Pharmaceutical composition containing a high concentration of bispecific BCMA / CD3 antibody

Abstract

This specification provides aqueous pharmaceutical compositions containing high-concentration formulations of bispecific BCMA / CD3 antibodies or their antigen-binding fragments, and methods for preparing them. It also provides methods for treating subjects requiring cancer treatment by administering the aqueous pharmaceutical compositions.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims priority to U.S. Provisional Patent Application No. 63 / 465,016, filed on May 9, 2023, the entire content of which is incorporated herein by reference in its entirety.

[0002] (Reference to Electronically Submitted Sequence Listing) This application includes a sequence listing submitted electronically in XML format, which is incorporated herein by reference in its entirety. The XML copy was created on April 30, 2024, named "258199062102(JBI6808WOPCT1)Sequence Listing.xml", and has a size of 23,203 bytes.

[0003] (Field of the Invention) Disclosed herein are compositions comprising high - concentration bispecific BCMA / CD3 antibodies and methods for formulating stable pharmaceutical compositions.

Background Art

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

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

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

[0007] While anti-BCMA / CD3 bispecific antibodies have shown promising results, there is still a need in the art for pharmaceutical compositions containing antibodies that are stable for extended periods at refrigerated temperatures (2-8°C) and ambient temperatures. Furthermore, there is still a need in the art for pharmaceutical compositions containing high concentrations of such antibodies while still possessing a viscosity suitable for subcutaneous administration, for example. [Overview of the project]

[0008] Aqueous pharmaceutical compositions comprising specific formulations of bispecific B-cell mature antigen (BCMA) / cluster of differentiation 3 (CD3) antibodies are disclosed herein. In certain embodiments, the compositions have a high concentration of bispecific antibody, e.g., 150 mg / mL or higher, a low viscosity, e.g., 25 centipoise (cP) or lower, and a stable shelf life. Pharmaceutical compositions with high concentrations of therapeutic antibodies allow patients to receive fewer subcutaneous injections to achieve a therapeutic dose than would be required with compositions with lower concentrations of antibodies, thus reducing the risk of complications such as injection site reactions and improving the patient's quality of life. The inventors have developed high-concentration compositions that are stable over time while having sufficiently low viscosity for subcutaneous injection.

[0009] In one general aspect, an aqueous pharmaceutical composition is provided herein, and the aqueous pharmaceutical composition is a) A bispecific B cell maturation antigen (BCMA) / differentiation antigen group 3 (CD3) antibody in a concentration of approximately 150 mg / mL to approximately 250 mg / mL, (1) A first heavy chain (HC1) comprising an HC1 variable region 1 (VH1), VH1 comprises a first heavy chain (HC1) containing heavy chain complementarity determination regions 1 (HCDR1), HCDR2, and HCDR3, each having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively. (2) A first light chain (LC1) including an LC1 variable region (VL1), VL1 comprises a first light chain (LC1) containing light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, each having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively. (3) A second heavy chain (HC2) comprising an HC2 variable region 2 (VH2), VH2 comprises a second heavy chain (HC2) containing heavy chain complementarity determination regions 1 (HCDR1), HCDR2, and HCDR3, each having the amino acid sequences of SEQ ID NOs. 11, 12, and 13, respectively. (4) A second light chain (LC2) including an LC2 variable region 2 (VL2), VL2 is a bispecific BCMA / CD3 antibody containing a second light chain (LC2) comprising light chain complementarity determining regions 1 (LCDR1), 15, and 16, respectively, having amino acid sequences of SEQ ID NOs: 14, 15, and 16, and LCDR3, and b) The composition comprises a viscosity-reducing agent (e.g., arginine HCl), and the composition has a viscosity of about 25 centipoise (cP) or less at 25°C. In the embodiments described herein, the pharmaceutical composition is stable.

[0010] In another embodiment, an aqueous pharmaceutical composition is provided herein, and the aqueous pharmaceutical composition is (a) A bispecific B cell maturation antigen (BCMA) / differentiation antigen group 3 (CD3) antibody in a concentration of approximately 100 mg / mL to approximately 300 mg / mL, or an antigen-binding fragment thereof. (1) A first heavy chain (HC1) comprising an HC1 variable region 1 (VH1), VH1 comprises a first heavy chain (HC1) containing heavy chain complementarity determination regions 1 (HCDR1), HCDR2, and HCDR3, each having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively. (2) A first light chain (LC1) including an LC1 variable region (VL1), VL1 comprises a first light chain (LC1) containing light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, each having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively. (3) A second heavy chain (HC2) comprising an HC2 variable region 2 (VH2), VH2 comprises a second heavy chain (HC2) containing heavy chain complementarity determination regions 1 (HCDR1), HCDR2, and HCDR3, each having the amino acid sequences of SEQ ID NOs. 11, 12, and 13, respectively. (4) A second light chain (LC2) including an LC2 variable region 2 (VL2), VL2 comprises a second light chain (LC2) containing light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, each having the amino acid sequences of SEQ ID NOs. 14, 15, and 16, respectively, and a bispecific BCMA / CD3 antibody or its antigen-binding fragment. (b) Approximately 10 mM to approximately 20 mM acetic acid and / or pharmaceutically acceptable acetate salts, (c) Sucrose at approximately 1% (w / v) to 7% (w / v), (d) Arginine HCl at a concentration of approximately 100 mM to 300 mM, (e) Ethylenediaminetetraacetic acid (EDTA) in a concentration of approximately 16 μg / mL to approximately 24 μg / mL, and (f) Contains approximately 0.01% to approximately 0.07% polysorbate 20, The composition has a pH of approximately 4.7 to approximately 5.7. In the embodiments described herein, the pharmaceutical composition is stable.

[0011] In another overall embodiment, an aqueous pharmaceutical composition is provided herein, and the aqueous pharmaceutical composition (a) A bispecific B cell maturation antigen (BCMA) / differentiation antigen group 3 (CD3) antibody or its antigen-binding fragment in a concentration of approximately 175 mg / mL to approximately 225 mg / mL, (1) A first heavy chain (HC1) comprising an HC1 variable region 1 (VH1), VH1 comprises a first heavy chain (HC1) containing heavy chain complementarity determination regions 1 (HCDR1), HCDR2, and HCDR3, each having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively. (2) A first light chain (LC1) including an LC1 variable region (VL1), VL1 comprises a first light chain (LC1) containing light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, each having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively. (3) A second heavy chain (HC2) comprising an HC2 variable region 2 (VH2), VH2 comprises a second heavy chain (HC2) containing heavy chain complementarity determination regions 1 (HCDR1), HCDR2, and HCDR3, each having the amino acid sequences of SEQ ID NOs. 11, 12, and 13, respectively. (4) A second light chain (LC2) including an LC2 variable region 2 (VL2), VL2 comprises a second light chain (LC2) containing light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, each having the amino acid sequences of SEQ ID NOs. 14, 15, and 16, respectively, and a bispecific BCMA / CD3 antibody or its antigen-binding fragment. (b) About 10 mM to about 20 mM acetic acid and / or a pharmaceutically acceptable acetate, (c) About 2% (w / v) to about 6% (w / v) sucrose, (d) About 175 mM to about 225 mM arginine HCl, (e) About 16 μg / mL to about 24 μg / mL ethylenediaminetetraacetic acid (EDTA), (f) About 0.01% to about 0.07% polysorbate 20, and having a pH of about 4.7 to about 5.7. In embodiments described herein, the pharmaceutical composition is stable.

[0012] In another aspect, an aqueous pharmaceutical composition is provided herein, the aqueous pharmaceutical composition comprising (a) About 7.5 mg / mL to about 12.5 mg / mL of a bispecific B cell maturation antigen (BCMA) / cluster of differentiation 3 (CD3) antibody or an antigen-binding fragment thereof, (1) A first heavy chain (HC1) comprising a HC1 variable region 1 (VH1), where 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, the first heavy chain (HC1), (2) A first light chain (LC1) comprising a LC1 variable region (VL1), where 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, the first light chain (LC1), (3) A second heavy chain (HC2) comprising a HC2 variable region 2 (VH2), where 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, the second heavy chain (HC2), (4) A second light chain (LC2) comprising a LC2 variable region 2 (VL2), VL2 comprises a second light chain (LC2) containing light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, each having the amino acid sequences of SEQ ID NOs. 14, 15, and 16, respectively, and a bispecific BCMA / CD3 antibody or its antigen-binding fragment. (b) Approximately 10 mM to approximately 20 mM acetic acid and / or pharmaceutically acceptable acetate salts, (c) Sucrose at approximately 6% (w / v) to 10% (w / v), (d) Arginine HCl at a concentration of approximately 6 mM to 14 mM (e) Ethylenediaminetetraacetic acid (EDTA) in a concentration of approximately 16 μg / mL to approximately 24 μg / mL, (f) Polysorbate 20 in an amount of approximately 0.01% to approximately 0.07%, and (g) Contains a pH of approximately 4.7 to approximately 5.7. In the embodiments described herein, the pharmaceutical composition is stable.

[0013] According to a preferred embodiment, the aqueous pharmaceutical composition described herein is a stable aqueous pharmaceutical composition.

[0014] This specification also provides a method for treating subjects requiring cancer treatment. This method involves administering an aqueous pharmaceutical composition disclosed herein to the subject. [Modes for carrying out the invention]

[0015] The compositions and methods disclosed can be more readily understood by referring to the following detailed description in relation to the accompanying drawings, which form part of this disclosure. It should be understood that the compositions and methods disclosed are not limited to the specific compositions and methods described and / or shown herein, and that the terms used herein are for illustrative purposes only and are not intended to limit the claimed compositions and methods.

[0016] Unless otherwise specified, any description of possible mechanisms of action or reasons for improvement is for illustrative purposes only, and the disclosed compositions and methods should not be limited by the validity of any such proposed mechanism of action or reasons for improvement.

[0017] Where a range of numbers is enumerated or established herein, this range includes its endpoints, as well as all individual integers and fractions within that range, and each of the narrower ranges formed by all the various possible combinations of these endpoints and internal integers and fractions, each of which forms a subgroup of the larger group of values ​​within the stated range to the same extent as explicitly enumerated. Where a range of numbers is described herein as greater than the values ​​to be described, the range is nevertheless finite, and its upper limit is defined by values ​​that are operable within the context of the invention as described herein. Where a range of numbers is described herein as less than the values ​​to be described, the range is nevertheless defined by non-zero values. The range of the invention is not intended to be limited to the specific values ​​enumerated when defining the range. All ranges include boundary values ​​and are combinable.

[0018] When a value is expressed as an approximation using the antecedent "approximately," that particular value is understood to form another embodiment. References to a specific numerical value should include at least that specific value unless the context explicitly indicates otherwise.

[0019] Furthermore, it should be understood that certain features of the compositions and methods of the Disclosure, which are described in this specification in the context of separate embodiments for clarity, may also be provided in combination in a single embodiment. Conversely, various features of the compositions and methods of the Disclosure, which are described in the context of a single embodiment for brevity, may also be provided separately or in any partial combination.

[0020] As used herein, the singular forms "a," "an," and "the" are to be interpreted as including the plural form.

[0021] Various terms relating to aspects of this specification will be used throughout this specification and the claims. Unless otherwise indicated, such terms shall be given their ordinary meanings in the art. Other specifically defined terms shall be construed to be consistent with the definitions provided herein.

[0022] Where used herein, “approximately” is used in relation to a numerical range, cutoff, or specific value to indicate that the listed values ​​may vary by up to 10% from the listed values. Since many of the numerical values ​​used herein are determined experimentally, those skilled in the art will understand that such determinations may vary between different experiments and, in many cases, will vary. The values ​​used herein should not be considered excessively limited by this inherent variation. Accordingly, the term “approximately” is used to encompass variations of ±10%, ±5%, ±1%, ±0.5%, or ±0.1% from a specified value.

[0023] The term “comprise” is intended to include examples that are encompassed by the terms “essentially derived from” and “consisting of.” Similarly, the term “essentially derived from” is intended to include examples that are encompassed by the term “consisting of.” Unless the context clearly indicates otherwise, throughout the specification and claims, words such as “comprise,” “comprising,” and so on should be interpreted in a comprehensive sense, as opposed to an exclusive or exhaustive sense, i.e., “including but not limited to.”

[0024] The term "antibody" and similar terms are intended in a broad sense and include immunoglobulin molecules or fragments thereof, including monoclonal antibodies (such as mouse, human, human-adapted, humanized, and chimeric monoclonal antibodies), antibody fragments, bispecific or multispecific antibodies, dimers, tetramers, or multimers, and single-chain antibodies.

[0025] Immunoglobulins can be assigned to five major classes, namely IgA, IgD, IgE, IgG, and IgM, depending on the amino acid sequence of their heavy chain constant domain. IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. The antibody light chains of any vertebrate species can be assigned to one of two distinct types, namely kappa (κ) and lambda (λ), based on the amino acid sequence of their constant domain.

[0026] An "antibody fragment" refers to a portion of an immunoglobulin molecule that retains the antigen-binding properties of a full-length parent antibody. Exemplary antibody fragments include heavy chain complementarity-determining regions (HCDRs) 1, 2, and 3, light chain complementarity-determining regions (LCDRs) 1, 2, and 3, heavy chain variable regions (VH), or light chain variable regions (VL). Antibody fragments include Fab fragments, which are monovalent fragments consisting of VL, VH, constant light chain (CL), and constant heavy chain 1 (CH1) domain; F(ab)2 fragments, which are bivalent fragments containing two Fab fragments linked by disulfide crosslinking at the hinge region; Fd fragments consisting of VH and CH1 domains; Fv fragments consisting of VL and VH domains of a single arm of the antibody; and domain antibody (dAb) fragments consisting of the VH domain (Ward et al., Nature, 341:544~546, 1989). The VH and VL domains can be manipulated and linked together via synthetic linkers to form various types of single-chain antibody designs. The VH / VL domains can pair intramolecularly or intermolecularly if the VH and VL domains are expressed in separate single-chain antibody constructs to form monovalent antigen-binding sites such as single-chain Fv (scFv) or diabodies. These are described, for example, in International Publications 1998 / 44001, 1988 / 01649, 1994 / 13804, and 1992 / 01047. These antibody fragments can be obtained using techniques known to those skilled in the art, and these fragments can be screened for utility in the same way as full-length antibodies.

[0027] The antibody variable region consists of a "framework" region interrupted by three "antigen-binding sites." Antigen-binding sites are defined using the following various terms: (i) The three complementarity determining regions (CDRs) within the VH (HCDR1, HCDR2, HCDR3) and the three within the VL (LCDR1, LCDR2, LCDR3) are based on sequence diversity (Wu and Kabat J Exp Med 132:211-50, 1970; Kabat et al. Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), and (ii) the three hypervariable regions (HVR or HV) within the VH (H1, H2, H3) and the three within the VL (L1, L2, L3) are based on Chothia and Lesk (Chothia and Lesk Mol Biol As defined in 196:901-17, 1987, it refers to the region of the antibody variable domain that is structurally hypervariable. Other terms include "IMGT-CDR" (Lefranc et al., Dev Comparat Immunol 27:55-77, 2003) and "Specificity Determining Residue Usage" (SDRU) (Almagro Mol Recognit 17:132-43, 2004). The International ImMunoGeneTics (IMGT) database (www_imgt_org) provides standard numbering and definitions for antigen-binding sites. The correspondence between the classifications of CDR, HV, and IMGT is described in Lefranc et al., Dev Comparat Immunol 27:55-77, 2003.

[0028] A "monoclonal antibody" refers to a preparation of an antibody molecule with a single molecular composition. A monoclonal antibody composition exhibits single binding specificity and affinity to a specific epitope, or, in the case of a bispecific monoclonal antibody, exhibits double binding specificity to two distinct epitopes. Therefore, a monoclonal antibody refers to a population of antibodies in which the amino acid composition of each heavy chain and each light chain is monoclonal, except for known possible modifications such as the removal of the C-terminal lysine from the antibody heavy chain. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibodies can be monospecific or multispecific, or monovalent, bivalent, or polyvalent. Bispecific antibodies are included in the term monoclonal antibody.

[0029] "Bispecificity" refers to an antibody that specifically binds to two different antigens, or to two different epitopes within the same antigen. Bispecific antibodies can cross-react to other related antigens, such as the same antigen (homolog) from other species, such as humans or monkeys, for example, cynomolgus monkeys (Macaca cynomolgus, cyno) or chimpanzees (Pan troglodytes), or they can bind to epitopes shared between two or more different antigens.

[0030] A “human antibody” refers to an antibody optimized to minimize the immune response when administered to a human subject. The variable region of a human antibody is derived from a human immunoglobulin sequence. If a human antibody contains a constant region or a portion of a constant region, that constant region is also derived from a human immunoglobulin sequence. If the variable region of a human antibody is obtained from a system using human germline immunoglobulin or a rearranged immunoglobulin gene, it will contain heavy-chain and light-chain variable regions that are “derived” from a human sequence. Examples of such systems include human immunoglobulin gene libraries presented to phages, and transgenic non-human animals possessing human immunoglobulin loci, such as mice or rats. A “human antibody” typically contains amino acid differences compared to immunoglobulin expressed in humans, due to differences in the system used to obtain the human antibody and the human immunoglobulin locus, or intentional introduction of somatic mutations or substitutions into the framework or CDR, or both. Typically, a “human antibody” is identical in amino acid sequence to that encoded by a human germline immunoglobulin or rearranged immunoglobulin gene by at least approximately 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some cases, a “human antibody” may include a consensus framework sequence derived from human framework sequence analysis, for example, as described in Knappik et al., (2000) J Mol Biol 296:57-86, or synthetic HCDR3 incorporated into a human immunoglobulin gene library presented on phages, for example, as described in Shi et al., (2010) J Mol Biol 397:385-96 and International Publication No. 2009 / 085462. Antibodies in which at least one CDR originates from a non-human species are not included in the definition of "human antibodies."

[0031] A "humanized antibody" refers to an antibody in which at least one CDR is derived from a non-human species and at least one framework is derived from a human immunoglobulin sequence. Because humanized antibodies can contain substitutions in their framework, the framework may not be an exact copy of the expressed human immunoglobulin or human immunoglobulin germline gene sequence.

[0032] "Identity" refers to the relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules, determined by aligning and comparing their sequences. The "percentage of sequence identity (%)" relative to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in the reference polypeptide sequence, after aligning the sequences and introducing gaps as necessary, without considering any conservative substitutions as part of sequence identity, to achieve the maximum possible percentage of sequence identity. Alignment for the purpose of determining the percentage of amino acid sequence identity can be achieved using various methods within the scope of skill in the art, such as publicly available computer software like BLAST, BLAST-2, ALIGN, or MEGALIGN (DNAStar, Inc.) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithm necessary to achieve the maximum possible alignment over the entire length of the sequences being compared.

[0033] "Isolated" refers to a homogeneous population of molecules (e.g., synthetic polynucleotides or proteins such as antibodies) that has been substantially separated and / or purified from other components of a system in which molecules are produced, such as recombinant cells, in addition to proteins subjected to at least one purification or isolation step. "Isolated antibody" refers to an antibody that is substantially free of other cellular material and / or chemical substances, and includes antibodies isolated to higher purities, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.

[0034] A “BCMA / CD3 bispecific antibody” (which may be used interchangeably with “BCMAxCD3 bispecific antibody”) refers to a bispecific antibody that specifically binds to BCMA and CD3. BCMA / CD3 bispecific antibodies are described in U.S. Patent No. 10,072,088, which is incorporated herein by reference in its entirety.

[0035] "BCMA" refers to the human B cell maturation antigen, also known as CD269 or TNFRSF17 (UniProt Q02223). The extracellular domain of BCMA encapsulates residues 1-54 of Q02223. Human BCMA contains the amino acid sequence of SEQ ID NO: 21. MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNAILWTCLGLSLIISLAVFVLMFLLRKINSEPLKDEFKNTGSGLLGMANIDLEKSRTGDEIILPRGLEYTVEECTCEDCIKSKPKVDSDHCFPLPAMEEGATILVTTKTNDYCKSLPAALSATEIEKSISAR(Sequence ID 21)

[0036] "CD3" refers to a human antigen expressed on T cells as part of a multimolecular T cell receptor (TCR) complex, consisting of a homodimer or heterodimer formed from the association of two or four receptor chains: CD3 epsilon, CD3 delta, CD3 zeta, and CD3 gamma. Human CD3 epsilon contains the amino acid sequence of SEQ ID NO: 22. SEQ ID NO: 23 shows the extracellular domain of CD3 epsilon. MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI (Sequence ID 22) DGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMD(Sequence ID 23)

[0037] An "epitope" refers to a portion of an antigen to which an antibody specifically binds. Epitopes typically consist of chemically active (polar, nonpolar, or hydrophobic, etc.) surface groups, such as amino acids or polysaccharide side chains, and may possess not only specific three-dimensional structural properties but also specific charge properties. Epitopes can be composed of continuous and / or discontinuous amino acids that form conformational spatial units. In discontinuous epitopes, amino acids from different parts of the linear sequence of the antigen come into very close proximity in three-dimensional space due to the folding of the protein molecule.

[0038] A "mutant" refers to a polypeptide or polynucleotide that differs from a reference polypeptide or reference polynucleotide due to one or more modifications, such as substitution, insertion, or deletion.

[0039] "In combination with..." means that two or more therapeutic agents can be administered to the subject together as a mixture, simultaneously as individual agents, or sequentially as individual agents in any order.

[0040] The terms “to treat,” “treatment,” and similar terms refer to both therapeutic treatment and prophylactic or preventative measures, including reducing the severity and / or frequency of symptoms, eliminating symptoms and / or their underlying causes, reducing the frequency or likelihood and / or underlying causes of symptoms, and improving or repairing damage directly or indirectly caused by malignancies. Treatment also includes extending survival compared to the expected survival of untreated subjects. Subjects treated include those suffering from a condition or disease, those susceptible to a condition or disease, or those for whom a condition or disease should be prevented.

[0041] "Therapeutic dose" refers to the amount of a disclosed composition that is therapeutically effective in achieving the desired treatment over the required period of time at the required dosage. The therapeutic dose may vary depending on factors such as the patient's condition, age, sex, and weight, as well as the ability of the combination therapy to induce the desired response in the patient. Exemplary indicators of the therapeutic dose include, for example, improvement in the patient's health, reduction in tumor burden, cessation or delay of tumor growth, and / or absence of metastasis of cancer cells to other parts of the body.

[0042] A "pharmaceutical composition" refers to a composition containing an active ingredient and a pharmaceutically acceptable carrier.

[0043] The terms "pharmaceutical" or "DP" may be used interchangeably with the term "aqueous pharmaceutical composition" in this specification.

[0044] "Pharmacologically acceptable carriers" or "excipients" refer to components in a pharmaceutical composition other than the active ingredient that are non-toxic to the target.

[0045] As used herein, the term “cancer” is defined as a disease characterized by the rapid and uncontrolled proliferation of abnormal cells. Cancer cells may spread locally or to other parts of the body via the bloodstream and lymphatic system. In certain embodiments, cancer is a hematological malignancy or a solid tumor. In some embodiments, hematological malignancies include 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), Waldenström macroglobulinemia, plasma cell leukemia, light chain amyloidosis (AL), precursor B-cell lymphoblastic leukemia, acute myeloid leukemia (AML), and myelodysplastic syndromes. These include syndrome (MDS), chronic lymphocytic leukemia (CLL), B-cell malignancies, chronic myeloid leukemia (CML), hairy cell leukemia (HCL), blastic plasmacytoid dendritic cell neoplasm, Hodgkin lymphoma, non-Hodgkin lymphoma, marginal zone B-cell lymphoma (MZL), mucosa-associated lymphatic tissue lymphoma (MALT), plasma cell leukemia, anaplastic large-cell lymphoma (ALCL), leukemia, or lymphoma.

[0046] "Tumor cells" or "cancer cells" refer to cancerous, precancerous, or transformed cells that exhibit spontaneous or induced phenotypic changes in vivo, ex vivo, or tissue culture. These changes do not necessarily involve the uptake of new genetic material. Transformation may occur through infection with transforming viruses and the incorporation of new genomic nucleic acids, the uptake of exogenous nucleic acids, or spontaneously or after exposure to carcinogens, thereby mutating endogenous genes. Transformation / cancer is exemplified by morphological changes, cell immortalization, abnormal growth control, lesion formation, proliferation, malignant lesions, regulation of tumor-specific marker levels, invasiveness, and tumor growth in suitable animal hosts such as nude mice, in vitro, in vivo, and ex vivo.

[0047] "T-cell retargeting therapy" refers to a molecule containing two or more binding domains, where one of the binding domains specifically binds to a cell surface antigen on a target cell or tissue, and the second binding domain of the molecule specifically binds to a T-cell antigen. Examples of cell surface antigens include tumor-associated antigens such as BCMA. An example of a T-cell antigen is CD3. This dual / multi-target binding capability recruits T cells to the target cell or tissue, leading to its eradication.

[0048] "Subject" includes any human or non-human animal. "Non-human animal" includes all vertebrates, such as non-human primates, mammals and non-mammals such as sheep, dogs, cats, horses, cattle, chickens, amphibians, and reptiles. The terms "subject" and "patient" may be used interchangeably herein.

[0049] As used herein, “stable” or “stability” means the extent to which a pharmaceutical composition, and a bispecific antibody or its antigen-binding fragment, retains, within specified limits, the same or substantially the same properties and characteristics it possessed at the time of manufacture throughout its storage and use period. These properties and characteristics of the antibody or its antigen-binding fragment may be, for example, activity, aggregation or lack thereof, degradation products or lack thereof, or other relevant measurements described herein.

[0050] explanation Throughout this specification, unless otherwise specified, the numbering of amino acid residues in the antibody constant region follows the EU index described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed., Public Health Service, National Institutes of Health, Bethesda, MD. (1991). The numbering of the antibody constant chain can be found, for example, in the IMGT Web resource of the IMGT Scientific chart on the ImMunoGeneTics website.

[0051] Conventional one-letter and three-letter amino acid codes are used herein as shown in Table 1.

[0052] [Table 1]

[0053] Composition containing a BCMAxCD3 bispecific antibody Aqueous pharmaceutical compositions containing a bispecific BCMA / CD3 antibody are disclosed herein. In certain embodiments, the pharmaceutical composition is stable. In certain embodiments, the composition has a high concentration of the bispecific antibody, e.g., 150 mg / mL or more, and a low viscosity, e.g., 25 centipoise (cP) or less. The inventors have found that compositions containing a higher concentration of the bispecific BCMA / CD3 antibody can be formulated to be stable and have a sufficiently low viscosity, making them suitable for subcutaneous administration to human subjects. Pharmaceutical compositions with a high concentration of therapeutic antibody allow patients to receive fewer subcutaneous injections to achieve a therapeutic dose than required with compositions with a lower concentration of antibody, thus reducing the risk of complications such as injection site reactions and improving the patient's quality of life.

[0054] Embodiments of the present invention provide aqueous pharmaceutical compositions having lower concentrations of antibodies that may be particularly useful as escalating doses in a therapeutic regime, and pharmaceutical concentrations having higher concentrations of antibodies that may be particularly useful as therapeutic doses in a therapeutic regime. As used herein, “escalating dose” refers to the dose of the active agent administered to a subject prior to the therapeutic dose. The escalating dose is lower than the therapeutic dose. A “priming” dosing strategy to prevent or mitigate certain toxicities, such as cytokine release syndrome (CRS), may include one or more lower escalating doses followed by a higher therapeutic dose. As used herein, “therapeutic dose” refers to the dose of the active agent administered to a subject to treat a disease. Therapeutic doses may be administered repeatedly (e.g., weekly) at regular dosing intervals. One or more escalating doses may precede the therapeutic dose.

[0055] In one general aspect, an aqueous pharmaceutical composition is provided herein, and the aqueous pharmaceutical composition is a) A bispecific B cell maturation antigen (BCMA) / differentiation antigen group 3 (CD3) antibody in a concentration of approximately 150 mg / mL to approximately 250 mg / mL, (1) A first heavy chain (HC1) comprising an HC1 variable region 1 (VH1), VH1 comprises a first heavy chain (HC1) containing heavy chain complementarity determination regions 1 (HCDR1), HCDR2, and HCDR3, each having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively. (2) A first light chain (LC1) including an LC1 variable region (VL1), VL1 comprises a first light chain (LC1) containing light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, each having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively. (3) A second heavy chain (HC2) comprising an HC2 variable region 2 (VH2), VH2 comprises a second heavy chain (HC2) containing heavy chain complementarity determination regions 1 (HCDR1), HCDR2, and HCDR3, each having the amino acid sequences of SEQ ID NOs. 11, 12, and 13, respectively. (4) A second light chain (LC2) including an LC2 variable region 2 (VL2), VL2 is a bispecific BCMA / CD3 antibody containing a second light chain (LC2) comprising light chain complementarity determining regions 1 (LCDR1), 15, and 16, respectively, having amino acid sequences of SEQ ID NOs: 14, 15, and 16, and LCDR3, and b) The composition comprises a viscosity-reducing agent (e.g., arginine HCl), and the composition has a viscosity of about 25 centipoise (cP) or less at 25°C. Such high-concentration compositions may be particularly useful as therapeutic doses. In the embodiments described herein, the pharmaceutical composition is stable.

[0056] In another embodiment, an aqueous pharmaceutical composition is provided herein, and the aqueous pharmaceutical composition is (a) A bispecific B cell maturation antigen (BCMA) / differentiation antigen group 3 (CD3) antibody in a concentration of approximately 7.5 mg / mL to approximately 12.5 mg / mL, or an antigen-binding fragment thereof. (1) A first heavy chain (HC1) comprising an HC1 variable region 1 (VH1), VH1 comprises a first heavy chain (HC1) containing heavy chain complementarity determination regions 1 (HCDR1), HCDR2, and HCDR3, each having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively. (2) A first light chain (LC1) including an LC1 variable region (VL1), VL1 comprises a first light chain (LC1) containing light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, each having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively. (3) A second heavy chain (HC2) comprising an HC2 variable region 2 (VH2), VH2 comprises a second heavy chain (HC2) containing heavy chain complementarity determination regions 1 (HCDR1), HCDR2, and HCDR3, each having the amino acid sequences of SEQ ID NOs. 11, 12, and 13, respectively. (4) A second light chain (LC2) including an LC2 variable region 2 (VL2), VL2 comprises a second light chain (LC2) containing light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, each having the amino acid sequences of SEQ ID NOs. 14, 15, and 16, respectively, and a bispecific BCMA / CD3 antibody or its antigen-binding fragment. (b) Approximately 10 mM to approximately 20 mM acetic acid and / or pharmaceutically acceptable acetate salts, (c) Sucrose at approximately 6% (w / v) to 10% (w / v), (d) Arginine HCl at a concentration of approximately 6 mM to 14 mM (e) Ethylenediaminetetraacetic acid (EDTA) in a concentration of approximately 16 μg / mL to approximately 24 μg / mL, and (f) Contains approximately 0.01% to approximately 0.07% polysorbate 20, The composition has a pH of approximately 4.7 to approximately 5.7. Such compositions may be particularly useful as gradual dose increases. In the embodiments described herein, the pharmaceutical composition is stable.

[0057] In another overall embodiment, an aqueous pharmaceutical composition is provided herein, and the aqueous pharmaceutical composition (a) A bispecific B cell maturation antigen (BCMA) / differentiation antigen group 3 (CD3) antibody in a concentration of approximately 100 mg / mL to approximately 300 mg / mL, or an antigen-binding fragment thereof. (1) A first heavy chain (HC1) comprising an HC1 variable region 1 (VH1), VH1 comprises a first heavy chain (HC1) containing heavy chain complementarity determination regions 1 (HCDR1), HCDR2, and HCDR3, each having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively. (2) A first light chain (LC1) including an LC1 variable region (VL1), VL1 comprises a first light chain (LC1) containing light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, each having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively. (3) A second heavy chain (HC2) comprising an HC2 variable region 2 (VH2), VH2 comprises a second heavy chain (HC2) containing heavy chain complementarity determination regions 1 (HCDR1), HCDR2, and HCDR3, each having the amino acid sequences of SEQ ID NOs. 11, 12, and 13, respectively. (4) A second light chain (LC2) including an LC2 variable region 2 (VL2), VL2 comprises a second light chain (LC2) containing light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, each having the amino acid sequences of SEQ ID NOs. 14, 15, and 16, respectively, and a bispecific BCMA / CD3 antibody or its antigen-binding fragment. (b) Approximately 10 mM to approximately 20 mM acetic acid and / or pharmaceutically acceptable acetate salts, (c) Sucrose at approximately 1% (w / v) to 7% (w / v), (d) Arginine HCl at a concentration of approximately 100 mM to 300 mM, (e) Ethylenediaminetetraacetic acid (EDTA) in a concentration of approximately 16 μg / mL to approximately 24 μg / mL, and (f) Contains approximately 0.01% to approximately 0.07% polysorbate 20, The composition has a pH of approximately 4.7 to approximately 5.7. Such high-concentration compositions are particularly useful as therapeutic doses. In the embodiments described herein, the pharmaceutical composition is stable.

[0058] In another overall embodiment, an aqueous pharmaceutical composition is provided herein, and the aqueous pharmaceutical composition (a) A bispecific B cell maturation antigen (BCMA) / differentiation antigen group 3 (CD3) antibody or its antigen-binding fragment in a concentration of approximately 175 mg / mL to approximately 225 mg / mL, (1) A first heavy chain (HC1) comprising an HC1 variable region 1 (VH1), VH1 comprises a first heavy chain (HC1) containing heavy chain complementarity determination regions 1 (HCDR1), HCDR2, and HCDR3, each having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively. (2) A first light chain (LC1) including an LC1 variable region (VL1), VL1 comprises a first light chain (LC1) containing light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, each having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively. (3) A second heavy chain (HC2) comprising an HC2 variable region 2 (VH2), VH2 comprises a second heavy chain (HC2) containing heavy chain complementarity determination regions 1 (HCDR1), HCDR2, and HCDR3, each having the amino acid sequences of SEQ ID NOs. 11, 12, and 13, respectively. (4) A second light chain (LC2) including an LC2 variable region 2 (VL2), VL2 comprises a second light chain (LC2) containing light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, each having the amino acid sequences of SEQ ID NOs. 14, 15, and 16, respectively, and a bispecific BCMA / CD3 antibody or its antigen-binding fragment. (b) Approximately 10 mM to approximately 20 mM acetic acid and / or pharmaceutically acceptable acetate salts, (c) Sucrose at approximately 2% (w / v) to 6% (w / v), (d) Arginine HCl at approximately 175 mM to 225 mM, (e) Ethylenediaminetetraacetic acid (EDTA) in a concentration of approximately 16 μg / mL to approximately 24 μg / mL, and (f) Contains approximately 0.01% to approximately 0.07% polysorbate 20, The composition has a pH of approximately 4.7 to 5.7. Such high-concentration compositions are particularly useful for therapeutic doses.

[0059] According to a preferred embodiment, the aqueous pharmaceutical composition described herein is a stable aqueous pharmaceutical composition.

[0060] In certain embodiments, the bispecific BCMA / CD3 antibody includes VH1 having the amino acid sequence of SEQ ID NO: 7 and VL1 having the amino acid sequence of SEQ ID NO: 8. In certain embodiments, the bispecific BCMA / CD3 antibody includes HC1 having the amino acid sequence of SEQ ID NO: 9 and LC1 having the amino acid sequence of SEQ ID NO: 10. In certain embodiments, the bispecific BCMA / CD3 antibody includes HC1 having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 9. In certain embodiments, the bispecific BCMA / CD3 antibody includes LC1 having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 10.

[0061] In certain embodiments, the bispecific BCMA / CD3 antibody includes VH2 having the amino acid sequence of SEQ ID NO: 17 and VL2 having the amino acid sequence of SEQ ID NO: 18. In certain embodiments, the bispecific BCMA / CD3 antibody includes HC2 having the amino acid sequence of SEQ ID NO: 19 and LC2 having the amino acid sequence of SEQ ID NO: 20. In certain embodiments, the bispecific BCMA / CD3 antibody includes HC2 having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 19. In certain embodiments, the bispecific BCMA / CD3 antibody includes LC2 having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 20.

[0062] Tables 2 and 3 provide sequences of exemplary embodiments of BCMA / CD3 bispecific antibodies according to the Kabat numbering system.

[0063] [Table 2]

[0064] [Table 3]

[0065] A bispecific BCMA / CD3 antibody could be, for example, teclistamaib.

[0066] Low-concentration aqueous pharmaceutical composition In certain embodiments, the bispecific BCMA / CD3 antibody has concentrations particularly suitable for dose escalation, for example, concentrations of about 7 mg / mL to about 13 mg / mL, about 7.5 mg / mL to about 12.5 mg / mL, about 8 mg / mL to about 12 mg / mL, or about 9 mg / mL to about 11 mg / mL. The bispecific BCMA / CD3 antibody may have concentrations of, for example, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 12.5 mg / mL, or about 13 mg / mL, or any value in between. In certain embodiments, the bispecific BCMA / CD3 antibody has a concentration of about 10 mg / mL.

[0067] In certain embodiments, the composition comprises about 5 mM to about 15 mM arginine HCl, or about 6 mM to about 14 mM arginine HCl, or about 7 mM to about 13 mM arginine HCl, or about 8 mM to about 12 mM arginine HCl, or about 9 mM to about 11 mM arginine HCl, or any value in between. In a particular embodiment, the composition comprises about 10 mM arginine HCl.

[0068] In certain embodiments, the composition contains about 10 mM to about 20 mM, about 12 mM to about 18 mM, or about 14 mM to about 16 mM of acetic acid and / or a pharmaceutically acceptable acetate. For example, the composition may contain 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 in between. In preferred embodiments, the composition contains about 15 mM of acetic acid or a pharmaceutically acceptable acetate.

[0069] In certain embodiments, the composition contains about 6% (w / v) to about 10% (w / v) or about 7% (w / v) to about 9% (w / v) of sucrose. The composition may contain, 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 in between. In one embodiment, the composition contains about 7.8% (w / v) of sucrose.

[0070] In certain embodiments, the composition contains about 16 mg / mL to about 24 mg / mL or about 18 mg / mL to about 22 mg / mL of EDTA. The composition may contain, for example, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, about 20 mg / mL, about 21 mg / mL, about 22 mg / mL, about 23 mg / mL, or about 24 mg / mL, or any value in between these. In certain embodiments, the composition contains about 20 mg / mL of EDTA.

[0071] In certain embodiments, the composition contains about 0.01% to about 0.07%, about 0.02% to about 0.06%, or about 0.03% to about 0.05% of polysorbate 20 (PS20) (w / v). The composition may contain, for example, 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 in between. In certain embodiments, the composition contains about 0.04% of PS20 (w / v). In certain embodiments, the composition contains about 0.06% of PS20 (w / v). In alternative embodiments, the composition includes P188 or polysorbate 80 (PS80) instead of PS20 (e.g., 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 in between these, of P188 or PS80 (w / v)).

[0072] In certain embodiments, the pH of the composition is about 4.7 to about 5.7, about 4.8 to about 5.6, or about 4.9 to about 5.5. The pH of the composition may 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 in between. In preferred embodiments, the pH of the composition is about 5.2.

[0073] High-concentration aqueous pharmaceutical composition In certain embodiments, the bispecific BCMA / CD3 antibody has a high concentration particularly suitable for therapeutic doses, and the high concentration allows for less subcutaneous injection of the composition into the subject to achieve a therapeutic dose compared to compositions with low concentrations of antibody. For example, the antibody may have concentrations of about 100 mg / mL to about 300 mg / mL, about 125 mg / mL to about 275 mg / mL, about 150 mg / mL to about 250 mg / mL, or about 175 mg / mL to about 225 mg / mL. Bispecific BCMA / CD3 antibodies are available in concentrations of approximately 185 mg / mL, 186 mg / mL, 187 mg / mL, 188 mg / mL, 189 mg / mL, 190 mg / mL, 191 mg / mL, 192 mg / mL, 193 mg / mL, 194 mg / mL, 195 mg / mL, 196 mg / mL, 197 mg / mL, 198 mg / mL, 199 mg / mL, and 200 mg / mL. The concentration may be approximately 201 mg / mL, 202 mg / mL, 203 mg / mL, 204 mg / mL, 205 mg / mL, 206 mg / mL, 207 mg / mL, 208 mg / mL, 209 mg / mL, 210 mg / mL, 211 mg / mL, 212 mg / mL, 213 mg / mL, 214 mg / mL, or 215 mg / mL, or any value in between. In certain embodiments, the bispecific BCMA / CD3 antibody has a concentration of approximately 200 mg / mL.

[0074] In certain embodiments, the composition comprises about 100 mM to about 300 mM arginine HCl, or about 150 mM to about 250 mM arginine HCl, or about 175 mM to about 225 mM arginine HCl, or about 185 mM to about 215 mM arginine HCl, or about 190 mM to about 210 mM arginine HCl, or any value in between. In a particular embodiment, the composition comprises about 200 mM arginine HCl.

[0075] In certain embodiments, the composition contains about 10 mM to about 20 mM, about 12 mM to about 18 mM, or about 14 mM to about 16 mM of acetic acid and / or a pharmaceutically acceptable acetate. For example, the composition may contain 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 in between. In preferred embodiments, the composition contains about 15 mM of acetic acid or a pharmaceutically acceptable acetate.

[0076] In certain embodiments, the composition contains about 1% (w / v) to about 7% (w / v) or about 2% (w / v) to about 6% (w / v) of sucrose. The composition may contain, for example, about 1% (w / v), about 2% (w / v), about 3% (w / v), about 4% (w / v), about 5% (w / v), about 6% (w / v), or about 7% (w / v), or any value in between. In a particular embodiment, the composition contains about 4% (w / v) of sucrose.

[0077] In certain embodiments, the composition contains about 16 mg / mL to about 24 mg / mL or about 18 mg / mL to about 22 mg / mL of EDTA. The composition may contain, for example, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, about 20 mg / mL, about 21 mg / mL, about 22 mg / mL, about 23 mg / mL, or about 24 mg / mL, or any value in between these. In certain embodiments, the composition contains about 20 mg / mL of EDTA.

[0078] In certain embodiments, the composition contains about 0.01% to about 0.07% (w / v), about 0.02% to about 0.06%, or about 0.03% to about 0.05% of polysorbate 20 (PS20). The composition may contain, for example, 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 in between. In certain embodiments, the composition contains about 0.04% of PS20 (w / v). In certain embodiments, the composition contains about 0.06% of PS20 (w / v). In alternative embodiments, the composition includes P188 or polysorbate 80 (PS80) instead of PS20 (e.g., 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 in between). The abbreviation "PS20" for Polaxamer 20 is also used interchangeably with "PS-20" and "PS20" in this specification.

[0079] In certain embodiments, the pH of the composition is about 4.7 to about 5.7, about 4.8 to about 5.6, or about 4.9 to about 5.5. The pH of the composition may 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 in between. In preferred embodiments, the pH of the composition is about 5.2.

[0080] Stable aqueous pharmaceutical composition In certain embodiments, the stability of the aqueous pharmaceutical composition of this disclosure, also called a drug product (DP), is determined based on a specific amount or proportion of the BCMA×CD3 antibody and other components of the aqueous pharmaceutical composition provided herein (such as, but not limited to, acetic acid and / or pharmaceutically acceptable acetates, sucrose, L-arginine, PS20, and EDTA), as well as an evaluation of various factors. These factors include, but are not limited to, the color of the solution, pH, turbidity, percentage of purity, number of particles invisible to the naked eye, percentage of new peaks, percentage of major components, percentage of high molecular weight species (HMWS), percentage of low molecular weight species (LMWS), percentage of total acidic peaks, percentage of total basic peaks, protein concentration, percentage of T cell activation, viscosity, and / or percentage of PS20.

[0081] In preferred embodiments, the aqueous pharmaceutical composition is a stable aqueous pharmaceutical composition. The stable aqueous pharmaceutical compositions disclosed herein should not be interpreted as requiring all of the stability factors listed herein, but rather as requiring at least one, at least two, or at least three or more of those factors. In some embodiments, the disclosed stable aqueous pharmaceutical compositions exhibit the following results for at least one, at least two, at least three, or more of the factors listed in detail below herein. In preferred embodiments, the stable aqueous pharmaceutical composition exhibits the following results for most of the factors listed in detail below herein. In the most preferred embodiment, the stable aqueous pharmaceutical composition exhibits the following results for all of the factors listed in detail below herein.

[0082] Color of the solution The color of the aqueous pharmaceutical composition solution may be monitored and evaluated to verify that the appearance of the solution is consistent with previous batches at the time of shipment and over the storage period. The color of the aqueous pharmaceutical composition solution may reflect stability. In one embodiment, the stability of an aqueous pharmaceutical composition is defined as having a solution color ranging from colorless to about BY2 or less, about BY4 or less, about B2 or less, about B4 or less, about Y2 or less, or about Y4 or less, as described in European Pharmacopoeia 2.2.2, Degree of Coloration of Liquids, European Pharmacopoeia (Ph.Eur.) 10th edition monograph no. 20202, July 2019.

[0083] In one embodiment, stability is defined as having a solution color ranging from colorless to approximately BY2 or less, approximately B2 or less, and approximately Y2 or less after storage at a temperature of approximately 5°C for approximately 12 months or more, after storage at a temperature of approximately 25°C for approximately 12 months or more, and / or after storage at a temperature of approximately 5°C for approximately 2 years or more. In a preferred embodiment, stability is defined as having a solution color ranging from colorless to approximately BY4 or less, approximately B4 or less, and approximately Y4 or less after storage at a temperature of approximately 5°C for approximately 12 months or more, after storage at a temperature of approximately 25°C for approximately 12 months or more, and / or after storage at a temperature of approximately 5°C for approximately 2 years or more. In the most preferred embodiment, stability is defined as having a solution color ranging from colorless to approximately BY5 or less, approximately B5 or less, and approximately Y5 or less after storage at a temperature of approximately 5°C for approximately 12 months or more, after storage at a temperature of approximately 25°C for approximately 12 months or more, and / or after storage at a temperature of approximately 5°C for approximately 2 years or more.

[0084] pH By measuring the pH of the aqueous pharmaceutical composition, it is possible to confirm that the pH is consistent with previous batches at the time of shipment and throughout the storage period. In one embodiment, the stability of the aqueous pharmaceutical composition is defined as having a pH of approximately 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 one embodiment, the pH of the aqueous pharmaceutical composition is approximately 5.2 after storage at a temperature of approximately 5°C for approximately 12 months or more, after storage at a temperature of approximately 25°C for approximately 12 months or more, and / or after storage at a temperature of approximately 5°C for approximately 2 years or more. In one embodiment, the pH is in the range of 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 a preferred embodiment, the stability of the aqueous pharmaceutical composition is defined as the pH being in the range of about 4.8 to about 5.6 after storage at a temperature of about 5°C for about 12 months or more, after storage at a temperature of about 25°C for about 12 months or more, and / or after storage at a temperature of about 5°C for about 2 years or more. In the most preferred embodiment, the stability of the aqueous pharmaceutical composition is defined as the pH being in the range of about 4.9 to about 5.5 after storage at a temperature of about 5°C for about 12 months or more, after storage at a temperature of about 25°C for about 12 months or more, and / or after storage at a temperature of about 5°C for about 2 years or more.

[0085] Turbidity Turbidity allows for the measurement of the presence of particles in the aqueous pharmaceutical composition to ensure consistency with previous batches and enables official compendium-compliant guidance applicable at the time of shipment and throughout the storage period. In one embodiment, the stability of an aqueous pharmaceutical composition is defined as having a turbidity value of approximately 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 approximately 5°C for approximately 12 months or more, after storage at a temperature of approximately 25°C for approximately 12 months or more, and / or after storage at a temperature of approximately 5°C for approximately 2 years or more. In one embodiment, the stability of an aqueous pharmaceutical composition is defined as having a turbidity value of approximately 18 NTU or less after storage at a temperature of approximately 5°C for approximately 12 months or more, after storage at a temperature of approximately 25°C for approximately 12 months or more, and / or after storage at a temperature of approximately 5°C for approximately 2 years or more. In a preferred embodiment, the stability of the aqueous pharmaceutical composition is defined as having a turbidity value of about 13 NTU or less after being stored at a temperature of about 5°C for about 12 months or more, at a temperature of about 25°C for about 12 months or more, and / or at a temperature of about 5°C for about 2 years or more. In a most preferred embodiment, the stability of the aqueous pharmaceutical composition is defined as having a turbidity value of about 8 NTU or less after being stored at a temperature of about 5°C for about 12 months or more, at a temperature of about 25°C for about 12 months or more, and / or at a temperature of about 5°C for about 2 years or more.

[0086] particle analysis The stability of an aqueous pharmaceutical composition is set to a specific threshold for particle contamination based on the average number of particles invisible to the naked eye. In one embodiment, the average number of particles present in the unit being 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 of 10 μm or larger. In one embodiment, the average number of particles present in the unit being tested should not exceed 6000 per container for particle sizes of 10 μm or larger. In one embodiment, the average number of particles present in the unit being tested should not exceed 100, 200, 300, 400, 500, or 600 per container for particle sizes of 25 μm or larger. In one embodiment, the average number of particles present in the unit being tested should not exceed 600 per container for particle sizes of 25 μm or larger.

[0087] cSDS conditions Non-reducing capillary SDS-PAGE (capillary SDS, cSDS) is a method for separating denatured proteins based on molecular weight, similar to gel-based SDS-PAGE. This process allows for the quantification of DP purity and monitoring of its stability at the time of shipment and throughout storage.

[0088] In one embodiment, the stability of the aqueous pharmaceutical composition is defined based on various results of cSDS variables (e.g., purity percentage or presence of new peaks) obtained when cSDS is performed under reducing or non-reducing conditions after storage at a temperature of about 5°C for about 12 months or more, after storage at a temperature of about 25°C for about 12 months or more, and / or after storage at a temperature of about 5°C for about 2 years or more.

[0089] In one embodiment, DP stability is defined as having a purity percentage of approximately 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or approximately 100%, equal to 100%, or any range in between these.

[0090] In one embodiment, DP stability is defined as not showing new peaks in the cSDS results that exceed 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 2% compared to the untreated reference material.

[0091] In one embodiment, DP stability is defined as having a purity percentage of about 90% or more compared to the reference material and having no new peaks exceeding 1.5%. In a preferred embodiment, DP stability is defined as having a purity percentage of about 95% or more compared to the reference material and having no new peaks exceeding 1.2%. In the most preferred embodiment, DP stability is defined as having a purity percentage of about 97% or more compared to the reference material and having no new peaks exceeding 1.0%.

[0092] As used herein, reference material refers to material produced in a controlled environment and used as a calibration material for producing additional substances or materials (e.g., materials of certified and documented purity by an analytical laboratory or other non-commercial facility). Often, reference materials are publicly available, such as commercially available pharmaceuticals (e.g., teclistamag is marketed as TECVAYLI®).

[0093] Size-exclusion HPLC (SE-HPLC) results consistent with stability The SE-HPLC procedure allows for the evaluation of DP purity and monitoring its stability under non-denaturing conditions during shipment and storage.

[0094] In one embodiment, DP stability is defined based on various SE-HPLC variables such as the main component (MC), high molecular weight species (HMWS), or low molecular weight species (LMWS), after storing the DP at a temperature of approximately 5°C for approximately 12 months or more, after storing it at a temperature of approximately 25°C for approximately 12 months or more, and / or after storing it at a temperature of approximately 5°C for approximately 2 years or more. As used herein, “main component” refers to the antibody monomer (i.e., the monomer species of the antibody).

[0095] In one embodiment, DP stability is defined as having an MC of approximately 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or equal to approximately 100%, or any range in between. In one embodiment, DP stability is defined as having an MC of approximately 90% or more. In a preferred embodiment, DP stability is defined as having an MC of approximately 95% or more. In the most preferred embodiment, DP stability is defined as having an MC of approximately 97% or more.

[0096] In one embodiment, DP stability is defined as having an HMWS of about 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or any range in between. In one embodiment, DP stability is defined as having an HMWS of about 10% or less. In a preferred embodiment, DP stability is defined as having an HMWS of about 5% or less. In the most preferred embodiment, DP stability is defined as having an HMWS of about 3% or less.

[0097] In one embodiment, DP stability is defined as having approximately 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% LMWS. In one embodiment, DP stability is defined as having approximately 5% or less LMWS. In a preferred embodiment, DP stability is defined as having approximately 2% or less LMWS. In the most preferred embodiment, DP stability is defined as having approximately 1% or less LMWS.

[0098] Capillary isoelectric focusing (cIEF) cIEF, similar to isoelectric focusing gel electrophoresis (IEF), separates proteins based on their overall charge or isoelectric point (pI). This procedure allows for monitoring the distribution of charge-based isoforms of a drug over time, both at the time of shipment and during storage. In one embodiment, DP stability is defined based on various results of cIEF variables, such as the main peak (MP), the sum of acidic peaks, or the sum of basic peaks, after storing the DP at a temperature of approximately 25°C for approximately 12 months or more, and / or at a temperature of approximately 5°C for approximately 2 years or more.

[0099] In one embodiment, DP stability is defined as having a cIEF with MP of approximately 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or any range in between, after storing DP at a temperature of approximately 25°C for approximately 12 months or more and / or at a temperature of approximately 5°C for approximately 2 years or more. In one embodiment, DP stability is defined as having a cIEF with MP ≥ 60% after storing DP at a temperature of approximately 25°C for approximately 12 months or more and / or at a temperature of approximately 5°C for approximately 2 years or more. In a preferred embodiment, DP stability is defined as having a cIEF with MP ≥ 65% after storing DP at a temperature of approximately 25°C for approximately 12 months or more and / or at a temperature of approximately 5°C for approximately 2 years or more. In the most preferred embodiment, DP stability is defined as having a cIEF with MP ≥ 70% after storing DP at a temperature of about 25°C for about 12 months or more and / or after storing it at a temperature of about 5°C for about 2 years or more.

[0100] In one embodiment, DP stability is defined as having a cIEF with a total of acidic peaks that amount to approximately 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or any range in between, after storing DP at a temperature of approximately 25°C for approximately 12 months or more and / or at a temperature of approximately 5°C for approximately 2 years or more. In one embodiment, DP stability is defined as having a cIEF with a total of ≤40% acidic peaks after storing DP at a temperature of approximately 25°C for approximately 12 months or more and / or at a temperature of approximately 5°C for approximately 2 years or more. In a preferred embodiment, DP stability is defined as having a cIEF with a total of acidic peaks that amount to approximately ≤30%, after storing DP at a temperature of approximately 25°C for approximately 12 months or more and / or at a temperature of approximately 5°C for approximately 2 years. In the most preferred embodiment, DP stability is defined as having a cIEF with a total of acidic peaks totaling approximately ≤25% after storing DP at a temperature of approximately 25°C for about 12 months or more and / or after storing it at a temperature of approximately 5°C for about 2 years or more.

[0101] In one embodiment, DP stability is defined as having a cIEF with a total of basic peaks that amount to approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%, or any range in between, after storing DP at a temperature of approximately 25°C for approximately 12 months or more, and / or at a temperature of approximately 5°C for approximately 2 years or more. In one embodiment, DP stability is defined as having a cIEF with a total of basic peaks that amount to approximately 15% or less, after storing DP at a temperature of approximately 25°C for approximately 12 months or more, and / or at a temperature of approximately 5°C for approximately 2 years or more. In a preferred embodiment, DP stability is defined as having a cIEF with a total of basic peaks that amount to approximately 10% or less, after storing DP at a temperature of approximately 25°C for approximately 12 months or more, and / or at a temperature of approximately 5°C for approximately 2 years or more. In the most preferred embodiment, DP stability is defined as having a cIEF with a total basic peak of about 8% or less after storing the DP at a temperature of about 25°C for about 12 months or more and / or after storing it at a temperature of about 5°C for about 2 years or more.

[0102] Protein concentration The protein concentration of the DP allows for verification that it matches that of previous DP batches at the time of shipment and throughout the storage period. Quantification of protein concentration can be achieved by measuring the UV light absorbance of the pharmaceutical solution at 280 nm (A280).

[0103] Stability of low-concentration aqueous pharmaceutical compositions In one embodiment, DP stability is defined as having a protein concentration of approximately 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, or any value in between (as determined by A280) after storing DP at a temperature of approximately 25°C for approximately 12 months or more, and / or after storing DP at a temperature of approximately 5°C (e.g., 2-8°C) for approximately 1 year or more, or after storing DP at a temperature of approximately 5°C (e.g., 2-8°C) for approximately 2 years or more.

[0104] In certain embodiments, for protein concentrations of approximately 5 mg / mL to approximately 15 mg / mL (e.g., approximately 10 mg / mL), the total volume of the aqueous pharmaceutical composition (or DP) is in the range of approximately 5 mL to approximately 10 mL. In one embodiment, the total volume of the aqueous pharmaceutical composition (or DP) is in the range of approximately 0.5 mL to approximately 20 mL, approximately 1 mL to approximately 15 mL, approximately 5 mL to approximately 10 mL, or approximately 6 mL to approximately 8 mL. In one embodiment, the total volume of the aqueous pharmaceutical composition is approximately 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, 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 range in between. In one embodiment, the total volume of the aqueous pharmaceutical composition is approximately 2 mL. For example, a 3.0 mL vial contains approximately 10 mg of antibody / mL (approximately 30 mg of antibody / vial).

[0105] In one embodiment, DP stability is defined as having a protein concentration of approximately 7 mg / mL to approximately 13 mg / mL (as determined by A280) after storing DP at a temperature of approximately 25°C for approximately 12 months or more, and / or after storing at a temperature of approximately 5°C (e.g., 2-8°C) for approximately 1 year or more, or after storing at a temperature of approximately 5°C (e.g., 2-8°C) for approximately 2 years or more. In a preferred embodiment, DP stability is defined as having a protein concentration of approximately 8 mg / mL to approximately 12 mg / mL (as determined by A280) after storing DP at a temperature of approximately 25°C for approximately 12 months or more, and / or after storing at a temperature of approximately 5°C (e.g., 2-8°C) for approximately 1 year or more, or after storing at a temperature of approximately 5°C (e.g., 2-8°C) for approximately 2 years or more. In the most preferred embodiment, DP stability is defined as having a protein concentration of about 9 mg / mL to about 11 mg / mL (as determined by A280) after storing DP at a temperature of about 25°C for about 12 months or more, and / or after storing at a temperature of about 5°C (e.g., 2–8°C) for about 1 year or more, or after storing at a temperature of about 5°C (e.g., 2–8°C) for about 2 years or more.

[0106] Stability of high-concentration aqueous pharmaceutical compositions In one embodiment, DP stability is determined by storing DP at a temperature of approximately 25°C for approximately 12 months or more, and / or at a temperature of approximately 5°C (e.g., 2-8°C) for approximately 1 year or more, or at a temperature of approximately 5°C (e.g., 2-8°C) for approximately 2 years or more, to approximately 185 mg / mL, approximately 186 mg / mL, approximately 187 mg / mL, approximately 188 mg / mL, approximately 189 mg / mL, approximately 190 mg / mL, approximately 191 mg / mL, approximately 192 mg / mL, approximately 193 mg / mL, approximately 194 mg / mL, approximately 195 mg / mL, and approximately 196 mg (as determined by A280). It is defined as having a protein concentration of approximately 197 mg / mL, approximately 198 mg / mL, approximately 199 mg / mL, approximately 200 mg / mL, approximately 201 mg / mL, approximately 202 mg / mL, approximately 203 mg / mL, approximately 204 mg / mL, approximately 205 mg / mL, approximately 206 mg / mL, approximately 207 mg / mL, approximately 208 mg / mL, approximately 209 mg / mL, approximately 210 mg / mL, approximately 211 mg / mL, approximately 212 mg / mL, approximately 213 mg / mL, approximately 214 mg / mL, or approximately 215 mg / mL, or any value in between.

[0107] In certain embodiments, for protein concentrations of approximately 185 mg / mL to approximately 215 mg / mL (e.g., approximately 200 mg / mL), the total volume of the aqueous pharmaceutical composition (or DP) is in the range of approximately 0.5 mL to approximately 2 mL. In one embodiment, the total volume of the aqueous pharmaceutical composition (or DP) is in the range of approximately 0.5 mL to approximately 2 mL, approximately 1 mL to approximately 2 mL, approximately 1.25 mL to approximately 1.75 mL, or approximately 1.4 mL to approximately 1.6 mL. In one embodiment, the total volume of the aqueous pharmaceutical composition is approximately 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, 1.6 mL, 1.7 mL, 1.8 mL, 1.9 mL, or 2 mL, or any range in between. In one embodiment, the total volume of the aqueous pharmaceutical composition is approximately 1.5 mL. For example, a 1.5 mL vial contains approximately 200 mg of antibody / mL (approximately 300 mg of antibody / vial).

[0108] In one embodiment, DP stability is defined as having a protein concentration of approximately 175 mg / mL to approximately 225 mg / mL (as determined by A280) after storing DP at a temperature of approximately 25°C for approximately 12 months or more, and / or after storing at a temperature of approximately 5°C (e.g., 2-8°C) for approximately 1 year or more, or after storing at a temperature of approximately 5°C (e.g., 2-8°C) for approximately 2 years or more. In a preferred embodiment, DP stability is defined as having a protein concentration of approximately 180 mg / mL to approximately 220 mg / mL (as determined by A280) after storing DP at a temperature of approximately 25°C for approximately 12 months or more, and / or after storing at a temperature of approximately 5°C (e.g., 2-8°C) for approximately 1 year or more, or after storing at a temperature of approximately 5°C (e.g., 2-8°C) for approximately 2 years or more. In another preferred embodiment, DP stability is defined as having a protein concentration of approximately 190 mg / mL to approximately 210 mg / mL (as determined by A280) after storing DP at a temperature of approximately 25°C for approximately 12 months or more, and / or after storing at a temperature of approximately 5°C (e.g., 2–8°C) for approximately 1 year or more, or after storing at a temperature of approximately 5°C (e.g., 2–8°C) for approximately 2 years or more.

[0109] According to one embodiment, the aqueous pharmaceutical composition has a protein concentration of BCMAxCD3 bispecific antibody of about 180 mg / mL to about 220 mg / mL (preferably about 200 mg / mL) over a storage period of about 6 months at 5°C (e.g., 2 to 8°C), or about 12 months at 5°C (e.g., 2 to 8°C), or about 18 months at 5°C (e.g., 2 to 8°C), or about 24 months at 5°C (e.g., 2 to 8°C), or about 30 months at 5°C (e.g., 2 to 8°C), or about 36 months at 5°C (e.g., 2 to 8°C). According to one embodiment, the aqueous pharmaceutical composition has a protein concentration of BCMAxCD3 bispecific antibody of about 180 mg / mL to about 220 mg / mL (preferably about 200 mg / mL) over a storage period of at least about 6 months at 5°C (e.g., 2 to 8°C), at least about 12 months at 5°C (e.g., 2 to 8°C), at least about 18 months at 5°C (e.g., 2 to 8°C), at least about 24 months at 5°C (e.g., 2 to 8°C), at least about 30 months at 5°C (e.g., 2 to 8°C), or at least about 36 months at 5°C (e.g., 2 to 8°C).

[0110] According to one embodiment, the aqueous pharmaceutical composition contains approximately 180 mg / mL to approximately 220 mg / mL (e.g., approximately 200 mg / mL) of BCMAxCD3 bispecific antibody in 15 mM acetic acid, 4.0% (w / v) sucrose, 200 mM arginine-HCl, 20 μg / mL EDTA, and 0.04% (w / v) polysorbate 20, and has a pH of 5.2. The composition is preferably contained in a vial, the nominal filling capacity of the vial is approximately 1.5 mL, and therefore the nominal antibody amount is approximately 300 mg / vial. Preferred temperature conditions are 5 ± 3°C (2 to 8°C), and the vial is preferably protected from light. The composition is preferably low viscosity (for example, about 25 centipoise (cP) or less, or about 22 cP or less, or about 20 cP or less, or about 18 cP or less, or about 17 cP or less, most preferably about 16.6 cP), and is suitable for subcutaneous administration to human subjects for the treatment of hematological cancers, such as multiple myeloma.

[0111] Peptide mapping Post-translational modifications (PTMs), such as oxidation, deamidation, and isomerization, are enzymatic modifications that can be detected within the structure of an antibody. In some embodiments, PD stability is assessed based on the level of PTMs in the antibody. The test sample is enzymatically digested to obtain peptide segments. These peptides are then evaluated, for example, by mass spectrometry (MS), tandem mass spectrometry (MS-MS), or ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS). Each analyzed peptide sequence is identified relative to its known position within the overall antibody structure. Post-translational modifications are determined by comparing the measured mass of the identified peptide sequence with its expected mass.

[0112] The efficacy of pharmaceuticals In vitro T cell activation assays allow for the assessment of DP stability levels. This activation can be assessed using, but is not limited to, a nuclear factor of activated T cells-Response Element (NFAT-RE) mediated luminescence assays.

[0113] T cell activation activity by BCMA × CD3 In one embodiment, DP stability is defined as having BMCA×CD3-mediated T cell activation activity of approximately 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, or 160%, or any range in between, compared to a reference, after storing DP at a temperature of approximately 5°C (e.g., 2-8°C) for approximately 12 months or more, after storing DP at a temperature of approximately 25°C for approximately 12 months or more, and / or after storing DP at a temperature of approximately 5°C (e.g., 2-8°C) for approximately 1 year or more or approximately 2 years or more. In preferred embodiments, DP stability is defined as having BMCA×CD3-mediated T cell activation activity in the range of about 60% to about 140% compared to a reference after storing DP at a temperature of about 25°C for about 12 months or more, and / or after storing DP at a temperature of about 5°C (e.g., 2-8°C) for about 1 year or about 2 years or more. In most preferred embodiments, DP stability is defined as having BMCA×CD3-mediated T cell activation activity in the range of about 80% to about 120% compared to a reference after storing DP at a temperature of about 25°C for about 12 months or more, and / or after storing DP at a temperature of about 5°C (e.g., 2-8°C) for about 1 year or about 2 years or more.

[0114] Polysorbate 20 (PS20) In one embodiment, DP stability is defined by the PS20 concentration at approximately 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, or any range in between, as a weight-to-volume percentage after storing DP at approximately 5°C for approximately 12 months or more, at approximately 25°C for approximately 12 months or more, and / or at approximately 5°C for approximately 2 years or more. In one embodiment, DP stability is defined by the PS20 concentration at approximately 0.02% to approximately 0.1% after storing DP at approximately 25°C for approximately 12 months or more, and / or at approximately 5°C for approximately 2 years or more. In one embodiment, DP stability is defined by the PS20 concentration at approximately 0.01% to approximately 0.07%. In a preferred embodiment, DP stability is defined by a PS20 concentration of about 0.02% to about 0.06% after storing DP at a temperature of about 25°C for about 12 months or more, and / or after storing at a temperature of about 5°C for about 2 years or more. In a most preferred embodiment, DP stability is defined by a PS20 concentration of about 0.03% to about 0.05% after storing DP at a temperature of about 25°C for about 12 months or more, and / or after storing at a temperature of about 5°C for about 2 years or more.

[0115] Embodiments of high-concentration, low-viscosity pharmaceutical compositions The inventors have discovered that the BCMA / CD3 bispecific antibody described herein can be formulated into low-viscosity, high-concentration compositions (e.g., antibody concentrations of approximately 150 mg / mL to approximately 250 mg / mL, or approximately 180 mg / mL to approximately 220 mg / mL, or approximately 200 mg / mL) suitable for subcutaneous administration to human subjects for the treatment of hematological cancers, such as multiple myeloma.

[0116] According to one embodiment, the composition includes a viscosity-reducing agent such as arginine-HCl.

[0117] According to a preferred embodiment, the aqueous pharmaceutical composition has a viscosity of about 25 centipoise (cP) or less, more preferably about 24 cP or less, or about 23 cP or less, or about 22 cP or less, or about 22 cP or less, or about 20 cP or less, or about 19 cP or less, or about 18 cP or less, or about 17 cP or less at 25°C. According to one embodiment, the pharmaceutical composition has a viscosity of about 12 cP to about 22 cP, or about 13 cP to about 21 cP, or about 14 cP to about 20 cP, or about 15 cP to about 19 cP, or about 12 cP to about 20 cP, or about 15 cP to about 18 cP, or about 15 cP to about 17 cP at 25°C. According to a particular embodiment, the composition has a viscosity of about 16.6 cP at 25°C.

[0118] According to certain embodiments, aqueous pharmaceutical compositions comprising the BCMA / CD3 bispecific antibody described herein can be formulated to have low viscosity (e.g., about 25 centipoise (cP) or less, or about 22 cP or less, or about 20 cP or less, or about 18 cP or less, or about 17 cP or less) and high concentration (e.g., antibody concentration of about 150 mg / mL to about 250 mg / mL, or about 180 mg / mL to about 220 mg / mL, or about 200 mg / mL), and the compositions are suitable for subcutaneous administration to human subjects for the treatment of hematological cancers, such as multiple myeloma.

[0119] According to one embodiment, the aqueous pharmaceutical composition comprises (a) a bispecific BCMA / CD3 antibody as specified herein in a concentration of about 150 mg / mL to about 250 mg / mL (e.g., about 180 mg / mL to about 220 mg / mL, or about 200 mg / mL), and (b) a viscosity-reducing agent (preferably arginine HCl), wherein the composition has a pH of about 4.7 to about 5.7 and is suitable for subcutaneous administration to human subjects for the treatment of hematological cancers, such as multiple myeloma, and the composition is (a) If the color of the solution is colorless, then ≤BY2, ≤B2, ≤Y2, (b) Gravimetric osmolality of approximately 612 to 828 mOsm / kg (c) BMCAxCD3-mediated T cell activation activity in the range of approximately 60% to 140% compared to tecristamag reference material. (d) Density of approximately 1.079 g / mL at 20-25°C. (e) Viscosity of approximately 15 to 18 cP at 25°C (for example, approximately 16.6 cP), (f) As determined by cSDS (reduced form), compared to the tecristamagb reference material, with a purity of ≥95.0% and no new peaks >1.0%, (g) As determined by cSDS (non-reduced form), compared to the tecristamagb reference material, it has a purity of ≥90.0%, no new peaks >1.0%, and / or (h) As determined by SE-HPLC, the principal component is ≥95.0%, HMWS is ≤5.0%, and LMWS is <5.0% (or as determined by SE-HPLC, the principal component is ≥90.0%, HMWS is ≤10.0%, and LMWS is <10.0%) It possesses one or more of the following characteristics.

[0120] According to a preferred embodiment, the aqueous pharmaceutical composition has a viscosity of about 25 centipoise (cP) or less, more preferably about 24 cP or less, or about 23 cP or less, or about 22 cP or less, or about 22 cP or less, or about 20 cP or less, or about 19 cP or less, or about 18 cP or less, or about 17 cP or less. According to one embodiment, the pharmaceutical composition has a viscosity of about 12 cP to about 22 cP, or about 13 cP to about 21 cP, or about 14 cP to about 20 cP, or about 15 cP to about 19 cP, or about 12 cP to about 20 cP, or about 15 cP to about 18 cP, or about 15 cP to about 17 cP. According to a particular embodiment, the composition has a viscosity of about 16.6 cP at 25°C.

[0121] Method of the present invention This specification provides a method for treating a subject requiring treatment for cancer, the method comprising administering an aqueous pharmaceutical composition disclosed herein to the subject. In certain embodiments, the administration is intravenous.

[0122] cancer In some embodiments, the cancer is a hematological malignancy or a solid tumor.

[0123] In some embodiments, hematological malignancies include multiple myeloma, smoldering multiple myeloma, monoclonal immunoglobulinemia of unknown significance (MGUS), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia, plasma cell leukemia, light chain amyloidosis (AL), and precursor B-cell lymphoblastic leukemia. These include precursor B-cell lymphoblastic leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), B-cell malignancies, chronic myeloid leukemia (CML), pilarid cell leukemia (HCL), blastic plasmacytoid dendritic cell neoplasm, Hodgkin lymphoma, non-Hodgkin lymphoma, marginal zone B-cell lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma (MALT), plasma cell leukemia, anaplastic large cell lymphoma (ALCL), leukemia, or lymphoma.

[0124] In certain embodiments, the hematological malignancy is multiple myeloma. In some embodiments, the subject has newly diagnosed multiple myeloma. In some embodiments, the subject is relapsed or refractory to treatment with one or more prior anti-cancer therapies, such as therapies used to treat multiple myeloma or other hematological malignancies.

[0125] In some embodiments, the subjects are refractory or relapsed to one or more treatments or therapies such as THALOMID® (thalidomide), REVLIMID® (lenalidomide), POMALYST® (pomalidomide), VELCADE® (bortezomib), NINLARO (ixazomib), KYPROLIS® (carfilzomib), FARADYK® (42-erinexorat 42at), AREDIA® (pamidronate), ZOMETA® (zoledronic acid), DARZALEX® (daratumumab), erotozumab or melphalan, Xpovio® (selinexol), Venclexta® (venetoclax), GSK 916, CAR-T therapy agents, or other BCMA-targeted therapies.

[0126] Various qualitative and / or quantitative methods can be used to determine the recurrence or refractory nature of the disease. Possible related symptoms include, for example, a decline or stabilization of the patient's health, recurrence or exacerbation of various symptoms associated with solid tumors, and / or metastasis of cancer cells within the body from one site to other organs, tissues, or cells.

[0127] In some embodiments, multiple myeloma is relapsed or refractory to treatment with anti-CD38 antibodies, selinexol, venetoclax, lenarinomide, bortezomib, pomalidomide, carfilzomib, erotozumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[0128] In some embodiments, multiple myeloma is high-risk multiple myeloma. Subjects with high-risk multiple myeloma are known to experience early relapses and have a poor prognosis and outcome. Subjects that can be classified as having high-risk multiple myeloma have one or more of the following cytogenetic abnormalities: t(4;14)(p16;q32), t(14;16)(q32;q23), del17p, 1qAmp, t(4;14)(p16;q32) and t(14;16)(q32;q23), t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p. In some embodiments, subjects with high-risk multiple myeloma have one or more chromosomal abnormalities, including t(4;14)(p16;q32), t(14;16)(q32;q23), del17p, 1qAmp, t(4;14)(p16;q32) and t(14;16)(q32;q23), t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof.

[0129] Cytogenetic abnormalities can be detected, for example, by fluorescence in situ hybridization (FISH). In chromosomal translocations, oncogenes are translocated to the IgH region on chromosome 14q32, resulting in dysregulation of these genes. T(4;14)(p16;q32) involves translocations of fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET (MMSET) domain-containing protein (also known as WHSC1 / NSD2), while t(14;16)(q32;q23) involves a translocation of the MAF transcription factor C-MAF. Deletion of 17p (del17p) involves the loss of the p53 locus.

[0130] Chromosome rearrangements can be identified using well-known methods, such as fluorescence in situ hybridization, karyotype analysis, pulsed-field gel electrophoresis, or sequencing.

[0131] In one embodiment, a method for treating a subject requiring treatment for a hematological cancer, such as multiple myeloma, comprises subcutaneous administration of one or more escalating doses of composition A to the subject, composition A comprising about 10 mg / mL of bispecific BCMA / CD3 antibody, about 15 mM acetic acid and / or pharmaceutically acceptable acetate, about 7.8% (w / v) sucrose, about 10 mM arginine HCl, about 20 μg / mL EDTA, and about 0.04% PS20, and composition A has a pH of about 5.2. Next, the treatment involves subcutaneously administering composition B to the subject once a week, wherein composition B comprises about 200 mg / mL of bispecific BMCA / CD3 antibody, about 15 mM acetic acid and / or a pharmaceutically acceptable acetate, about 4% (w / v) sucrose, about 200 mM arginine HCl, about 20 μg / mL EDTA, and about 0.04% PS20, and composition B has a pH of about 5.2. Preferably, the bispecific BMCA / CD3 antibody comprises HC2 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 19, and LC2 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 20.

[0132] This specification also provides a method for preparing an aqueous pharmaceutical composition of a bispecific B cell maturation antigen (BCMA) / differentiation antigen group 3 (CD3) antibody or its antigen-binding fragment, wherein the bispecific BCMA / CD3 antibody or its antigen-binding fragment comprises: a first heavy chain (HC1) comprising an HC1 variable region 1 (VH1), VH1 comprising 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 an LC1 variable region (VL1), VL1 comprising light chain complementarity-determining regions 1 (LCDR1), LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs. 4, 5, and 6, respectively; and a second heavy chain (HC2), H The method comprises a second heavy chain (HC2) comprising a C2 variable region 2 (VH2), where VH2 comprises heavy chain complementarity determining regions 1 (HCDR1), HCDR2, and HCDR3 having amino acid sequences of SEQ ID NOs. 11, 12, and 13, respectively, and a second light chain (LC2) comprising an LC2 variable region 2 (VL2), where VL2 comprises light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3 having amino acid sequences of SEQ ID NOs. 14, 15, and 16, respectively, and the method comprises combining a bispecific BCMA / CD3 antibody with amounts of acetic acid and / or pharmaceutically acceptable acetate, arginine HCl, sucrose, EDTA, and polysorbate (PS) 20 as described herein, wherein the aqueous pharmaceutical composition has a pH of about 5.2.

[0133] In certain embodiments, the bispecific BCMA / CD3 antibody includes VH1 having the amino acid sequence of SEQ ID NO: 7 and VL1 having the amino acid sequence of SEQ ID NO: 8. In certain embodiments, the bispecific BCMA / CD3 antibody includes HC1 having the amino acid sequence of SEQ ID NO: 9 and LC1 having the amino acid sequence of SEQ ID NO: 10. In certain embodiments, the bispecific BCMA / CD3 antibody includes VH2 having the amino acid sequence of SEQ ID NO: 17 and VL2 having the amino acid sequence of SEQ ID NO: 18. In certain embodiments, the bispecific BCMA / CD3 antibody includes HC2 having the amino acid sequence of SEQ ID NO: 19 and LC2 having the amino acid sequence of SEQ ID NO: 20. The bispecific BCMA / CD3 antibody may be, for example, teclistamag.

[0134] The aqueous pharmaceutical compositions disclosed herein may be packaged in kits, containers, packs, dispensers, or vials.

[0135] A kit comprising the aqueous pharmaceutical product and instructions for use thereof is provided herein.

[0136] Products comprising a container for holding the aqueous pharmaceutical composition of the present disclosure are also provided herein. In some embodiments, the container is a vial having a stopper that can be punctured by a syringe.

[0137] Embodiment Exemplary embodiments of the technology of this disclosure are provided herein. These embodiments are for illustrative purposes only and do not limit the scope of this disclosure or the claims appended herein.

[0138] 1. a) A bispecific B cell maturation antigen (BCMA) / differentiation antigen group 3 (CD3) antibody in a concentration of approximately 150 mg / mL to approximately 250 mg / mL, (5) The first heavy chain (HC1), which includes an HC1 variable region 1 (VH1), VH1 comprises a first heavy chain (HC1) containing heavy chain complementarity determination regions 1 (HCDR1), HCDR2, and HCDR3, each having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively. (6) A first light chain (LC1) including an LC1 variable region (VL1), VL1 comprises a first light chain (LC1) and light chain complementarity determination regions 1 (LCDR1), LCDR2, and LCDR3, each having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively. (7) A second heavy chain (HC2) comprising an HC2 variable region 2 (VH2), VH2 comprises a second heavy chain (HC2) containing heavy chain complementarity determination regions 1 (HCDR1), HCDR2, and HCDR3, each having the amino acid sequences of SEQ ID NOs. 11, 12, and 13, respectively. (8) A second light chain (LC2) including an LC2 variable region 2 (VL2), VL2 is a bispecific BCMA / CD3 antibody containing a second light chain (LC2) comprising light chain complementarity determining regions 1 (LCDR1), 15, and 16, respectively, having amino acid sequences of SEQ ID NOs: 14, 15, and 16, and LCDR3, and b) Contains arginine HCl, An aqueous pharmaceutical composition having a viscosity of approximately 25 centipoise (cP) or less at 25°C. 2. The aqueous pharmaceutical composition according to Embodiment 1, wherein the bispecific BCMA / CD3 antibody comprises VH1 having the amino acid sequence of SEQ ID NO: 7 and VL1 having the amino acid sequence of SEQ ID NO: 8. 3. The aqueous pharmaceutical composition according to Embodiment 1 or 2, wherein the bispecific BCMA / CD3 antibody comprises VH2 having the amino acid sequence of SEQ ID NO: 17 and VL2 having the amino acid sequence of SEQ ID NO: 18. 4. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 3, wherein the bispecific BCMA / CD3 antibody comprises HC1 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 9 and LC1 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 10. 5. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 3, wherein the bispecific BCMA / CD3 antibody comprises HC1 having the amino acid sequence of SEQ ID NO: 9 and LC1 having the amino acid sequence of SEQ ID NO: 10. 6. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 5, wherein the bispecific BCMA / CD3 antibody comprises HC2 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 19 and LC2 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 20. 7. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 5, wherein the bispecific BCMA / CD3 antibody comprises HC2 having the amino acid sequence of SEQ ID NO: 19 and LC2 having the amino acid sequence of SEQ ID NO: 20. 8. The aqueous pharmaceutical composition according to Embodiment 1, wherein the bispecific BCMA / CD3 antibody is teclistamagb. 9. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 8, wherein the composition contains a bispecific BCMA / CD3 antibody in an amount of approximately 180 mg / mL to approximately 220 mg / mL. 10. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 8, wherein the composition contains approximately 200 mg / mL of a bispecific BCMA / CD3 antibody. 11. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 10, wherein the composition contains about 100 mM to about 300 mM arginine HCl. 12. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 10, wherein the composition contains about 150 mM to about 250 mM arginine HCl. 13. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 10, wherein the composition contains about 200 mM arginine HCl. 14. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 13, wherein the composition has a viscosity of about 22 centipoise (cP) or less at 25°C. 15. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 13, wherein the composition has a viscosity of about 20 centipoise (cP) or less at 25°C. 16. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 13, wherein the composition has a viscosity of about 18 centipoise (cP) or less at 25°C. 17. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 13, wherein the composition has a viscosity of about 10 centipoise (cP) to about 20 cP at 25°C. 18. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 13, wherein the composition has a viscosity of about 15 centipoise (cP) to about 18 cP at 25°C. 19. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 13, wherein the composition has a viscosity of about 16 centipoise (cP) to about 17 cP (e.g., about 16.6 cP) at 25°C. 20. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 19, wherein the composition contains a high molecular weight species of bispecific BCMA / CD3 antibody in an amount of approximately 10% or less of the bispecific BCMA / CD3 antibody. 21. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 19, wherein the composition contains a high molecular weight species of bispecific BCMA / CD3 antibody in an amount of approximately 7.5% or less of the bispecific BCMA / CD3 antibody. 22. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 19, wherein the composition contains a high molecular weight species of bispecific BCMA / CD3 antibody in an amount of approximately 5% or less of the bispecific BCMA / CD3 antibody. 23. The composition is (a) If the color of the solution is colorless, then ≤BY2, ≤B2, ≤Y2, (b) Gravimetric osmolality of approximately 612 to 828 mOsm / kg (c) BMCAxCD3-mediated T-cell activation activity ranging from approximately 60% to approximately 140% relative to the tecristamag reference material, and / or (d) As determined by SE-HPLC, the principal component is ≥95.0%, HMWS is ≤5.0%, and LMWS is <5.0% (or as determined by SE-HPLC, the principal component is ≥90.0%, HMWS is ≤10.0%, and LMWS is <10.0%) An aqueous pharmaceutical composition according to any one of Embodiments 1 to 19, having one or more of the characteristics of the above. 24. The composition is (a) If the color of the solution is colorless, then ≤BY2, ≤B2, ≤Y2, (b) Gravimetric osmolality of approximately 612 to 828 mOsm / kg (c) BMCAxCD3-mediated T cell activation activity in the range of approximately 60% to 140% compared to tecristamag reference material. (d) As determined by cSDS (reduced form), compared to the tecristamagb reference material, with a purity of ≥95.0% and no new peaks >1.0%, (e) As determined by cSDS (non-reduced form), compared to the tecristamagb reference material, with a purity of ≥90.0%, no new peaks >1.0%, and / or (f) As determined by SE-HPLC, the principal component is ≥95.0%, HMWS is ≤5.0%, and LMWS is <5.0% (or as determined by SE-HPLC, the principal component is ≥90.0%, HMWS is ≤10.0%, and LMWS is <10.0%) An aqueous pharmaceutical composition according to any one of Embodiments 1 to 19, having one or more of the characteristics of the above. 25. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 24, wherein the composition is stable. 26. The aqueous pharmaceutical composition according to Embodiment 25, wherein the stability of the composition is defined based on the color, pH, turbidity, purity percentage, new peak percentage, main component percentage, high molecular weight species (HWMS), low molecular weight species (LMWS), total acidic peak percentage, total basic peak percentage, protein concentration, T cell activation percentage, PS20 (w / v) percentage, or any combination thereof. 27. The aqueous pharmaceutical composition according to Embodiment 25 or 26, wherein the aqueous pharmaceutical composition is stable for at least two years at a temperature of about 2 to 8°C. 28. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 27, wherein the composition contains about 180 mg / mL to about 220 mg / mL (preferably about 200 mg / mL) of BCMAxCD3 bispecific antibody over a storage period of at least about 6 months at 2 to 8°C, or at least about 12 months at 2 to 8°C, or at least about 18 months at 2 to 8°C, or at least about 24 months at 2 to 8°C, or at least about 30 months at 2 to 8°C, or at least about 36 months at 2 to 8°C. 29. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 28, wherein the composition is suitable for subcutaneous administration to a human subject for the treatment of blood cancer, such as multiple myeloma. 30. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 29, wherein the composition contains about 1% (w / v) to about 7% (w / v) of sucrose, or about 2% (w / v) to about 6% (w / v) of sucrose. 31. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 29, wherein the composition contains about 3% (w / v) to about 5% (w / v) sucrose. 32. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 29, wherein the composition contains about 4% (w / v) sucrose. 33. The aqueous pharmaceutical composition according to any one of claims 1 to 32, wherein the composition comprises about 10 mM to about 20 mM acetic acid, or about 12 mM to about 18 mM acetic acid and / or a pharmaceutically acceptable acetate salt. 34. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 32, wherein the composition comprises about 14 mM to about 16 mM acetic acid and / or a pharmaceutically acceptable acetate salt. 35. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 32, wherein the composition comprises about 15 mM acetic acid and / or a pharmaceutically acceptable acetate salt. 36. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 35, wherein the composition contains EDTA in an amount of about 16 μg / mL to about 24 μg / mL, or about 18 μg / mL to about 22 μg / mL. 37. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 35, wherein the composition contains approximately 20 μg / mL of EDTA. 38. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 37, wherein the composition contains approximately 0.01% to approximately 0.07%, or approximately 0.02% to approximately 0.06% of PS-20(w / v). 39. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 37, wherein the composition contains about 0.03 to about 0.05% PS-20 (w / v). 40. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 37, wherein the composition contains about 0.04% or about 0.06% PS-20 (w / v). 41. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 40, wherein the pH of the composition is approximately 4.7 to approximately 5.7, or approximately 4.8 to approximately 5.6. 42. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 40, wherein the pH of the composition is approximately 4.9 to approximately 5.5. 43. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 40, wherein the pH of the composition is approximately 5.2. 44. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 40, wherein the composition comprises about 200 mg / mL of bispecific BCMA / CD3 antibody, about 15 mM acetic acid and / or a pharmaceutically acceptable acetate, about 4% (w / v) sucrose, about 200 mM arginine HCl, about 20 μg / mL EDTA, and about 0.04% (w / v) PS20, and the composition has a pH of about 5.2. 45. A vial containing approximately 1.5 mL of the composition described in Embodiment 44, and further containing approximately 300 mg of bispecific BCMA / CD3 antibody. 46. ​​A vial containing the composition described in any of Embodiments 1 to 44. 47. The vial according to embodiment 45 or 46, wherein the vial is equipped with a stopper that can be punctured by a syringe. 48. A method for treating a subject requiring treatment for a blood cancer, such as multiple myeloma, comprising subcutaneously administering a therapeutically effective amount of a composition described in any of Embodiments 1 to 44 to the subject. 49. A method for treating a subject in need of treatment for a blood cancer, such as multiple myeloma, comprising subcutaneously administering to the subject once a week, as a therapeutic dose, a composition described in any of Embodiments 1 to 44 in a therapeutically effective amount. 50. A method for treating a subject in need of treatment for a hematological cancer, such as multiple myeloma, comprising subcutaneously administering a therapeutic dose of any of the compositions described in Embodiments 1 to 44 to the subject once a week, wherein the subject has relapsed / refractory multiple myeloma. 51. A method for treating a subject requiring treatment for a hematological cancer, such as multiple myeloma, comprising subcutaneously administering one or more escalating doses of the same bispecific BCMA / CD3 antibody contained in a composition to the subject once weekly before administering the composition described in any of Embodiments 1 to 44 to the subject. 52. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 44 for use in the treatment of cancer. 53. An aqueous pharmaceutical composition according to any one of Embodiments 1 to 44, for use in the preparation of pharmaceuticals for the treatment of cancer. 54. Use of an aqueous pharmaceutical composition according to any one of Embodiments 1 to 44 for the treatment of a subject requiring treatment, comprising administering the aqueous pharmaceutical composition to the subject requiring treatment. 55. The use described in Embodiment 54, wherein the administration is by subcutaneous administration. 56. a) A bispecific B cell maturation antigen (BCMA) / differentiation antigen group 3 (CD3) antibody in a concentration of approximately 150 mg / mL to approximately 250 mg / mL, (1) A first heavy chain (HC1) comprising an HC1 variable region 1 (VH1), VH1 comprises a first heavy chain (HC1) containing heavy chain complementarity determination regions 1 (HCDR1), HCDR2, and HCDR3, each having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively. (2) A first light chain (LC1) including an LC1 variable region (VL1), VL1 comprises a first light chain (LC1) containing light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, each having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively. (3) A second heavy chain (HC2) comprising an HC2 variable region 2 (VH2), VH2 comprises a second heavy chain (HC2) containing heavy chain complementarity determination regions 1 (HCDR1), HCDR2, and HCDR3, each having the amino acid sequences of SEQ ID NOs. 11, 12, and 13, respectively. (4) A second light chain (LC2) including an LC2 variable region 2 (VL2), VL2 comprises a second light chain (LC2) containing light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, each having the amino acid sequences of SEQ ID NOs. 14, 15, and 16, respectively, and a bispecific BCMA / CD3 antibody or its antigen-binding fragment. (g) Approximately 10 mM to approximately 20 mM acetic acid and / or pharmaceutically acceptable acetate salts, (h) Sucrose at approximately 1% (w / v) to 7% (w / v), (i) Arginine HCl at a concentration of approximately 100 mM to 300 mM, (j) Ethylenediaminetetraacetic acid (EDTA) in a concentration of approximately 16 μg / mL to approximately 24 μg / mL, and (k) Contains approximately 0.01% to 0.07% polysorbate 20 (w / v), An aqueous pharmaceutical composition having a pH of approximately 4.7 to 5.7. 57. The aqueous pharmaceutical composition according to Embodiment 56, wherein the bispecific BCMA / CD3 antibody comprises VH1 having the amino acid sequence of SEQ ID NO: 7 and VL1 having the amino acid sequence of SEQ ID NO: 8. 58. The aqueous pharmaceutical composition according to Embodiment 56 or 57, wherein the bispecific BCMA / CD3 antibody comprises VH2 having the amino acid sequence of SEQ ID NO: 17 and VL2 having the amino acid sequence of SEQ ID NO: 18. 59. An aqueous pharmaceutical composition according to any one of embodiments 56 to 58, wherein the bispecific BCMA / CD3 antibody comprises HC1 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 9 and LC1 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 10. 60. An aqueous pharmaceutical composition according to any one of embodiments 56 to 58, wherein the bispecific BCMA / CD3 antibody comprises HC1 having the amino acid sequence of SEQ ID NO: 9 and LC1 having the amino acid sequence of SEQ ID NO: 10. 61. An aqueous pharmaceutical composition according to any one of embodiments 56 to 60, wherein the bispecific BCMA / CD3 antibody comprises HC2 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 19 and LC2 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 20. 62. An aqueous pharmaceutical composition according to any one of embodiments 56 to 60, wherein the bispecific BCMA / CD3 antibody comprises HC2 having the amino acid sequence of SEQ ID NO: 19 and LC2 having the amino acid sequence of SEQ ID NO: 20. 63. The aqueous pharmaceutical composition according to Embodiment 56, wherein the bispecific BCMA / CD3 antibody is teclistamaib. 64. An aqueous pharmaceutical composition according to any one of embodiments 56 to 63, wherein the composition contains a bispecific BCMA / CD3 antibody in a concentration of approximately 180 mg / mL to approximately 220 mg / mL. 65. An aqueous pharmaceutical composition according to any one of embodiments 56 to 63, wherein the composition contains approximately 200 mg / mL of a bispecific BCMA / CD3 antibody. 66. An aqueous pharmaceutical composition according to any one of embodiments 56 to 65, wherein the composition contains about 100 mM to about 300 mM arginine HCl. 67. An aqueous pharmaceutical composition according to any one of embodiments 56 to 65, wherein the composition contains about 150 mM to about 250 mM arginine HCl. 68. An aqueous pharmaceutical composition according to any one of embodiments 56 to 65, wherein the composition contains about 200 mM arginine HCl. 69. An aqueous pharmaceutical composition according to any one of embodiments 56 to 68, wherein the composition contains about 2% (w / v) to about 6% (w / v) sucrose. 70. An aqueous pharmaceutical composition according to any one of embodiments 56 to 68, wherein the composition contains about 3% (w / v) to about 5% (w / v) sucrose. 71. An aqueous pharmaceutical composition according to any one of embodiments 56 to 68, wherein the composition contains about 4% (w / v) sucrose. 72. An aqueous pharmaceutical composition according to any one of Embodiments 56 to 71, wherein the composition comprises about 12 mM to about 18 mM acetic acid and / or a pharmaceutically acceptable acetate salt. 73. An aqueous pharmaceutical composition according to any one of Embodiments 56 to 71, wherein the composition comprises about 14 mM to about 16 mM acetic acid and / or a pharmaceutically acceptable acetate salt. 74. An aqueous pharmaceutical composition according to any one of Embodiments 56 to 71, wherein the composition comprises about 15 mM acetic acid and / or a pharmaceutically acceptable acetate. 75. An aqueous pharmaceutical composition according to any one of embodiments 56 to 74, wherein the composition contains approximately 18 μg / mL to approximately 22 μg / mL of EDTA. 76. An aqueous pharmaceutical composition according to any one of embodiments 56 to 74, wherein the composition contains approximately 20 μg / mL of EDTA. 77. An aqueous pharmaceutical composition according to any one of Embodiments 56 to 76, wherein the composition contains approximately 0.02% to approximately 0.06% PS-20 (w / v). 78. An aqueous pharmaceutical composition according to any one of Embodiments 56 to 76, wherein the composition contains about 0.03 to about 0.05% PS-20 (w / v). 79. An aqueous pharmaceutical composition according to any one of Embodiments 56 to 76, wherein the composition contains about 0.04% or about 0.06% PS-20 (w / v). 80. An aqueous pharmaceutical composition according to any one of embodiments 56 to 79, wherein the pH is approximately 4.8 to approximately 5.6. 81. An aqueous pharmaceutical composition according to any one of embodiments 56 to 79, wherein the pH is approximately 4.9 to approximately 5.5. 82. An aqueous pharmaceutical composition according to any one of embodiments 56 to 79, wherein the pH is approximately 5.2. 83. An aqueous pharmaceutical composition according to any one of Embodiments 56 to 82, wherein the composition comprises about 200 mg / mL of bispecific BCMA / CD3 antibody, about 15 mM acetic acid and / or a pharmaceutically acceptable acetate, about 4% (w / v) sucrose, about 200 mM arginine HCl, about 20 μg / mL EDTA, and about 0.04% (w / v) PS20, and the composition has a pH of about 5.2. 84. An aqueous pharmaceutical composition according to any one of embodiments 56 to 83, wherein the composition has a viscosity of about 25 centipoise (cP) or less at 25°C. 85. An aqueous pharmaceutical composition according to any one of embodiments 56 to 83, wherein the composition has a viscosity of about 22 centipoise (cP) or less at 25°C. 86. An aqueous pharmaceutical composition according to any one of embodiments 56 to 83, wherein the composition has a viscosity of about 20 centipoise (cP) or less at 25°C. 87. An aqueous pharmaceutical composition according to any one of embodiments 56 to 83, wherein the composition has a viscosity of about 18 centipoise (cP) or less at 25°C. 88. An aqueous pharmaceutical composition according to any one of embodiments 56 to 83, wherein the composition has a viscosity of about 10 centipoise (cP) to about 20 cP at 25°C. 89. An aqueous pharmaceutical composition according to any one of embodiments 56 to 83, wherein the composition has a viscosity of about 15 centipoise (cP) to about 18 cP at 25°C. 90. An aqueous pharmaceutical composition according to any one of embodiments 56 to 83, wherein the composition has a viscosity of about 16 centipoise (cP) to about 17 cP (e.g., about 16.6 cP) at 25°C. 91. An aqueous pharmaceutical composition according to any one of Embodiments 56 to 90, wherein the composition contains a high molecular weight species of bispecific BCMA / CD3 antibody in an amount of about 10% or less of the bispecific BCMA / CD3 antibody. 92. An aqueous pharmaceutical composition according to any one of Embodiments 56 to 90, wherein the composition contains a high molecular weight species of bispecific BCMA / CD3 antibody in an amount of approximately 7.5% or less of the bispecific BCMA / CD3 antibody. 93. An aqueous pharmaceutical composition according to any one of Embodiments 56 to 90, wherein the composition contains a high molecular weight species of bispecific BCMA / CD3 antibody in an amount of approximately 5% or less of the bispecific BCMA / CD3 antibody. 94. The composition is (a) If the color of the solution is colorless, then ≤BY2, ≤B2, ≤Y2, (b) Gravimetric osmolality of approximately 612 to 828 mOsm / kg (c) BMCAxCD3-mediated T-cell activation activity ranging from approximately 60% to approximately 140% relative to the tecristamag reference material, and / or (d) As determined by SE-HPLC, the principal component is ≥95.0%, HMWS is ≤5.0%, and LMWS is <5.0% (or as determined by SE-HPLC, the principal component is ≥90.0%, HMWS is ≤10.0%, and LMWS is <10.0%) An aqueous pharmaceutical composition according to any one of embodiments 56 to 93, having one or more of the characteristics of the above. 95. The composition is (a) If the color of the solution is colorless, then ≤BY2, ≤B2, ≤Y2, (b) Gravimetric osmolality of approximately 612 to 828 mOsm / kg (c) BMCAxCD3-mediated T cell activation activity in the range of approximately 60% to 140% compared to tecristamag reference material. (d) As determined by cSDS (reduced form), compared to the tecristamagb reference material, with a purity of ≥95.0% and no new peaks >1.0%, (e) As determined by cSDS (non-reduced form), compared to the tecristamagb reference material, with a purity of ≥90.0%, no new peaks >1.0%, and / or (f) As determined by SE-HPLC, the principal component is ≥95.0%, HMWS is ≤5.0%, and LMWS is <5.0% (or as determined by SE-HPLC, the principal component is ≥90.0%, HMWS is ≤10.0%, and LMWS is <10.0%) An aqueous pharmaceutical composition according to any one of embodiments 56 to 93, having one or more of the characteristics of the above. 96. An aqueous pharmaceutical composition according to any one of embodiments 56 to 95, wherein the composition is stable. 97. The aqueous pharmaceutical composition according to Embodiment 96, wherein the stability of the composition is defined based on the color, pH, turbidity, purity percentage, new peak percentage, main component percentage, high molecular weight species (HWMS) percentage, low molecular weight species (LMWS) percentage, total acidic peak percentage, total basic peak percentage, protein concentration, T cell activation percentage, PS20 (w / v) percentage, or any combination thereof. 98. The aqueous pharmaceutical composition according to Embodiment 96 or 97, wherein the aqueous pharmaceutical composition is stable for at least two years at a temperature of about 2 to 8°C. 99. An aqueous pharmaceutical composition according to any one of Embodiments 56 to 98, wherein the composition contains about 180 mg / mL to about 220 mg / mL (preferably about 200 mg / mL) of BCMAxCD3 bispecific antibody over a storage period of at least about 6 months at 2 to 8°C, or at least about 12 months at 2 to 8°C, or at least about 18 months at 2 to 8°C, or at least about 24 months at 2 to 8°C, or at least about 30 months at 2 to 8°C, or at least about 36 months at 2 to 8°C. 100. An aqueous pharmaceutical composition according to any one of embodiments 56 to 99, wherein the composition is suitable for subcutaneous administration to a human subject for the treatment of blood cancer, such as multiple myeloma. 101. A vial containing approximately 1.5 mL of the composition described in Embodiment 83, and further containing approximately 300 mg of bispecific BCMA / CD3 antibody. 102. A vial containing the composition described in any of Embodiments 56 to 100. 103. The vial according to embodiment 101 or 102, wherein the vial is equipped with a stopper that can be punctured by a syringe. 104. A method for treating a subject requiring treatment for a blood cancer, such as multiple myeloma, comprising subcutaneously administering a therapeutically effective amount of the composition described in any of embodiments 56 to 100 to the subject. 105. A method for treating a subject in need of treatment for a blood cancer, such as multiple myeloma, comprising subcutaneously administering to the subject once a week, as a therapeutic dose, a composition described in any of embodiments 56 to 100 in a therapeutically effective amount. 106. A method for treating a subject in need of treatment for a hematological cancer, such as multiple myeloma, comprising subcutaneously administering a therapeutic dose of any of embodiments 56 to 100 of a therapeutically effective amount to the subject once a week, wherein the subject has relapsed / refractory multiple myeloma. 107. A method for treating a subject in need of treatment for a hematological cancer, such as multiple myeloma, comprising subcutaneously administering one or more escalating doses of the same bispecific BCMA / CD3 antibody contained in any of embodiments 56 to 100 to the subject once weekly. 108. An aqueous pharmaceutical composition according to any one of embodiments 56 to 100, for use in the treatment of cancer. 109. An aqueous pharmaceutical composition according to any of Embodiments 56 to 100, for use in the preparation of pharmaceuticals for the treatment of cancer. 110. Use of an aqueous pharmaceutical composition according to any of embodiments 56 to 100 for the treatment of a subject requiring treatment, comprising administering the aqueous pharmaceutical composition to the subject requiring treatment. 111. The use described in Embodiment 110, wherein the administration is by subcutaneous administration. 112. a) A bispecific B cell maturation antigen (BCMA) / differentiation antigen group 3 (CD3) antibody in a concentration of approximately 7.5 mg / mL to approximately 12.5 mg / mL, (1) A first heavy chain (HC1) comprising an HC1 variable region 1 (VH1), VH1 comprises a first heavy chain (HC1) containing heavy chain complementarity determination regions 1 (HCDR1), HCDR2, and HCDR3, each having the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively. (2) A first light chain (LC1) including an LC1 variable region (VL1), VL1 comprises a first light chain (LC1) containing light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, each having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively. (3) A second heavy chain (HC2) comprising an HC2 variable region 2 (VH2), VH2 comprises a second heavy chain (HC2) containing heavy chain complementarity determination regions 1 (HCDR1), HCDR2, and HCDR3, each having the amino acid sequences of SEQ ID NOs. 11, 12, and 13, respectively. (4) A second light chain (LC2) including an LC2 variable region 2 (VL2), VL2 comprises a second light chain (LC2) containing light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, each having the amino acid sequences of SEQ ID NOs. 14, 15, and 16, respectively, and a bispecific BCMA / CD3 antibody or its antigen-binding fragment. (b) Approximately 10 mM to approximately 20 mM acetic acid and / or pharmaceutically acceptable acetate salts, (c) Sucrose at approximately 6% (w / v) to 10% (w / v), (d) Arginine HCl at a concentration of approximately 6 mM to 14 mM (e) Ethylenediaminetetraacetic acid (EDTA) in a concentration of approximately 16 μg / mL to approximately 24 μg / mL, and (f) Contains approximately 0.01% to approximately 0.07% polysorbate 20, An aqueous pharmaceutical composition having a pH of approximately 4.7 to 5.7. 113. The aqueous pharmaceutical composition according to Embodiment 112, wherein the bispecific BCMA / CD3 antibody comprises VH1 having the amino acid sequence of SEQ ID NO: 7 and VL1 having the amino acid sequence of SEQ ID NO: 8. 114. The aqueous pharmaceutical composition according to Embodiment 112 or 113, wherein the bispecific BCMA / CD3 antibody comprises VH2 having the amino acid sequence of SEQ ID NO: 17 and VL2 having the amino acid sequence of SEQ ID NO: 18. 115. An aqueous pharmaceutical composition according to any one of embodiments 112 to 114, wherein the bispecific BCMA / CD3 antibody comprises HC1 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 9 and LC1 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 10. 116. An aqueous pharmaceutical composition according to any one of embodiments 112 to 114, wherein the bispecific BCMA / CD3 antibody comprises HC1 having the amino acid sequence of SEQ ID NO: 9 and LC1 having the amino acid sequence of SEQ ID NO: 10. 117. An aqueous pharmaceutical composition according to any one of embodiments 112 to 116, wherein the bispecific BCMA / CD3 antibody comprises HC2 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 19 and LC2 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 20. 118. An aqueous pharmaceutical composition according to any one of embodiments 112 to 116, wherein the bispecific BCMA / CD3 antibody comprises HC2 having the amino acid sequence of SEQ ID NO: 19 and LC2 having the amino acid sequence of SEQ ID NO: 20. 119. The aqueous pharmaceutical composition according to Embodiment 112, wherein the bispecific BCMA / CD3 antibody is teclistamagb. 120. An aqueous pharmaceutical composition according to any one of Embodiments 112 to 119, wherein the composition contains a bispecific BCMA / CD3 antibody in a concentration of approximately 9 mg / mL to approximately 11 mg / mL. 121. An aqueous pharmaceutical composition according to any one of Embodiments 112 to 119, wherein the composition comprises approximately 10 mg / mL of a bispecific BCMA / CD3 antibody. 122. An aqueous pharmaceutical composition according to any one of Embodiments 112 to 121, wherein the composition contains about 7 mM to about 13 mM arginine HCl. 123. An aqueous pharmaceutical composition according to any one of Embodiments 112 to 121, wherein the composition contains about 8 mM to about 12 mM arginine HCl. 124. An aqueous pharmaceutical composition according to any one of Embodiments 112 to 121, wherein the composition contains about 10 mM arginine HCl. 125. An aqueous pharmaceutical composition according to any one of embodiments 112 to 124, wherein the composition contains about 6% (w / v) to about 9% (w / v) sucrose. 126. An aqueous pharmaceutical composition according to any one of embodiments 112 to 124, wherein the composition contains about 7% (w / v) to about 8% (w / v) sucrose. 127. An aqueous pharmaceutical composition according to any one of embodiments 112 to 124, wherein the composition contains about 7.8% (w / v) sucrose. 128. An aqueous pharmaceutical composition according to any one of Embodiments 112 to 127, wherein the composition comprises about 12 mM to about 18 mM acetic acid and / or a pharmaceutically acceptable acetate salt. 129. An aqueous pharmaceutical composition according to any one of Embodiments 112 to 127, wherein the composition comprises about 14 mM to about 16 mM acetic acid and / or a pharmaceutically acceptable acetate salt. 130. An aqueous pharmaceutical composition according to any one of Embodiments 112 to 127, wherein the composition comprises about 15 mM acetic acid and / or a pharmaceutically acceptable acetate salt. 131. An aqueous pharmaceutical composition according to any one of Embodiments 112 to 130, wherein the composition contains approximately 18 μg / mL to approximately 22 μg / mL of EDTA. 132. An aqueous pharmaceutical composition according to any one of Embodiments 112 to 130, wherein the composition contains approximately 20 μg / mL of EDTA. 133. An aqueous pharmaceutical composition according to any one of Embodiments 112 to 132, wherein the composition contains approximately 0.02% to approximately 0.06% PS-20 (w / v). 134. An aqueous pharmaceutical composition according to any one of Embodiments 112 to 132, wherein the composition contains about 0.03 to about 0.05% PS-20 (w / v). 135. An aqueous pharmaceutical composition according to any one of Embodiments 112 to 132, wherein the composition contains about 0.04% or 0.06% PS-20 (w / v). 136. An aqueous pharmaceutical composition according to any one of embodiments 112 to 135, wherein the pH is approximately 4.8 to approximately 5.6. 137. An aqueous pharmaceutical composition according to any one of embodiments 112 to 135, wherein the pH is approximately 4.9 to approximately 5.5. 138. An aqueous pharmaceutical composition according to any one of embodiments 112 to 135, wherein the pH is approximately 5.2. 139. An aqueous pharmaceutical composition according to any one of Embodiments 112 to 138, wherein the composition comprises about 10 mg / mL of bispecific BCMA / CD3 antibody, about 15 mM acetic acid and / or a pharmaceutically acceptable acetate, about 7.8% (w / v) sucrose, about 10 mM arginine HCl, about 20 μg / mL EDTA, and about 0.04% (w / v) PS20, and the composition has a pH of about 5.2. 140. The composition is (a) If the color of the solution is colorless, then ≤BY2, ≤B2, ≤Y2, (b) Gravimetric osmolality of approximately 612 to 828 mOsm / kg (c) BMCAxCD3-mediated T cell activation activity in the range of approximately 60% to 140% compared to tecristamag reference material. (d) As determined by cSDS (reduced form), compared to the tecristamagb reference material, with a purity of ≥95.0% and no new peaks >1.0%, (e) As determined by cSDS (non-reduced form), compared to the tecristamagb reference material, with a purity of ≥90.0%, no new peaks >1.0%, and / or (f) As determined by SE-HPLC, the principal component is ≥95.0%, HMWS is ≤5.0%, and LMWS is <5.0% (or as determined by SE-HPLC, the principal component is ≥90.0%, HMWS is ≤10.0%, and LMWS is <10.0%) An aqueous pharmaceutical composition according to any one of embodiments 112 to 139, having one or more of the characteristics of the above. 141. An aqueous pharmaceutical composition according to any one of embodiments 112 to 140, wherein the composition is stable. 142. The aqueous pharmaceutical composition according to Embodiment 141, wherein the stability of the composition is defined based on the color, pH, turbidity, purity percentage, percentage of new peaks, percentage of main components, percentage of high molecular weight species (HWMS), percentage of low molecular weight species (LMWS), percentage of total acidic peaks, percentage of total basic peaks, protein concentration, percentage of T cell activation, percentage of PS20 (w / v), or any combination thereof. 143. The aqueous pharmaceutical composition according to Embodiment 141 or 142, wherein the aqueous pharmaceutical composition is stable for at least two years at a temperature of about 2 to 8°C. 144. An aqueous pharmaceutical composition according to any one of Embodiments 112 to 143, wherein the composition contains about 8 mg / mL to about 12 mg / mL (preferably about 10 mg / mL) of BCMAxCD3 bispecific antibody over a storage period of at least about 6 months at 2 to 8°C, or at least about 12 months at 2 to 8°C, or at least about 18 months at 2 to 8°C, or at least about 24 months at 2 to 8°C, or at least about 30 months at 2 to 8°C, or at least about 36 months at 2 to 8°C. 145. An aqueous pharmaceutical composition according to any one of embodiments 112 to 144, wherein the composition is suitable for subcutaneous administration to a human subject for the treatment of blood cancer, such as multiple myeloma. 146. An aqueous pharmaceutical composition according to any one of Embodiments 112 to 144, wherein the composition is suitable for subcutaneous administration to a human subject as a gradual dose for the treatment of blood cancer, such as multiple myeloma. 147. A vial containing approximately 3 mL of the composition described in Embodiment 139, and further containing approximately 30 mg of bispecific BCMA / CD3 antibody. 148. A vial containing the composition described in any of embodiments 112 to 146. 149. The vial according to embodiment 147 or 148, wherein the vial is equipped with a stopper that can be punctured by a syringe. 150. A method for treating a subject requiring treatment for blood cancer, such as multiple myeloma, the method being: The method involves subcutaneous administration of one or more gradually increasing doses of composition A, wherein composition A contains approximately 10 mg / mL of bispecific BCMA / CD3 antibody, approximately 15 mM acetic acid and / or a pharmaceutically acceptable acetate, approximately 7.8% (w / v) sucrose, approximately 10 mM arginine HCl, approximately 20 μg / mL EDTA, and approximately 0.04% (w / v) PS20, and composition A has a pH of approximately 5.2, and is administered subcutaneously. Next, Composition B is administered subcutaneously once a week to the target, wherein Composition B contains approximately 200 mg / mL of bispecific BMCA / CD3 antibody, approximately 15 mM acetic acid and / or a pharmaceutically acceptable acetate, approximately 4% (w / v) sucrose, approximately 200 mM arginine HCl, approximately 20 μg / mL EDTA, and approximately 0.04% (w / v) PS20, and Composition B has a pH of approximately 5.2, and is administered subcutaneously. A method for preparing a bispecific BMCA / CD3 antibody comprising HC2 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 19, and LC2 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 20. 151. A method for treating a patient requiring treatment for blood cancer, such as multiple myeloma, the method being: The method involves subcutaneous administration of one or more gradually increasing doses of composition A, wherein composition A contains approximately 10 mg / mL of bispecific BCMA / CD3 antibody, approximately 15 mM acetic acid and / or a pharmaceutically acceptable acetate, approximately 7.8% (w / v) sucrose, approximately 10 mM arginine HCl, approximately 20 μg / mL EDTA, and approximately 0.04% (w / v) PS20, and composition A has a pH of approximately 5.2, and is administered subcutaneously. Next, Composition B is administered subcutaneously once a week to the target, wherein Composition B contains approximately 200 mg / mL of bispecific BMCA / CD3 antibody, approximately 15 mM acetic acid and / or a pharmaceutically acceptable acetate, approximately 4% (w / v) sucrose, approximately 200 mM arginine HCl, approximately 20 μg / mL EDTA, and approximately 0.04% (w / v) PS20, and Composition B has a pH of approximately 5.2, and is administered subcutaneously. A method for developing a bispecific BMCA / CD3 antibody comprising HC2 having the amino acid sequence of SEQ ID NO: 19 and LC2 having the amino acid sequence of SEQ ID NO: 20. 152. A method for preparing an aqueous pharmaceutical composition according to any one of embodiments 56-100 or 112-146, comprising combining a bispecific BCMA / CD3 antibody with acetic acid and / or a pharmaceutically acceptable acetate, sucrose, arginine HCl, EDTA, and PS20 to form an aqueous pharmaceutical composition.

[0139] Description of the analytical tests used in this specification Analytical testing - Overall characterization Color of the solution The color of pharmaceutical solutions is monitored to evaluate their appearance and ensure they match previous batches at the time of shipment and throughout the storage period. Solution color can be an indicator of product stability. To determine the solution color, the test sample is visually compared to a specified set of reference solutions.

[0140] Transfer the specified amount of liquid contents into an ampoule pre-marked with the same dimensions as the reference solution. Next, visually compare the contents of the ampoule to the color reference solution of the European Pharmacopoeia. The degree of color is determined by diffuse daylight observed against a white background.

[0141] Color and method of solution materials The materials and methods are described in European Pharmacopoeia 2.2.2, Degree of Coloration of Liquids, 10th edition, monograph number 20202, July 2019. Briefly, the test sample is compared to a set of B (brown), BY (brownish-yellow), and Y (yellow) color reference solutions.

[0142] The result of the solution color is consistent with stability. In one embodiment, stability is defined as having a solution color ranging from colorless to about BY2 or less, about B2 or less, and 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 a preferred embodiment, stability is defined as having a solution color ranging from colorless to about BY4 or less, about B4 or less, and 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 the most preferred embodiment, stability is defined as having a solution color ranging from colorless to about BY5 or less, about B5 or less, and 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.

[0143] pH pH materials and methods - The pH of the test specimen is measured using a daily calibrated electronic pH meter with a standardized pH electrode. All calibration solutions, reference buffers, and test specimens are equilibrated to 25°C before testing and maintained at 25°C during testing.

[0144] The pH result is consistent with stability. In one embodiment, stability is defined as having a pH range of 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 a preferred embodiment, stability is defined as a pH range of 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 the most preferred embodiment, stability is defined as having a pH range of 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.

[0145] Turbidity Materials and methods for turbidity measurement - The materials and methods are based on European Pharmacopoeia 2.2.1, Clarity and Degree of Opalescence of Liquids.

[0146] The turbidity results are consistent with stability. Test results are reported in turbidimetric turbidity units (NTU). In one embodiment, stability is defined as having a turbidity value of approximately 18 NTU or less after storage at approximately 5°C for approximately 12 months or more, after storage at approximately 25°C for approximately 12 months or more, and / or after storage at approximately 5°C for approximately 2 years or more. In a preferred embodiment, stability is defined as having a turbidity value of approximately 13 NTU or less after storage at approximately 5°C for approximately 12 months or more, after storage at approximately 25°C for approximately 12 months or more, and / or after storage at approximately 5°C for approximately 2 years or more. In the most preferred embodiment, stability is defined as having a turbidity value of approximately 8 NTU or less after storage at approximately 5°C for approximately 12 months or more, after storage at approximately 25°C for approximately 12 months or more, and / or after storage at approximately 5°C for approximately 2 years or more.

[0147] Analytical testing - Particulate matter Materials and methods for particulate matter (invisible to the naked eye) - All materials and methods are as specified in the United States Pharmacopeia. <788> The test conforms to Particulate Matter standards. A pharmacopoeia-compliant liquid particle counter with pharmacopoeia volume sampler settings is used. Test particles are equilibrated at room temperature for at least 60 minutes but no more than 10 hours before testing. The test particle vial conforms to the United States Pharmacopoeia standards. <788> Pool the data in a format compliant with Particulate Matter. United States Pharmacopeia <788> As instructed by Particulate Matter, take four appropriate volumes from each pooled test sample and count the number of particles 10 μm and larger than 25 μm for each portion. Ignore the result obtained for the first portion and use the results of the remaining three portions to calculate the average number of particles in the tested preparation.

[0148] Particle analysis (invisible to the naked eye) results in accordance with the official pharmacopoeia - Test results are in accordance with the United States Pharmacopoeia. <788> Particulate Matter, European Pharmacopoeia 2.9.19, and Japanese Pharmacopoeia XVII / 6.07, particulate contamination: conforms to particles invisible to the naked eye. Therefore, the average number of particles present in the tested unit should not exceed 6,000 particles per container for particle sizes of 10 μm or larger, and should not exceed 600 particles per container for particle sizes of 25 μm or larger.

[0149] Analysis Test - Purity Capillary electrophoresis of sodium dodecyl sulfate (cSDS) - reduced form Materials and Methods for Reduced cSDS - Analysis is performed using a commercially available capillary electrophoresis system with a bare fused silica capillary in a temperature-controlled cartridge, having an inner diameter of 50 μm × length of 30.2 cm. The capillary is equipped with a detection window that is transparent to ultraviolet light. The capillary is electrokinetically rinsed before each injection. Before each sample analysis, a sieving matrix consisting of an entangled polymer solution is packed into the capillary. This method utilizes SDS-MW gel electrophoresis buffer and protein molecular weight certification standards ranging from approximately 10 to 148 kDa. The instrument's ultraviolet absorption spectrophotometer detector is set to a wavelength of 220 nm, and the capillary temperature is set to 25°C. To reduce sample handling conditions, the test specimen (two strips) is mixed with SDS and 2-mercaptoethanol, and then heated for a specified time and temperature to completely denaturate and reduce the protein. The reduced sample is electrokinetically injected into the entire capillary by applying a voltage of 5 kV for approximately 20 seconds, and then analyzed by applying a larger electric field for approximately 35 minutes. Detection is achieved by the absorbance in the far-ultraviolet region of the spectrum at 220 nm. Percentages of total signal data are collected for the light chain, heavy chain, and aglycosylated heavy chain (AGHC).

[0150] The results for reduced cSDS are consistent with stability. In one embodiment, stability is defined as having a purity percentage of ≥90.0% and no new peaks >1.5% compared to a verified stock of tecristamagb reference material after storage at a temperature of approximately 5°C for approximately 12 months or more, after storage at a temperature of approximately 25°C for approximately 12 months or more, and / or after storage at a temperature of approximately 5°C for approximately 2 years or more. In a preferred embodiment, stability is defined as having a purity percentage of approximately 95.0% or more and no new peaks greater than 1.2% compared to the reference material after storage at a temperature of approximately 5°C for approximately 12 months or more, after storage at a temperature of approximately 25°C for approximately 12 months or more, and / or after storage at a temperature of approximately 5°C for approximately 2 years or more. In the most preferred embodiment, stability is defined as having a purity percentage of approximately 97.0% or more and no new peaks greater than 1.0% compared to the reference material after storage at a temperature of approximately 5°C for approximately 12 months or more, after storage at a temperature of approximately 25°C for approximately 12 months or more, and / or after storage at a temperature of approximately 5°C for approximately 2 years or more.

[0151] Capillary electrophoresis of sodium dodecyl sulfate (cSDS) - non-reduced type Materials and Methods for Non-Reducing cSDS Analysis are performed using a commercially available capillary electrophoresis system with a bare fused silica capillary in a temperature-controlled cartridge, having an inner diameter of 50 μm and a length of 30.2 cm. The capillary is equipped with a detection window transparent to ultraviolet light. The capillary is electrokinetically rinsed before each injection. Before each sample analysis, a sieving matrix consisting of an entangled polymer solution is packed into the capillary. This method utilizes SDS-MW gel electrophoresis buffer, protein molecular weight certification standards ranging from approximately 10 to 148 kDa, and validated tecristamab reference material samples. The instrument's ultraviolet absorption spectrophotometer detector is set to a wavelength of 220 nm, and the capillary temperature is set to 25°C. For non-reducing sample processing conditions, the test specimen (two strands) is mixed with SDS and an alkylating reagent (N-ethylmaleimide, to prevent shuffling or reformation of disulfide bonds). Next, this is heated for a specified time and temperature to completely denature the protein and minimize the formation of fragments and artifact bands. The non-reduced sample is electrokinetically injected into the entire capillary by applying a voltage of 5 kV for approximately 20 seconds, and then analyzed by applying a larger electric field for approximately 35 minutes. Detection is achieved by absorbance in the far-ultraviolet region of the 220 nm spectrum. Percentages of all signal data are collected. The data is also analyzed for the presence of new peaks compared to the tecrista-mab reference material. Purity percentage is defined as percent heavy chain + percent light chain.

[0152] The results for non-reduced cSDS are consistent with stability. In one embodiment, stability is defined as having a purity percentage of about 90.0% or more compared to the reference material and no new peaks exceeding 1.5% after storage at a temperature of about 5°C for about 12 months or more, storage at a temperature of about 25°C for about 12 months or more, and / or storage at a temperature of about 5°C for about 2 years or more. In a preferred embodiment, stability is defined as having a purity percentage of about 95.0% or more compared to the reference material and no new peaks exceeding 1.2% after storage at a temperature of about 5°C for about 12 months or more, storage at a temperature of about 25°C for about 12 months or more, and / or storage at a temperature of about 5°C for about 2 years or more. In the most preferred embodiment, stability is defined as having a purity percentage of about 97.0% or more compared to the reference material and no new peaks exceeding 1.0% after storage at a temperature of about 5°C for about 12 months or more, storage at a temperature of about 25°C for about 12 months or more, and / or storage at a temperature of about 5°C for about 2 years or more.

[0153] Size exclusion high-performance liquid chromatography (SE-HPLC) SE-HPLC Materials and Methods - Dilute the reference material and test specimen to the target protein concentration. Inject a 20 μL volume of analyte into a 7.8 mm × 30 cm size exclusion column with a silica base of 5 μm particle size and a fractionation range of 10–500 kDa. Use aqueous phosphate buffer as the mobile phase at a flow rate of 0.7 mL / min and continuously monitor the absorbance of the eluate at 280 nm. Monomers (main component or main peak), aggregates (high molecular weight species, or HMWS), and fragments (low molecular weight species, or LMWS) are separated on the column and elute with different retention times. The amounts of these species are measured by monitoring the peak absorbance at 280 nm.

[0154] SE-HPLC results are consistent with stability. Main component - In one embodiment, stability is defined as the main component being about 90.0% or more 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 a preferred embodiment, stability is defined as the main component being about 95.0% or more 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 the most preferred embodiment, stability is defined as the main component being about 97.0% 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.

[0155] High molecular weight species (HMWS) - In one embodiment, stability is defined as HMWS being about 10.0% 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 a preferred embodiment, stability is defined as HMWS being about 5.0% 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 the most preferred embodiment, stability is defined as HMWS being about 3.0% 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.

[0156] Low molecular weight species (LMWS) - In one embodiment, stability is defined as LMWS being about 5.0% 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 a preferred embodiment, stability is defined as LMWS being about 2.0% 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 the most preferred embodiment, stability is defined as LMWS being about 1.0% 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.

[0157] Capillary isoelectric focusing (cIEF) The cIEF materials and methods—analytical procedure—are performed using a commercially available imaging cIEF analyzer equipped with an autosampler. A 100 μm inner-wall coated silica capillary with an outer-wall polyimide coating is used for the analysis. Furthermore, dilute phosphoric acid and methylcellulose analyte solutions, sodium hydroxide and methylcellulose cathode solutions, and a predetermined type and amount of amphoteric electrolyte are used. The test specimens are treated with carboxypeptidase B (CPB) to remove C-terminal lysine and eliminate ambiguity introduced by the presence of multiple C-terminal variants for each charged species. The instrument's autosampler is set to 4°C for both preliminary and main electrophoresis. The voltage and time for preliminary electrophoresis are 1500 V and 1 minute, respectively. The voltage and time for main electrophoresis are 3000 V and 7 minutes, respectively.

[0158] The cIEF results are consistent with stability. Main Peak - In one embodiment, stability is defined as having a main peak of ≤60% after storage at a temperature of approximately 5°C for approximately 12 months or more, after storage at a temperature of approximately 25°C for approximately 12 months or more, and / or after storage at a temperature of approximately 5°C for approximately 2 years or more. In a preferred embodiment, stability is defined as having a main peak of ≤65% after storage at a temperature of approximately 5°C for approximately 12 months or more, after storage at a temperature of approximately 25°C for approximately 12 months or more, and / or after storage at a temperature of approximately 5°C for approximately 2 years or more. In the most preferred embodiment, stability is defined as having a main peak of ≤70% after storage at a temperature of approximately 5°C for approximately 12 months or more, after storage at a temperature of approximately 25°C for approximately 12 months or more, and / or after storage at a temperature of approximately 5°C for approximately 2 years or more.

[0159] Total Acid Peaks - In one embodiment, stability is defined as having a total of ≤40% acid peaks 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 a preferred embodiment, stability is defined as having a total of ≤30% acid peaks 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 the most preferred embodiment, stability is defined as having a total of ≤25% acid peaks 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.

[0160] Total basic peak - In one embodiment, stability is defined as having a total of basic peaks ≤ 15% 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 a preferred embodiment, stability is defined as having a total of basic peaks ≤ 10% 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 the most preferred embodiment, stability is defined as having a total of basic peaks ≤ 8% 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.

[0161] Analytical test - Quantity Protein concentration by A280 The protein concentration of the pharmaceutical product is determined by quantifying the absorbance at 280 nm (A280).

[0162] Materials and methods for protein concentration by A280 The measurement of protein concentration is performed using a qualified and calibrated double - beam UV - Vis spectrophotometer. The test sample is diluted 1:125 with 0.9% (w / v) NaCl. The sample is measured using a quartz semi - microcuvette (1.4 mL) with a path length of 1 cm and a black or matte surface. The spectrophotometer is set at a wavelength of 280 nm, a slit width of 1 nm, and a response of 1 second. 0.9% (w / v) NaCl is used as a blank control. The protein concentration (mg / mL) is calculated by dividing the product of the absorbance of the test sample and the dilution factor by the product of the absorbance constant of the antibody and the path length of the instrument (e.g., the absorbance constant of teclistamab is 1.58 (mg / mL) -1 cm -1 and the path length of the instrument is 1 cm, but not limited thereto).

[0163] The results of the formulation protein concentration of 10 mg / mL are consistent with stability In one embodiment, stability is defined as having a protein concentration of 7.5 to 12.5 mg / mL after storage at a temperature of approximately 5°C for approximately 12 months or more, after storage at a temperature of approximately 25°C for approximately 12 months or more, and / or after storage at a temperature of approximately 5°C for approximately 2 years or more. In a preferred embodiment, stability is defined as having a protein concentration of 8 to 12 mg / mL after storage at a temperature of approximately 5°C for approximately 12 months or more, after storage at a temperature of approximately 25°C for approximately 12 months or more, and / or after storage at a temperature of approximately 5°C for approximately 2 years or more. In the most preferred embodiment, stability is defined as having a protein concentration of 9 mg / mL to 11 mg / mL after storage at a temperature of approximately 5°C for approximately 12 months or more, after storage at a temperature of approximately 25°C for approximately 12 months or more, and / or after storage at a temperature of approximately 5°C for approximately 2 years or more.

[0164] The results for a 90 mg / mL formulation protein concentration are consistent with stability. In one embodiment, stability is defined as having a protein concentration of 76.5 to 103.5 mg / mL after storage at a temperature of approximately 5°C for approximately 12 months or more, after storage at a temperature of approximately 25°C for approximately 12 months or more, and / or after storage at a temperature of approximately 5°C for approximately 2 years or more. In a preferred embodiment, stability is defined as having a protein concentration of 85 to 95 mg / mL after storage at a temperature of approximately 5°C for approximately 12 months or more, after storage at a temperature of approximately 25°C for approximately 12 months or more, and / or after storage at a temperature of approximately 5°C for approximately 2 years or more. In the most preferred embodiment, stability is defined as having a protein concentration of 87 mg / mL to 93 mg / mL after storage at a temperature of approximately 5°C for approximately 12 months or more, after storage at a temperature of approximately 25°C for approximately 12 months or more, and / or after storage at a temperature of approximately 5°C for approximately 2 years or more.

[0165] Analytical testing - efficacy Efficacy (BCMA × CD3 T cell activation) In vitro T cell activation by BCMA×CD3 is demonstrated using a nuclear factor (NFAT-RE)-mediated luminescence assay of activated T cell response elements.

[0166] 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 as a surrogate measure of target cell death. Daudi B lymphoblasts expressing BCMA on their cell surface are used as target cells. Both engagement between the anti-BCMA Fab region and BCMA-expressing target cells, and engagement between the anti-CD3 Fab region and genetically engineered CD3+ T cells are required for T cell activation and subsequent NFAT-RE-mediated luminescence.

[0167] Materials and methods for BCMA×CD3 T cell activation. Qualified teclistamag is used as reference material and control. 1.0 × 10⁶ cells in culture medium (4% thermo-inactivated fetal bovine serum in RPMI). 6 Solution of Jurkat TCR / CD3 effector cells and culture medium at a concentration of 100 cells / mL 5 Prepare a solution of Daudi B lymphoblast target cells at a concentration of 100 viable cells / mL. Divide equal volumes of effector and target cells equally into individual wells on a 96-well cell culture plate. Then, incubate the plate at 37°C (±2°C) for 16–24 hours using 5% (±2%) CO2. After incubation, add Bio-Glo™ luciferase substrate to each well and gently mix on a plate shaker for at least 5 minutes. Within 30 minutes of substrate addition, measure luminescence (Relative Light Unit (RLU) value) using a microtitanium luminescence plate reader. The data are reported as a percentage of bioactivity relative to the reference material.

[0168] The results for BCMA×CD3 T-cell activity are consistent with stability. In one embodiment, stability is defined as 50% to 150% of the biological activity compared to the reference material after storage at approximately 5°C for approximately 12 months or more, after storage at approximately 25°C for approximately 12 months or more, and / or after storage at approximately 5°C for approximately 2 years or more. In a preferred embodiment, stability is defined as 60% to 140% of the biological activity compared to the reference material after storage at approximately 5°C for approximately 12 months or more, after storage at approximately 25°C for approximately 12 months or more, and / or after storage at approximately 5°C for approximately 2 years or more. In the most preferred embodiment, stability is defined as biological activity in the range of approximately 80% to 120% compared to the reference material after storage at approximately 5°C for approximately 12 months or more, after storage at approximately 25°C for approximately 12 months or more, and / or after storage at approximately 5°C for approximately 2 years or more.

[0169] Analytical testing - Surfactants Quantification of polysorbate 20 Polysorbate 20 is quantitatively determined by mixed-mode ion exchange / hydrophobic HPLC.

[0170] Materials and methods for PS20. Analysis is performed by gradient HPLC with a 2.1 × 20 mm online column containing 30 μm water-wettable mixed-mode polymer spherical adsorbent particles, ELSD, and a temperature-controlled column compartment at 30°C. The flow rate is set to 1 mL / min and the ELSD evaporator temperature is set to 50°C. Mobile phase A is 2% v / v formic acid in water, and mobile phase B is 2% v / v formic acid in isopropyl alcohol. Calibration and check standards are prepared using undiluted polysorbate 20. Test samples are injected undiluted.

[0171] The results for polysorbate 20 are consistent with stability. In one embodiment, stability is defined as a PS20 concentration of 0.01-0.07% 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 a preferred embodiment, stability is defined as a PS20 concentration of 0.02-0.06% 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 the most preferred embodiment, stability is defined as a PS20 concentration of 0.03-0.05% 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.

[0172] Analytical Testing - Routine Characterization Peptide Map The purpose of this test is to measure the level of post-translational modifications, such as oxidation, deamidation, and isomerization, that may be present in the antibody structure. The test sample is enzymatically digested to obtain peptide segments. These peptides are then evaluated by ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS). Each analyzed peptide sequence is identified in relation to its known position within the overall antibody structure. Post-translational modifications are determined by comparing the measured mass of the identified peptide sequence with its expected mass.

[0173] Materials and methods for peptide mapping. The sample is denatured with 6M guanidine, 50mM Tris pH 8.0, and 5mM EDTA, and filtered using a 30kDa centrifugal filter (the flow-through is discarded). The denatured sample is reduced with 1M dithiothreitol (DTT), subsequently alkylated with 1M sodium iodoacetate, and the reaction is further quenched with DTT. The reaction mixture is replaced with digestion buffer (50mM Tris pH 7.0 containing 1mM CaCl2) via a Sephadex G-25 column with separate columns used for the blank, reference material, and test sample. Aliquots of 1 mg / mL trypsin stock solution are added to the sample in the digestion buffer to obtain a trypsin concentration of 20 μL / mL. The solution is incubated at 37°C for 2 hours ± 30 minutes. The trypsinized solution is cooled to room temperature, and the enzyme is inactivated with trifluoroacetic acid. The processed samples are evaluated by ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS) using a Waters Acquity BEH (ethylene-crosslinked hybrid) C18 column, 2.1 × 100 mm, 1.7 μm, 130 Å, and an accompanying autosampler. Mobile phase A is 0.1% formic acid in water, and mobile phase B is 0.1% FA (mobile phase B) in acetonitrile. The autosampler is set to 2–8°C, the column to 40°C, and the flow rate to 500 μL / min. The eluted peptides are subjected to electrospray ionization and detected using calibrated online mass spectrometry. [Examples]

[0174] To further illustrate some of the embodiments disclosed herein, the following examples are provided. These examples are illustrative and not intended to limit the embodiments of the present disclosure. The experimental methods described in the following examples were carried out using the analytical tests described above.

[0175] The anti-BCMA / anti-CD3 antibody teclistamab (also called Tec) (e.g., described in International Publication No. 2017 / 031104 (A1), the entire content of which is incorporated herein by reference) was used in the following examples and was made by Janssen Pharmaceuticals. Teclistamab contains a BCMA-binding arm BCMB69 and a CD3-binding arm CD3B219, and their amino acid sequences are shown in Tables 2 and 3, respectively.

[0176] Example 1: mAb Concentration vs. Viscosity Test Tests were conducted to evaluate the viscosity of BCMAxCD3 by increasing the mAb concentration. Five test formulations were evaluated with mAbs in the range of 50 - 150 mg / mL. The formulations of all test articles were 15 mM acetic acid, 8.0% (w / v) sucrose, 0.04% (w / v) polysorbate 20, and 20 μg / mL EDTA, pH 5.2. The viscosity of each test formulation was measured with a pressure-driven slit viscometer.

[0177] As shown in Table 4, there was a positive non-linear correlation between protein concentration and viscosity when formulated at pH 5.2 in 15 mM acetic acid, 8.0% (w / v) sucrose, 0.04% (w / v) polysorbate 20, and 20 μg / mL EDTA. Furthermore, the viscosity values observed at high mAb concentrations may be inappropriate for subcutaneous administration.

[0178] [Table 4]

[0179] Example 2: Effects of pH and Excipient Types on the Viscosity of High-Concentration BCMAxCD3 Formulations Screening viscosity tests were performed to evaluate 12 high-protein concentration formulations with various excipients and pH values ​​(see Table X below). All test formulations contained 180 mg / mL of BCMAxCD3 and 8% (w / v) sucrose. The test formulations differed in buffer type (10 mM acetate or histidine), pH (5.2, 5.6, 6.4), and excipient type (none, proline, arginine-HCl, 100 mM NaCl). The viscosity of each test formulation was measured using a pressure-driven slit viscometer.

[0180] The test results are shown in Table 5 below. The data show a positive correlation between increased pH and increased viscosity, regardless of the presence of excipients in the formulation. The addition of Arg-HCl or NaCl reduced viscosity at all pH values ​​compared to the formulation without excipients, with Arg-HCl consistently showing the strongest effect. Proline slightly reduced viscosity at pH 5.6, but slightly increased viscosity at pH 5.2 and dramatically increased viscosity at pH 6.4 compared to the corresponding test formulation without excipients. In summary, the test results demonstrate that the high-concentration BCMAxCD3 formulation containing Arg-HCl showed the greatest viscosity reduction at pH 5.2.

[0181] [Table 5]

[0182] Example 3: Effect of Arg-HCl concentration on the viscosity of high-concentration BCMAxCD3 formulations A study was conducted to evaluate the effect of Arg-HCl concentration on the viscosity of high-concentration BCMAxCD3 formulations. The formulations were evaluated using BCMAxCD3 at concentrations of 120 mg / mL and 150 mg / mL. Each protein concentration was evaluated using Arg-HCl at concentrations of 25–200 mM and a control formulation without Arg-HCl. The remaining formulation components for all test products were 15 mM acetic acid, 8.0% (w / v) sucrose, 0.04% (w / v) polysorbate 20, and 20 μg / mL EDTA, with a pH of 5.2. The viscosity of each test formulation was measured using a pressure-driven slit viscometer.

[0183] As shown in Table 6, when formulated in 15 mM acetic acid, 8.0% (w / v) sucrose, 0.04% (w / v) polysorbate 20, and 20 μg / mL EDTA at pH 5.2, a negative correlation exists between Arg-HCl concentration and viscosity. This trend was observed in both 120 mg / mL and 150 mg / mL BCMAxCD3 formulations, and consistent with previous data, the 120 mg / mL formulation exhibited generally lower viscosity values ​​than the 150 mg / mL formulation.

[0184] [Table 6]

[0185] Example 4: Effects of Arg-HCl and sucrose concentrations on the viscosity of high-concentration BCMAxCD3 formulations Tests were conducted to evaluate the effects of Arg-HCl and sucrose concentrations on the viscosity of high-concentration BCMAxCD3 formulations. Test formulations were evaluated with either 4% or 8% (w / v) sucrose and 100–400 mM Arg-HCl. The remaining formulation components for all test samples were 200 mg / mL mAb, 15 mM acetic acid, 0.04% (w / v) polysorbate 20, and 20 μg / mL EDTA, with a pH of 5.2. The viscosity of each test formulation was measured using a pressure-driven slit viscometer.

[0186] As shown in Table 7, within a given Arg-HCl concentration, formulations containing 4% (w / v) sucrose consistently exhibited lower viscosity values ​​than the corresponding 8% (w / v) formulation when formulated at pH 5.2 with 200 mg / mL mAb in 200 mg / mL mAb, 15 mM acetic acid, 0.04% (w / v) polysorbate 20, and 20 μg / mL EDTA. Furthermore, when formulated at 200 mg / mL, an overall negative correlation was observed between increased Arg-HCl concentration and viscosity, regardless of sucrose concentration. However, the viscosity value at 400 mM Arg-HCl did not persistently differ from that at 200 mM Arg-HCl, and the viscosity value of the 4% (w / v) sucrose test formulation at 400 mM Arg-HCl was slightly higher than that of 4% (w / v) sucrose at 200 mM Arg-HCl. Therefore, with 200 mg / mL mAb and 4-8% (w / v) sucrose, the negative correlation between Arg-HCl concentration and viscosity appeared to stabilize at 200 mM Arg-HCl.

[0187] [Table 7]

[0188] Example 5: Effect of surfactant species on the viscosity of high-concentration BCMAxCD3 formulations Tests were conducted to evaluate the effect of surfactant species on the viscosity of high-concentration BCMAxCD3 formulations. P188 was evaluated at 0.5% and 0.05% (w / v). PS80 and PS20 were evaluated at 0.04% (w / v), respectively. The remaining formulation components of all test products were 200 mg / mL mAb, 15 mM acetic acid, 4% (w / v) sucrose, and 20 μg / mL EDTA, with a pH of 5.2. The viscosity of each test formulation was measured using a pressure-driven slit viscometer.

[0189] As shown in Table 8, the P188 test formulation had a slightly higher viscosity than the polysorbate-containing test formulation containing 0.5% (w / v) P188, and a slightly higher viscosity than 0.05% (w / v) P188. The viscosity values ​​of the polysorbate-containing test products were almost identical. Therefore, at 200 mg / mL mAb, 15 mM acetic acid, 4% (w / v) sucrose, and 20 μg / mL EDTA, and pH 5.2, the polysorbate species did not have a practical effect on viscosity.

[0190] [Table 8]

[0191] Example 6: 200 mg / mL pharmaceutical preparation: composition and components of the primary container Table 9 provides a tabular summary of the composition of an exemplary 200 mg / mL teclistamagab pharmaceutical formulation.

[0192] [Table 9]

[0193] The primary packaging for 200 mg / mL teclistamagb (DP) consists of a glass vial, a polymer vial stopper, and an aluminum seal. Table 9A lists the specific components of the primary packaging materials for 200 mg / mL DP.

[0194] [Table 10]

[0195] Example 7: Stability test of 200 mg / mL This test was conducted to monitor the properties of high-concentration BCMAxCD3 pharmaceuticals when kept stable under various environmental conditions and time periods.

[0196] BCMAxCD3 DP was formulated at a concentration of 200 mg / mL in 15 mM acetate, 4% sucrose (w / v), 200 mM ArgHCl, 20 ug / mL EDTA, and 0.04% PS20 (w / v), at a pH of 5.2.

[0197] The study sample was prepared by dividing the formulated DP equally into 2R vials with a filling volume of 1.5 mL. The vials were stoppered, capped, and crimped to seal.

[0198] All tests were performed with the vials inverted. The test parameters are shown in Table 10.

[0199] [Table 11]

[0200] Stability test results The stability results for teclistamaib DP held under recommended, accelerated, and stress conditions are listed below. The results observed for teclistamaib DP held under recommended storage conditions are consistent with those of a stable pharmaceutical composition.

[0201] The results for teclistamaib DP held under accelerated and stress conditions indicate the degradation rate of the drug when exposed to long-term accelerated and stress storage conditions. Of particular note is that the results observed for teclistamaib DP held under accelerated conditions (25°C) were similar to those observed for teclistamaib DP held under recommended storage conditions (2–8°C).

[0202] 5℃ data

[0203] [Table 12]

[0204] [Table 13]

[0205] Table 14

[0206] 25℃データ

[0207] Table 15

[0208] Table 16

[0209] Table 17

[0210] Table 18

[0211] 40℃データ

[0212] Table 19

[0213] Table 20

[0214] Table 21

[0215] Table 22

Claims

1. a) A bispecific B cell maturation antigen (BCMA) / differentiation antigen group 3 (CD3) antibody in a concentration of approximately 150 mg / mL to approximately 250 mg / mL, (1) A first heavy chain (HC1) comprising an HC1 variable region 1 (VH1), The VH1 comprises a first heavy chain (HC1) including heavy chain complementarity determining regions 1 (HCDR1), HCDR2, and HCDR3, respectively, having the amino acid sequences of SEQ ID NOs: 1, 2, and 3. (2) A first light chain (LC1) including an LC1 variable region (VL1), The VL1 comprises a first light chain (LC1) including light chain complementarity determination regions 1 (LCDR1), LCDR2, and LCDR3, each having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively. (3) A second heavy chain (HC2) comprising an HC2 variable region 2 (VH2), The VH2 comprises a second heavy chain (HC2) including heavy chain complementarity determining regions 1 (HCDR1), HCDR2, and HCDR3, respectively, having the amino acid sequences of SEQ ID NOs: 11, 12, and 13. (4) A second light chain (LC2) including an LC2 variable region 2 (VL2), The VL2 comprises a second light chain (LC2) having light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, respectively, having the amino acid sequences of SEQ ID NOs: 14, 15, and 16. A bispecific BCMA / CD3 antibody containing, b) Contains arginine HCl, An aqueous pharmaceutical composition having a viscosity of approximately 25 centipoise (cP) or less at 25°C.

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

8.

3. The aqueous pharmaceutical composition according to claim 1 or 2, wherein the bispecific BCMA / CD3 antibody comprises VH2 having the amino acid sequence of SEQ ID NO: 17 and VL2 having the amino acid sequence of SEQ ID NO:

18.

4. The aqueous pharmaceutical composition according to any one of claims 1 to 3, wherein the bispecific BCMA / CD3 antibody comprises HC1 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 9, and LC1 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:

10.

5. The aqueous pharmaceutical composition according to any one of claims 1 to 3, wherein the bispecific BCMA / CD3 antibody comprises HC1 having the amino acid sequence of SEQ ID NO: 9 and LC1 having the amino acid sequence of SEQ ID NO:

10.

6. The aqueous pharmaceutical composition according to any one of claims 1 to 5, wherein the bispecificity BCMA / CD3 antibody comprises HC2 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 19 and LC2 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:

20.

7. The aqueous pharmaceutical composition according to any one of claims 1 to 5, wherein the bispecific BCMA / CD3 antibody comprises HC2 having the amino acid sequence of SEQ ID NO: 19 and LC2 having the amino acid sequence of SEQ ID NO:

20.

8. The aqueous pharmaceutical composition according to claim 1, wherein the bispecific BCMA / CD3 antibody is tecristamag.

9. The aqueous pharmaceutical composition according to any one of claims 1 to 8, wherein the composition comprises the bispecific BCMA / CD3 antibody in an amount of about 180 mg / mL to about 220 mg / mL.

10. The aqueous pharmaceutical composition according to any one of claims 1 to 8, wherein the composition comprises about 200 mg / mL of the bispecific BCMA / CD3 antibody.

11. The aqueous pharmaceutical composition according to any one of claims 1 to 10, wherein the composition comprises about 100 mM to about 300 mM arginine HCl.

12. The aqueous pharmaceutical composition according to any one of claims 1 to 10, wherein the composition comprises about 150 mM to about 250 mM arginine HCl.

13. The aqueous pharmaceutical composition according to any one of claims 1 to 10, wherein the composition comprises about 200 mM arginine HCl.

14. The aqueous pharmaceutical composition according to any one of claims 1 to 13, wherein the composition has a viscosity of about 22 centipoise (cP) or less at 25°C.

15. The aqueous pharmaceutical composition according to any one of claims 1 to 13, wherein the composition has a viscosity of about 20 centipoise (cP) or less at 25°C.

16. The aqueous pharmaceutical composition according to any one of claims 1 to 13, wherein the composition has a viscosity of about 18 centipoise (cP) or less at 25°C.

17. The aqueous pharmaceutical composition according to any one of claims 1 to 13, wherein the composition has a viscosity of about 10 centipoise (cP) to about 20 cP at 25°C.

18. The aqueous pharmaceutical composition according to any one of claims 1 to 13, wherein the composition has a viscosity of about 15 centipoise (cP) to about 18 cP at 25°C.

19. The aqueous pharmaceutical composition according to any one of claims 1 to 13, wherein the composition has a viscosity of about 16 centipoise (cP) to about 17 cP at 25°C.

20. The aqueous pharmaceutical composition according to any one of claims 1 to 19, wherein the composition comprises a high molecular weight species of the bispecific BCMA / CD3 antibody in an amount of about 10% or less of the bispecific BCMA / CD3 antibody.

21. The aqueous pharmaceutical composition according to any one of claims 1 to 19, wherein the composition contains a high molecular weight species of the bispecific BCMA / CD3 antibody in an amount of about 7.5% or less of the bispecific BCMA / CD3 antibody.

22. The aqueous pharmaceutical composition according to any one of claims 1 to 19, wherein the composition contains a high molecular weight species of the bispecific BCMA / CD3 antibody in an amount of about 5% or less of the bispecific BCMA / CD3 antibody.

23. The composition is (a) The color of the solution ranges from colorless to ≤BY2, ≤B2, ≤Y2, (b) Osmolality by weight of approximately 612 to approximately 828 mOsm / kg (c) BMCAxCD3-mediated T-cell activation activity ranging from approximately 60% to approximately 140% relative to the tecristamag reference material, and / or (d) Principal components ≥ 95.0%, HMWS ≤ 5.0%, LMWS < 5.0% as determined by SE-HPLC (or principal components ≥ 90.0%, HMWS ≤ 10.0%, LMWS < 10.0%) An aqueous pharmaceutical composition according to any one of claims 1 to 19, having one or more of the characteristics of the following:

24. The composition is (a) The color of the solution ranges from colorless to ≤BY2, ≤B2, ≤Y2, (b) Osmolality by weight of approximately 612 to approximately 828 mOsm / kg (c) BMCAxCD3-mediated T-cell activation activity in the range of approximately 60% to approximately 140% relative to the tecristamag reference material. (d) As determined by cSDS (reduced form), compared to the tecristamagb reference material, with a purity of ≥95.0% and no new peaks >1.0%, (e) As determined by cSDS (non-reduced form), compared to the tecristamagb reference material, with a purity of ≥90.0%, no new peaks >1.0%, and / or (f) Principal components ≥ 95.0%, HMWS ≤ 5.0%, LMWS < 5.0% as determined by SE-HPLC (or principal components ≥ 90.0%, HMWS ≤ 10.0%, LMWS < 10.0%) An aqueous pharmaceutical composition according to any one of claims 1 to 19, having one or more of the characteristics of the following:

25. The aqueous pharmaceutical composition according to any one of claims 1 to 24, wherein the composition is stable.

26. The aqueous pharmaceutical composition according to claim 25, wherein the stability of the stable composition is defined based on the color of the solution, pH, turbidity, percentage of purity, percentage of new peaks, percentage of main components, percentage of high molecular weight species (HWMS), percentage of low molecular weight species (LMWS), percentage of total acidic peaks, percentage of total basic peaks, protein concentration, percentage of T cell activation, percentage of PS20 (w / v), or any combination thereof.

27. The aqueous pharmaceutical composition according to claim 25 or 26, wherein the aqueous pharmaceutical composition is stable for at least two years at a temperature of about 2 to 8°C.

28. The aqueous pharmaceutical composition according to any one of claims 1 to 27, wherein the composition contains about 180 mg / mL to about 220 mg / mL of the BCMAxCD3 bispecific antibody for a storage period of at least about 6 months at 2 to 8°C, or at least about 12 months at 2 to 8°C, or at least about 18 months at 2 to 8°C, or at least about 24 months at 2 to 8°C, or at least about 30 months at 2 to 8°C, or at least about 36 months at 2 to 8°C.

29. The aqueous pharmaceutical composition according to any one of claims 1 to 28, wherein the composition is suitable for subcutaneous administration to a human subject for the treatment of blood cancer, such as multiple myeloma.

30. The aqueous pharmaceutical composition according to any one of claims 1 to 29, wherein the composition contains about 2% (w / v) to about 6% (w / v) sucrose.

31. The aqueous pharmaceutical composition according to any one of claims 1 to 29, wherein the composition contains about 3% (w / v) to about 5% (w / v) sucrose.

32. The aqueous pharmaceutical composition according to any one of claims 1 to 29, wherein the composition contains about 4% (w / v) sucrose.

33. The aqueous pharmaceutical composition according to any one of claims 1 to 32, wherein the composition comprises about 12 mM to about 18 mM acetic acid and / or a pharmaceutically acceptable acetate salt.

34. The aqueous pharmaceutical composition according to any one of claims 1 to 32, wherein the composition comprises about 14 mM to about 16 mM acetic acid and / or a pharmaceutically acceptable acetate salt.

35. The aqueous pharmaceutical composition according to any one of claims 1 to 32, wherein the composition comprises about 15 mM acetic acid and / or a pharmaceutically acceptable acetate.

36. The aqueous pharmaceutical composition according to any one of claims 1 to 35, wherein the composition comprises about 18 μg / mL to about 22 μg / mL of EDTA.

37. The aqueous pharmaceutical composition according to any one of claims 1 to 35, wherein the composition comprises about 20 μg / mL of EDTA.

38. The aqueous pharmaceutical composition according to any one of claims 1 to 37, wherein the composition comprises about 0.02% to about 0.06% PS-20 (w / v).

39. The aqueous pharmaceutical composition according to any one of claims 1 to 37, wherein the composition comprises about 0.03 to about 0.05% PS-20 (w / v).

40. The aqueous pharmaceutical composition according to any one of claims 1 to 37, wherein the composition comprises about 0.04% PS-20 (w / v).

41. The aqueous pharmaceutical composition according to any one of claims 1 to 40, wherein the pH of the composition is about 4.8 to about 5.

6.

42. The aqueous pharmaceutical composition according to any one of claims 1 to 40, wherein the pH of the composition is about 4.9 to about 5.

5.

43. The aqueous pharmaceutical composition according to any one of claims 1 to 40, wherein the pH of the composition is approximately 5.

2.

44. The aqueous pharmaceutical composition according to any one of claims 1 to 40, wherein the composition comprises about 200 mg / mL of the bispecific BCMA / CD3 antibody, about 15 mM acetic acid and / or a pharmaceutically acceptable acetate, about 4% (w / v) sucrose, about 200 mM arginine HCl, about 20 μg / mL EDTA, and about 0.04% (w / v) PS20, and the composition has a pH of about 5.

2.

45. A vial containing approximately 1.5 mL of the composition according to claim 44, the vial containing approximately 300 mg of the bispecific BCMA / CD3 antibody.

46. A vial containing the composition according to any one of claims 1 to 44.

47. The vial according to claim 45 or 46, wherein the vial is equipped with a stopper that can be punctured by a syringe.

48. A method for treating a subject in need of treatment for a blood cancer, such as multiple myeloma, comprising subcutaneously administering a therapeutically effective amount of the composition described in any one of claims 1 to 44 to the subject.

49. A method for treating a subject in need of treatment for a blood cancer, such as multiple myeloma, comprising subcutaneously administering a therapeutically effective amount of the composition described in any one of claims 1 to 44 to the subject once a week as a therapeutic dose.

50. A method for treating a subject requiring treatment for a blood cancer, such as multiple myeloma, comprising subcutaneously administering a therapeutically effective amount of the composition described in any one of claims 1 to 44 to the subject once a week as a therapeutic dose, wherein the subject has relapsed / refractory multiple myeloma.

51. A method for treating a subject in need of treatment for a blood cancer, such as multiple myeloma, comprising subcutaneously administering one or more escalating doses of the same bispecific BCMA / CD3 antibody contained in the composition to the subject once a week, prior to subcutaneously administering the composition according to any one of claims 1 to 44 to the subject.

52. An aqueous pharmaceutical composition according to any one of claims 1 to 44, for use in the treatment of cancer.

53. An aqueous pharmaceutical composition according to any one of claims 1 to 44, for use in the preparation of pharmaceuticals for the treatment of cancer.

54. Use of the aqueous pharmaceutical composition according to any one of claims 1 to 44 for the treatment of a subject requiring treatment, comprising administering the aqueous pharmaceutical composition to the subject requiring treatment.

55. The use according to claim 54, wherein the administration is subcutaneous.

56. a) A bispecific B cell maturation antigen (BCMA) / differentiation antigen group 3 (CD3) antibody in a concentration of approximately 150 mg / mL to approximately 250 mg / mL, (1) A first heavy chain (HC1) comprising an HC1 variable region 1 (VH1), The VH1 comprises a first heavy chain (HC1) including heavy chain complementarity determining regions 1 (HCDR1), HCDR2, and HCDR3, respectively, having the amino acid sequences of SEQ ID NOs: 1, 2, and 3. (2) A first light chain (LC1) including an LC1 variable region (VL1), The VL1 comprises a first light chain (LC1) including light chain complementarity determination regions 1 (LCDR1), LCDR2, and LCDR3, each having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively. (3) A second heavy chain (HC2) comprising an HC2 variable region 2 (VH2), The VH2 comprises a second heavy chain (HC2) including heavy chain complementarity determining regions 1 (HCDR1), HCDR2, and HCDR3, respectively, having the amino acid sequences of SEQ ID NOs: 11, 12, and 13. (4) A second light chain (LC2) including an LC2 variable region 2 (VL2), The VL2 comprises a second light chain (LC2) having light chain complementarity determining regions 1 (LCDR1), LCDR2, and LCDR3, respectively, having the amino acid sequences of SEQ ID NOs: 14, 15, and 16. A bispecific BCMA / CD3 antibody containing (b) Approximately 10 mM to approximately 20 mM acetic acid and / or pharmaceutically acceptable acetate salts (c) Sucrose at approximately 1% (w / v) to approximately 7% (w / v), (d) Arginine HCl at approximately 100 mM to 300 mM (e) Ethylenediaminetetraacetic acid (EDTA) in a concentration of approximately 16 μg / mL to approximately 24 μg / mL, and (f) Contains approximately 0.01% to approximately 0.07% polysorbate 20 (w / v), An aqueous pharmaceutical composition having a pH of approximately 4.7 to approximately 5.

7.

57. The aqueous pharmaceutical composition according to claim 56, wherein the bispecific BCMA / CD3 antibody comprises VH1 having the amino acid sequence of SEQ ID NO: 7 and VL1 having the amino acid sequence of SEQ ID NO:

8.

58. The aqueous pharmaceutical composition according to claim 56 or 57, wherein the bispecific BCMA / CD3 antibody comprises VH2 having the amino acid sequence of SEQ ID NO: 17 and VL2 having the amino acid sequence of SEQ ID NO:

18.

59. The aqueous pharmaceutical composition according to any one of claims 56 to 58, wherein the bispecificity BCMA / CD3 antibody comprises HC1 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 9 and LC1 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:

10.

60. The aqueous pharmaceutical composition according to any one of claims 56 to 58, wherein the bispecific BCMA / CD3 antibody comprises HC1 having the amino acid sequence of SEQ ID NO: 9 and LC1 having the amino acid sequence of SEQ ID NO:

10.

61. The aqueous pharmaceutical composition according to any one of claims 56 to 60, wherein the bispecific BCMA / CD3 antibody comprises HC2 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 19 and LC2 having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:

20.

62. The aqueous pharmaceutical composition according to any one of claims 56 to 60, wherein the bispecific BCMA / CD3 antibody comprises HC2 having the amino acid sequence of SEQ ID NO: 19 and LC2 having the amino acid sequence of SEQ ID NO:

20.

63. The aqueous pharmaceutical composition according to claim 56, wherein the bispecific BCMA / CD3 antibody is tecristamag.

64. The aqueous pharmaceutical composition according to any one of claims 56 to 63, wherein the composition comprises the bispecific BCMA / CD3 antibody in an amount of about 180 mg / mL to about 220 mg / mL.

65. The aqueous pharmaceutical composition according to any one of claims 56 to 63, wherein the composition comprises about 200 mg / mL of the bispecific BCMA / CD3 antibody.

66. The aqueous pharmaceutical composition according to any one of claims 56 to 65, wherein the composition comprises about 100 mM to about 300 mM arginine HCl.

67. The aqueous pharmaceutical composition according to any one of claims 56 to 65, wherein the composition comprises about 150 mM to about 250 mM arginine HCl.

68. The aqueous pharmaceutical composition according to any one of claims 56 to 65, wherein the composition comprises about 200 mM arginine HCl.

69. The aqueous pharmaceutical composition according to any one of claims 56 to 68, wherein the composition contains about 2% (w / v) to about 6% (w / v) sucrose.

70. The aqueous pharmaceutical composition according to any one of claims 56 to 68, wherein the composition contains about 3% (w / v) to about 5% (w / v) sucrose.

71. The aqueous pharmaceutical composition according to any one of claims 56 to 68, wherein the composition contains about 4% (w / v) sucrose.

72. The aqueous pharmaceutical composition according to any one of claims 56 to 71, wherein the composition comprises about 12 mM to about 18 mM acetic acid and / or a pharmaceutically acceptable acetate salt.

73. The aqueous pharmaceutical composition according to any one of claims 56 to 71, wherein the composition comprises about 14 mM to about 16 mM acetic acid and / or a pharmaceutically acceptable acetate salt.

74. The aqueous pharmaceutical composition according to any one of claims 56 to 71, wherein the composition comprises about 15 mM acetic acid and / or a pharmaceutically acceptable acetate.

75. The aqueous pharmaceutical composition according to any one of claims 56 to 74, wherein the composition comprises about 18 μg / mL to about 22 μg / mL of EDTA.

76. The aqueous pharmaceutical composition according to any one of claims 56 to 74, wherein the composition comprises about 20 μg / mL of EDTA.

77. The aqueous pharmaceutical composition according to any one of claims 56 to 76, wherein the composition comprises about 0.02% to about 0.06% PS-20 (w / v).

78. The aqueous pharmaceutical composition according to any one of claims 56 to 76, wherein the composition comprises about 0.03 to about 0.05% PS-20 (w / v).

79. The aqueous pharmaceutical composition according to any one of claims 56 to 76, wherein the composition comprises about 0.04% PS-20 (w / v).

80. An aqueous pharmaceutical composition according to any one of claims 56 to 79, wherein the pH is approximately 4.8 to approximately 5.

6.

81. An aqueous pharmaceutical composition according to any one of claims 56 to 79, wherein the pH is approximately 4.9 to approximately 5.

5.

82. An aqueous pharmaceutical composition according to any one of claims 56 to 79, wherein the pH is approximately 5.

2.

83. The aqueous pharmaceutical composition according to any one of claims 56 to 82, wherein the composition comprises about 200 mg / mL of the bispecific BCMA / CD3 antibody, about 15 mM acetic acid and / or a pharmaceutically acceptable acetate, about 4% (w / v) sucrose, about 200 mM arginine HCl, about 20 μg / mL EDTA, and about 0.04% (w / v) PS20, and the composition has a pH of about 5.

2.

84. The aqueous pharmaceutical composition according to any one of claims 56 to 83, wherein the composition has a viscosity of about 25 centipoise (cP) or less at 25°C.

85. The aqueous pharmaceutical composition according to any one of claims 56 to 83, wherein the composition has a viscosity of about 22 centipoise (cP) or less at 25°C.

86. The aqueous pharmaceutical composition according to any one of claims 56 to 83, wherein the composition has a viscosity of about 20 centipoise (cP) or less at 25°C.

87. The aqueous pharmaceutical composition according to any one of claims 56 to 83, wherein the composition has a viscosity of about 18 centipoise (cP) or less at 25°C.

88. The aqueous pharmaceutical composition according to any one of claims 56 to 83, wherein the composition has a viscosity of about 10 centipoise (cP) to about 20 cP at 25°C.

89. The aqueous pharmaceutical composition according to any one of claims 56 to 83, wherein the composition has a viscosity of about 15 centipoise (cP) to about 18 cP at 25°C.

90. The aqueous pharmaceutical composition according to any one of claims 56 to 83, wherein the composition has a viscosity of about 16 centipoise (cP) to about 17 cP at 25°C.

91. The aqueous pharmaceutical composition according to any one of claims 56 to 90, wherein the composition contains a high molecular weight species of the bispecific BCMA / CD3 antibody in an amount of about 10% or less of the bispecific BCMA / CD3 antibody.

92. The aqueous pharmaceutical composition according to any one of claims 56 to 90, wherein the composition contains a high molecular weight species of the bispecific BCMA / CD3 antibody in an amount of about 7.5% or less of the bispecific BCMA / CD3 antibody.

93. The aqueous pharmaceutical composition according to any one of claims 56 to 90, wherein the composition comprises a high molecular weight species of the bispecific BCMA / CD3 antibody in an amount of about 5% or less of the bispecific BCMA / CD3 antibody.

94. The composition is (a) The color of the solution ranges from colorless to ≤BY2, ≤B2, ≤Y2, (b) Osmolality by weight of approximately 612 to approximately 828 mOsm / kg (c) BMCAxCD3-mediated T-cell activation activity ranging from approximately 60% to approximately 140% relative to the tecristamag reference material, and / or (d) Principal components ≥ 95.0%, HMWS ≤ 5.0%, LMWS < 5.0% as determined by SE-HPLC (or principal components ≥ 90.0%, HMWS ≤ 10.0%, LMWS < 10.0%) An aqueous pharmaceutical composition according to any one of claims 56 to 93, having one or more of the characteristics of the following:

95. The composition is (a) The color of the solution ranges from colorless to ≤BY2, ≤B2, ≤Y2, (b) Osmolality by weight of approximately 612 to approximately 828 mOsm / kg (c) BMCAxCD3-mediated T-cell activation activity in the range of approximately 60% to approximately 140% relative to the tecristamag reference material. (d) As determined by cSDS (reduced form), compared to the tecristamagb reference material, with a purity of ≥95.0% and no new peaks >1.0%, (e) As determined by cSDS (non-reduced form), compared to the tecristamagb reference material, with a purity of ≥90.0%, no new peaks >1.0%, and / or (f) Principal components ≥ 95.0%, HMWS ≤ 5.0%, LMWS < 5.0% as determined by SE-HPLC (or principal components ≥ 90.0%, HMWS ≤ 10.0%, LMWS < 10.0%) An aqueous pharmaceutical composition according to any one of claims 56 to 93, having one or more of the characteristics of the following:

96. The aqueous pharmaceutical composition according to any one of claims 56 to 95, wherein the composition is stable.

97. The aqueous pharmaceutical composition according to claim 96, wherein the stability of the stable composition is defined based on the color of the solution, pH, turbidity, percentage of purity, percentage of new peaks, percentage of main components, percentage of high molecular weight species (HWMS), percentage of low molecular weight species (LMWS), percentage of total acidic peaks, percentage of total basic peaks, protein concentration, percentage of T cell activation, percentage of PS20 (w / v), or any combination thereof.

98. The aqueous pharmaceutical composition according to claim 96 or 97, wherein the aqueous pharmaceutical composition is stable for at least two years at a temperature of about 2 to 8°C.

99. The aqueous pharmaceutical composition according to any one of claims 56 to 98, wherein the composition contains about 180 mg / mL to about 220 mg / mL of BCMAxCD3 bispecific antibody over a storage period of at least about 6 months at 2 to 8°C, or at least about 12 months at 2 to 8°C, or at least about 18 months at 2 to 8°C, or at least about 24 months at 2 to 8°C, or at least about 30 months at 2 to 8°C, or at least about 36 months at 2 to 8°C.

100. The aqueous pharmaceutical composition according to any one of claims 56 to 99, wherein the composition is suitable for subcutaneous administration to a human subject for the treatment of blood cancer, such as multiple myeloma.

101. A vial containing approximately 1.5 mL of the composition according to claim 83, the vial containing approximately 300 mg of the bispecific BCMA / CD3 antibody.

102. A vial containing the composition according to any one of claims 56 to 100.

103. The vial according to claim 101 or 102, wherein the vial is equipped with a stopper that can be punctured by a syringe.

104. A method for treating a subject in need of treatment for a blood cancer, such as multiple myeloma, comprising subcutaneously administering a therapeutically effective amount of the composition described in any one of claims 56 to 100 to the subject.

105. A method for treating a subject in need of treatment for a blood cancer, such as multiple myeloma, comprising subcutaneously administering a therapeutically effective amount of the composition described in any one of claims 56 to 100 to the subject once a week as a therapeutic dose.

106. A method for treating a subject requiring treatment for a blood cancer, such as multiple myeloma, comprising subcutaneously administering a therapeutically effective amount of the composition described in any one of claims 56 to 100 to the subject once a week as a therapeutic dose, wherein the subject has relapsed / refractory multiple myeloma.

107. A method for treating a subject in need of treatment for a blood cancer, such as multiple myeloma, comprising subcutaneously administering one or more escalating doses of the same bispecific BCMA / CD3 antibody contained in the composition to the subject once weekly, prior to subcutaneously administering the composition according to any one of claims 56 to 100 to the subject.

108. An aqueous pharmaceutical composition according to any one of claims 56 to 100, for use in the treatment of cancer.

109. An aqueous pharmaceutical composition according to any one of claims 56 to 100, for use in the preparation of pharmaceuticals for the treatment of cancer.

110. Use of the aqueous pharmaceutical composition according to any one of claims 56 to 100 for the treatment of a subject requiring treatment, comprising administering the aqueous pharmaceutical composition to the subject requiring treatment.

111. The use according to claim 110, wherein the administration is subcutaneous.

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