the amino acid sequence of SEQ ID NO: 19 and a LC2 having the amino acid sequence of SEQ ID NO: 20.

[0176] 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 as provided in Table 6a and Table 6b.

[0177] Table 6a: Sequences of GPRC5D binding arms of GPRC5D / CD3 bispecific antibodies.

[0178]

[0179] Table 6b Table 6a: Sequences of GPRC5D binding arms of GPRC5DxCD3 bispecific antibodies.

[0180]

[0181]

[0182] In some embodiments, the bispecific GPRC5D / CD3 antibody can 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, wherein HC1 and LC1 form a first antigen binding site that immunospecifically binds GPRC5D, and wherein HC2 and LC2 form a second antigen binding site that immunospecifically binds CD3. In some embodiments, talquetamab comprises HC1 of SEQ ID NO: 9, LC1 of SEQ ID NO: 10, HC2 of SEQ ID NO: 19, and 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.

[0183] 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 therein. In some embodiments, the bispecific GPRC5D / CD3 antibody can have, for example, a concentration of 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 therein. In some embodiments, the bispecific GPRC5D / CD3 antibody can have, for example, a concentration of about 2 mg / mL, about 30 mg / mL, about 40 mg / mL, about 60 mg / mL, or about 90 mg / mL.

[0184] 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 therein.

[0185] 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.

[0186] 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.

[0187] In some embodiments, the bispecific GPRC5D / CD3 antibody can have, for example, a concentration of 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] In some embodiments, the bispecific GPRC5D / CD3 antibody can have, for example, a concentration of 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.

[0192] 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.

[0193] In some embodiments, the taquiglimatant is present at a concentration of about 0.5 mg / mL to about 3.5 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 1.0 mg / mL to about 3.5 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 1.5 mg / mL to about 3.5 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 2.0 mg / mL to about 3.5 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 2.5 mg / mL to about 3.5 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 3.0 mg / mL to about 3.5 mg / mL.

[0194] In some embodiments, the taquiglimatant is present at a concentration of about 0.5 mg / mL to about 3.5 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 0.5 mg / mL to about 3.0 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 0.5 mg / mL to about 2.5 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 0.5 mg / mL to about 2.0 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 0.5 mg / mL to about 1.5 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 0.5 mg / mL to about 1.0 mg / mL.

[0195] In some embodiments, the taquiglimatant 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, the taquiglimatant is present at a concentration of about 0.5 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 1.0 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 1.5 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 2 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 2.5 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 3 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 3.5 mg / mL.

[0196] In some embodiments, the taquiglimatant 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.

[0197] 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.

[0198] 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.

[0199] In some embodiments, the taquiglimatant is present at a concentration of, e.g., 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 or range therebetween. In some embodiments, the taquiglimatant is present at a concentration of about 25 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 30 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 35 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 36 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 37 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 38 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 39 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 40 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 41 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 42 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 43 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 44 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 45 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 50 mg / mL. In some embodiments, the taquiglimatant is present at a concentration of about 55 mg / mL.

[0200] 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, or any value or range therebetween, of acetate and / or a pharmaceutically acceptable acetate.

[0201] In some embodiments, the composition comprises about 10 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 11 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 12 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 13 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 14 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 15 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 16 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 17 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 18 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 19 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate.

[0202] In some embodiments, the composition comprises about 10 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 10 mM to about 19 mM acetate and / or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 10 mM to about 18 mM acetate and / or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 10 mM to about 17 mM acetate and / or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 10 mM to about 16 mM acetate and / or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 10 mM to about 15 mM acetate and / or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 10 mM to about 14 mM acetate and / or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 10 mM to about 13 mM acetate and / or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 10 mM to about 12 mM acetate and / or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 10 mM to about 11 mM acetate and / or a pharmaceutically acceptable acetate.

[0203] In some embodiments, the composition can comprise, 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, or any value or range therebetween, acetate and / or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 10 mM acetate or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 11 mM acetate or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 12 mM acetate or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 13 mM acetate or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 14 mM acetate or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 15 mM acetate or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 16 mM acetate or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 17 mM acetate or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 18 mM acetate or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 19 mM acetate or a pharmaceutically acceptable acetate. In some embodiments, the composition comprises about 20 mM acetate or a pharmaceutically acceptable acetate.

[0204] 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), or any value or range therebetween, sucrose.

[0205] 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.

[0206] 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.

[0207] In some embodiments, the composition can comprise, for example, about 6% (w / v), about 7% (w / v), about 8% (w / v), about 9% (w / v), or about 10% (w / v), or any value therebetween, of sucrose. 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.

[0208] In some embodiments, the composition comprises about 7 pg / mL to about 33 pg / mL, 12 pg / mL to about 28 pg / mL, or about 15 pg / mL to about 21 pg / mL, or any value or range therebetween, of EDTA.

[0209] In some embodiments, the composition comprises about 7 pg / mL to about 33 pg / mL of EDTA. In some embodiments, the composition comprises about 12 pg / mL to about 33 pg / mL of EDTA. In some embodiments, the composition comprises about 15 pg / mL to about 33 pg / mL of EDTA. In some embodiments, the composition comprises about 16 pg / mL to about 33 pg / mL of EDTA. In some embodiments, the composition comprises about 17 pg / mL to about 33 pg / mL of EDTA. In some embodiments, the composition comprises about 18 pg / mL to about 33 pg / mL of EDTA. In some embodiments, the composition comprises about 19 pg / mL to about 33 pg / mL of EDTA. In some embodiments, the composition comprises about 20 pg / mL to about 33 pg / mL of EDTA. In some embodiments, the composition comprises about 21 pg / mL to about 33 pg / mL of EDTA. In some embodiments, the composition comprises about 24 pg / mL to about 33 pg / mL of EDTA. In some embodiments, the composition comprises about 28 pg / mL to about 33 pg / mL of EDTA.

[0210] In some embodiments, the composition comprises about 7 pg / mL to about 33 pg / mL EDTA. In some embodiments, the composition comprises about 7 pg / mL to about 28 pg / mL EDTA. In some embodiments, the composition comprises about 7 pg / mL to about 24 pg / mL EDTA. In some embodiments, the composition comprises about 7 pg / mL to about 21 pg / mL EDTA. In some embodiments, the composition comprises about 7 pg / mL to about 20 pg / mL EDTA. In some embodiments, the composition comprises about 7 pg / mL to about 19 pg / mL EDTA. In some embodiments, the composition comprises about 7 pg / mL to about 18 pg / mL EDTA. In some embodiments, the composition comprises about 7 pg / mL to about 17 pg / mL EDTA. In some embodiments, the composition comprises about 7 pg / mL to about 16 pg / mL EDTA. In some embodiments, the composition comprises about 7 pg / mL to about 15 pg / mL EDTA. In some embodiments, the composition comprises about 7 pg / mL to about 12 pg / mL EDTA.

[0211] In some embodiments, the composition can comprise, for example, about 7 pg / mL, 12 pg / mL, 15 pg / mL, 16 pg / mL, about 17 pg / mL, about 18 pg / mL, about 19 pg / mL, about 20 pg / mL, about 21 pg / mL, about 22 pg / mL, about 23 pg / mL, about 24 pg / mL, about 28 pg / mL, or about 33 pg / mL EDTA, or any value in between. In some embodiments, the composition comprises about 7 pg / mL EDTA. In some embodiments, the composition comprises about 12 pg / mL EDTA. In some embodiments, the composition comprises about 15 pg / mL EDTA. In some embodiments, the composition comprises about 16 pg / mL EDTA. In some embodiments, the composition comprises about 17 pg / mL EDTA. In some embodiments, the composition comprises about 18 pg / mL EDTA. In some embodiments, the composition comprises about 19 pg / mL EDTA. In some embodiments, the composition comprises about 20 pg / mL EDTA. In some embodiments, the composition comprises about 21 pg / mL EDTA. In some embodiments, the composition comprises about 22 pg / mL EDTA. In some embodiments, the composition comprises about 23 pg / mL EDTA. In some embodiments, the composition comprises about 24 pg / mL EDTA. In some embodiments, the composition comprises about 28 pg / mL EDTA. In some embodiments, the composition comprises about 33 pg / mL EDTA.

[0212] 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%, or any value or range therebetween, of polysorbate 20 (PS20).

[0213] In some embodiments, the composition comprises about 0.01% to about 0.07% of PS20. In some embodiments, the composition comprises about 0.02% to about 0.07% of PS20. In some embodiments, the composition comprises about 0.03% to about 0.07% of PS20. In some embodiments, the composition comprises about 0.04% to about 0.07% of PS20. In some embodiments, the composition comprises about 0.05% to about 0.07% of PS20. In some embodiments, the composition comprises about 0.06% to about 0.07% of PS20.

[0214] In some embodiments, the composition comprises about 0.01% to about 0.07% of PS20. In some embodiments, the composition comprises about 0.01% to about 0.06% of PS20. In some embodiments, the composition comprises about 0.01% to about 0.05% of PS20. In some embodiments, the composition comprises about 0.01% to about 0.04% of PS20. In some embodiments, the composition comprises about 0.01% to about 0.03% of PS20. In some embodiments, the composition comprises about 0.01% to about 0.02% of PS20.

[0215] In some embodiments, the composition may, for example, comprise about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, or about 0.07%, or any value therebetween, of PS20. In some embodiments, the composition comprises about 0.01% PS20. In some embodiments, the composition comprises about 0.02% PS20. In some embodiments, the composition comprises about 0.03% PS20. In some embodiments, the composition comprises about 0.04% PS20. In some embodiments, the composition comprises about 0.05% PS20. In some embodiments, the composition comprises about 0.06% PS20. In some embodiments, the composition comprises about 0.07% PS20.

[0216] In some embodiments, the pH of the composition is about 4.7 to about 5.7, about 4.8 to about 5.6, about 4.9 to about 5.5, or any value or range therebetween.

[0217] 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.

[0218] 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.

[0219] 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.

[0220] The stability of the aqueous pharmaceutical compositions (also referred to as drug products (DP)) disclosed herein is determined based on the evaluation of specific amounts or ratios of GPRC5D / CD3 antibody and other components of the DP as provided herein, such as, but not limited to, acetate and / or pharmaceutically acceptable acetate, sucrose, PS20, and EDTA, and various factors. These factors include, but are not limited to, solution color, pH, turbidity, percent purity, number of sub-visible particles, percent of new peaks, percent of major components, percent of high molecular weight species (HMWS), percent of low molecular weight species (LMWS), percent of total acidic peaks, percent of total basic peaks, protein concentration, percent of T cell activation, and / or percent of PS20.

[0221] A stable DP as disclosed herein should not be interpreted as requiring all of the factors listed herein, but at least one, at least two, or at least three or more of these factors. In some embodiments, the disclosed stable DP exhibits the following results for at least one, at least two, at least three, or more of the factors listed in detail below. In some embodiments, the stable DP exhibits the following results for most of the factors listed in detail below. In some embodiments, the stable DP exhibits the following results for all of the factors listed in detail below.

[0222] Solution Color

[0223] DP solution color is monitored and can be evaluated to verify that the appearance of the solution is consistent with previous batches at release and over shelf life. DP solution color can reflect stability. In some embodiments, a stable DP is defined as a solution color from colorless to about BY2 or lower, to about BY4 or lower, to about B2 or lower, to about B4 or lower, to about Y2 or lower, or to about Y4 or lower, as described in European Pharmacopoeia 2.2.2, Liquid Chromatography of the Degree of Colour, European Pharmacopoeia 10thEdition, Monograph Number 20202, July 2019.

[0224] In some embodiments, a stable DP is defined as having a solution color of colorless to about BY2 or less, about B2 or less, 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 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 BY4 or less, to about B4 or less, to 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, to about B5 or less, to 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.

[0225] pH

[0226] Measuring the pH of a DP solution enables confirmation that it is consistent with previous batches of DP at release and over 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, a DP has a pH of 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 ranging from 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 ranging from 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.

[0227] Turbidity

[0228] Turbidity allows for the measurement of the presence of particles in the DP solution to ensure consistency with previous batches of DP and applicable pharmacopeia guidelines at release and over shelf life. Turbidity of the solution 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.

[0229] Particle Analysis

[0230] Based on the average number of sub-visible particles, the stability of the DP is set to a particular threshold of particulate contamination. In some embodiments, the average number of particles present in the DP units tested should not exceed 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, or 6000 per container for particle sizes equal to 10 pm or greater. In some embodiments, the average number of particles present in the DP units tested should not exceed 6000 per container for particle sizes equal to 10 pm or greater. In some embodiments, the average number of particles present in the DP units tested should not exceed 100, 200, 300, 400, 500, or 600 per container for particle sizes equal to 25 pm or greater. In some embodiments, the average number of particles present in the DP units tested should not exceed 600 per container for particle sizes equal to 25 pm or greater.

[0231] cSDS Conditions

[0232] Similar to gel-based SDS-PAGE, capillary SDS-PAGE (cSDS) is a method for separating denatured proteins based on molecular weight. This method allows for quantification of DP purity and monitoring of its stability at release and over shelf life.

[0233] In some embodiments, DP stability is defined based on various outcomes of cSDS variables (e.g., percent purity or presence of new peaks) 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, wherein the cSDS is performed under reducing or non-reducing conditions.

[0234] In some embodiments, a stable DP is defined as having a percent purity 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, under reducing conditions 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.

[0235] In some embodiments, a stable DP is defined as showing no more than 0.5%, 0.8%, 0.9%, 1.0%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, or more than 2% of new peaks in the reducing cSDS results when compared to an untreated 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.

[0236] In some embodiments, a stable DP is defined as having a percent purity of about 90% or greater under reducing conditions and no more than 1.5% new peaks after DP is stored at a temperature of about 5°C for about 12 months or greater, after DP is stored at a temperature of about 25°C for about 12 months or greater, and / or after DP is stored at a temperature of about 5°C for about 2 years or greater as compared to a reference material. In some embodiments, a stable DP is defined as having a percent purity of about 95% or greater and no more than 1.2% new peaks after DP is stored at a temperature of about 5°C for about 12 months or greater, after DP is stored at a temperature of about 25°C for about 12 months or greater, and / or after DP is stored at a temperature of about 5°C for about 2 years or greater as compared to a reference material. In some embodiments, a stable DP is defined as having a percent purity of about 97% or greater and no more than 1.0% new peaks after DP is stored at a temperature of about 5°C for about 12 months or greater, after DP is stored at a temperature of about 25°C for about 12 months or greater, and / or after DP is stored at a temperature of about 5°C for about 2 years or greater as compared to a reference material.

[0237] In some embodiments, a stable DP is defined as having a percent purity 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 range therebetween under non-reducing conditions after DP is stored at a temperature of about 5°C for about 12 months or greater, after DP is stored at a temperature of about 25°C for about 12 months or greater, and / or after DP is stored at a temperature of about 5°C for about 2 years or greater.

[0238] In some embodiments, a stable DP is defined as showing no more than 0.5%, 0.8%, 0.9%, 1.0%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, or greater than 2% new peaks in non-reducing cSDS results when compared to an untreated reference material after DP is stored at a temperature of about 5°C for about 12 months or greater, after DP is stored at a temperature of about 25°C for about 12 months or greater, and / or after DP is stored at a temperature of about 5°C for about 2 years or greater.

[0239] In some embodiments, a stable DP is defined as having a percent purity of about 90% or greater under non-reducing conditions and no more than 1.5% new peaks compared to a reference material after the DP is stored at a temperature of about 5 °C for about 12 months or more, after the DP is stored at a temperature of about 25 °C for about 12 months or more, and / or after the DP is stored 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 more than 1.2% new peaks compared to a reference material after the DP is stored at a temperature of about 5 °C for about 12 months or more, after the DP is stored at a temperature of about 25 °C for about 12 months or more, and / or after the DP is stored 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 more than 1.0% new peaks compared to a reference material after the DP is stored at a temperature of about 5 °C for about 12 months or more, after the DP is stored at a temperature of about 25 °C for about 12 months or more, and / or after the DP is stored at a temperature of about 5 °C for about 2 years or more.

[0240] Volume Exclusion HPLC (SE-HPLC) results are consistent with stability

[0241] The SE-HPLC procedure allows for the assessment of the purity of the DP and the monitoring of its stability under non-denaturing conditions at the time of release and over the shelf life.

[0242] In some embodiments, DP stability is defined based on various outcomes of SE-HPLC variables such as major component (MC), high molecular weight species (HMWS), or low molecular weight species (LMWS) after the DP is stored at a temperature of about 5 °C for about 12 months or more, after the DP is stored at a temperature of about 25 °C for about 12 months or more, and / or after the DP is stored at a temperature of about 5 °C for about 2 years or more.

[0243] In some embodiments, a stable DP is defined as having a MC of about: 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or equal to about 100%, or any value or range therebetween, after the DP is stored at a temperature of about 5°C for about 12 months or more, after the DP is stored at a temperature of about 25°C for about 12 months or more, and / or after the DP is stored at a temperature of about 5°C for about 2 years or more. In some embodiments, a stable DP is defined as having a MC of about 90% or more, after the DP is stored at a temperature of about 5°C for about 12 months or more, after the DP is stored at a temperature of about 25°C for about 12 months or more, and / or after the DP is stored at a temperature of about 5°C for about 2 years or more. In some embodiments, a stable DP is defined as having a MC of about 95% or more, after the DP is stored at a temperature of about 5°C for about 12 months or more, after the DP is stored at a temperature of about 25°C for about 12 months or more, and / or after the DP is stored at a temperature of about 5°C for about 2 years or more. In some embodiments, a stable DP is defined as having a MC of about 97% or more, after the DP is stored at a temperature of about 5°C for about 12 months or more, after the DP is stored at a temperature of about 25°C for about 12 months or more, and / or after the DP is stored at a temperature of about 5°C for about 2 years or more.

[0244] In some embodiments, a stable DP is defined as having a 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 the DP is stored at a temperature of about 5°C for about 12 months or more, after the DP is stored at a temperature of about 25°C for about 12 months or more, and / or after the DP is stored at a temperature of about 5°C for about 2 years or more. In some embodiments, a stable DP is defined as having a HMWS of about 10% or less, after the DP is stored at a temperature of about 5°C for about 12 months or more, after the DP is stored at a temperature of about 25°C for about 12 months or more, and / or after the DP is stored at a temperature of about 5°C for about 2 years or more. In some embodiments, a stable DP is defined as having a HMWS of about 5% or less, after the DP is stored at a temperature of about 5°C for about 12 months or more, after the DP is stored at a temperature of about 25°C for about 12 months or more, and / or after the DP is stored at a temperature of about 5°C for about 2 years or more. In some embodiments, a stable DP is defined as having a HMWS of about 3% or less, after the DP is stored at a temperature of about 5°C for about 12 months or more, after the DP is stored at a temperature of about 25°C for about 12 months or more, and / or after the DP is stored at a temperature of about 5°C for about 2 years or more.

[0245] In some embodiments, a stable DP is defined as having a 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 the DP is stored at a temperature of about 5°C for about 12 months or more, after the DP is stored at a temperature of about 25°C for about 12 months or more, and / or after the DP is stored at a temperature of about 5°C for about 2 years or more. In some embodiments, a stable DP is defined as having a LMWS of about 5% or less, after the DP is stored at a temperature of about 5°C for about 12 months or more, after the DP is stored at a temperature of about 25°C for about 12 months or more, and / or after the DP is stored at a temperature of about 5°C for about 2 years or more. In some embodiments, a stable DP is defined as having a LMWS of about 2% or less, after the DP is stored at a temperature of about 5°C for about 12 months or more, after the DP is stored at a temperature of about 25°C for about 12 months or more, and / or after the DP is stored at a temperature of about 5°C for about 2 years or more. In some embodiments, a stable DP is defined as having a LMWS of about 1% or less, after the DP is stored at a temperature of about 5°C for about 12 months or more, after the DP is stored at a temperature of about 25°C for about 12 months or more, and / or after the DP is stored at a temperature of about 5°C for about 2 years or more.

[0246] Ion Exchange Chromatography (IEX)

[0247] IEX methods separate proteins based on total charge. This procedure allows monitoring of the distribution of charge-based isoforms of the drug product at release and over shelf life. In some embodiments, DP stability is defined based on various outcomes of IEX variables (such as main peak (MP), sum of acidic peaks, or sum of basic peaks) after the DP is stored 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.

[0248] In some embodiments, a stable DP is defined as having a MP of about: 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or any value or range therebetween, by IEX after the DP is stored for about 12 months or more at a temperature of about 25 °C, and / or for about 2 years or more at a temperature of about 5 °C. In some embodiments, a stable DP is defined as having a MP > 50% by IEX after the DP is stored for about 12 months or more at a temperature of about 25 °C, and / or for about 2 years or more at a temperature of about 5 °C. In some embodiments, a stable DP is defined as having a MP > 55% by IEX after the DP is stored for about 12 months or more at a temperature of about 25 °C, and / or for about 2 years or more at a temperature of about 5 °C. In some embodiments, a stable DP is defined as having a MP > 60% by IEX after the DP is stored for about 12 months or more at a temperature of about 25 °C, and / or for about 2 years or more at a temperature of about 5 °C.

[0249] In some embodiments, a stable DP is defined as having a total sum of acidic peaks of about: 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or any value or range therebetween, by IEX after the DP is stored for about 12 months or more at a temperature of about 25 °C, and / or for about 2 years or more at a temperature of about 5 °C. In some embodiments, a stable DP is defined as having a total sum of acidic peaks < 50% by IEX after the DP is stored for about 12 months or more at a temperature of about 25 °C, and / or for about 2 years or more at a temperature of about 5 °C. In some embodiments, a stable DP is defined as having a total sum of acidic peaks of about < 40% by IEX after the DP is stored for about 12 months or more at a temperature of about 25 °C, and / or for about 2 years or more at a temperature of about 5 °C. In some embodiments, a stable DP is defined as having a total sum of acidic peaks of about < 30% by IEX after the DP is stored for about 12 months or more at a temperature of about 25 °C, and / or for about 2 years or more at a temperature of about 5 °C.

[0250] In some embodiments, a stable DP is defined as having a total sum of basic peaks in IEX 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 storage of the DP for about 12 months or more at a temperature of about 25 °C, and / or for about 2 years or more at a temperature of about 5 °C. In some embodiments, a stable DP is defined as having a total sum of basic peaks in IEX of about 25% or less after storage of the DP for about 12 months or more at a temperature of about 25 °C, and / or for about 2 years or more at a temperature of about 5 °C. In some embodiments, a stable DP is defined as having a total sum of basic peaks in IEX of less than or about 15% after storage of the DP for about 12 months or more at a temperature of about 25 °C, and / or for about 2 years or more at a temperature of about 5 °C. In some embodiments, a stable DP is defined as having a total sum of basic peaks in IEX of less than or about 10% after storage of the DP for about 12 months or more at a temperature of about 25 °C, and / or for about 2 years or more at a temperature of about 5 °C.

[0251] Protein Concentration

[0252] The protein concentration of the DP enables verification that it is consistent with previous batches of the DP at the time of release and over the shelf life. Quantification of the protein concentration can be accomplished by measuring the ultraviolet light absorbance of the drug product solution at 280 nm (A280).

[0253] 2 mg / mL DP Formulation

[0254] 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 storage of the DP for about 12 months or more at a temperature of about 25 °C, and / or after storage for about 2 years or more 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 storage of the DP for about 12 months or more at a temperature of about 25 °C, and / or after storage for about 2 years or more 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 storage of the DP for about 12 months or more at a temperature of about 25 °C, and / or after storage for about 2 years or more 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 2.1 mg / mL after storage of the DP for about 12 months or more at a temperature of about 25 °C, and / or after storage for about 2 years or more at a temperature of about 5 °C.

[0255] 40 mg / mL DP Formulation

[0256] 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 storage of the DP for about 12 months or more at a temperature of about 25 °C, and / or after storage for about 2 years or more 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 storage of the DP for about 12 months or more at a temperature of about 25 °C, and / or after storage for about 2 years or more 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 storage of the DP for about 12 months or more at a temperature of about 25 °C, and / or after storage for about 2 years or more 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 42 mg / mL after storage of the DP for about 12 months or more at a temperature of about 25 °C, and / or after storage for about 2 years or more at a temperature of about 5 °C.

[0257] Peptide Mapping

[0258] Post-translational modifications (PTMs), such as oxidation, deamidation, and isomerization, are enzymatic modifications that can be detected in antibody structures. In some embodiments, DP stability is assessed based on the level of PTMs in the antibody. The test article is enzymatically digested to produce peptide fragments. These peptides are then evaluated by, for example, mass spectrometry (MS), by tandem mass spectrometry (MS-MS), or ultra-performance liquid chromatography mass spectrometry (UPLC-MS). Each peptide sequence analyzed is identified relative to its known position in the overall antibody structure. Post-translational modifications are determined by comparing the measured mass of the identified peptide sequence to its expected mass.

[0259] Drug Product Potency

[0260] In vitro T cell activation assays allow for the assessment of the level of DP stability. Such activation can be assessed by using, but not limited to, a luciferase assay mediated by the activation T cell nuclear factor-response element (NFAT-RE).

[0261] GPRC5D / CD3 T cell activation activity

[0262] 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%, or any value or range therebetween, of GPRC5D / CD3-mediated T cell activation activity relative to a reference after the DP is stored at a temperature of about 5°C for about 12 months or more, after the DP is stored at a temperature of about 25°C for about 12 months or more, and / or after the DP is stored at a temperature of about 5°C for about 2 years or more. In some embodiments, a stable DP is defined as having GPRC5D / CD3-mediated T cell activation activity in the range of about 50% to about 150% relative to a reference after the DP is stored at a temperature of about 25°C for about 12 months or more, and / or after the DP is stored at a temperature of about 5°C for about 2 years or more. 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 the DP is stored at a temperature of about 25°C for about 12 months or more, and / or after the DP is stored at a temperature of about 5°C for about 2 years or more. In some embodiments, a stable DP 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 the DP is stored at a temperature of about 25°C for about 12 months or more, and / or after the DP is stored at a temperature of about 5°C for about 2 years or more. In some embodiments, the GPRC5D / CD3-mediated T cell activation activity is talquetamab-mediated T cell activation activity.

[0263] Polysorbate 20 (PS20)

[0264] In some embodiments, a stable DP is defined as having a PS20 weight volume percent 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, 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. 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 storage of the DP 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 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 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 PS20 concentration of about 0.02% (w / v) to about 0.06% (w / v), after storage of the DP 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 PS20 concentration of about 0.03% (w / v) to about 0.05% (w / v), after storage of the DP 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.

[0265] Total Volume of Aqueous Pharmaceutical Composition

[0266] 2 mg / mL Formulation

[0267] 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) ranges 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.

[0268] 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.

[0269] 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.

[0270] 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.

[0271] 40 mg / mL Formulation

[0272] 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) ranges 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.

[0273] 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.

[0274] 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.

[0275] 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.

[0276] Methods

[0277] In some embodiments, methods of treating cancer in a subject in need thereof are provided. In some embodiments, the methods comprise administering to the subject an aqueous pharmaceutical composition as 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 administration.

[0278] Cancer

[0279] In some embodiments, the cancer is a hematological malignancy.

[0280] In some embodiments, the hematological malignancy is multiple myeloma. In some embodiments, the subject has newly diagnosed multiple myeloma. In some embodiments, the subject has relapsed or refractory to treatment with a prior anti-cancer therapeutic, such as a therapeutic used to treat multiple myeloma or other hematological malignancy.

[0281] In some embodiments, the subject has relapsed or refractory to treatment with one or more treatments or therapies, such as: (Thalidomide), (Lenalidomide), (Pomalidomide), (Bortezomib), NINLARO (ixazomib), (Carfilzomib), (Panobinostat), (Pamidronate), (Zoledronic acid), (Daratumumab), elotozumab, or melphalan, (Cerulenin), (Venetoclax), GSK 916, CAR-T therapy, BCMA-directed therapy, or other GPRC5D-directed therapy.

[0282] Various qualitative and / or quantitative methods can be used to determine the relapsed or refractory nature of the disease. Symptoms that can be associated are, for example, a decline or stabilization in the patient's health, or a reestablishment or worsening of various symptoms associated with solid tumors, and / or the spread of cancer cells in the body from one site to other organs, tissues or cells.

[0283] In some embodiments, the multiple myeloma is relapsed or refractory to treatment with at least four prior therapies, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody, e.g., selected from daratumumab, selinexor, lenalidomide, bortezomib, pomalidomide, carfilzomib, or thalidomide, or any combination thereof. In some embodiments, the multiple myeloma is relapsed or refractory to treatment with at least 3 prior therapies, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody, e.g., selected from daratumumab, selinexor, lenalidomide, bortezomib, pomalidomide, carfilzomib, or thalidomide, or any combination thereof, and the patient exhibits disease progression or no response to the last therapy.

[0284] In some embodiments, the multiple myeloma is relapsed or refractory to treatment with an anti-CD38 antibody, selinexor, venetoclax, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[0285] In some embodiments, the multiple myeloma is high-risk multiple myeloma. Subjects known to have high-risk multiple myeloma relapse early and have poor prognosis and outcomes. A subject can be classified as having high-risk multiple myeloma if the subject has one or more of the following cytogenetic abnormalities: t(4; 14)(p16; q32), t(14; 16)(q32; q23), del 17p, 1q Amp, t(4; 14)(p16; q32) and t(14; 16)(q32; q23), t(4; 14)(p16; q32) and del 17p, t(14; 16)(q32; q23) and del 17p, or t(4; 14)(p16; q32), t(14; 16)(q32; q23) and del 17p. In some embodiments, a subject having high-risk multiple myeloma has one or more chromosomal abnormalities comprising: t(4; 14)(p16; q32), t(14; 16)(q32; q23), del 17p, 1q Amp, t(4; 14)(p16; q32) and t(14; 16)(q32; q23), t(4; 14)(p16; q32) and del 17p, t(14; 16)(q32; q23) and del 17p; or t(4; 14)(p16; q32), t(14; 16)(q32; q23) and del 17p, or any combination thereof.

[0286] Cytogenetic abnormalities can be detected, for example, by fluorescence in situ hybridization (FISH). In two of the chromosomal translocations, oncogenes are translocated to the IgH region on chromosome 14q32, resulting in deregulation of these genes. t(4; 14)(p16; q32) involves translocation of fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain protein (MMSET) (also known as WHSC1 / NSD2), and t(14; 16)(q32; q23) involves translocation of the MAF transcription factor C-MAF. del 17p involves loss of the p53 locus.

[0287] Chromosomal rearrangements can be identified using well-known methods, such as fluorescence in situ hybridization, chromosome karyotyping, pulsed field gel electrophoresis, or sequencing.

[0288] Methods of treating multiple myeloma with a GPRC5DxCD3 bispecific antibody, such as talquetamab, are described in WO 2022 / 058445, which is incorporated herein by reference. A phase 1 clinical study evaluating talquetamab is also 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.

[0289] According to one embodiment, a method of treating a human subject having relapsed or refractory multiple myeloma comprises administering a stable aqueous pharmaceutical composition of the present application according to a dosing regimen to the subject based on the subject’s body weight, wherein the dosing regimen comprises: administering the aqueous pharmaceutical composition to the subject subcutaneously 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 administering the aqueous pharmaceutical composition to the subject subcutaneously at a therapeutic dose of 0.8 mg / kg once every two weeks, wherein the aqueous pharmaceutical composition comprising 2 mg / mL talquetamab is administered for the 0.01 mg / kg and 0.06 mg / kg doses, and the aqueous pharmaceutical composition comprising 40 mg / mL talquetamab is administered for each of the 0.4 mg / kg and 0.8 mg / kg doses. As used herein with respect to the dosing regimen, mg / kg refers to mg antibody (such as talquetamab) per kg of subject body weight.

[0290] According to one alternative embodiment, a method of treating a human subject having relapsed or refractory multiple myeloma comprises administering a stable aqueous pharmaceutical composition of the present application according to a dosing regimen to the subject based on the subject’s body weight, wherein the dosing regimen comprises: administering the aqueous pharmaceutical composition to the subject subcutaneously 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 administering the aqueous pharmaceutical composition to the subject subcutaneously at a therapeutic dose of 0.8 mg / kg once every two weeks, wherein the aqueous pharmaceutical composition comprising 2 mg / mL talquetamab is administered for the 0.01 mg / kg and 0.06 mg / kg doses, and the aqueous pharmaceutical composition comprising 40 mg / mL talquetamab is administered for each of the 0.3 mg / kg and 0.8 mg / kg doses.

[0291] According to an alternative embodiment, the method of treating a human subject having relapsed or refractory multiple myeloma comprises administering the stable aqueous pharmaceutical composition of the present application according to a dosing regimen based on the subject's body weight, wherein the dosing regimen comprises: subcutaneous administration of 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 subcutaneous administration of the aqueous pharmaceutical composition to the subject at a therapeutic dose of 0.4 mg / kg once weekly, wherein the aqueous pharmaceutical composition comprises 2 mg / mL of talquetenevumab for the 0.01 mg / kg and 0.06 mg / kg doses and 40 mg / mL of talquetenevumab for each of the 0.4 mg / kg doses.

[0292] In preferred embodiments, the pharmaceutical composition is therapeutically effective in treating relapsed or refractory multiple myeloma in a human subject, in particular, the composition is effective in eliciting a partial remission, a very good partial remission, a complete remission, or a stringent complete remission, as determined by the International Myeloma Working Group (IMWG) remission criteria. As used herein, overall remission rate (ORR) refers to the percentage of patients in a population who achieve a partial remission (PR) or better (i.e., partial remission, very good partial remission, complete remission, or stringent complete remission). The IMWG criteria for remission of multiple myeloma treatment are provided in Table A below.

[0293] Table A

[0294]

[0295] CR = complete remission; FLC = free light chain; IMWG = International Myeloma Working Group; M protein = monoclonal paraprotein; MR = minimal remission; PC = plasma cell; PD = progressive disease; PR = partial remission; sCR = stringent complete remission; SD = stable disease; VGPR = very good partial remission

[0296] a The presence / absence of clonal cells is based on the kappa / lambda ratio. An abnormal kappa / lambda ratio determined by immunohistochemistry or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio that reflects the presence of an abnormal clone is a kappa / lambda > 4: 1 or < 1:2.

[0297] *Note on IMWG criteria for CR and VGPR in subjects for whom the only measurable disease is by serum FLC levels: In addition to the CR criteria listed above, a CR in such subjects indicates a normal FLC ratio of 0.26 to 1.65. A VGPR in such subjects requires a > 90% reduction in the difference between involved and uninvolved FLC levels.

[0298] IMWG criteria for treatment response in multiple myeloma are also described in, e.g., Durie et al., Kumar et al., and Rajkumar et al., which are incorporated herein by reference: Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9): 1467-1473; Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-346; Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform reporting of clinical Trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117(18):4691-4695.

[0299] In certain embodiments, the pharmaceutical composition of the application elicits an overall response rate (ORR) (as defined by IMWG criteria) of at least 70% in a patient population when administered subcutaneously to each subject according to the dosing regimen set forth in Table B, Table C, or Table D:

[0300] Table B

[0301]

[0302] a Based on actual body weight.

[0303] b The dose can be administered between 2 days and 4 days after the preceding dose, and can be administered up to 7 days after the preceding dose, so that adverse reactions are resolved.

[0304] c A minimum of 6 days is maintained between each weekly dose, and a minimum of 12 days is maintained between each biweekly (every 2 weeks) dose.

[0305] Table C

[0306]

[0307] a based on actual body weight.

[0308] b Doses can be administered between 2 and 4 days after the previous dose and can be given up to 7 days after the previous dose for adverse reactions to be resolved.

[0309] c A minimum of 6 days is maintained between each weekly dose and a minimum of 12 days is maintained between each biweekly (every 2 weeks) dose.

[0310] Table D

[0311]

[0312] a based on actual body weight.

[0313] b Doses can be administered between 2 and 4 days after the previous dose and can be given up to 7 days after the previous dose for adverse reactions to be resolved.

[0314] c A minimum of 6 days is maintained between each weekly dose and a minimum of 12 days is maintained between each biweekly (every 2 weeks) dose.

[0315] In certain embodiments, the aqueous pharmaceutical composition comprising 2 mg / mL talqueteneqant (for administration of 0.01 mg / kg and 0.06 mg / kg doses in Tables B-D) has the composition shown in Table 26 or Table 27, and the aqueous pharmaceutical composition comprising 40 mg / mL talqueteneqant (for administration of 0.3 mg / kg, 0.4 mg / kg, and 0.8 mg / kg doses in Tables B-D) has the composition shown in Table 22 or Table 23.

[0316] In certain embodiments, the aqueous pharmaceutical composition comprising 2 mg / mL talqueteneqant for 0.01 mg / kg and 0.06 mg / kg doses has the following composition per 1.5 mL: 3 mg talqueteneqant, 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.

[0317] In certain embodiments, the aqueous pharmaceutical composition comprising 40 mg / mL talquetupamab for 0.3 mg / kg, 0.4 mg / kg, and 0.8 mg / kg doses has the following composition per 1 mL: 40 mg talquetupamab, 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.

[0318] According to certain embodiments, the method of treatment further comprises administering a pre-treatment medication 1 hour to 3 hours prior to each escalation, wherein the pre-treatment medication comprises: a corticosteroid (oral or intravenous dexamethasone, 16 mg or equivalent dose); an antihistamine (oral or intravenous diphenhydramine, 50 mg or equivalent dose); and an antipyretic (oral or intravenous acetaminophen, 650 mg to 1000 mg or equivalent dose).

[0319] According to certain embodiments, the method of treatment described herein is effective in eliciting clinical remission in a subject according to International Myeloma Working Group (IMWG) diagnostic criteria. In certain embodiments, the method produces an overall remission 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 IMWG criteria, e.g., as described in Example 14.

[0320] Also provided herein is a method for preparing an aqueous pharmaceutical composition of a bispecific G Protein-Coupled Receptor Family, Class 5, Member D (GPRC5D) antibody or antigen binding fragment thereof comprising: a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1), wherein VH1 comprises heavy chain complementarity determining regions 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; a first light chain (LC1) comprising a LC1 variable region (VL1), wherein VL1 comprises light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; a second heavy chain (HC2) comprising a HC2 variable region 2 (VH2), wherein VH2 comprises heavy chain complementarity determining regions 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 a LC2 variable region 2 (VL2), wherein VL2 comprises light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively; the method comprising admixing a composition comprising about 2 mg / mL of the bispecific GPRC5D / CD3 antibody, about 15 mM acetate and / or a pharmaceutically acceptable acetate salt, about 8% (w / v) sucrose, about 18 pg / 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, wherein the stability of the aqueous pharmaceutical composition is as defined and provided herein.

[0321] 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 a HC1 having the amino acid sequence of SEQ ID NO: 9 and a 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 a HC2 having the amino acid sequence of SEQ ID NO: 19 and a LC2 having the amino acid sequence of SEQ ID NO: 20.

[0322] In some embodiments, the bispecific GPRC5D / CD3 antibody can 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, wherein HC1 and LC1 form a first antigen binding site that immunospecifically binds GPRC5D, and wherein HC2 and LC2 form a second antigen binding site that immunospecifically binds CD3. In some embodiments, talquetamab comprises HC1 of SEQ ID NO: 9, LC1 of SEQ ID NO: 10, HC2 of SEQ ID NO: 19, and 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.

[0323] Also provided herein is a method for preparing a stable aqueous pharmaceutical composition of a bispecific G-protein coupled receptor class 5, member D (GPRC5D) antibody or antigen binding fragment thereof, the bispecific GPRC5D / CD3 antibody or antigen binding fragment thereof comprising: a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1), wherein VH1 comprises heavy chain complementarity determining regions 1 (HCDR1), HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; a first light chain (LC1) comprising a LC1 variable region (VL1), wherein VL1 comprises light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; a second heavy chain (HC2) comprising a HC2 variable region 2 (VH2), wherein VH2 comprises heavy chain complementarity determining regions 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 a LC2 variable region 2 (VL2), wherein VL2 comprises light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively; the method comprising admixing a composition comprising about 40 mg / mL of the bispecific GPRC5D / CD3 antibody, about 15 mM acetate and / or a pharmaceutically acceptable acetate salt, about 8% (w / v) sucrose, about 18 pg / 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.

[0324] 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 a HC1 having the amino acid sequence of SEQ ID NO: 9 and a 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 a HC2 having the amino acid sequence of SEQ ID NO: 19 and a LC2 having the amino acid sequence of SEQ ID NO: 20.

[0325] In some embodiments, the bispecific GPRC5D / CD3 antibody can 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, wherein HC1 and LC1 form a first antigen binding site that immunospecifically binds GPRC5D, and wherein HC2 and LC2 form a second antigen binding site that immunospecifically binds CD3. In some embodiments, talquetamab comprises a HC1 of SEQ ID NO: 9, a LC1 of SEQ ID NO: 10, a HC2 of SEQ ID NO: 19, and a 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.

[0326] The aqueous pharmaceutical compositions disclosed herein can be packaged into a kit, container, package, 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.

[0327] Provided herein is a kit comprising the disclosed aqueous pharmaceutical composition 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.

[0328] Also provided herein is an article of manufacture comprising a container holding the disclosed aqueous pharmaceutical composition. 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 pierced by a syringe.

[0329] Embodiments

[0330] Illustrative embodiments of the disclosed technology are provided herein. These embodiments are merely exemplary and do not limit the scope of the present disclosure or the appended claims.

[0331] In some embodiments, the following embodiments are provided:

[0332] 1a. An aqueous pharmaceutical composition comprising:

[0333] a) a bispecific G Protein-Coupled Receptor Family 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, the bispecific GPRC5D / CD3 antibody, or antigen-binding fragment thereof, comprising:

[0334] (1) a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1),

[0335] wherein the VH1 comprises a heavy chain complementarity determining region 1 (HCDR1), an HCDR2, and an HCDR3, having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively;

[0336] (2) a first light chain (LC1) comprising a LC1 variable region (VL1),

[0337] wherein the VL1 comprises a light chain complementarity determining region 1 (LCDR1), an LCDR2, and an LCDR3, having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively;

[0338] (3) a second heavy chain (HC2) comprising a HC2 variable region 2 (VH2),

[0339] wherein the VH2 comprises a heavy chain complementarity determining region 1 (HCDR1), an HCDR2, and an HCDR3, having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; and

[0340] (4) a second light chain (LC2) comprising a LC2 variable region 2 (VL2),

[0341] wherein the VL2 comprises light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively;

[0342] b) about 10 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt;

[0343] c) about 6% (w / v) to about 10% (w / v) sucrose;

[0344] d) about 7 pg / mL to about 33 pg / mL ethylenediaminetetraacetic acid (EDTA);

[0345] e) about 0.01% to about 0.07% polysorbate 20; and

[0346] f) a pH of about 4.6 to about 5.8.

[0347] 1b. An aqueous pharmaceutical composition comprising:

[0348] a) a bispecific G protein-coupled receptor family 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, the bispecific GPRC5D / CD3 antibody, or antigen binding fragment thereof, comprising:

[0349] (1) a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1),

[0350] wherein the VH1 comprises heavy chain complementarity determining regions 1 (HCDR1), HCDR2, and HCDR3, having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively;

[0351] (2) a first light chain (LC1) comprising a LC1 variable region (VL1),

[0352] wherein the VL1 comprises light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively;

[0353] (3) a second heavy chain (HC2) comprising a HC2 variable region 2 (VH2),

[0354] wherein the VH2 comprises heavy chain complementarity determining regions 1 (HCDR1), HCDR2, and HCDR3, having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; and

[0355] (4) a second light chain (LC2) comprising a LC2 variable region 2 (VL2),

[0356] wherein the VL2 comprises light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively;

[0357] b) about 10 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt;

[0358] c) about 6% (w / v) to about 10% (w / v) sucrose;

[0359] d) about 7 pg / mL to about 33 pg / mL ethylenediaminetetraacetic acid (EDTA);

[0360] e) about 0.01% to about 0.07% polysorbate 20; and

[0361] f) a pH of about 4.6 to about 5.8.

[0362] 2. An aqueous pharmaceutical composition, comprising:

[0363] a) a bispecific G protein-coupled receptor family 5 member C (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, the bispecific GPRC5D / CD3 antibody, or antigen binding fragment thereof, comprising:

[0364] (1) a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1),

[0365] wherein the VH1 comprises heavy chain complementarity determining regions 1 (HCDR1), HCDR2, and HCDR3, having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively;

[0366] (2) a first light chain (LC1) comprising a LC1 variable region (VL1),

[0367] wherein the VL1 comprises light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively;

[0368] (3) a second heavy chain (HC2) comprising a HC2 variable region 2 (VH2),

[0369] wherein the VH2 comprises heavy chain complementarity determining regions 1 (HCDR1), HCDR2, and HCDR3, having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; and

[0370] (4) a second light chain (LC2) comprising a LC2 variable region 2 (VL2),

[0371] wherein the VL2 comprises light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively;

[0372] b) about 10 mM to about 20 mM acetate and / or a pharmaceutically acceptable acetate salt;

[0373] c) about 6% (w / v) to about 10% (w / v) sucrose;

[0374] d) about 7 pg / mL to about 33 pg / mL ethylenediaminetetraacetic acid (EDTA);

[0375] e) about 0.01% to about 0.07% polysorbate 20; and

[0376] f) a pH of about 4.6 to about 5.8.

[0377] 3. The aqueous pharmaceutical composition according to 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.

[0378] 4. The aqueous pharmaceutical composition according to embodiment 1a, 1b, or 2, wherein the bispecific GPRC5D / CD3 antibody comprises a HC1 having the amino acid sequence of SEQ ID NO: 9 and a LC1 having the amino acid sequence of SEQ ID NO: 10.

[0379] 5. The aqueous pharmaceutical composition according to 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.

[0380] 6. The aqueous pharmaceutical composition according to embodiment 1a, 1b, or 2, wherein the bispecific GPRC5D / CD3 antibody comprises a HC2 having the amino acid sequence of SEQ ID NO: 19 and a LC2 having the amino acid sequence of SEQ ID NO: 20.

[0381] 7. The aqueous pharmaceutical composition according to embodiment 1a, 1b, or 2, wherein the bispecific GPRC5D / CD3 antibody is talquetamab.

[0382] 8. The aqueous pharmaceutical composition according to embodiment 1 b, wherein the bispecific GPRC5D / CD3 antibody has a concentration of about 1 mg / mL to about 3 mg / mL.

[0383] 9. The aqueous pharmaceutical composition according to embodiment 8, wherein the bispecific GPRC5D / CD3 antibody has a concentration of about 1.5 mg / mL to about 2.5 mg / mL.

[0384] 10. The aqueous pharmaceutical composition according to embodiment 9, wherein the bispecific GPRC5D / CD3 antibody has a concentration of about 2 mg / mL.

[0385] 11. The aqueous pharmaceutical composition according to embodiment 2, wherein the bispecific GPRC5D / CD3 antibody has a concentration of about 30 mg / mL to about 50 mg / mL.

[0386] 12. The aqueous pharmaceutical composition according to embodiment 11, wherein the bispecific GPRC5D / CD3 antibody has a concentration of about 35 mg / mL to about 45 mg / mL.

[0387] 13. The aqueous pharmaceutical composition according to embodiment 12, wherein the bispecific GPRC5D / CD3 antibody has a concentration of about 40 mg / mL.

[0388] 14. The aqueous pharmaceutical composition according to embodiment 1 a, 1 b or 2, wherein the composition comprises about 12 mM to about 18 mM acetate and / or a pharmaceutically acceptable acetate.

[0389] 15. The aqueous pharmaceutical composition according to embodiment 1 a, 1 b or 2, wherein the composition comprises about 14 mM to about 16 mM acetate and / or a pharmaceutically acceptable acetate.

[0390] 16. The aqueous pharmaceutical composition according to embodiment 1 a, 1 b or 2, wherein the composition comprises about 15 mM acetate and / or a pharmaceutically acceptable acetate.

[0391] 17. The aqueous pharmaceutical composition according to embodiment 1 a, 1 b or 2, wherein the composition comprises about 7% (w / v) to about 9% (w / v) sucrose.

[0392] 18. The aqueous pharmaceutical composition according to embodiment 17, wherein the composition comprises about 8% (w / v) sucrose.

[0393] 19. The aqueous pharmaceutical composition according to embodiment 1a, 1b, or 2, wherein the composition comprises about 15 pg / mL to about 21 pg / mL of EDTA.

[0394] 20. The aqueous pharmaceutical composition according to embodiment 1a, 1b, or 2, wherein the composition comprises about 18 pg / mL of EDTA.

[0395] 21. The aqueous pharmaceutical composition according to embodiment 1a, 1b, or 2, wherein the composition comprises about 0.02% to about 0.06% of PS-20.

[0396] 22. The aqueous pharmaceutical composition according to embodiment 21, wherein the composition comprises about 0.03% to about 0.05% of PS-20.

[0397] 23. The aqueous pharmaceutical composition according to embodiment 22, wherein the composition comprises about 0.04% of PS-20.

[0398] 24. The aqueous pharmaceutical composition according to embodiment 1a, 1b, or 2, wherein the pH is about 4.8 to about 5.6.

[0399] 25. The aqueous pharmaceutical composition according to embodiment 24, wherein the pH is about 4.9 to about 5.5.

[0400] 26. The aqueous pharmaceutical composition according to embodiment 25, wherein the pH is about 5.2.

[0401] 27. The aqueous pharmaceutical composition according to embodiment 1b, wherein the composition comprises 2 mg / mL of the bispecific GPRC5D / CD3 antibody, 15 mM acetate and / or a pharmaceutically acceptable acetate salt, 8% (w / v) sucrose, 18 pg / mL EDTA, 0.04% PS20 and has a pH of 5.2.

[0402] 28. The aqueous pharmaceutical composition according to embodiment 2, wherein the composition comprises 40 mg / mL of the bispecific GPRC5D / CD3 antibody, 15 mM acetate and / or a pharmaceutically acceptable acetate salt, 8% (w / v) sucrose, 18 pg / mL EDTA, 0.04% PS20 and has a pH of 5.2.

[0403] 29. The aqueous pharmaceutical composition according to any one of embodiments 1a, 1b, or 2 to 28, wherein the aqueous pharmaceutical composition is stable.

[0404] 30. The aqueous pharmaceutical composition of embodiment 29, wherein stability is defined based on solution color, pH, turbidity, percent purity, percent new peaks, percent major components, percent high molecular weight species (HWMS), percent low molecular weight species (LMWS), percent sum of acidic peaks, percent sum of basic peaks, protein concentration, percent T cell activation, percent PS20 (w / v), or any combination thereof.

[0405] 31. The aqueous pharmaceutical composition of embodiment 29 or 30, wherein the aqueous pharmaceutical composition is stable at a temperature of about 2 °C to 8 °C for at least two years.

[0406] 32. A method of treating cancer in a human subject in need thereof, the method comprising administering to the subject the aqueous pharmaceutical composition of any one of embodiments la, lb, or 2-31.

[0407] 33. The method of embodiment 32, wherein the administration is subcutaneous administration.

[0408] 34. A method for preparing a stable aqueous pharmaceutical composition of a bispecific G Protein-Coupled Receptor Family, Member 5D (GPRC5D) / Cluster of Differentiation 3 (CD3) antibody or antigen-binding fragment thereof, the bispecific GPRC5D / CD3 antibody or antigen-binding fragment thereof comprising:

[0409] (1) a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1),

[0410] wherein the VH1 comprises a heavy chain complementarity determining region 1 (HCDR1), a HCDR2, and a HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively;

[0411] (2) a first light chain (LC1) comprising a LC1 variable region (VL1),

[0412] 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;

[0413] (3) a second heavy chain (HC2) comprising a HC2 variable region 2 (VH2),

[0414] wherein the VH2 comprises a heavy chain complementarity determining region 1 (HCDR1), a HCDR2, and a HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; and

[0415] (4) a second light chain (LC2) comprising a LC2 variable region 2 (VL2), wherein the VL2 comprises a light chain complementarity determining region 1 (LCDR1), an LCDR2, and an LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively;

[0416] The method comprises admixing a composition comprising about 2 mg / mL of the bispecific GPRC5D / CD3 antibody, about 15 mM acetate and / or a pharmaceutically acceptable acetate salt, about 8% (w / v) sucrose, about 18 pg / mL EDTA, and about 0.04% polysorbate (PS) 20, wherein the stable aqueous pharmaceutical composition has a pH of about 5.2.

[0417] 35. A method for making a stable aqueous pharmaceutical composition of a bispecific G protein- coupled receptor class C, group 5, member 5 (GPRC5D) / cluster of differentiation 3 (CD3) antibody or antigen binding fragment thereof, the bispecific GPRC5D / CD3 antibody or antigen binding fragment thereof comprising:

[0418] (1) a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1),

[0419] wherein the VH1 comprises a heavy chain complementarity determining region 1 (HCDR1), an HCDR2, and an HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively;

[0420] (2) a first light chain (LC1) comprising a LC1 variable region (VL1),

[0421] wherein the VL1 comprises a light chain complementarity determining region 1 (LCDR1), an LCDR2, and an LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively;

[0422] (3) a second heavy chain (HC2) comprising a HC2 variable region 2 (VH2),

[0423] wherein the VH2 comprises a heavy chain complementarity determining region 1 (HCDR1), an HCDR2, and an HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; and

[0424] (4) a second light chain (LC2) comprising a LC2 variable region 2 (VL2), wherein the VL2 comprises a light chain complementarity determining region 1 (LCDR1), an LCDR2, and an LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively;

[0425] The method comprises admixing a composition comprising about 40 mg / mL of the bispecific GPRC5D / CD3 antibody, about 15 mM acetate and / or a pharmaceutically acceptable acetate salt, about 8% (w / v) sucrose, about 18 pg / mL EDTA, and about 0.04% polysorbate (PS) 20, wherein the stable aqueous pharmaceutical composition has a pH of about 5.2.

[0426] 36. The method of either 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.

[0427] 37. The method of either embodiment 34 or 35, wherein the bispecific GPRC5D / CD3 antibody comprises a HC1 having the amino acid sequence of SEQ ID NO: 9 and a LC1 having the amino acid sequence of SEQ ID NO: 10.

[0428] 38. The method of either 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.

[0429] 39. The method of either embodiment 34 or 35, wherein the bispecific GPRC5D / CD3 antibody comprises a HC2 having the amino acid sequence of SEQ ID NO: 19 and a LC2 having the amino acid sequence of SEQ ID NO: 20.

[0430] 40. The method of either embodiment 34 or 35, wherein the bispecific GPRC5D / CD3 antibody is talquetamab.

[0431] 41. The method of any one of embodiments 34 to 40, wherein the aqueous pharmaceutical composition is stable.

[0432] 42. The method of embodiment 41, wherein stability is defined based on solution color, pH, turbidity, percent purity, percent new peaks, percent major components, percent high molecular weight species (HWMS), percent low molecular weight species (LMWS), percent sum of acidic peaks, percent sum of basic peaks, protein concentration, percent T cell activation, percent (w / v) of PS20, or any combination thereof.

[0433] 43. A kit comprising the aqueous pharmaceutical composition of any one of embodiments 1a, 1b, or 2-31 and instructions for use.

[0434] 44. An article of manufacture comprising a container holding the aqueous pharmaceutical composition of any one of embodiments 1a, 1b, or 2-31.

[0435] 45. The article of manufacture of embodiment 44, wherein the container is a vial having a stopper that can be pierced by a syringe.

[0436] 46. The aqueous pharmaceutical composition of any one of embodiments 1a, 1b, or 2-31 for use in the treatment of cancer.

[0437] 47. The aqueous pharmaceutical composition of any one of embodiments 1a, 1b, or 2-31 for use in the manufacture of a medicament for the treatment of cancer.

[0438] 48. Use of the aqueous pharmaceutical composition of any one of embodiments 1a, 1b, or 2-31 for the treatment of cancer in a subject in need thereof, comprising administering the aqueous pharmaceutical composition to the subject in need thereof.

[0439] 49. The method of embodiment 48, wherein the administration is subcutaneous administration.

[0440] 50. The method of embodiment 32 or 33, wherein the human subject is an adult human having relapsed or refractory multiple myeloma and has received at least four prior therapies, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody.

[0441] 51. The method of embodiment 32 or 33, wherein the human subject is an adult human having relapsed and refractory multiple myeloma and has received at least 3 prior therapies, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody, and the human subject exhibits disease progression or does not respond to the last therapy.

[0442] 52a. The method of embodiment 50 or 51, comprising administering the aqueous pharmaceutical composition according to a dosing regimen based on the weight of the subject, wherein the dosing regimen comprises:

[0443] the aqueous pharmaceutical composition is administered subcutaneously to the subject at an escalating dose 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 the aqueous pharmaceutical composition administered subcutaneously to the subject at a therapeutic dose of 0.8 mg / kg once every two weeks,

[0444] wherein the aqueous pharmaceutical composition comprising 2 mg / mL talquetmumab is administered for the 0.01 mg / kg and 0.06 mg / kg doses, and the aqueous pharmaceutical composition comprising 40 mg / mL talquetmumab is administered for each of the 0.3 mg / kg and 0.8 mg / kg doses.

[0445] 52b. The method of embodiment 50 or 51, comprising administering the aqueous pharmaceutical composition according to a dosing regimen based on the subject’s body weight, wherein the dosing regimen comprises:

[0446] the aqueous pharmaceutical composition is administered subcutaneously to the subject at an escalating dose 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 the aqueous pharmaceutical composition administered subcutaneously to the subject at a therapeutic dose of 0.8 mg / kg once every two weeks,

[0447] wherein the aqueous pharmaceutical composition comprising 2 mg / mL talquetmumab is administered for the 0.01 mg / kg and 0.06 mg / kg doses, and the aqueous pharmaceutical composition comprising 40 mg / mL talquetmumab is administered for each of the 0.3 mg / kg and 0.8 mg / kg doses.

[0448] 53. The method of embodiment 50 or 51, comprising administering the aqueous pharmaceutical composition according to a dosing regimen based on the subject’s body weight, wherein the dosing regimen comprises:

[0449] the aqueous pharmaceutical composition is administered subcutaneously to the subject at an escalating dose of 0.01 mg / kg, 0.06 mg / kg, and 0.4 mg / kg on days 1, 3, and 5, respectively, followed by the aqueous pharmaceutical composition administered subcutaneously to the subject at a therapeutic dose of 0.4 mg / kg once every week,

[0450] wherein the aqueous pharmaceutical composition comprising 2 mg / mL talquetmumab is administered for the 0.01 mg / kg and 0.06 mg / kg doses, and the aqueous pharmaceutical composition comprising 40 mg / mL talquetmumab is administered for each of the 0.4 mg / kg doses.

[0451] 54. The method of any one of embodiments 52a, 52b, or 53, wherein the aqueous pharmaceutical composition comprising 2 mg / mL talquetupamab per 1.5 mL has the following composition: 3 mg talquetupamab, disodium edetate (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.

[0452] 55. The method of any one of embodiments 52a, 52b, 53, or 54, wherein the aqueous pharmaceutical composition comprising 40 mg / mL talquetupamab per 1 mL has the following composition: 40 mg talquetupamab, disodium edetate (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.

[0453] 56. The method of any one of embodiments 50, 51, 52a, 52b, or 53-55, further comprising administering a pre-treatment medication 1 hour to 3 hours prior to each escalation dose, wherein the pre-treatment medication comprises: a corticosteroid (oral or intravenous dexamethasone, 16 mg or equivalent dose); an antihistamine (oral or intravenous diphenhydramine, 50 mg or equivalent dose); and a fever-reducing agent (oral or intravenous acetaminophen, 650 mg to 1000 mg or equivalent dose).

[0454] 57. The method of any one of embodiments 50, 51, 52a, 52b, or 53-55, wherein the method is effective to induce partial response, very good partial response, complete response, or stringent complete response in the subject according to IMWG criteria.

[0455] 58. The method of any one of embodiments 50, 51, 52a, 52b, or 53-55, wherein the method produces an overall response rate (ORR) of at least 70% in a population of human subjects according to IMWG criteria.

[0456] 59. The aqueous pharmaceutical composition of any one of embodiments 1a, 1b, or 2-31, comprising talquetupamab,

[0457] wherein the composition is administered subcutaneously to a population of patients diagnosed with relapsed or refractory multiple myeloma based on the weight of each patient according to a dosing regimen that elicits an overall response rate (ORR) of at least 70% in the population after administration according to the IMWG criteria, the dosing regimen comprising subcutaneous administration of the composition at a dose of 0.01 mg / kg on day 1, 0.06 mg / kg on day 3, and 0.4 mg / kg on day 5, followed by subcutaneous administration of the composition to the subjects once a week at a dose of 0.4 mg / kg,

[0458] wherein the composition comprising 2 mg / mL talquetamab is administered for the doses of 0.01 mg / kg and 0.06 mg / kg, and the aqueous pharmaceutical composition comprising 40 mg / mL talquetamab is administered for each dose of 0.4 mg / kg,

[0459] wherein each patient in the population has received at least three or four prior therapies, the prior therapies comprising a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody.

[0460] 60. The aqueous pharmaceutical composition according to any one of embodiments 1a, 1b, or 2 to 31, comprising talquetamab,

[0461] wherein the composition is administered subcutaneously to a population of patients diagnosed with relapsed or refractory multiple myeloma based on the weight of each patient according to a dosing regimen that elicits an overall response rate (ORR) of at least 70% in the population after administration according to the IMWG criteria, the dosing regimen comprising subcutaneous administration of the composition at a dose of 0.01 mg / kg on day 1, 0.06 mg / kg on day 3, 0.3 mg / kg on day 5, and 0.8 mg / kg on day 7, followed by subcutaneous administration of the composition to the subjects every two weeks at a dose of 0.8 mg / kg,

[0462] wherein the composition comprising 2 mg / mL talquetamab is administered for the doses of 0.01 mg / kg and 0.06 mg / kg, and the aqueous pharmaceutical composition comprising 40 mg / mL talquetamab is administered for each dose of 0.3 mg / kg and 0.8 mg / kg,

[0463] wherein each patient in the population has received at least three or four prior therapies, the prior therapies comprising a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody.

[0464] 61. The aqueous pharmaceutical composition according to any one of embodiments 1a, 1b, or 2 to 31, comprising talquetamab,

[0465] wherein the composition is administered subcutaneously to a population of patients diagnosed with relapsed or refractory multiple myeloma based on the body weight of each patient according to a dosing regimen that elicits an overall response rate (ORR) of at least 70% in the population after administration according to IMWG criteria, the dosing regimen comprising subcutaneous administration of the composition at a dose of 0.01 mg / kg on day 1, 0.06 mg / kg on day 3, 0.4 mg / kg on day 5, and 0.8 mg / kg on day 7, followed by subcutaneous administration of the composition to the subjects at a dose of 0.8 mg / kg every two weeks,

[0466] wherein the composition comprising 2 mg / mL talquetmumab is administered for the doses of 0.01 mg / kg and 0.06 mg / kg, and the aqueous pharmaceutical composition comprising 40 mg / mL talquetmumab is administered for each of the doses of 0.4 mg / kg and 0.8 mg / kg,

[0467] wherein each patient in the population has received at least three or four prior therapies, the prior therapies comprising a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody.

[0468] Examples

[0469] The following examples are provided to further describe some of the embodiments disclosed herein. These examples are intended to be illustrative and not limiting of the disclosed embodiments.

[0470] Description of analytical tests used herein

[0471] Analytical Tests - General characterization

[0472] Solution Color

[0473] Solution color of the drug product is monitored to assess appearance and ensure that it is consistent with previous batches at release and over the shelf life. Solution color can be an indicator of product stability. To determine solution color, test samples are compared visually to a defined set of reference solutions.

[0474] A defined volume of the liquid content is transferred to a pre-scored ampoule of the same size as the reference solution. The contents of the ampoule are then compared visually to the European Pharmacopoeia color reference solutions. The colorimetry is determined under diffused daylight, observed against a white background.

[0475] Solution Color Materials and Methods

[0476] Materials and methods are as described in European Pharmacopoeia 2.2.2, Degree of colouring of liquids, European Pharmacopoeia 10th edition, monograph number 20202, July 2019. Briefly, the test article is compared to the B (brown), BY (brown-yellow) and Y (yellow) colour reference solutions. The stability of the aqueous pharmaceutical composition by pH determination is defined as provided herein.

[0477] pH

[0478] pH Materials and Methods - The pH of the test article is measured using a daily calibrated electronic pH meter with a standardized pH electrode. All calibration solutions, reference buffers and test articles are equilibrated and maintained at 25 °C before and during the test. The stability of the aqueous pharmaceutical composition by pH determination is defined as provided herein.

[0479] Turbidity

[0480] Turbidity Materials and Methods - Materials and methods are based on European Pharmacopoeia 2.2.1, Transparency and opalescence of liquids. The stability of the aqueous pharmaceutical composition by turbidity determination is defined as provided herein.

[0481] Analytical Tests - Sub-visible particles

[0482] Subvisible Particulate Material and Methods - All materials and methods comply with US Pharmacopeia <788> Particulate Matter. A compendial liquid particle counter instrument, equipped with a compendial volumetric sampling device, is used. The test article is equilibrated to room temperature for at least 60 minutes, but not more than 10 hours, before testing. The test article vials are pooled in a manner consistent with US Pharmacopeia <788> Particulate Matter. Four portions of the pooled test article are taken, each with an appropriate volume, and the number of particles equal to or greater than 10 pm and 25 pm in each portion is calculated, according to the guidance of US Pharmacopeia <788> Particulate Matter. The results obtained from the first portion are disregarded, and the remaining three results are used to calculate the average number of particles for the examined preparation.

[0483] Results in Accordance with the Particle Analysis (Subvisible) Pharmacopeia - The test results comply with US Pharmacopeia <788> Particulate Matter, European Pharmacopoeia 2.9.19 and Japanese Pharmacopoeia XVII / 6.07 Particulate contamination: sub-visible particles. Therefore, the average number of particles present in the tested unit should not exceed 6000 particles per container for particles equal to or greater than 10 pm in size, and 600 particles per container for particles equal to or greater than 25 pm in size.

[0484] Analytical Tests - Purity

[0485] Reduced Capillary Electrophoresis Sodium Dodecyl Sulfate (cSDS)

[0486] Reduced cSDS Materials and Methods - Analysis was performed using a commercial capillary electrophoresis system with bare fused silica capillaries of 50 pm internal diameter and 30.2 cm length in a temperature-controlled cartridge; the capillary was equipped with a detection window transparent to ultraviolet light. The capillary was electrically rinsed prior to each injection. The capillary was loaded with a sieving matrix composed of a coiled polymer solution prior to each sample analysis. The method utilized SDS-MW gel migration buffer and certified protein molecular weight standards spanning approximately 10 kDa to 148 kDa. The wavelength of the ultraviolet absorbance spectrophotometer detector of the instrument was set at 220 nm, and the capillary temperature was set at 25 °C. To reduce sample handling conditions, the test article (in duplicate) was mixed with SDS and 2-mercaptoethanol and then heated at a defined time and temperature to fully denature and reduce the proteins. The reduced sample was electrically injected by applying a voltage of 5 kV across both ends of the capillary for approximately 20 seconds and then analyzed by applying a larger electric field for approximately 35 minutes. Detection was accomplished by absorbance at 220 nm in the far ultraviolet region of the spectrum. The percent data signal was collected for 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.

[0487] Non-reduced Capillary Electrophoresis Sodium Dodecyl Sulfate (cSDS)

[0488] Non-reduced cSDS Materials and Methods- Analysis was performed using a commercial capillary electrophoresis system with bare fused silica capillaries in a temperature-controlled cartridge, 50 pm internal diameter, 30.2 cm in length; the capillary was equipped with a detection window transparent to UV light. The capillary was electrically rinsed prior to each injection. The capillary was loaded with a sieving matrix consisting of a coiled polymer solution prior to each sample analysis. The method utilized SDS-MW gel migration buffer, certified protein molecular weight standards spanning approximately 10 kDa to 148 kDa, and a validated talquetmab reference material sample. The wavelength of the UV absorbance spectrophotometer detector of the instrument was set at 220 nm, and the capillary temperature was set at 25 °C. For non-reduced sample treatment conditions, the test article (in duplicate) was mixed with SDS and an alkylating agent (N-ethylmaleimide to prevent disulfide bond scrambling or reformation). The protein was then denatured completely and the formation of fragments and artifacts bands was minimized by heating at a specified time and temperature. The non-reduced sample was then injected electrokinetically by applying a voltage of 5 kV across both ends of the capillary for approximately 20 seconds, and then analyzed by applying a larger electric field for approximately 35 minutes. Detection was accomplished by absorbance at 220 nm in the far UV region of the spectrum. The percent of total signal data was collected. The data was also analyzed for the presence of new peaks compared to the talquetmab reference material. The percent purity was defined as the percent heavy chain + percent light chain. The stability of the aqueous pharmaceutical composition as determined by cSDS is defined as provided herein.

[0489] Volume Exclusion High Performance Liquid Chromatography (SE-HPLC)

[0490] SE-HPLC Materials and Methods - The reference material and test article were diluted to a target protein concentration. A 20 mΐ volume of the analyte was injected onto a 7.8 mm x 30 cm size exclusion column with a 5 pm particle size silica matrix, with a fractionation range of 10 kDa to 500 kDa. An aqueous phosphate buffer was used as the mobile phase at a flow rate of 0.7 mL / min, and the absorbance of the eluent was continuously monitored at 280 nm. Monomer (the main component or main peak), 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 amount of these species was measured by monitoring the peak absorbance at 280 nm. The stability of the aqueous pharmaceutical composition as determined by SE-HPLC is defined as provided herein. The stability of the aqueous pharmaceutical composition as determined by MC of SE-HPLC is defined as provided herein. The stability of the aqueous pharmaceutical composition as determined by HMWS of SE-HPLC is defined as provided herein. The stability of the aqueous pharmaceutical composition as determined by LMWS of SE-HPLC is defined as provided herein.

[0491] Ion Exchange Chromatography (IEX)

[0492] IEX Materials and Methods

[0493] The analytical procedure was performed using an HPLC system with a diode array or UV detector, column heating capability, and temperature control. The stationary phase was a MAbPac SCX-10, 4 x 250 mm, 10 pm particle size, cation exchange column maintained at 35 °C + / - 2 °C. The mobile phase A was ThermoFisher CX-1 pH gradient buffer A at pH 5.6 diluted 1 : 10 in DI water. The mobile phase B was ThermoFisher CX-1 pH gradient buffer B at pH 10.2 diluted 1 : 10 in DI water. The reference material and test articles were diluted to the target protein concentration. A 10-100 pl aliquot was transferred to a sample vial and placed in the temperature controlled HPLC autosampler set to 5 °C + / - 2 °C. The run time for each sample was 16 minutes at a flow rate of 0.75 mL / minute. A gradient mediated by mobile phases A and B was applied, gradually increasing the mobile phase pH during the run. As the pH increased, isoforms became neutral and eluted from the column. The eluate was continuously monitored at 280 nm and the relative amount of each isoform was measured by comparing peak area counts. The largest peak observed was designated the main peak. All peaks / peak groups eluting prior to the main peak were designated acidic species and all peaks / peak groups eluting after the main peak were designated basic species. The stability of an aqueous pharmaceutical composition as determined by IEX is defined as provided herein. The stability of an aqueous pharmaceutical composition as determined by the main peak (MP) by IEX is defined as provided herein. The stability of an aqueous pharmaceutical composition as determined by the sum of acidic peaks by IEX is defined as provided herein. The stability of an aqueous pharmaceutical composition as determined by the sum of basic peaks by IEX is defined as provided herein.

[0494] Analytical Tests - Quantification

[0495] Protein Concentration by A280

[0496] The protein concentration of the drug product was determined by quantifying the absorbance at 280 nm (A280).

[0497] Protein Concentration by A280 Materials and Methods

[0498] Protein concentration was measured using a qualified and calibrated dual beam UV-visible spectrophotometer. The 40 mg / mL talquetamab test article was diluted 1 :80 using 0.9% (w / v) NaCl. The 2 mg / mL talquetamab test article was diluted 1 :6.7 using 0.9% (w / v) NaCl. Samples were measured using a quartz semi-micro cuvette with a 1 cm path length and black or frosted sides (1.4 mL). The spectrophotometer was set to a wavelength of 280 nm, a slit width of 1 nm, and a response of one (1) second. 0.9% (w / v) NaCl was used as a blank control. Protein concentration (mg / mL) was calculated by dividing the product of the test article absorbance and dilution factor by the product of the absorbance constant for the antibody and the path length of the instrument (e.g., but not limited to, the absorbance constant for talquetamab is 1.49 (mg / mL) -1cm-1 and the path length of the instrument is 1 cm). The stability of the 2 mg / mL aqueous pharmaceutical composition as determined by A280 protein concentration is defined as provided herein. The stability of the 40 mg / mL aqueous pharmaceutical composition as determined by A280 protein concentration is defined as provided herein.

[0499] Analytical Tests - Potency

[0500] Potency (GPRC5D / CD3 T cell activation)

[0501] An activated T cell nuclear factor-response element (NFAT-RE)-mediated luminescence assay was used to demonstrate in vitro T cell activation of the GPRC5D / CD3 bispecific antibodies as provided herein.

[0502] 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 were used as target cells. Engagement of the anti-GPRC5D Fab region with the target cells expressing GPRC5D and the anti-CD3 Fab region with the genetically engineered CD3+ T cells is required for T cell activation and subsequent NFAT-RE-mediated luminescence.

[0503] GPRC5D / CD3 T cell activation Materials and Methods Qualified talquetamab was used as a reference material and control. A solution of 1.3 x 10 6 live cells / mL Jurkat TCR / CD3 effector cells in culture medium (4% heat inactivated fetal bovine serum in RPMI) and 1.75 x 10 5MM.1R B lymphoblast cell target cell solution at 1 x 105viable cells / mL. Equal volumes of effector and target cells were aliquoted into individual wells of a 96-well cell culture plate. The plate was then incubated at 37°C (± 2°C) with 5% (± 2%) CO2for 16-24 hours. Following incubation, Bio-Glo™ luciferase substrate was added to each well and agitated moderately on a plate shaker for at least 5 minutes. Luminescence (relative light units (RLU) values) was measured within 30 minutes of substrate addition using a microtiter luminometer. Data is reported as percent bioactivity relative to a reference material. Stability of the aqueous pharmaceutical composition as determined by GPRC5D / CD3 T cell activation activity is defined as provided herein.

[0504] Analytical Tests - surfactants

[0505] Polysorbate-20 Quantitation

[0506] Polysorbate 20 was quantified by mixed mode ion exchange / hydrophobic HPLC.

[0507] PS20 Materials and Methods Analysis was performed using a gradient HPLC equipped with a 2.1 x 20 mm online column containing 30 pm water-wettable mixed mode polymeric spherical sorbent particles, ELSD, and a 30 °C temperature-controlled column compartment. The flow rate was set to 1 mL / min, and both the ELSD atomizer temperature and vaporizer temperature were set to 50 °C. Mobile phase A was 2% v / v formic acid in water, and mobile phase B was 2% v / v formic acid in isopropanol. Pure polysorbate 20 was used to generate calibration and check standard. Pure test article sample was injected. Stability of the aqueous pharmaceutical composition as determined by polysorbate 20 quantitation is defined as provided herein.

[0508] Analytical Tests - routine characterization

[0509] Peptide Mapping

[0510] The purpose of this test is to measure the level of post-translational modifications that can be present in the antibody structure, such as oxidation, deamidation, and isomerization. The test article is enzymatically digested to produce peptide fragments. These peptides are then evaluated by ultra-performance liquid chromatography mass spectrometry (UPLC-MS). Each peptide sequence analyzed is identified relative to its known position in the overall antibody structure. Post-translational modifications are determined by comparing the measured mass of the identified peptide sequence to its expected mass.

[0511] Peptide Mapping Materials and MethodsThe sample was denatured with 6M guanidine, 50mM Tris pH 8.0, and 5mM EDTA, and filtered using a 30kDa centrifugal filter (discarding the flow-through). The denatured sample was reduced with 1M dithiothreitol (DTT), followed by alkylation with 1M sodium iodoacetate, and further quenched with DTT. The reaction mixture was exchanged for digestion buffer (50mM Tris pH 7.0, containing 1mM CaCl2) through a Sephadex G-25 column, with separate columns for blank, reference, and test products. An aliquot of 1 mg / mL trypsin stock solution was added to the sample in the digestion buffer to produce a trypsin concentration of 20 μL / mL. The solution was incubated at 37°C for 2 h ± 30 min. The trypsin-digested solution was cooled to room temperature and the enzyme was inactivated with trifluoroacetic acid. The solution was then processed using a Waters Acquity BEH (ethylene-bridged hybrid) C18 column, 2.1 × 100 mm, 1.7 μm, The processed sample was evaluated using ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) with the column and connected autosampler. Mobile phase A was an aqueous solution of 0.1% formic acid, and mobile phase B was an acetonitrile solution of 0.1% FA. The autosampler was set to 2°C to 8°C, the column to 40°C, and the flow rate to 500 μL / min. The eluted peptides were electrospray ionized and detected using a calibrated online mass spectrometer.

[0512] Example 1: Early Formulation Development

[0513] High Throughput (HTP) Multi-Factor Screening Study

[0514] High-throughput (HTP) multifactor screening studies were conducted to select the combination of buffer type and concentration, excipient type, and pH. This was achieved by generating multiple test formulations consisting of various combinations of buffer type and concentration, excipient, and pH. The target antibody concentration used in all test formulations was 2 mg / mL. Sucrose was evaluated at 8.5% (w / v), and sorbitol was evaluated at 5.0% (w / v).

[0515] In this study, approximately 200 μL of each test formulation was aliquoted into 96-well plates, sealed to prevent evaporation, and maintained under stress (40 °C) stability conditions for three weeks. The test formulations were then analyzed by SEC. The composition of the test formulations and their corresponding SEC results are listed in Tables 7, 8, and 9 below, categorized by buffer type. Main effect plots calculated from all test formulation data were generated using Minitab 19.0 statistical software. Figure 1 , Figure 2 and Figure 3 ).

[0516] Table 7: Composition of acetate formulations and corresponding SEC results

[0517]

[0518]

[0519] Table 8: Composition of Histidine Formulations and Corresponding SEC Results

[0520]

[0521]

[0522] Table 9: Composition of Phosphate Formulations and Corresponding SEC Results

[0523]

[0524]

[0525] As seen in Figure 1 , the pH appears to have a strong nonlinear biphasic effect on the response of % monomer, with the pH value at the vertex of the curve being about 5.4. As seen in Figure 2 and Figure 3 , respectively, the test formulations above 5.4 resulted in loss of monomer primarily due to aggregation, while the test formulations below pH 5.4 appeared to result in loss of monomer due to fragmentation. The monomer values at pH 5.1 and 5.6 were slightly lower than at 5.4. However, when the pH was above 5.6 or below 5.1, the loss of monomer was steeply nonlinear, indicating that there is a limited pH range in which the formulation can remain stable. Based on the relationship of the pH curve to the buffer species, histidine and phosphate were eliminated as buffers.

[0526] To further evaluate the acetate buffer, a second set of main effects plots was generated using only the data from the acetate test formulations Figure 4 , Figure 5 , Figure 6 ).

[0527] Figure 5 and Figure 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 monomer. However, the curve appears to plateau at pH 5.1.

[0528] Figure 4 and Figure 6 show that decreasing the concentration of acetate buffer is associated with increased stability, while Figure 5 shows that the concentration of acetate buffer has no significant effect on aggregation. Figure 4 and Figure 5DP showed a slight increase in stability compared to sucrose, while Figure 6 DP showed a slight increase in stability compared to sucrose, while

[0529] In summary, these early screening studies identified the optimal formulation consisting of a low concentration of acetate buffer and a pH between 5.1 and 5.4. Based on practical considerations, sucrose was selected as the excipient.

[0530] Oxidative Stress Screening Study

[0531] 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 the DP test formulation, and the test formulation was stored under stress (40°C) stability conditions for one month. As a mitigation strategy, EDTA was also added to the test formulation to evaluate its ability to mitigate oxidation.

[0532] The study included three experimental formulations: 1) no metals, 2) with metals, and 3) with metals and EDTA. The no metals 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 with metals test formulation consisted of the no metals test formulation spiked with trace (low ppb) metals. The species of metals selected for this study were based on the composition of metal alloy components that can be present in the manufacturing process. The concentrations of trace metals used in this study were 2x to 20x the values of trace metals historically reported in the literature for the DP manufacturing process. The with metals and EDTA test formulation was formulated on the basis of the with metals test formulation supplemented with 20 pg / mL EDTA.

[0533] The test formulations were aliquoted into 8R vials at 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. The samples were then removed and assayed.

[0534] The metal-free test formulation showed an increase in HMWS as measured by SE-HPLC and a decrease in purity as measured by non-reduced and reduced cSDS after one month of storage under stress (40 °C) stability conditions (Table 10). These results are consistent with the monoclonal antibody stored under stress (40 °C) stability conditions for one month. The metal-containing test formulation showed a significant increase in HMWS and a significant decrease in purity compared to the metal-free test formulation at the same time point. This data indicates that the species and concentration of trace metals used in this study resulted in an increase in degradation compared to the similar test formulation without metals after one month of storage under stress (40 °C) stability conditions. However, the metal-containing and EDTA test formulation showed assay values consistent with the metal-free test formulation. These data indicate that the addition of EDTA to the test formulation mitigated the increased effect of trace metals on degradation of the metal-containing test formulation after one month of storage under stress (40 °C) stability conditions.

[0535] Table 10: Effect of Metal Ions on Stability of DP at 40 °C for 1 Month Storage

[0536]

[0537]

[0538] Based on the results of this preliminary oxidative stress screening study, EDTA was added to the DP formulation.

[0539] Example 2: Oscillating within a range of polysorbate concentrations

[0540] An oscillatory stress study was performed to evaluate a range of polysorbate concentrations that were able to maintain the stability of the mAb to mechanical stress. This study evaluated formulations containing PS20 at concentrations ranging from 0.01% to 0.08% (w / v). PS20 was incorporated into formulations containing 2 mg / mL and 40 mg / mL of talquetenevum at PS20 concentrations of 0.01%, 0.02%, 0.04%, 0.06%, and 0.08% (w / v) in 15 mM acetate, 8% (w / v) sucrose, 0.02 mg / mL EDTA (pH 5.2). The 2 mg / mL formulations were filled into 6 mL Type 1 glass vials at a fill volume of 2.0 mL and the 40 mg / mL formulations were filled into 2 mL Type 1 glass vials at a fill volume of 1.4 mL. The vials were placed on an orbital platform shaker and shaken at 250 rpm for 24 hours at ambient temperature. Samples were analyzed and the results are shown in Tables 11 and 12.

[0541] No significant changes were observed between formulations for PS20 concentrations ranging between 0.02% and 0.08% (w / v) after stirring for at least 24 hours. The sub-visible results for all PS20 concentrations and conditions can be considered essentially identical when viewed in the context of the size of the compendial acceptance criteria values and overall methodology. For the formulation containing 0.01% PS20, there was a slight increase in HMWS (%) and loss of major component (%) (aggregates and monomers %, respectively). However, these values are consistent with the definition of a stable aqueous pharmaceutical composition provided herein.

[0542] This study demonstrates that talquetene mab formulations containing 0.01% to 0.08% (w / v) PS20 remain stable under conditions of mechanical stress.

[0543] Table 11: Results of stirring stress study of different concentrations of PS20 (2 mg / mL and 40 mg / mL DP formulations)

[0544]

[0545] a) Formulations were composed of 2 mg / mL or 40 mg / mL talquetene mab in 15 mM acetate, 8% (w / v) sucrose, 0.02 mg / mL EDTA (pH 5.2) and PS20 was added according to the levels described in the table.

[0546] Table 12: Results of stirring stress study of different concentrations of PS20 (2 mg / mL and 40 mg / mL DP formulations)

[0547]

[0548] a) Formulations were composed of 2 mg / mL or 40 mg / mL talquetene mab in 15 mM acetate, 8% (w / v) sucrose, 0.02 mg / mL EDTA (pH 5.2) and PS20 was added according to the levels described in the table.

[0549] Example 3: Freeze-thaw stress study

[0550] A study was conducted to demonstrate the robustness of the formulation to the physical-chemical stress induced by repeated freeze-thaw cycles.

[0551] In this study, 2 mg / mL and 40 mg / mL formulations (15 mM acetate, 8% (w / v) sucrose, 20 pg / mL EDTA, 0.04% (w / v) PS20, pH 5.2) were filled into 5 mL size polycarbonate vials and placed upright in a -70 °C freezer. Upon completion of freezing, the vials were removed from the freezer and placed at ambient temperature for thawing. Once completely thawed, the vials were gently rotated to ensure solution homogeneity and then repeated freeze-thaw (F / T) until a total of 5 cycles were completed. Control samples did not undergo any freeze-thaw cycles. Both control and freeze-thaw samples were analyzed.

[0552] As shown in Table 13, the quality attributes of the samples that underwent five F / T cycles were nearly identical to the control samples that were stored at 2 °C to 8 °C and did not experience freeze-thaw conditions. Additionally, no significant changes in protein concentration, solution color, pH, or turbidity were observed.

[0553]

[0554] The results of this study demonstrate the robustness of the 2 mg / mL and 40 mg / mL formulations to freeze-thaw induced stress.

[0555] Example 4: Study of Metal Spirals

[0556] A study was conducted to further evaluate the impact of metal ions that can be present or introduced in the drug product during the manufacturing process on the 2 mg / mL and 40 mg / mL teplizumab DP formulations.

[0557] The test formulations consisted of 2 mg / mL or 40 mg / mL teplizumab, 15 mM acetate, 8% sucrose, 20 pg / mL EDTA, and 0.04% PS20 (pH 5.2) with or without addition of iron (Fe 3+ ), chromium (Cr 3+ ), copper (Cu 2+ ), nickel (Ni 2+ ), and molybdenum (Mo 5 + ). The selection of metals was based on the composition of metal alloy components that can be present in the manufacturing process. To demonstrate robustness, the stress conditions were intensified by utilizing metal concentrations that were 5- to 13-fold higher than the trace metal values historically reported in the literature for the DP manufacturing process.

[0558] Test formulations at 2 mg / mL were aliquoted into 6R vials at a fill volume of 3.5 mL and test formulations at 40 mg / mL were aliquoted into 2 mL vials at a fill volume of 2.0 mL. All vials were stoppered, capped, and crimp-sealed. Vials were placed on stability at both the recommended (5°C) and accelerated (25°C) conditions for up to 6 months. At the designated time points, samples were withdrawn and assayed.

[0559] As shown in Table 14, the quality attributes of the 2 mg / mL and 40 mg / mL formulations stressed with metal ions were nearly identical to their respective control formulations after 6 months of storage at 2°C to 8°C. Furthermore, there was little change in the quality attribute values at 6 months compared to the T=0 values for all test formulations stored at 2°C to 8°C. Finally, the quality attribute values for all formulations spiked with metals and stored at 2°C to 8°C for six months were consistent with the definition of a stable aqueous pharmaceutical composition provided herein.

[0560] As shown in Table 15, the quality attributes of the 2 mg / mL and 40 mg / mL formulations stressed with metal ions were nearly identical to their respective control formulations after 6 months of storage at 25°C. There was a slight to minimal change in some of the quality attribute values observed at 6 months compared to the T=0 values for all test formulations. The degree of change was consistent with the expected degradation of those monoclonal antibody quality attributes when stored at 25°C for six months. Finally, the quality attribute values for all formulations spiked with metals and stored at 25°C for six months were consistent with the definition of a stable aqueous pharmaceutical composition provided herein.

[0561] In summary, the data demonstrate the robustness of the 2 mg / mL and 40 mg / mL formulations to potential oxidative stress experienced during normal and / or intensified drug product manufacturing processes and storage conditions.

[0562]

[0563]

[0564] Example 5: Development of Formulation Robustness

[0565] Research Design

[0566] A stable monoclonal antibody formulation is the net effect of complex interactions between formulation components. To evaluate these interactions, a design of experiments (DOE) methodology was used to create a multi-factor stability study in which a statistically determined number of experimental test formulations were generated that simultaneously varied parameters of the formulation components. Statistical analysis of the study results provided a quantitative understanding of how the formulation parameters interacted to affect the stability attributes and, in turn, demonstrated the robustness of the formulation.

[0567] The experimental test formulations of the GPRC5DxCD3 drug product were maintained for up to 12 months under recommended (5°C) conditions and up to 6 months under accelerated (25°C) conditions. The formulation components evaluated included protein concentration, acetate concentration, sucrose concentration, polysorbate 20 concentration, EDTA concentration, and pH. The concentration ranges of the tested factors are listed in Table 16 (target formulation values ​​are included in the table for context). This study covered both 2 mg / mL and 40 mg / mL DP formulations. The typical protein concentration range used for evaluation was + / - 12% of the target value. Therefore, the upper limit of protein concentration selected in this study corresponds to 112% of the 40 mg / mL formulation. For convenience, a lower protein concentration of 1 mg / mL (50% of the 2 mg / mL formulation) was used.

[0568] Table 16: Range of tested factor concentrations

[0569] Test Factor Low Target high Protein (mg / mL) 1 n / a 45 pH 4.6 5.2 5.8 Acetate (mM) 10 15 20 Sucrose concentration (%w / v) 6 8 10 EDTA concentration (μg / mL) 7.5 20 32.5 PS20 concentration (% w / v) 0.015 0.04 0.065

[0570] Based on this standard, use Statistical software was used to create a partial factorial design with 6 factors and type IV resolution (Table 17).

[0571] Table 17: Composition of the test formulation

[0572]

[0573] Stopper, cap, and seal the vial with a rolled edge. Stabilize the vial under recommended (5°C) and accelerated (25°C) conditions. At the specified time points, extract samples and perform measurements.

[0574] Research Results

[0575] The test results for each attribute of the sixteen formulations at the start of the study (time zero), after 6 months at accelerated temperature (25°C), and after 6 and 12 months under recommended storage conditions (5°C) are shown in Table 18. Data are reported as the range, mean, and standard deviation for each attribute of the sixteen formulations.

[0576] Analytical results for all formulations stored at 5°C for 12 months showed almost no change in the measured test values, indicating stability. The ability of all formulations with multivariable ranges of excipient concentrations to produce narrow ranges of measured test values ​​demonstrates the robustness of the formulations within the tested boundaries and storage conditions. Furthermore, the full range of values ​​observed in this study is consistent with the definition provided herein of aqueous pharmaceutical compositions that are stable when stored at 5°C for 12 months.

[0577] Analytical results for all formulations held at accelerated (25°C) for 6 months showed degradation effects consistent with the stability characteristics of GPRC5DxCD3 antibodies exposed to extended accelerated storage conditions, as evidenced by the increased range of result values ​​compared to both at the start of the study (time zero) and after 12 months at 5°C. However, when held at accelerated (25°C) for 6 months, the calculated mean and full range of values ​​observed for all nine assays were consistent with the definition of stable aqueous pharmaceutical compositions provided herein.

[0578]

[0579] Statistical analysis of research results

[0580] Factorial regression models were used to statistically analyze the 2℃ to 8℃ data from 12M to determine which factors had a statistically significant effect on a given response. Table 19 lists the calculated p-values ​​for each factor relative to a given response and the corresponding adjusted R-squared values ​​generated by the model. A p-value less than 0.05 was considered statistically significant.

[0581] Table 19: Calculated p-values ​​for each factor relative to a given response

[0582]

[0583] API concentration

[0584] API concentration showed a statistically significant negative correlation with monomer percentage and a correspondingly significant positive correlation with aggregate percentage. These trends suggest that increasing API concentration is associated with decreased stability as measured by SEC. However, within the concentration range evaluated in this study (1 mg / mL to 90 mg / mL), the observed monomer percentage and aggregate percentage results are consistent with the definition of a stable aqueous pharmaceutical composition as provided herein.

[0585] API concentration also showed a statistically significant positive correlation with peak percentage (%). However, as shown in Table 19, the range of peak percentage results for this attribute was considered very narrow. Therefore, although calculated to be statistically significant, API concentrations from 1 mg / mL to 90 mg / mL were not considered to have a practical effect on peak percentage.

[0586] Formulation pH

[0587] 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 an increase in pH is associated with a decrease in stability as measured by SEC. However, within the pH range evaluated in this study (4.7 to 5.7), the range of % monomer and % aggregate determinations observed is consistent with the definition of a stable aqueous pharmaceutical composition as provided herein.

[0588] pH also showed a statistically significant negative correlation with % main peak, while also showing a corresponding statistically significant positive correlation with % acidic peak. However, similar to API concentration, and as shown in Table 19, the range of result values for % acidic peak and % main peak was considered very narrow for these three attributes. Therefore, although statistically significant as calculated, the pH of 4.7 to 5.7 was not considered to have a practical impact on % acidic peak and % main peak.

[0589] Example 6: Preparation of drugs for mass production

[0590] Method Description

[0591] Treatment solution

[0592] Table 20: Target Composition and Scope of the Treatment Solution

[0593]

[0594] Ultrafiltration / difiltration (UF / DF)

[0595] Ultrafiltration / diafiltration (UF / DF) was performed to reconstitute the talimogene laherparapovec Planova filtrate intermediate manufacturing solution into a pre-formulated bulk (pFB) solution consisting of 90 mg / mL talimogene laherparapovec, 10 mM acetate, 8% (w / v) sucrose, pH 5.2.

[0596] Preparation of Taquituzumab formulation (FB)

[0597] A polysorbate 20 (4.0% w / v) and EDTA (2 mg / mL) stock solution was added to the pFB at a 1 : 100 dilution to achieve a final concentration of 0.04% (w / v) polysorbate 20 and 20 pg / mL EDTA, resulting in a formulated bulk (FB) consisting of 90 mg / mL talimogene laherparapovec, 15 mM acetate, 8% (w / v) sucrose, 0.04% polysorbate 20, 20 pg / mL EDTA, pH 5.2. The FB solution was then mixed uniformly. Final filtration of the formulated bulk was achieved using a sterile 0.45 pm / 0.22 pm filter, followed by subsequent use of an in-line 0.22 pm filter.

[0598] Final body filling

[0599] After final filtration, the FB is filled into a polycarbonate bioreactor. The fill volume is between 20% and 90% of the specified volume of the bioreactor.

[0600] Final storage and transportation

[0601] The storage and transportation conditions for the drug product preformulation bulk are: if the FB is stored for about one week or less, at 5 °C ± 3 °C protected from light, if the FB is stored for more than one week, at -40 °C ± 10 °C protected from light.

[0602] Example 7: Production of 40 mg / mL DP solution

[0603] Dilution of Taquituzumab formulation (FB)

[0604] Dilution is performed to reconstitute the daratumumab preformulation bulk intermediate manufacturing solution into a drug product solution consisting of 40 mg / mL daratumumab, 15 mM acetate, 8% (w / v) sucrose, 20 pg / mL EDTA, pH 5.2.

[0605] Dilution buffer

[0606] A tabular summary of the composition of the dilution buffer in Table 21 is provided herein. Final filtration of the dilution buffer is achieved using a sterile 0.22 pm filter.

[0607]

[0608] Preparation of Taquitumab 40 mg / mL drug product solution

[0609] The dilution buffer is added to 90 mg / mL FB, resulting in a 40 mg / mL drug product solution consisting of 40 mg / mL daratumumab, 15 mM acetate, 8% (w / v) sucrose, 0.04% polysorbate 20, 20 pg / mL EDTA, pH 5.2.

[0610] Example 8: 40 mg / mL pharmaceutical product formulation: composition and components of primary packaging

[0611] A tabular summary of the composition of the 40 mg / mL daratumumab drug product formulation in Tables 22 and 23 is provided herein.

[0612] Table 22: Composition of 40 mg / mL daratumumab drug product

[0613]

[0614]

[0615] Table 23: Composition of the 40 mg / mL Taquitumab drug product

[0616] Components Amount per mL Taquituzumab 40mg Sodium acetate 0.90mg glacial acetic acid 0.240mg sucrose 80mg Polysorbate 20 0.40mg Disodium EDTA 0.018mg Water for Injection Add an appropriate amount to 1.0 mL.

[0617] 40 mg / mL taspoglutamab drug product (DP) primary packaging consists of a glass vial, a polymeric vial stopper, and an aluminum seal. Table 24 provides the specific components of the primary packaging materials for the 40 mg / mL DP packaging configuration.

[0618] Table 24: Components of 40 mg / mL DP Primary Packaging Material

[0619] Components describe glass bottle 2mL glass type 1 borosilicate plug 13mm ear tips 4432 / 50 grey with Flurotec coating, RTS Seals 13mm aluminum seal with flip cover

[0620] Example 9: Production of 2 mg / mL DP solution

[0621] Dilution of Taquituzumab formulation (FB)

[0622] Dilution was performed to reconstitute the taspoglutamab formulation bulk intermediate manufacturing solution into a drug product solution consisting of 2 mg / mL taspoglutamab, 15 mM acetate, 8% (w / v) sucrose, 20 pg / mL EDTA, pH 5.2.

[0623] Dilution buffer

[0624] A tabular summary of the composition of the dilution buffer in Table 25 is provided herein. Final filtration of the dilution buffer was achieved using a sterile 0.22 pm filter.

[0625] Table 25: Composition of dilution buffer

[0626]

[0627] Preparation of Taquitumab 2 mg / mL drug product solution

[0628] Dilution buffer was added to 90 mg / mL FB, resulting in a 2 mg / mL drug product solution consisting of 2 mg / mL taspoglutamab, 15 mM acetate, 8% (w / v) sucrose, 0.04% polysorbate 20, 20 pg / mL EDTA, pH 5.2.

[0629] Example 10: 2 mg / mL pharmaceutical product formulation: composition and components of primary packaging

[0630] A tabular summary of the composition of the 2 mg / mL taspoglutamab drug product formulation in Tables 26 and 27 is provided herein.

[0631] Table 26: Composition of the 2 mg / mL Taquitumab drug product

[0632] Components Amount per mL Taquituzumab 2mg Sodium acetate trihydrate 1.497mg glacial acetic acid 0.240mg sucrose 80mg Polysorbate 20 0.40mg EDTA disodium salt dihydrate 0.02mg Water for Injection Add an appropriate amount to 1.0 mL.

[0633] Table 27: Composition of the 2 mg / mL Taquitumab drug product

[0634] Components per 1.5 mL Taquituzumab 3mg Sodium acetate 1.39mg glacial acetic acid 0.36mg sucrose 120mg Polysorbate 20 0.60mg Disodium EDTA 0.027mg Water for Injection Add an appropriate amount to 1.5 mL.

[0635] 2 mg / mL taspoglutamab drug product (DP) primary packaging 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 packaging configuration.

[0636] Table 28: Components of Primary Packaging Material for 2 mg / mL DP

[0637] Components describe glass bottle 6R glass type 1 borosilicate plug 20 mm stopper 4023 / 50 gray with Flurotec coating, RTS Seal 20 mm aluminum seal with flip-off

[0638] Example 11: Description of the 40 mg / mL stability study

[0639] This study was conducted to monitor the stability attributes of taspoglutamab 40 mg / mL drug product under various environmental conditions and lengths of time. The study test articles were prepared by aliquoting the formulated bulk into 2 mL vials at a fill volume of 1.4 mL. The vials were stoppered, capped, and crimp-sealed

[0640] All studies were conducted with the vials in an inverted orientation.

[0641] Table 29: Study parameters

[0642] Stability classification Storage condition Duration (months) Real time 5±3℃ 36 Accelerated 25 ± 2 °C / 60% RH 12 Stressed 40 ± 2 °C / 75% RH 6

[0643] Stability study results

[0644] The stability results for taspoglutamab DP held under recommended, accelerated, and stressed conditions are shown below. At all time points for 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 in each assay study exceeded the criteria consistent with the definition of a stable aqueous pharmaceutical composition provided herein. Similarly, peptide map results showed little or no subsequent change in the percentage of post-translational modifications measured over time.

[0645] The results for taspoglutamab DP held under accelerated and stressed conditions show the expected rate of degradation of the drug product over long-term exposure to accelerated and stressed storage conditions. Of particular note, all test parameter result values observed in each assay study for DP held at accelerated conditions (25 °C) for 12 months showed results consistent with the definition of a stable aqueous pharmaceutical composition provided herein.

[0646] 5 °C data

[0647]

[0648]

[0649] 25 °C data

[0650]

[0651]

[0652] 40℃ data

[0653]

[0654]

[0655] Example 12: Description of the 2 mg / mL stability study

[0656] This study was conducted to monitor the stability properties of the taquitumab 2 mg / mL drug product under various environmental conditions and time durations. The study test product was prepared by aliquoting the formulation into 6R vials at 2.0 mL filler volumes. The vials were then capped, stoppered, and crimped for sealing.

[0657] All studies were conducted with the vials in an inverted orientation.

[0658] Table 42: Study parameters

[0659]

[0660] Stability study results

[0661] The stability results of taquitumab DP maintained under recommended, accelerated, and stress conditions are shown below. At all time points of DP maintained under recommended storage conditions (after approximately 12 months or longer storage at approximately 5°C, and / or after approximately 2 years or longer storage at approximately 5°C), all test parameter results observed in each assay study exceeded the criteria consistent with the definition of a stable aqueous pharmaceutical composition presented herein. Similarly, peptide mapping results showed little or no subsequent change in the measured percentage of post-translational modifications over time.

[0662] Results for tanezumab DP held under accelerated and stressed conditions show the expected rate of degradation of the drug product upon long-term exposure to accelerated and stressed storage conditions. Of particular note, the majority of test parameter result values observed for each of the assay studies for DP held at 12 months under accelerated conditions (25°C) show results consistent with the definition of a stable aqueous pharmaceutical composition provided herein, with the exception of one result, all results fell within the defined stability parameters. Interestingly, the only outlier was at the six-month time point, with nine-month data indicating that DP was stable at nine months under accelerated conditions. This can suggest that the six-month data for T-cell activation represents an outlier, and thus for all test parameter results, DP can be considered consistent with the definition of a stable aqueous pharmaceutical composition provided herein.

[0663] 5 °C data

[0664]

[0665]

[0666]

[0667] 25 °C data

[0668]

[0669]

[0670] 40 °C data

[0671]

[0672]

[0673] Example 13: Stability of formulations containing 30 mg / mL, 60 mg / mL, and 90 mg / mL talquetmumab

[0674] To examine the stability of formulations with higher tanezumab concentrations, three formulations containing 30 mg / mL, 60 mg / mL, and 90 mg / mL tanezumab, respectively, were placed in stability at 2°C to 8°C and 25°C for up to 18 months. For all three formulations, the target composition was 15 mM acetate, 8% (w / v) sucrose, 20 pg / mL EDTA disodium, 0.04% (w / v) PS20 (pH 5.2). The formulations were analyzed for major components, aggregate and fragment content by SE-HPLC, purity by cSDS (reduced and non-reduced), charge heterogeneity by cIEF, and sub-visible particulate matter by light obscuration (LO).

[0675] No substantial changes were observed for cIEF and cSDS (reduced and non-reduced) data and sub-visible particle counts (data not shown).

[0676] SE-HPLC data for all three formulations (Table 55) showed nearly identical stability profiles at 2°C to 8°C over 18 months, with all reported values consistent with the most preferred embodiment of stability.

[0677] Comparing the stability profiles of all three formulations at 25°C over 3 months showed a slight but present correlation of increasing protein concentration and decreasing major component. However, the magnitude of the decrease occurred in a narrow range, with all protein concentrations showing major component values consistent with the most preferred stability embodiment.

[0678] Table 55: SE-HPLC data for 30 mg / mL, 60 mg / mL, and 90 mg / mL formulations

[0679]

[0680] a30 mg / mL formulation sample drawn at 6-month time point

[0681] NA = not applicable

[0682] Example 14: Phase 1 study of talquetmumab as monotherapy for relapsed or refractory multiple myeloma Table 56: Efficacy results of MMY1001 (MonumenTAL-1) in patients receiving 0.4 mg / kg talquetmumab weekly

[0683] In a single-arm, open-label, multicenter study, MMY1001 (MonumenTAL-1) (NCT03399799, NCT04634552), the efficacy of talquetamab monotherapy was evaluated in patients with relapsed or refractory multiple myeloma. The study included patients who had received at least three prior therapies, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. The study included patients who received prior T cell redirecting therapy (N = 34). During the first week of treatment, patients received 0.4 mg / kg talquetamab subcutaneously weekly after two escalating doses (0.01 mg / kg and 0.06 mg / kg), or 0.8 mg / kg talquetamab subcutaneously every two weeks (every 2 weeks) after three escalating doses (0.01 mg / kg, 0.06 mg / kg, and 0.3 mg / kg), until disease progression or unacceptable toxicity occurred. During the escalation phase, patients were hospitalized for monitoring for at least 48 hours after each talquetamab dosing.

[0684] In the subcutaneous administration cohort, a significant number of patients received formulations of talquetamab at a concentration of 2 mg / mL (escalating doses of 0.01 mg / kg and 0.06 mg / kg) and formulations of talquetamab at a concentration of 40 mg / mL (doses of 0.4 mg / kg and 0.8 mg / kg) as shown in Tables 27 and 23, respectively.

[0685] In the 122 patients who were unexposed to prior T cell redirecting therapies treated with 0.4 mg / kg talquetamab weekly, the median age was 67 (range: 47 to 86) years, 53% were male, 92% were White, and 7% were Black or African American. Patients received a median of 5 (range: 3 to 13) prior therapies, and 77% of patients had previously received autologous stem cell transplant (ASCT). 93% of patients were refractory to their last therapy, and 75% were refractory to proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies. Among the 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.

[0686] In the 109 patients who were unexposed to prior T cell redirecting therapies treated with 0.8 mg / kg talquetamab every two weeks, the median age was 67 (range: 38 to 82) years, 61% were male, 87% were White, and 6% were Black or African American. Patients received a median of 5 (range: 3 to 12) prior therapies, and 79% of patients had previously received autologous stem cell transplant (ASCT). 95% of patients were refractory to their last therapy, and 69% were refractory to proteasome inhibitors (PIs), immunomodulatory drugs, 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.

[0687] Efficacy results were based on overall response rate (ORR) assessed by an independent review committee using IMWG criteria.

[0688] Table 57: Efficacy results of MMY1001 (MonumenTAL-1) in patients receiving 0.8 mg / kg talquetmumab every two weeks (q2w) ​

[0689]

[0690]

[0691] CI = confidence interval; MRD = minimal residual disease; NE = not estimable. The median duration of follow-up was 14.7 months.

[0692] a MRD-negative rate was defined as the proportion of participants who achieved MRD-negative status at any time point after initial dose and prior to disease progression (PD) or subsequent anti-myeloma therapy (10 -5 test threshold) until death / progression / subsequent therapy (excluding subsequent therapy).

[0693] b MRD assessments performed within 3 months of achieving CR / sCR (10 -5 test threshold) until death / progression / subsequent therapy (excluding subsequent therapy).

[0694] ​ ​

[0695]

[0696] CI = confidence interval; MRD = minimal residual disease; NE = not estimable

[0697] Median duration of follow-up = 8.1 months.

[0698] a MRD-negative rate was defined as the proportion of participants who achieved MRD-negative status at any time point after initial dose and prior to disease progression (PD) or subsequent anti-myeloma therapy (10 -5 test threshold) until death / progression / subsequent therapy (excluding subsequent therapy).

[0699] b MRD assessments performed within 3 months of achieving CR / sCR (10 -5 test threshold) until death / progression / subsequent therapy (excluding subsequent therapy).

[0700] For the dosing regimen of 0.4 mg / kg every week and 0.8 mg / kg every two weeks (every 2 weeks), the median time to first response was 1.2 (range: 0.2 to 10.9) months and 1.3 (range: 0.2 to 9.2) months, respectively. ORR results were consistent across pre-specified subgroups, including number of prior lines of therapy, refractoriness to prior therapies, and cytogenetic risk at baseline.

[0701] MMY1001 also included 34 patients who were exposed to prior T cell redirecting therapies and had received at least three prior therapies including PI, immunomodulatory drugs, and anti-CD38 monoclonal antibodies. Patients received 0.4 mg / kg of talquetamab subcutaneously once weekly after 2 ascending doses (0.01 mg / kg and 0.06 mg / kg) until disease progression or unacceptable toxicity occurred. Median age was 60 (range: 38 to 78) years, 59% were male, 97% were White, and 3% were Black or African American. Patients received a median of 6 (range: 3 to 15) prior therapies. Prior T cell redirecting therapies were CAR-T cell therapy in 82% of patients and bispecific antibody treatment in 24% of patients. The median duration of follow-up was 9.9 months, and ORR was 71% at each IRC assessment.

[0702] Talquetamab exposure was comparable in both dosing regimens. No clinically significant impact of anti-talquetamab antibodies on PK, efficacy, or AEs was observed. PD changes were comparable in both dosing regimens and were consistent with talquetamab activity, including T cell activation, redistribution, and cytokine induction. Overall, talquetamab showed robust efficacy and manageable safety in heavily pretreated patients with relapsed or refractory multiple myeloma.

Claims

1. An aqueous pharmaceutical composition comprising: a) a bispecific G Protein-Coupled Receptor Family 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, the bispecific GPRC5D / CD3 antibody, or antigen-binding fragment thereof, comprising: (1) a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1), wherein the VH1 comprises a 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 a LC1 variable region (VL1), wherein the 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 a HC2 variable region 2 (VH2), wherein the VH2 comprises a 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 (4) a second light chain (LC2) comprising a LC2 variable region 2 (VL2), wherein the 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; 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 pg / mL to about 33 pg / 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.

2. An aqueous pharmaceutical composition comprising: a) a bispecific G Protein-Coupled Receptor Family 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, the bispecific GPRC5D / CD3 antibody, or antigen-binding fragment thereof, comprising: (1) a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1), wherein the VH1 comprises a 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 a LC1 variable region (VL1), wherein the 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 a HC2 variable region 2 (VH2), wherein the VH2 comprises a 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 (4) a second light chain (LC2) comprising a LC2 variable region 2 (VL2), wherein the 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; wherein the VH2 comprises heavy chain complementarity determining regions 1 (HCDR1), HCDR2, and HCDR3, respectively, having the amino acid sequences of SEQ ID NOs: 11, 12, and 13; and (4) a second light chain (LC2) comprising a LC2 variable region 2 (VL2), wherein the VL2 comprises light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, respectively, having the amino acid sequences of SEQ ID NOs: 14, 15, and 16; 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 pg / mL to about 33 pg / 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.

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

10.

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

20.

7. The aqueous pharmaceutical composition according to claim 1 or 2, wherein, The bispecific GPRC5D / CD3 antibody is talquetamab.

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

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

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

14. The aqueous pharmaceutical composition according to claim 1 or 2, wherein, The composition comprises about 12 mM to about 18 mM acetate and / or a pharmaceutically acceptable acetate salt.

15. The aqueous pharmaceutical composition according to claim 1 or 2, wherein, The composition comprises about 14 mM to about 16 mM acetate and / or a pharmaceutically acceptable acetate salt.

16. The aqueous pharmaceutical composition according to claim 1 or 2, wherein, The composition comprises about 15 mM acetate and / or a pharmaceutically acceptable acetate salt.

17. The aqueous pharmaceutical composition according to claim 1 or 2, wherein, The composition comprises about 7% (w / v) to about 9% (w / v) sucrose.

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

19. The aqueous pharmaceutical composition according to claim 1 or 2, wherein, The composition comprises about 15 pg / mL to about 21 pg / mL EDTA.

20. The aqueous pharmaceutical composition according to claim 1 or 2, wherein, The composition comprises about 18 pg / mL EDTA.

21. The aqueous pharmaceutical composition according to claim 1 or 2, wherein, The composition comprises about 0.02% to about 0.06% PS-20.

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

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

24. The aqueous pharmaceutical composition of claim 1 or 2, wherein, The pH is about 4.8 to about 5.

6.

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

5.

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

2.

27. The aqueous pharmaceutical composition of claim 1, wherein, The composition comprises 2 mg / mL of the bispecific G Protein-Coupled Receptor Family 5 Member 5D (GPRC5D) / Cluster of Differentiation 3 (CD3) antibody, 15 mM acetate and / or a pharmaceutically acceptable acetate salt, 8% (w / v) sucrose, 18 pg / mL EDTA, 0.04% PS20 and has a pH of 5.

2.

28. The aqueous pharmaceutical composition of claim 2, wherein, The composition comprises 40 mg / mL of the bispecific G Protein-Coupled Receptor Family 5 Member 5D (GPRC5D) / Cluster of Differentiation 3 (CD3) antibody, 15 mM acetate and / or a pharmaceutically acceptable acetate salt, 8% (w / v) sucrose, 18 pg / mL EDTA, 0.04% PS20 and has a pH of 5.

2.

29. The aqueous pharmaceutical composition of any one of claims 1-28, wherein, The aqueous pharmaceutical composition is stable.

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

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

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

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

34. A method for preparing an aqueous pharmaceutical composition of a bispecific G Protein-Coupled Receptor Family 5 Member 5D (GPRC5D) / Cluster of Differentiation 3 (CD3) antibody or antigen binding fragment thereof, the bispecific GPRC5D / CD3 antibody or antigen binding fragment thereof comprising: (1) a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1), wherein the VH1 comprises a heavy chain complementarity determining region 1 (HCDR1), a HCDR2, and a HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; (2) a first light chain (LC1) comprising a LC1 variable region (VL1), 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 a HC2 variable region 2 (VH2), wherein the VH2 comprises a heavy chain complementarity determining region 1 (HCDR1), a HCDR2, and a HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; and (4) a second light chain (LC2) comprising a LC2 variable region (VL2), 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. (4) a second light chain (LC2) comprising a VL2 variable region 2, wherein the VL2 comprises a light chain complementarity determining region 1 (LCDR1), an LCDR2, and an LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively; The method comprises admixing a composition comprising about 2 mg / mL of the bispecific G Protein-Coupled Receptor Family 5 Member 5D (GPRC5D) / Cluster of Differentiation 3 (CD3) antibody, about 15 mM acetate and / or a pharmaceutically acceptable acetate salt, about 8% (w / v) sucrose, about 18 pg / 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 Family 5 Member 5D (GPRC5D) / Cluster of Differentiation 3 (CD3) antibody or antigen binding fragment thereof, the bispecific GPRC5D / CD3 antibody or antigen binding fragment thereof comprising: (1) a first heavy chain (HC1) comprising a VH1 variable region 1, wherein the VH1 comprises a heavy chain complementarity determining region 1 (HCDR1), an HCDR2, and an HCDR3 having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; (2) a first light chain (LC1) comprising a VL1 variable region, wherein the VL1 comprises a light chain complementarity determining region 1 (LCDR1), an LCDR2, and an LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively; (3) a second heavy chain (HC2) comprising a VH2 variable region 2, wherein the VH2 comprises a heavy chain complementarity determining region 1 (HCDR1), an HCDR2, and an HCDR3 having the amino acid sequences of SEQ ID NOs: 11, 12, and 13, respectively; and (4) a second light chain (LC2) comprising a VL2 variable region 2, wherein the VL2 comprises a light chain complementarity determining region 1 (LCDR1), an LCDR2, and an LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively; The method comprises admixing a composition comprising about 40 mg / mL of the bispecific G Protein-Coupled Receptor Family 5 Member 5D (GPRC5D) / Cluster of Differentiation 3 (CD3) antibody, about 15 mM acetate and / or a pharmaceutically acceptable acetate salt, about 8% (w / v) sucrose, about 18 pg / 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. The method of claim 34 or 35, wherein, The bispecific GPRC5D / CD3 antibody comprises a HC1 having the amino acid sequence of SEQ ID NO: 9 and a 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 HC2 having an amino acid sequence of SEQ ID NO: 19 and a LC2 having an amino acid sequence of SEQ ID NO:

20.

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

20.

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

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

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

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

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

45. The article of claim 44, wherein, The container is a vial having a stopper that can be pierced by a syringe.

46. The aqueous pharmaceutical composition of any one of claims 1-31 for use in treating cancer.

47. The aqueous pharmaceutical composition of any one of claims 1-31 for use in the manufacture of a medicament for treating cancer.

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

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

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