WO2023086817A1 - Stable formulations comprising a bispecific bcma/cd3 antibody - Google Patents

Stable formulations comprising a bispecific bcma/cd3 antibody Download PDF

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Publication number
WO2023086817A1
WO2023086817A1 PCT/US2022/079535 US2022079535W WO2023086817A1 WO 2023086817 A1 WO2023086817 A1 WO 2023086817A1 US 2022079535 W US2022079535 W US 2022079535W WO 2023086817 A1 WO2023086817 A1 WO 2023086817A1
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Prior art keywords
pharmaceutical composition
aqueous pharmaceutical
stable aqueous
antibody
seq
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French (fr)
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Salman MUZAMMIL
Matthew Joseph MISTILIS
Shyamal CHOUDHARI
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Janssen Biotech Inc
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Janssen Biotech Inc
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Priority to JP2024527460A priority Critical patent/JP2024544523A/ja
Priority to IL312700A priority patent/IL312700A/en
Priority to MX2024005727A priority patent/MX2024005727A/es
Priority to EP22893801.5A priority patent/EP4430082A4/en
Priority to CN202280074899.4A priority patent/CN118251417A/zh
Priority to CA3238152A priority patent/CA3238152A1/en
Priority to KR1020247018754A priority patent/KR20240099432A/ko
Priority to AU2022383848A priority patent/AU2022383848A1/en
Publication of WO2023086817A1 publication Critical patent/WO2023086817A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39591—Stabilisation, fragmentation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL

Definitions

  • compositions and methods for formulating a stable pharmaceutical composition comprising bispecific BCMA/CD3 antibodies.
  • BCMA B-cell maturation antigen
  • CD269 and tumor necrosis factor (TNF) receptor superfamily member 17 B-cell maturation antigen
  • TNF tumor necrosis factor
  • BCMA binds 2 ligands: A proliferation-inducing ligand (APRIL; CD256) and BAFF.
  • APRIL and BAFF are type II transmembrane proteins that are readily cleaved by Furin and secreted as soluble trimers by many cells (B cells [autocrine], monocytes, dendritic cells, T cells, osteoclasts, etc.) and can bind to the BCMA receptor.
  • B cells [autocrine], monocytes, dendritic cells, T cells, osteoclasts, etc. can bind to the BCMA receptor.
  • BCMA is exclusively expressed in B-lineage cells and is selectively induced during plasma cell differentiation.
  • a human BCMA receptor is a 184 amino acid protein that neither has a secretory signal sequence nor any specific protease cleavage site in the N-terminal 54 amino acid extracellular domain.
  • the N-terminal fragment is observed as a soluble protein in the serum as a result of gamma secretase activity that cleaves BCMA protein at the transmembrane domain. Inhibition of gamma secretase treatment results in significant increase of BCMA surface protein in human primary B-cells.
  • High levels of soluble BCMA (sBCMA) were measured in multiple myeloma patient serum samples (data not shown) and correlated with the plasma cell counts.
  • BCMA mRNA and protein were universally detected in MM cell lines and in all malignant plasma cells from multiple myeloma patients by Applicants (data not shown) and others. Similarly, in multiple myeloma cell lines and patient samples, BCMA is more stably expressed compared with a key plasma cell marker (CD138) that is also expressed on normal fibroblasts and epithelial cells. BCMA expression is selective for B cell lineage and was not detected in any major tissues except for infiltrating plasma cells as determined by immunohistochemistry (IHC) methods. Taken together, the selective expression of BCMA on the B cell lineage makes it an appealing target for T-cell mediated therapy to treat plasma cell disorders like multiple myeloma.
  • IHC immunohistochemistry
  • T cell redirected killing is a desirable mode of action in many therapeutic areas.
  • T cell redirecting molecules are engineered to have at least two antigen binding sites wherein one site binds a surface antigen on a target cell and the other site binds a T cell surface antigen.
  • T cell surface antigens the human CD3 epsilon subunit from the TCR protein complex has been the most targeted to redirect T cell killing.
  • Various bispecific antibody formats have been shown to mediate T cell redirection in both in pre-clinical and clinical investigations.
  • the role of both BCMA and CD3 in cancer is well established, making these targets attractive for combination therapy.
  • anti-BCMA antibodies for the treatment of lymphomas and multiple myeloma is mentioned in W02002066516 and W02010104949.
  • Antibodies against BCMA are described, e.g. in Gras M-P. et al. Int Immunol. 1997 ;7: 1093- 1106, W0200124811, and W0200124812.
  • Bispecific antibodies against BCMA and CD3 are described e.g. in W02017/031104.
  • anti-BCMA/CD3 antibodies have shown promising results, there remains a need in the art for pharmaceutical compositions comprising such antibodies that are stable for long periods of time at refrigerated (2- 8 °C) and ambient temperatures.
  • stable aqueous pharmaceutical compositions comprising specific formulations of a bispecific B-cell mature antigen (BCMA)/cluster of differentiation 3 (CD3) antibody.
  • BCMA bispecific B-cell mature antigen
  • CD3 cluster of differentiation 3
  • stable aqueous pharmaceutical compositions comprising:
  • BCMA bispecific B-cell mature antigen
  • CD3 cluster of differentiation 3
  • HC1 HC1 variable region 1
  • VH1 HC1 variable region 1
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 heavy chain complementarity determining region 1
  • HCDR3 amino acid sequences of SEQ ID NOs:l, 2, and 3, respectively;
  • LC1 LC1 variable region
  • VL1 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively;
  • HC2 HC2 variable region 2
  • VH2 HC2 variable region 2
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 HC2 variable region 2
  • HCDR3 heavy chain complementarity determining region 1
  • LC2 LC2 variable region 2
  • VL2 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively;
  • stable aqueous pharmaceutical compositions comprising:
  • BCMA bispecific B-cell mature antigen
  • CD3 cluster of differentiation 3
  • HC1 HC1 variable region 1
  • VH1 HC1 variable region 1
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 heavy chain complementarity determining region 1
  • HCDR3 amino acid sequences of SEQ ID NOs:l, 2, and 3, respectively;
  • LC1 LC1 variable region
  • VL1 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively;
  • HC2 HC2 variable region 2
  • VH2 HC2 variable region 2
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 HC2 variable region 2
  • HCDR3 heavy chain complementarity determining region 1
  • LC2 LC2 variable region 2
  • VL2 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively;
  • the methods comprise administering to the subject the stable aqueous pharmaceutical compositions, as disclosed herein.
  • bispecific B-cell mature antigen (BCMA)/cluster of differentiation 3 (CD3) antibody or antigen-binding fragment thereof can, for example, comprise:
  • HC1 HC1 variable region 1
  • VH1 HC1 variable region 1
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 heavy chain complementarity determining region 1
  • HCDR3 amino acid sequences of SEQ ID NOs:l, 2, and 3, respectively;
  • LC1 LC1 variable region
  • VL1 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively;
  • HC2 HC2 variable region 2
  • VH2 HC2 variable region 2
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 HC2 variable region 2
  • HCDR3 heavy chain complementarity determining region 1
  • LC2 LC2 variable region 2
  • VL2 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively;
  • the methods can, for example, comprise combining a composition comprising about 10 mg/mL or about 90 mg/mL of the bispecific BCMA/CD3 antibody, about 15 mM of acetate and/or a pharmaceutically acceptable acetate salt, about 8% (w/v) sucrose, about 20 mg/mL of EDTA, and about 0.04% polysorbate (PS) 20, wherein the stable aqueous pharmaceutical composition has a pH of about 5.2.
  • kits comprising the stable pharmaceutical aqueous compositions, as disclosed herein, and instructions for use thereof.
  • articles of manufacture comprising a container holding the stable aqueous pharmaceutical compositions, as disclosed herein.
  • FIG. 1 shows a graph demonstrating purity by SE-HPLC for the teclistamab acetate and histidine buffer formulations.
  • compositions and methods may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures, which form a part of this disclosure. It is to be understood that the disclosed compositions and methods are not limited to the specific compositions and methods described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed compositions and methods.
  • any description as to a possible mechanism or mode of action or reason for improvement is meant to be illustrative only, and the disclosed compositions and methods are not to be constrained by the correctness or incorrectness of any such suggested mechanism or mode of action or reason for improvement.
  • range includes the endpoints thereof and all the individual integers and fractions within the range, and also includes each of the narrower ranges therein formed by all the various possible combinations of those endpoints and internal integers and fractions to form subgroups of the larger group of values within the stated range to the same extent as if each of those narrower ranges was explicitly recited.
  • range of numerical values is stated herein as being greater than a stated value, the range is nevertheless finite and is bounded on its upper end by a value that is operable within the context of the invention as described herein.
  • compositions and methods which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.
  • antibody and like terms is meant in a broad sense and includes immunoglobulin molecules or fragments thereof, including monoclonal antibodies (such as murine, human, human-adapted, humanized, and chimeric monoclonal antibodies), antibody fragments, bispecific or multispecific antibodies, dimeric, tetrameric or multimeric antibodies, and single chain antibodies.
  • monoclonal antibodies such as murine, human, human-adapted, humanized, and chimeric monoclonal antibodies
  • antibody fragments bispecific or multispecific antibodies, dimeric, tetrameric or multimeric antibodies, and single chain antibodies.
  • Immunoglobulins can be assigned to five major classes, namely IgA, IgD, IgE, IgG, and IgM, depending on the heavy chain constant domain amino acid sequence.
  • IgA and IgG are further sub-classified as the isotypes IgAl, IgA2, IgGl, IgG2, IgG3, and IgG4.
  • Antibody light chains of any vertebrate species can be assigned to one of two clearly distinct types, namely kappa (K) and lambda ( ), based on the amino acid sequences of their constant domains.
  • Antibody fragment refers to a portion of an immunoglobulin molecule that retains the antigen binding properties of the parental full-length antibody.
  • Exemplary antibody fragments are heavy chain complementarity determining regions (HCDR) 1, 2, and 3, light chain complementarity determining regions (LCDR) 1, 2, and 3, a heavy chain variable region (VH), or a light chain variable region (VL).
  • Antibody fragments include: a Fab fragment, a monovalent fragment consisting of the VL, VH, constant light (CL), and constant heavy 1 (CHI) domains; a F(ab)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the VH and CHI domains; a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; and a domain antibody (dAb) fragment (Ward et al., Nature 341:544- 546, 1989), which consists of a VH domain.
  • a Fab fragment a monovalent fragment consisting of the VL, VH, constant light (CL), and constant heavy 1 (CHI) domains
  • F(ab)2 fragment a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region
  • a Fd fragment consisting of the VH and CHI domains
  • VH and VL domains can be engineered and linked together via a synthetic linker to form various types of single chain antibody designs where the VH/VL domains pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are expressed by separate single chain antibody constructs, to form a monovalent antigen binding site, such as single chain Fv (scFv) or diabody; described for example in Int’l Pat. Pub. Nos. WO 1998/44001, WO1988/01649, WO1994/13804, and W01992/01047.
  • scFv single chain Fv
  • WO 1998/44001 WO1988/01649
  • WO1994/13804 WO1994/13804
  • W01992/01047 W01992/01047.
  • An antibody variable region consists of a “framework” region interrupted by three “antigen binding sites.”
  • the antigen binding sites are defined using various terms: (i) Complementarity Determining Regions (CDRs), three in the VH (HCDR1, HCDR2, HCDR3), and three in the VL (LCDR1, LCDR2, LCDR3) are based on sequence variability (Wu and Kabat J Exp Med 132:211-50, 1970; Kabat et al. Sequences of Proteins of Immunological Interest, 5th Ed.
  • HVR Hypervariable regions
  • Other terms include “IMGT-CDRs” (Lefranc et al., Dev Comparat Immunol 27:55-77, 2003) and “Specificity Determining Residue Usage” (SDRU) (Almagro Mol Recognit 17:132-43, 2004).
  • IMGT International ImMunoGeneTics
  • “Monoclonal antibody” refers to a preparation of antibody molecules of a single molecular composition.
  • a monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope, or in a case of a bispecific monoclonal antibody, a dual binding specificity to two distinct epitopes.
  • Monoclonal antibody therefore refers to an antibody population with single amino acid composition in each heavy and each light chain, except for possible well-known alterations such as removal of C-terminal lysine from the antibody heavy chain.
  • Monoclonal antibodies may have heterogeneous glycosylation within the antibody population.
  • Monoclonal antibody may be monospecific or multispecific, or monovalent, bivalent or multivalent.
  • bispecific antibody refers to an antibody that specifically binds two distinct antigens or two distinct epitopes within the same antigen.
  • the bispecific antibody can have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca cynomolgus (cynomolgus, cyno) or Pan troglodytes, or can bind an epitope that is shared between two or more distinct antigens.
  • Human antibody refers to an antibody that is optimized to have minimal immune response when administered to a human subject. Variable regions of human antibody are derived from human immunoglobulin sequences. If human antibody contains a constant region or a portion of the constant region, the constant region is also derived from human immunoglobulin sequences. Human antibody comprises heavy and light chain variable regions that are “derived from” sequences of human origin if the variable regions of the human antibody are obtained from a system that uses human germline immunoglobulin or rearranged immunoglobulin genes. Such exemplary systems are human immunoglobulin gene libraries displayed on phage, and transgenic non- human animals such as mice or rats carrying human immunoglobulin loci.
  • Human antibody typically contains amino acid differences when compared to the immunoglobulins expressed in humans due to differences between the systems used to obtain the human antibody and human immunoglobulin loci, introduction of somatic mutations or intentional introduction of substitutions into the frameworks or CDRs, or both.
  • “human antibody” is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical in amino acid sequence to an amino acid sequence encoded by human germline immunoglobulin or rearranged immunoglobulin genes.
  • human antibody can contain consensus framework sequences derived from human framework sequence analyses, for example as described in Knappik et al., (2000) J Mol Biol 296:57-86, or synthetic HCDR3 incorporated into human immunoglobulin gene libraries displayed on phage, for example as described in Shi et al., (2010) J Mol Biol 397:385-96, and in Int. Patent Publ. No. W02009/085462.
  • Antibodies in which at least one CDR is derived from a non-human species are not included in the definition of “human antibody”.
  • Humanized antibody refers to an antibody in which at least one CDR is derived from non-human species and at least one framework is derived from human immunoglobulin sequences. Humanized antibody can include substitutions in the frameworks so that the frameworks cannot be exact copies of expressed human immunoglobulin or human immunoglobulin germline gene sequences.
  • isolated refers to a homogenous population of molecules (such as synthetic polynucleotides or a protein such as an antibody) which have been substantially separated and/or purified away from other components of the system the molecules are produced in, such as a recombinant cell, as well as a protein that has been subjected to at least one purification or isolation step.
  • molecules such as synthetic polynucleotides or a protein such as an antibody
  • isolated antibody refers to an antibody that is substantially free of other cellular material and/or chemicals and encompasses antibodies that are isolated to a higher purity, such as to 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% purity.
  • BCMA/CD3 bispecific antibody refers to a bispecific antibody that specifically binds BCMA and CD3.
  • BCMA/CD3 bispecific antibodies are described in U.S. Pat. No. 10,072,088, which is incorporated by reference herein in its entirety.
  • BCMA refers to human B-cell maturation antigen, also known as CD269 or TNFRSF17 (UniProt Q02223).
  • the extracellular domain of BCMA encompasses residues 1-54 of Q02223.
  • Human BCMA comprises the amino acid sequence of SEQ ID NO: 21.
  • CD3 refers to a human antigen which is expressed on T cells as part of the multimolecular T cell receptor (TCR) complex and which consists of a homodimer or heterodimer formed from the association of two or four receptor chains: CD3 epsilon, CD3 delta, CD3 zeta and CD3 gamma.
  • Human CD3 epsilon comprises the amino acid sequence of SEQ ID NO: 22.
  • SEQ ID NO: 23 shows the extracellular domain of CD3 epsilon.
  • Epitope refers to a portion of an antigen to which an antibody specifically binds.
  • Epitopes usually consist of chemically active (such as polar, non-polar, or hydrophobic) surface groupings of moieties such as amino acids or polysaccharide side chains and can have specific three-dimensional structural characteristics, as well as specific charge characteristics.
  • An epitope can be composed of contiguous and/or discontiguous amino acids that form a conformational spatial unit. For a discontiguous epitope, amino acids from differing portions of the linear sequence of the antigen come in close proximity in 3-dimensional space through the folding of the protein molecule.
  • Variant refers to a polypeptide or a polynucleotide that differs from a reference polypeptide or a reference polynucleotide by one or more modifications for example, substitutions, insertions, or deletions.
  • “In combination with” means that two or more therapeutics can be administered to a subject together in a mixture, concurrently as single agents, or sequentially as single agents in any order.
  • Treatment refers to both therapeutic treatment and prophylactic or preventative measures, and includes reducing the severity and/or frequency of symptoms, eliminating symptoms and/or the underlying cause of the symptoms, reducing the frequency or likelihood of symptoms and/or their underlying cause, improving or remediating damage caused, directly or indirectly, by the malignancy. Treatment also includes prolonging survival as compared to the expected survival of a subject not receiving treatment. Subjects to be treated include those that have the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • “Therapeutically effective amount” refers to an amount of the disclosed composition, which is therapeutically effective at dosages and for periods of time necessary, to achieve a desired treatment.
  • a therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the combination therapy to elicit a desired response in the subject.
  • Exemplary indicators of a therapeutically effect amount include, for example, improved well-being of the patient, reduction of a tumor burden, arrested or slowed growth of a tumor, and/or absence of metastasis of cancer cells to other locations in the body.
  • “Pharmaceutical composition” refers to composition that comprises an active ingredient and a pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable carrier” or “excipient” refers to an ingredient in a pharmaceutical composition, other than the active ingredient, which is nontoxic to a subject.
  • the term “cancer” as used herein is defined as disease characterized by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. In certain embodiments, the cancer is a hematological malignancy or a solid tumor.
  • the hematological malignancy is a multiple myeloma, a smoldering multiple myeloma, a monoclonal gammopathy of undetermined significance (MGUS), an acute lymphoblastic leukemia (ALL), a diffuse large B-cell lymphoma (DLBCL), a Burkitt's lymphoma (BL), a follicular lymphoma (FL), a mantlecell lymphoma (MCL), Waldenstrom’s macroglobulinema, a plasma cell leukemia, a light chain amyloidosis (AL), a precursor B-cell lymphoblastic leukemia, a precursor B-cell lymphoblastic leukemia, an acute myeloid leukemia (AML), a myelodysplastic syndrome (MDS), a chronic lymphocytic leukemia (CLL), a B cell malignancy, a chronic myeloid leukemia (CML), a hairy cell leuk
  • Tumor cell or a “cancer cell” refers to a cancerous, pre-cancerous or transformed cell, either in vivo, ex vivo, or in tissue culture, that has spontaneous or induced phenotypic changes. These changes do not necessarily involve the uptake of new genetic material. Although transformation can arise from infection with a transforming virus and incorporation of new genomic nucleic acid, uptake of exogenous nucleic acid or it can also arise spontaneously or following exposure to a carcinogen, thereby mutating an endogenous gene.
  • Transformation/cancer is exemplified by morphological changes, immortalization of cells, aberrant growth control, foci formation, proliferation, malignancy, modulation of tumor specific marker levels, invasiveness, tumor growth in suitable animal hosts such as nude mice, and the like, in vitro, in vivo, and ex vivo.
  • T cell redirecting therapeutic refers to a molecule containing two or more binding regions, wherein one of the binding regions specifically binds a cell surface antigen on a target cell or tissue and wherein a second binding region of the molecule specifically binds a T cell antigen.
  • cell surface antigen include a tumor associated antigen, such as BCMA.
  • T cell antigen include, e.g., CD3. This dual/multi-target binding ability recruits T cells to the target cell or tissue leading to the eradication of the target cell or tissue.
  • Subject includes any human or nonhuman animal.
  • Nonhuman animal includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc.
  • the terms “subject” and “patient” can be used interchangeably herein.
  • the invention is based, at least in part, on the finding that the therapeutic agent teclistamab, a bispecific BCMA/CD3 antibody, can be used to treat multiple myeloma in subjects that are relapsed or refractory to treatment with a prior anti-cancer therapeutic.
  • BCMA B-cell maturation antigen
  • B-cell maturation antigen is a cell membrane bound tumor necrosis factor receptor family member involved in differentiation of B-cells to plasma cells. Expression of BCMA is restricted to the B-cell lineage where it is predominantly expressed in the interfollicular region of germinal centers and on differentiated plasma cells and plasmablasts. BCMA is virtually absent on naive and memory B cells (Tai and Anderson, Immunotherapy 7: 1187-99, 2015).
  • compositions comprising a bispecific BCMA/CD3 antibody.
  • stable aqueous pharmaceutical compositions comprising:
  • BCMA bispecific B-cell mature antigen
  • CD3 cluster of differentiation 3
  • HC1 HC1 variable region 1
  • VH1 HC1 variable region 1
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 heavy chain complementarity determining region 1
  • HCDR3 amino acid sequences of SEQ ID NOs:l, 2, and 3, respectively;
  • LC1 LC1 variable region
  • VL1 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively;
  • HC2 HC2 variable region 2
  • VH2 HC2 variable region 2
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 HC2 variable region 2
  • HCDR3 heavy chain complementarity determining region 1
  • LC2 LC2 variable region 2
  • VL2 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively;
  • compositions comprising:
  • BCMA bispecific B-cell mature antigen
  • CD3 cluster of differentiation 3
  • HC1 HC1 variable region 1
  • VH1 HC1 variable region 1
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 heavy chain complementarity determining region 1
  • HCDR3 amino acid sequences of SEQ ID NOs:l, 2, and 3, respectively;
  • LC1 LC1 variable region
  • VL1 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively;
  • HC2 HC2 variable region 2
  • VH2 HC2 variable region 2
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 HC2 variable region 2
  • HCDR3 heavy chain complementarity determining region 1
  • LC2 LC2 variable region 2
  • VL2 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively;
  • the bispecific BCMA/CD3 antibody comprises a VH1 having the amino acid sequence of SEQ ID NO:7 and a VL1 having the amino acid sequence of SEQ ID NO:8.
  • the bispecific BCMA/CD3 antibody comprises a HC1 having the amino acid sequence of SEQ ID NO:9, and a LC1 having the amino acid sequence of SEQ ID NO: 10.
  • the bispecific BCMA/CD3 antibody comprises a VH2 having the amino acid sequence of SEQ ID NO: 17, and a VL2 having the amino acid sequence of SEQ ID NO: 18.
  • the bispecific BCMA/CD3 antibody comprises a HC2 having the amino acid sequence of SEQ ID NO: 19, and a LC2 having the amino acid sequence of SEQ ID NO:20.
  • the bispecific BCMA/CD3 antibody can, for example, be teclistamab.
  • the bispecific BCMA/CD3 antibody has a concentration 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 can, for example, have a concentration of about 7 mg/mL, about 7.5 mg/mL, about 8mg/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.
  • the bispecific BCMA/CD3 antibody has a concentration of about 10 mg/mL.
  • the bispecific BCMA/CD3 antibody has a concentration of about 76.5 mg/mL to about 103.5 mg/mL, about 81 mg/mL to about 99 mg/mL, about 85 mg/mL to about 95 mg/mL, or about 87 mg/mL to about 93 mg/mL.
  • the bispecific BCMA/CD3 antibody can, for example, have a concentration of about 76.5 mg/mL, about 77 mg/mL, about 78 mg/mL, about 79 mg/mL, about 80 mg/mL, about 81 mg/mL, about 82 mg/mL, about 83 mg/mL, about 84 mg/mL, about 85 mg/mL, about 86 mg/mL, about 87 mg/mL, about 88 mg/mL, about 89 mg/mL, about 90 mg/mL, about 91 mg/ML, about 92 mg/mL, about 93 mg/mL, about 94 mg/mL, about 95 mg/mL, about 96 mg/mL, about 97 mg/mL, about 98 mg/mL, about 99 mg/mL, about 100 mg/mL, about 101 mg/mL, about 102 mg/mL, about 103 mg/mL, or about 103.5 mg/mL, or any value in between.
  • the bispecific BCMA/CD3 antibody has a concentration of about 90 mg/mL.
  • the composition comprises about 10 mM to about 20 mM, about 12 mM to about 18 mM, or about 14 mM to about 16 mM of acetate and/or a pharmaceutically acceptable acetate salt.
  • the composition can, for example, comprise 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 of acetate and/or a pharmaceutically acceptable acetate salt.
  • the composition comprises about 15 mM of acetate or a pharmaceutically acceptable acetate salt.
  • the composition comprises about 6% (w/v) to about 10% (w/v) or about 7% (w/v) to about 9% (w/v) of sucrose.
  • the composition can, for example comprise 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 of sucrose.
  • the composition comprises about 16 mg/mL to about 24 mg/mL or about 18 mg/mL to about 22 mg/mL of EDTA.
  • the composition can, for example, comprise 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 of EDTA.
  • the composition comprises about 20 mg/mL of EDTA.
  • the composition comprises about 0.01% to about 0.07%, about 0.02% to about 0.06%, or about 0.03% to about 0.05% of polysorbate 20 (PS 20).
  • PS 20 polysorbate 20
  • the composition can, for example, comprise about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, or about 0.07%, or any value in between of PS 20.
  • the composition comprises about 0.04% PS 20.
  • the pH of the composition is about 4.7 to about 5.7, about 4.8 to about 5.6, about 4.9 to about 5.5.
  • the pH of the composition can, for example, be 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.
  • the pH of the composition is about 5.2.
  • the stability of the presently disclosed aqueous pharmaceutical compositions is determined based on specific amount or proportion of the BCMAxCD3 antibody and other constituents of the DP as provided herein (such as, but not limited to, acetate and/or pharmaceutically acceptable acetate salts, sucrose, PS20, and EDTA), as well as the assessment of various factors.
  • Stable DP as disclosed herein should not be construed to require all the factors listed herein but rather at least one, at least two, or at least three or more of those factors.
  • the stable disclosed DP exhibits the following results for at least one, at least two, at least three or more of the factors listed in detail below herein.
  • the stable DP exhibits the following results for most of the factors listed in detail below herein.
  • the stable DP exhibits the following results for all the factors listed in detail below herein.
  • the Color of a DP solution is monitored and can be assessed to verify that the appearance of the solution is consistent with previous batches at release and over the shelf life.
  • the color of the DP solution can reflect stability.
  • the stability of the DP is defined when having a color of solution spanning from colorless to about BY2 or less, to about BY4 or less, to about B2 or less, to about B4 or less, to about Y2 or less or to about Y4 or less as described in the European Pharmacopoeia 2.2.2, Degree of Coloration of Liquids European Pharmacopoeia (Ph. Eur.) 10th Edition monograph number 20202, July 2019.
  • the stability is defined as having a color of solution of colorless to about BY2 or less, about B2 or less, about Y2 or less after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a color of solution of colorless to about BY4 or less, to about B4 or less, to about Y4 or less after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a color of solution of colorless to about BY5 or less, to about B5 or less, to about Y5 or less after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the stability of the DP is defined when its pH is about: 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0.
  • the pH of the DP is about 5.2 after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5°C. In one embodiment, the pH ranges from about 4.7 to about 5.7 after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the stability of the DP is defined when its pH ranges from about 4.8 to about 5.6 after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5°C. In a most preferred embodiment, the stability of the DP is defined when its pH ranges from about 4.9 to about 5.5 after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5°C.
  • Turbidity allows measuring the presence of particles in the DP solution in order to ensure consistency with previous DP batches and applicable compendia guidance at release and over the shelf life.
  • the stability of the DP is defined when its turbidity value is about: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nephelometric turbidity units (NTU) after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • NTU nephelometric turbidity units
  • the stability of the DP is defined when its turbidity value is about or less than 18 NTU after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5°C. In a preferred embodiment, the stability of the DP is defined when its turbidity value is about or less than 13 NTU after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the stability of the DP is defined when its turbidity value is about or less than 8 NTU after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the stability of the DP is set to a specific threshold of particles contamination based on the average number of sub- visible particles.
  • the average number of particles present in the DP units tested should not exceed 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, or 6000, per container for particle size equal to 10 pm or greater.
  • the average number of particles present in the DP units tested should not exceed 6000 per container for particle size equal to 10 pm or greater.
  • the average number of particles present in the DP units tested should not exceed 100, 200, 300, 400, 500, or 600, per container for particle size equal to 25 pm or greater.
  • the average number of particles present in the DP units tested should not exceed 600 per container for particle size equal to 25 pm or greater.
  • cSDS Capillary SDS-PAGE
  • cSDS Capillary SDS-PAGE
  • This process allows quantifying DP purity and monitoring its stability at release and over the shelf life.
  • the DP stability is defined based upon various results of cSDS variables (e.g. percent purity or presence of new peak) where the cSDS was performed under reduced or non-reduced conditions after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5°C.
  • cSDS variables e.g. percent purity or presence of new peak
  • the DP stability is defined as having a percent purity about: 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or about or equal to 100% or any range in between.
  • the DP stability is defined as showing no new peak in the cSDS results of more than 0.5%, 0.8%, 0.9%, 1.0%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9% or more than 2% when compared to an untreated reference material.
  • the DP stability is defined with a percent purity of about 90% or more and no new peak of more than 1.5% as compared to a reference material. In a preferred embodiment, the DP stability is defined with a percent purity of about 95% or more, and with no new peak of more than 1.2% compared to a reference material. In a most preferred embodiment, the DP stability is defined as having a percent purity of about 97% or more and with no new peak of more than 1.0% as compared to a reference material.
  • SE-HPLC procedure allows assessing purity of the DP and monitoring its stability under non-denaturing conditions at release and over the shelf life.
  • the DP stability is defined based upon various results of SE-HPLC variables such as the Main Component (MC), High Molecular Weight Species (HMWS), or Low Molecular Weight Species (LMWS), after storage of the DP for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5°C.
  • MC Main Component
  • HMWS High Molecular Weight Species
  • LMWS Low Molecular Weight Species
  • the DP stability is defined as having a MC of about: 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or equal to about 100% or any range in between.
  • the DP stability is defined as having a MC of about 90% or more.
  • the DP stability is defined as having a MC of about 95% or more.
  • the DP stability is defined as having a MC of about 97% or more.
  • the DP stability is defined as having a HMWS of about: 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or any range in between.
  • the DP stability is defined as having a HMWS of about 10% or less.
  • the DP stability is defined as having a HMWS of about 5% or less.
  • the DP stability is defined as having a HMWS of about to 3% or less.
  • the DP stability is defined as having a LMWS of about: 0.1%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10%.
  • the DP stability is defined as having a LMWS of about 5% or less.
  • the DP stability is defined as having a LMWS of about 2% or less.
  • the DP stability is defined as having a LMWS of about 1% or less.
  • the cIEF like isoelectric gel electrophoresis (IEF) methods, separates proteins on the basis of overall charge or isoelectric point (pl). This procedure allows monitoring the distribution of charge-based isoforms of the drug product at release and over the shelf life.
  • the DP stability is defined based upon various results of cIEF variables such as the Main Peak (MP), the sum of acidic peaks or the sum of basic peaks, after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • MP Main Peak
  • the sum of acidic peaks or the sum of basic peaks after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the DP stability is defined as having a cIEF with a MP of about: 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% or any range in between after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the DP stability is defined as having a cIEF with a MP > 60% after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the DP stability is defined as having a cIEF with a MP > 65% after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the DP stability is defined as having a cIEF with a MP > 70% after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the DP stability is defined as having a cIEF with a with a sum of acidic peaks totaling to about: 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or any range therein between after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5°C.
  • the DP stability is defined as having a cIEF with a sum of acidic peaks ⁇ 40% after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the DP stability is defined as having a cIEF with a sum of acidic peaks totaling to about ⁇ 30% after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the DP stability is defined as having a cIEF with a sum of acidic peaks totaling to about ⁇ 25% after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the DP stability is defined as having a cIEF with a sum of basic peaks totaling about: 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 DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the DP stability is defined as having a cIEF with a sum of basic peaks totaling about 15% or less after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the DP stability is defined as having a cIEF with a sum of basic peaks totaling less than or about 10% after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the DP stability is defined as having a cIEF with a sum of basic peaks totaling less than or about 8% after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • Protein concentration of the DP allows verifying that it is consistent with previous DP batches at release and over the shelf life. Quantification of protein concentration can be accomplished by measuring the UV light absorbance of the drug product solution at 280 nm (A280).
  • the DP stability is defined as having a protein concentration of about: 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, after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the DP stability is defined as having a protein concentration of about 7 mg/mL to about 13 mg/mL after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C. In a preferred embodiment, the DP stability is defined as having a protein concentration of about 8 mg/mL to about 12 mg/mL after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the DP stability is defined as having a protein concentration of about 9 mg/mL to 11 mg/mL after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the DP stability is defined as having a protein concentration of about: 75 mg/mL, 76 mg/mL, 77 mg/mL, 78 mg/mL, 79 mg/mL, 80 mg/mL, 81 mg/mL, 82 mg/mL, 83 mg/mL, 84 mg/mL, 85 mg/mL, 86 mg/mL, 87 mg/mL, 88 mg/mL, 89 mg/mL, 90 mg/mL, 91 mg/mL, 92 mg/mL, 93 mg/mL, 94 mg/mL, 95 mg/mL, 96 mg/mL, 97 mg/mL, 98 mg/mL, 99 mg/mL, 100 mg/mL, 101 mg/mL, 102 mg/mL, 103 mg/mL, 104 mg/mL, or 105 mg/mL or any value in between, after DP
  • the DP stability is defined as having a protein concentration of about 81 mg/mL to about 99 mg/mL after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C. In a preferred embodiment, the DP stability is defined as having a protein concentration of about 85 mg/mL to about 95 mg/mL after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the DP stability is defined as having a protein concentration of about 87 mg/mL to 93 mg/mL after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • Post-translational modifications such as oxidation, deamidation, and isomerization, are enzymatic modifications that may be detected in the structure of an antibody.
  • the PD stability is assessed based on level of PTMs in the antibody.
  • Test articles are enzymatically digested to yield peptide segments. These peptides are then evaluated by for instance by mass spectrometry (MS), by tandem mass spectrometry (MS-MS) or Ultra High-Performance Liquid Chromatography Mass Spectroscopy (UPLC-MS). Each analyzed peptide sequence is identified relative to its known location within the overall antibody structure. Post-translational modifications are determined by comparing the measured mass of the identified peptide sequence with its expected mass.
  • MS mass spectrometry
  • MS-MS tandem mass spectrometry
  • UPLC-MS Ultra High-Performance Liquid Chromatography Mass Spectroscopy
  • T-cell activation assay allows assessing the level of DP stability. This activation can be assessed by using, but not limited to, a Nuclear factor of activated T cells- Response Element (NFAT-RE)-mediated luminescence assay.
  • NFAT-RE Nuclear factor of activated T cells- Response Element
  • the DP stability is defined as having a BMCAxCD3-mediated T- cell activation activity, relative to a reference, of about: 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, or 160% or any range in between after DP storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the DP stability is defined as having an BMCAxCD3-mediated T-cell activation activity ranging from about 50% to about 150% relative to a reference after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the DP stability is defined as having an BMCAxCD3-mediated T-cell activation activity ranging from about 60% to about 140% relative to a reference after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the DP stability is defined as having an BMCAxCD3-mediated T-cell activation activity ranging from about 80% to about 120% relative to a reference after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the DP stability is defined by a PS20 concentration in percentage weight to volume of about: 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, or any range in between after DP storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5°C.
  • the DP stability is defined by a PS20 concentration of about
  • the DP stability is defined by a PS20 concentration of about 0.01% to about 0.07%. In a preferred embodiment, the DP stability is defined by a PS20 concentration of about 0.02% to about 0.06% after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the DP stability is defined with a PS20 concentration of about 0.03% to about 0.05% after DP storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • the total volume of the stable aqueous pharmaceutical composition (or DP) ranges from about 5mL to about lOmL. In one embodiment, the total volume of the stable aqueous pharmaceutical composition (or DP) ranges from about 0.5 mL to about 20mL, from about ImL to about 15mL, from about 5mL to about lOmL, or from about 6mL to about 8mL.
  • the total volume of the stable aqueous pharmaceutical composition is about: 0.5mL, 0.6mL, 0.7mL, 0.8mL, 0.9mL, ImL, 2mL, 3mL, 4mL, 5mL, 6mL, 8mL, 9mL, lOmL, l lmL, 12mL, 13mL, 14mL, 15mL, 16mL, 18mL, 19mL, 20mL, 25mL, or 30mL or any range in between.
  • the total volume of the stable aqueous pharmaceutical composition is 2mL.
  • the total volume of the stable aqueous pharmaceutical composition (or DP) ranges from about 5mL to about lOmL. In one embodiment, the total volume of the stable aqueous pharmaceutical composition (or DP) ranges from about 0.5 mL to about 20mL, from about ImL to about 15mL, from about 5mL to about lOmL, or from about 6mL to about 8mL.
  • the total volume of the stable aqueous pharmaceutical composition is about: 0.5mL, 0.6mL, 0.7mL, 0.8mL, 0.9mL, ImL, 2mL, 3mL, 4mL, 5mL, 6mL, 8mL, 9mL, lOmL, l lmL, 12mL, 13mL, 14mL, 15mL, 16mL, 18mL, 19mL, 20mL, 25mL, or 30mL or any range in between.
  • the total volume of the stable aqueous pharmaceutical composition is 3.5mL.
  • a method of treating cancer in a subject in need thereof comprises administering to the subject a stable aqueous pharmaceutical composition as disclosed herein.
  • the administration is subcutaneous.
  • the cancer is a hematological malignancy or a solid tumor.
  • the hematological malignancy is a multiple myeloma, a smoldering multiple myeloma, a monoclonal gammopathy of undetermined significance (MGUS), an acute lymphoblastic leukemia (ALL), a diffuse large B-cell lymphoma (DLBCL), a Burkitt's lymphoma (BL), a follicular lymphoma (FL), a mantle-cell lymphoma (MCL), Waldenstrom’s macroglobulinema, a plasma cell leukemia, a light chain amyloidosis (AL), a precursor B-cell lymphoblastic leukemia, a precursor B-cell lymphoblastic leukemia, an acute myeloid leukemia (AML), a myelodysplastic syndrome (MDS), a chronic lymphocytic leukemia
  • MGUS monoclonal gammopathy of un
  • the hematological malignancy is multiple myeloma.
  • the subject has a newly diagnosed multiple myeloma.
  • the subject is relapsed or refractory to treatment with a prior anti-cancer therapeutic, such as a therapeutic used to treat multiple myeloma or other hematological malignancies.
  • the subject is refractory or relapsed to treatment with one or more treatments or therapies, such as THALOMID® (thalidomide), REVLIMID® (lenalidomide), POMALYST® (pomalidomide), VELCADE® (bortezomib), NINLARO (ixazomib), KYPROLIS® (carfilzomib), FARADYK® (panobinostat), AREDIA® (pamidronate), ZOMETA® (zoledronic acid), DARZALEX® (daratumumab), elotozumab or melphalan, Xpovio ® (Selinexor), Venclexta ® (Venetoclax), GSK 916, CAR-T therapies, other BCMA-directed therapies.
  • THALOMID® thalidomide
  • REVLIMID® lenalidomide
  • POMALYST® pomalidomide
  • VELCADE® b
  • Symptoms that can be associated are for example a decline or plateau of the well-being of the patient or re-establishment or worsening of various symptoms associated with solid tumors, and/or the spread of cancerous cells in the body from one location to other organs, tissues or cells.
  • the multiple myeloma is relapsed or refractory to treatment with an anti-CD38 antibody, selinexor, venetoclax, lenalinomide, bortezomib, pomalidomide, carfilzomib, elotozumab, ixazomib, melphalan or thalidomide, or any combination thereof.
  • the multiple myeloma is a high-risk multiple myeloma. Subjects with high-risk multiple myeloma are known to relapse early and have poor prognosis and outcome.
  • Subjects can be classified as having high-risk multiple myeloma is they have one or more of the following cytogenetic abnormalities: t(4; 14)(p 16;q32), t( 14; 16)(q32;q23), dell7p, IqAmp, t(4; 14)(p 16;q32) and t( 14; 16)(q32;q23), t(4; 14)(p 16;q32) and dell7p, t( 14; 16)(q32;q23) and dell7p, or t(4; 14)(p 16;q32), t( 14; 16)(q32;q23) and dell7p.
  • the subject having the high-risk multiple myeloma has one or more chromosomal abnormalities comprising: t(4;14)(pl6;q32), t( 14; 16)(q32;q23), dell7p, IqAmp, t(4;14)(pl6;q32) and t( 14; 16)(q32;q23), t(4; 14)(p 16;q32) and dell7p, t(14; 16)(q32;q23) and dell7p; or t(4; 14)(p 16;q32), t( 14; 16)(q32;q23) and dell7p, or any combination thereof.
  • the cytogenetic abnormalities can be detected for example by fluorescent in situ hybridization (FISH).
  • FISH fluorescent in situ hybridization
  • an oncogene is translocated to the IgH region on chromosome 14q32, resulting in dysregulation of these genes.
  • t(4; 14)(p 16;q32) involves translocation of fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain containing protein (MMSET) (also called WHSC1/NSD2)
  • t( 14; 16)(q32;q23) involves translocation of the MAF transcription factor C-MAF.
  • Deletion of 17p (dell7p) involves loss of the p53 gene locus.
  • a method for preparing a stable aqueous pharmaceutical composition of a bispecific B-cell mature antigen (BCMA)/cluster of differentiation 3 (CD3) antibody or antigen-binding fragment thereof comprising: a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1), wherein the VH1 comprises a heavy chain complementarity determining region 1 (HCDR1), a HCDR2, and a HCDR3 having the amino acid sequences of SEQ ID NOs:l, 2, and 3, respectively; a first light chain (LC1) comprising a LC1 variable region (VL1), wherein the VL1 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and
  • the bispecific BCMA/CD3 antibody comprises a VH1 having the amino acid sequence of SEQ ID NO:7 and a VL1 having the amino acid sequence of SEQ ID NO:8.
  • the bispecific BCMA/CD3 antibody comprises a HC1 having the amino acid sequence of SEQ ID NO:9, and a LC1 having the amino acid sequence of SEQ ID NO: 10.
  • the bispecific BCMA/CD3 antibody comprises a VH2 having the amino acid sequence of SEQ ID NO: 17, and a VL2 having the amino acid sequence of SEQ ID NO: 18.
  • the bispecific BCMA/CD3 antibody comprises a HC2 having the amino acid sequence of SEQ ID NO: 19, and a LC2 having the amino acid sequence of SEQ ID NO:20.
  • the bispecific BCMA/CD3 antibody can, for example, be teclistamab.
  • the stable aqueous pharmaceutical compositions disclosed herein can be packaged into kits, containers, packs, dispensers, or vials.
  • kits comprising the disclosed stable aqueous pharmaceutical and instructions for use thereof.
  • an article of manufacture comprising a container holding the disclosed stable aqueous pharmaceutical composition.
  • the container is a vial with a stopper pierceable by a syringe.
  • Embodiment 1 is a stable aqueous pharmaceutical composition comprising: a) a concentration of about 7.5 mg/mL to about 12.5 mg/mL of a bispecific B-cell mature antigen (BCMA)/cluster of differentiation 3 (CD3) antibody or antigen-binding fragment thereof, the bispecific BCMA/CD3 antibody or antigen-binding fragment thereof comprising:
  • HC1 HC1 variable region 1
  • VH1 HC1 variable region 1
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 heavy chain complementarity determining region 1
  • HCDR3 amino acid sequences of SEQ ID NOs:l, 2, and 3, respectively;
  • LC1 LC1 variable region
  • VL1 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively;
  • HC2 HC2 variable region 2
  • VH2 HC2 variable region 2
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 HC2 variable region 2
  • HCDR3 heavy chain complementarity determining region 1
  • LC2 comprising a LC2 variable region 2 (VL2), wherein the VL2 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs:14, 15, and 16, respectively; b) about 10 mM to about 20 mM of acetate and/or pharmaceutically acceptable acetate salt; c) about 6% (w/v) to about 10% (w/v) of sucrose; d) about 16 pg/mL to about 24 pg/mL of ethylenediaminetetraacetic acid (EDTA); e) about 0.01% to about 0.07% polysorbate 20; and f) a pH from about 4.7 to about 5.7.
  • LCDR1 light chain complementarity determining region 1
  • LCDR2 variable region 2
  • LCDR3 having the amino acid sequences of SEQ ID NOs:14, 15, and 16, respectively
  • Embodiment la is a stable aqueous pharmaceutical composition comprising: a) a concentration of about 76.5 mg/mL to about 103.5 mg/mL of a bispecific B-cell mature antigen (BCMA)/cluster of differentiation 3 (CD3) antibody or antigen-binding fragment thereof, the bispecific BCMA/CD3 antibody or antigen-binding fragment thereof comprising:
  • HC1 HC1 variable region 1
  • VH1 HC1 variable region 1
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 heavy chain complementarity determining region 1
  • HCDR3 amino acid sequences of SEQ ID NOs:l, 2, and 3, respectively;
  • LC1 LC1 variable region
  • VL1 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively;
  • HC2 HC2 variable region 2
  • VH2 HC2 variable region 2
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 HC2 variable region 2
  • HCDR3 heavy chain complementarity determining region 1
  • LC2 comprising a LC2 variable region 2 (VL2), wherein the VL2 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs:14, 15, and 16, respectively; b) about 10 mM to about 20 mM of acetate and/or pharmaceutically acceptable acetate salt; c) about 6% (w/v) to about 10% (w/v) of sucrose; d) about 16 pg/mL to about 24 pg/mL of ethylenediaminetetraacetic acid (EDTA); e) about 0.01% to about 0.07% polysorbate 20; and f) a pH from about 4.7 to about 5.7.
  • LCDR1 light chain complementarity determining region 1
  • LCDR2 variable region 2
  • LCDR3 having the amino acid sequences of SEQ ID NOs:14, 15, and 16, respectively
  • Embodiment 2 is the stable aqueous pharmaceutical composition of embodiment 1 or la, wherein the bispecific BCMA/CD3 antibody comprises a VH1 having the amino acid sequence of SEQ ID NO:7, and a VL1 having the amino acid sequence of SEQ ID NO:8.
  • Embodiment 3 is the stable aqueous pharmaceutical composition of embodiment 1 or la, wherein the bispecific BCMA/CD3 antibody comprising a HC having the amino acid sequence of SEQ ID NO:9, and a LC1 having the amino acid sequence of SEQ ID NO: 10.
  • Embodiment 4 is the stable aqueous pharmaceutical composition of embodiment 1 or la, wherein the bispecific BCMA/CD3 antibody comprises a VH2 having the amino acid sequence of SEQ ID NO: 17, and a VL2 having the amino acid sequence of SEQ ID NO: 18.
  • Embodiment 5 is the stable aqueous pharmaceutical composition of embodiment 1 or la, wherein the bispecific BCMA/CD3 antibody comprises a HC2 having the amino acid sequence of SEQ ID NO: 19, and a LC2 having the amino acid sequence of SEQ ID NO:20.
  • Embodiment 6 is the stable aqueous pharmaceutical composition of embodiment 1 or la, wherein the bispecific BCMA/CD3 antibody is teclistamab.
  • Embodiment 7 is the stable aqueous pharmaceutical composition of embodiment 1 or la, wherein the bispecific BCMA/CD3 antibody has a concentration of about 8 mg/mL to about 12 mg/mL.
  • Embodiment 8 is the stable aqueous pharmaceutical composition of embodiment 7, wherein the bispecific BCMA/CD3 antibody has a concentration of about 9 mg/mL to about 11 mg/mL.
  • Embodiment 9 is the stable aqueous pharmaceutical composition of embodiment 8, wherein the bispecific BCMA/CD3 antibody has a concentration of about 10 mg/mL.
  • Embodiment 10 is the stable aqueous pharmaceutical composition of embodiment 1 or la, wherein the bispecific BCMA/CD3 antibody has a concentration of about 85 mg/mL to about 95 mg/mL.
  • Embodiment 11 is the stable aqueous pharmaceutical composition of embodiment 10, wherein the bispecific BCMA/CD3 antibody has a concentration of about 87 mg/mL to about 93 mg/mL.
  • Embodiment 12 is the stable aqueous pharmaceutical composition of embodiment 11, wherein the bispecific BCMA/CD3 antibody has a concentration of about 90 mg/mL.
  • Embodiment 13 is the stable aqueous pharmaceutical composition of embodiment 1 or la, wherein the composition comprises about 12 mM to about 18 mM of acetate and/or pharmaceutically acceptable acetate salt.
  • Embodiment 14 is the stable aqueous pharmaceutical composition of embodiment 1 or la, wherein the composition comprises about 14 mM to about 16 mM of acetate and/or pharmaceutically acceptable acetate salt.
  • Embodiment 15 is the stable aqueous pharmaceutical composition of embodiment 1 or la, wherein the composition comprises about 15 mM of acetate and/or pharmaceutically acceptable acetate salt.
  • Embodiment 16 is the stable aqueous pharmaceutical composition of embodiment 1 or la, wherein the composition comprises about 7% (w/v) to about 9% (w/v) of sucrose.
  • Embodiment 17 is the stable aqueous pharmaceutical composition of embodiment 16, wherein the composition comprises about 8% (w/v) of sucrose.
  • Embodiment 18 is the stable aqueous pharmaceutical composition of embodiment 1 or la, wherein the composition comprises about 18 [ig/inL to about 22 [Ig/inL of EDTA.
  • Embodiment 19 is the stable aqueous pharmaceutical composition of embodiment 1 or la, wherein the composition comprises about 20 pg/mL of EDTA.
  • Embodiment 20 is the stable aqueous pharmaceutical composition of embodiment 1 or la, wherein the composition comprises about 0.02% to about 0.06% of PS-20.
  • Embodiment 21 is the stable aqueous pharmaceutical composition of embodiment 20, wherein the composition comprises about 0.03 to about 0.05% of PS-20.
  • Embodiment 22 is the stable aqueous pharmaceutical composition of embodiment 21, wherein the composition comprises about 0.04% of PS-20.
  • Embodiment 23 is the stable aqueous pharmaceutical composition of embodiment 1 or la, wherein the pH is about 4.8 to about 5.6.
  • Embodiment 24 is the stable aqueous pharmaceutical composition of embodiment 23, wherein the pH is about 4.9 to about 5.5.
  • Embodiment 25 is the stable aqueous pharmaceutical composition of embodiment 24, wherein the pH is about 5.2.
  • Embodiment 26 is the stable aqueous pharmaceutical composition of embodiment 1 or la, wherein the composition comprises 10 mg/mL of the bispecific BCMA/CD3 antibody, 15 mM of acetate and/or pharmaceutically acceptable acetate salt, 8% (w/v) sucrose, 20 pg/inL of EDTA, 0.04% PS 20, and a pH of 5.2.
  • Embodiment 27 is the stable aqueous pharmaceutical composition of embodiment 1 or la, wherein the stable aqueous pharmaceutical composition is stable at a temperature of about 2- 8°C for at least two years.
  • Embodiment 28 is the stable aqueous pharmaceutical composition of embodiment 1 or la, wherein stability is defined based on color of solution, pH, turbidity, percentage of purity, percentage of new peaks, percentage of main component, percentage of high molecular weight species (HWMS), percentage of low molecular weight species (LMWS), percentage of sum of acidic peaks, percentage of sum of basic peaks, protein concentration, percentage of T cell activation, percentage of PS 20 (w/v), or any combination thereof.
  • Embodiment 29 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject the stable aqueous pharmaceutical composition of embodiment 1 or la.
  • Embodiment 30 is the method of embodiment 29, wherein the administering is subcutaneous.
  • Embodiment 31 is a method for preparing a stable aqueous pharmaceutical composition of a bispecific B-cell mature antigen (BCMA)/cluster of differentiation 3 (CD3) antibody or antigen-binding fragment thereof, the bispecific BCMA/CD3 antibody or antigenbinding fragment thereof comprising:
  • HC1 HC1 variable region 1
  • VH1 HC1 variable region 1
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 heavy chain complementarity determining region 1
  • HCDR3 amino acid sequences of SEQ ID NOs:l, 2, and 3, respectively;
  • LC1 LC1 variable region
  • VL1 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively;
  • HC2 HC2 variable region 2
  • VH2 HC2 variable region 2
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 HC2 variable region 2
  • HCDR3 heavy chain complementarity determining region 1
  • LC2 LC2 variable region 2
  • VL2 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively
  • the method comprising combining a composition comprising about 10 mg/mL of the bispecific BCMA/CD3 antibody, about 15 mM of acetate and/or a pharmaceutically acceptable acetate salt, about 8% (w/v) sucrose, about 20 mg/mL of EDTA, and about 0.04% polysorbate (PS) 20, wherein the stable aqueous pharmaceutical composition has a pH of about 5.2.
  • Embodiment 31a is a method for preparing a stable aqueous pharmaceutical composition of a bispecific B-cell mature antigen (BCMA)/cluster of differentiation 3 (CD3) antibody or antigen-binding fragment thereof, the bispecific BCMA/CD3 antibody or antigenbinding fragment thereof comprising:
  • HC1 HC1 variable region 1
  • VH1 HC1 variable region 1
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 heavy chain complementarity determining region 1
  • HCDR3 amino acid sequences of SEQ ID NOs:l, 2, and 3, respectively;
  • LC1 LC1 variable region
  • VL1 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively;
  • HC2 HC2 variable region 2
  • VH2 HC2 variable region 2
  • HCDR1 heavy chain complementarity determining region 1
  • HCDR2 HC2 variable region 2
  • HCDR3 heavy chain complementarity determining region 1
  • LC2 LC2 variable region 2
  • VL2 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2, and a LCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15, and 16, respectively
  • the method comprising combining a composition comprising about 90 mg/mL of the bispecific BCMA/CD3 antibody, about 15 mM of acetate and/or a pharmaceutically acceptable acetate salt, about 8% (w/v) sucrose, about 20 mg/mL of EDTA, and about 0.04% polysorbate (PS) 20, wherein the stable aqueous pharmaceutical composition has a pH of about 5.2.
  • Embodiment 32 is the method of embodiment 31 or 31a, wherein the bispecific BCMA/CD3 antibody comprises a VH1 having the amino acid sequence of SEQ ID NO:7, and a VL1 having the amino acid sequence of SEQ ID NO:8.
  • Embodiment 33 is the method of embodiment 31 or 31a, wherein the bispecific BCMA/CD3 antibody comprising a HC having the amino acid sequence of SEQ ID NO:9, and a LC1 having the amino acid sequence of SEQ ID NO: 10.
  • Embodiment 34 is the method of embodiment 31 or 31a, wherein the bispecific BCMA/CD3 antibody comprises a VH2 having the amino acid sequence of SEQ ID NO: 17, and a VL2 having the amino acid sequence of SEQ ID NO: 18.
  • Embodiment 35 is the method of embodiment 31 or 31a, wherein the bispecific BCMA/CD3 antibody comprises a HC2 having the amino acid sequence of SEQ ID NO: 19, and a LC2 having the amino acid sequence of SEQ ID NO:20.
  • Embodiment 36 is the method of embodiment 31 or 31a, wherein the bispecific BCMA/CD3 antibody is teclistamab.
  • Embodiment 37 is a kit comprising the stable aqueous pharmaceutical composition of embodiment 1 and instructions for use.
  • Embodiment 38 is an article of manufacture comprising a container holding a stable aqueous pharmaceutical composition of embodiment 1 or la.
  • Embodiment 39 is the article of manufacture of embodiment 38, wherein the container is a vial with a stopper pierceable by a syringe.
  • Embodiment 40 is the stable aqueous pharmaceutical composition of embodiment 1 or la for use in the treatment of cancer.
  • Embodiment 41 is the stable aqueous pharmaceutical composition of embodiment 1 or la for use in the preparation of a medicament for the treatment of cancer.
  • Embodiment 42 is the use of the stable aqueous pharmaceutical composition of embodiment 1 or la for treating in a subject in need thereof, the use comprising administering the stable aqueous pharmaceutical composition to the subject in need thereof.
  • Embodiment 43 is the use of embodiment 42, wherein the administration is subcutaneous.
  • Color of solution is monitored for drug product to assess appearance and ensure it is consistent with previous batches at release and over the shelf life. Color of solution may be an indicator of product stability. To determine Color of solution, test samples are visually compared to a defined set of reference solutions.
  • a defined volume of liquid content is transferred into a pre-scored ampoule of same dimensions as the reference solutions. Then the content of the ampoule is visually compared to European Pharmacopoeia color reference solutions. The degree of color is determined in diffuse daylight, viewed against a white background.
  • stability is defined as having a color of solution of colorless to about BY2 or less, about B2 or less, about Y2 or less after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a color of solution of colorless to about BY4 or less, to about B4 or less, to about Y4 or less after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a color of solution of colorless to about BY5 or less, to about B5 or less, to about Y5 or less after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5°C.
  • pH Materials and Methods A daily calibrated electronic pH meter with standardized pH electrode is used to measure the pH of test articles. All calibration solutions, reference buffers, and test articles are equilibrated to, and maintained at, 25°C prior to and during testing. [00189] pH results consistent with stability. In one embodiment, stability is defined as having a pH range of 4.7 to about 5.7 after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined a pH range of 4.8 to about 5.6 after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a pH range of 4.9 to about 5.5 after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • Turbidity Materials and Methods- The materials and methods are based on European Pharmacopoeia 2.2.1, Clarity and Degree of Opalescence of Liquids.
  • Turbidity results consistent with stability are reported in nephelometric turbidity units (NTU).
  • stability is defined as having a turbidity value of about 18 NTU or less after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a turbidity value of about 13 NTU or less after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a turbidity value of about 8 NTU or less after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5°C.
  • Particle Analysis (sub- vis) compendia compliant results- Testing results are to comply with United States Pharmacopoeia ⁇ 788> Particulate Matter, European Pharmacopoeia 2.9.19, and Japanese Pharmacopoeia XVII / 6.07 Particulate Contamination: Sub- visible particles. As such, the average number of particles present in the units tested should not exceed 6000 particles per container for particles size equal to 10 pm or greater and should not exceed 600 particles per container for particles size equal to 25 pm or greater.
  • cSDS Reduced Materials and Methods- Analysis employs a commercial capillary electrophoresis system with a bare fused silica capillary, 50 pm i.d. x 30.2 cm length in a temperature-controlled cartridge; the capillary is equipped with a detection window transparent to ultraviolet light. The capillary is rinsed electrokinetically before each injection. The capillary is loaded with a sieving matrix consisting of an entangled polymer solution before each sample analysis. The method utilizes an SDS-MW gel migration buffer and certified protein molecular weight standards spanning a range of approximately 10 to 148 kDa.
  • the instrument ultraviolet absorption spectrophotometer detector is set at a wavelength of 220 nm and the capillary temperature is set to 25°C.
  • the test article in duplicate
  • the reduced sample is injected electrokinetically by applying a voltage of 5kV across the capillary for approximately 20 seconds, and then analyzed by application of a greater electric field for approximately 35 minutes. Detection is accomplished by absorbance in the far ultraviolet region of the spectrum, 220 nm. Percent of total signal data is collected for the light chain, heavy chain, and a glycosylated heavy chain (AG HC).
  • AG HC glycosylated heavy chain
  • stability is defined as having a percent purity >90.0%, and no new peak >1.5% compared to a validated stock of teclistamab Reference Material after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a percent purity about or more than 95.0% and no new peak more than 1.2% compared to Reference Material after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a percent purity about or more than 97.0% and no new peak more than 1.0% compared to Reference Material after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • cSDS Non-reduced Materials and Methods- Analysis employs a commercial capillary electrophoresis system with a bare fused silica capillary, 50 pm i.d. x 30.2 cm length in a temperature-controlled cartridge; the capillary is equipped with a detection window transparent to ultraviolet light. The capillary is rinsed electrokinetically before each injection. The capillary is loaded with a sieving matrix consisting of an entangled polymer solution before each sample analysis. The method utilizes an SDS-MW gel migration buffer, certified protein molecular weight standards spanning a range of approximately 10 to 148 kDa, and a validated teclistamab reference material sample.
  • the instrument ultraviolet absorption spectrophotometer detector is set at a wavelength of 220 nm and the capillary temperature is set to 25 °C.
  • the test article in duplicate
  • the alkylating reagent N-Ethylmaleimide, to prevent disulfide bond shuffling or reformation. It is then heated for a defined time and temperature to fully denature the protein and minimize formation of fragments and artifact bands.
  • the non-reduced sample is injected electrokinetically by applying a voltage of 5kV across the capillary for approximately 20 seconds, and then analyzed by application of a greater electric field for approximately 35 minutes.
  • Detection is accomplished by absorbance in the far ultraviolet region of the spectrum, 220 nm. Percent of total signal data is collected. The data is also analyzed for the presence of new peaks versus teclistamab reference material. Percent purity is defined as percent heavy chain + percent light chain.
  • stability is defined as having a percent purity of about 90.0% or more and no new peak more than 1.5% compared to Reference Material after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a percent purity of about 95.0% or more and no new peak more than 1.2% compared to Reference Material after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a percent purity of about 97.0% or more and no new peak more than 1.0% compared to Reference Material after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • SE-HPLC Size Exclusion High Performance Liquid Chromatography
  • Monomer main component or main peak
  • aggregates high molecular weight species, or HMWS
  • fragments low molecular weight species, or LMWS
  • Main Component- In one embodiment, stability is defined as having a Main Component about 90.0% or more after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a Main Component about 95.0% or more after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C
  • stability is defined as having a Main Component about 97.0% after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5°C .
  • HMWS High Molecular Weight Species
  • stability is defined as having a HMWS of about 10.0% or less after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5°C.
  • stability is defined as having a HMWS of about 5.0% or less after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a HMWS of about 3.0% or less after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5°C.
  • LMWS Low Molecular Weight Species
  • stability is defined as having a LMWS about 5.0% or less after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5°C.
  • stability is defined as having a LMWS of about 2.0% or less after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a LMWS about 1.0% or less after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5°C.
  • cIEF Materials and Methods- The analytical procedure is performed on a commercially available imaging cIEF analyzer equipped with an auto sampler. Analysis employs a 100-pm inner wall-coated silica capillary with an outer wall polyimide coating. In addition, an analyte solution of dilute phosphoric acid and methylcellulose, a catholyte solution of sodium hydroxide and methylcellulose, and defined type and amount of ampholytes are used.
  • the test articles are treated with carboxypeptidase B (CPB) to remove C-terminal lysine and eliminate ambiguities introduced by the presence of multiple C-terminal variants for each charged species.
  • the instrument’s autosampler is set to 4 °C for both pre-focusing and focusing.
  • the Pre-focusing voltage and time are 1500 V and 1 minute respectively.
  • the Focusing voltage and time are 3000 V and 7 minutes respectively.
  • stability is defined as having a Main Peak ⁇ 60% after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a Main Peak ⁇ 65 % after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a Main Peak ⁇ 70 % after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a Sum of acidic peaks totaling ⁇ 40 % after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a Sum of acidic peaks totaling ⁇ 30 % after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a Sum of acidic peaks totaling ⁇ 25 % after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5°C.
  • stability is defined as having a Sum of basic peaks totaling about ⁇ 15% after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a Sum of basic peaks totaling about ⁇ 10% after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a Sum of basic peaks totaling about ⁇ 8 % after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • Protein concentration of the drug product is determined by quantification of the absorbance at 280 nm (A280).
  • Measurement of protein concentration is performed using a qualified and calibrated double beam UV-Vis spectrophotometer.
  • Test articles are diluted 1:125 using 0.9% (w/v) NaCl.
  • Samples are measured using quartz semi- micro cuvettes (1.4 ml) with a 1 em path length and black or frosted sides.
  • the Spectrophotometer is set to a Wavelength of 280 nm, a slit width of 1 nm, and a response of one (1) second. 0.9% (w/v) NaCl is used as the Blank control.
  • Protein concentration (mg/mL) is calculated by dividing the product of the Test article absorbance and dilution factor by the product of the antibody’s Absorptivity Constant and instrument’s path length (for example, but not limited to teclistamab’s Absorptivity Constant of 1.58 (mg/mL)' 1 cm' 1 and instrument’s path length of 1 cm).
  • stability is defined as having a protein concentration of 7.5 to 12.5 mg/mL after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a protein concentration of 8 to 12 mg/mL after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a protein concentration of 9 mg/mL to 11 mg/mL after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5°C.
  • stability is defined as having a protein concentration of 76.5 to 103.5 mg/mL after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a protein concentration of 85 to 95 mg/mL after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as having a protein concentration of 87 mg/mL to 93 mg/mL after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5°C.
  • This reporter assay uses luminescence induced by activation of the NF AT (nuclear factor of activated T cells) pathway in CD3-expressing engineered effector cells as a read-out for target cell/effector cell co-engagement and is a surrogate measure of target cell killing.
  • Daudi B lymphoblast cells which expresses BCMA on its cell surface, are used as the target cells.
  • the engagement of both the anti-BCMA Fab region with the BCMA expressing target cells and the anti-CD3 Fab region with the genetically engineered CD3+ T-cells are required for T-cell activation and subsequent NFAT-RE-mediated luminescence.
  • BCMAxCD3 T-cell Activation Materials and Methods Qualified teclistamab is used as Reference Material and Controls. Solutions of Jurkat TCR/CD3 effector cells at 1.0 x 10 6 viable cells/mL in culture media (4% Heat- Inactivated Fetal Bovine Serum in RPMI) and a solution of Daudi B lymphoblast target cells at 4 x 10 5 viable cells/mL in cell culture media are prepared. Equal volumes of effector cells and target cells are aliquoted into individual wells on a 96-well cell culture plate. The plate is then incubated at 37°C ( ⁇ 2°C) with 5% ( ⁇ 2%) CO2 for 16-24 hours.
  • Bio-GloTM Luciferase substrate is added to each well and agitated moderately on a plate shaker for at least 5 minutes. Within 30 minutes of the addition of the substate, luminescence (Relative Light Unit (RLU) values) is measured using a microtiter luminescence plate reader. Data is reported as percent bioactivity relative to Reference Material.
  • RLU Relative Light Unit
  • stability is defined as 50% - 150% bioactivity relative to Reference Material after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined 60% - 140% bioactivity relative to Reference Material after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5°C.
  • stability is defined as ranging between about 80% to 120% bioactivity relative to Reference Material after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5°C.
  • Polysorbate 20 is quantitatively determined by mixed-mode ion-exchange/ hydrophobic HPLC.
  • PS 20 Materials and Methods. Analysis conducted with a gradient HPLC equipped with a 2.1 x 20 mm on-line column containing a 30 pm water- wetable, mixed-mode polymeric spherical sorbent particles, an ELSD, and a temperature-controlled column compartment at 30°C. The flow rate is set to ImL/minute 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. Neat Polysorbate 20 is used to create calibration and check standards. Test article samples are injected neat.
  • stability is defined as a PS20 concentration of 0.01-0.07% after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5°C.
  • stability is defined as a PS 20 concentration of 0.02-0.06% after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5 °C.
  • stability is defined as a PS 20 concentration of 0.03-0.05% after storage for about 12 months or more and at a temperature of about 5°C, after storage for about 12 months or more and at a temperature of about 25°C, and/or after storage for about 2 years or more and at a temperature of about 5°C.
  • the purpose of this test is to measure the levels of post-translational modifications, such as oxidation, deamidation, and isomerization, that may be present in the antibody structure.
  • Test articles are enzymatically digested to yield peptide segments. These peptides are then evaluated by Ultra High-Performance Liquid Chromatography Mass Spectroscopy (UPLC-MS). Each analyzed peptide sequence is identified relative to its known location within the overall antibody structure. Post-translational modifications are determined by comparing the measured mass of the identified peptide sequence with its expected mass.
  • Mobile phase A is 0.1% Formic Acid in water
  • Mobile phase B is, 0.1% FA in acetonitrile (mobile phase B).
  • the autosampler is set to 2-8°C
  • the column is set to 40°C and the flow rate is set to 500p L/minutc.
  • Eluted peptides are subjected to electrospray ionization and detected using a calibrated on-line mass spectrometry.
  • Target composition was 10 mM acetate, 8% (w/v) sucrose, 20 g/mL EDTA disodium, 0.04% (w/v) PS 20 at pH 5.2 for both 30 and 90 mg/mL formulation. The data was compared with the 10 mg/mL formulation with the same target composition.
  • the formulations were analyzed for main component, aggregate and fragment content by SE-HPLC, purity by cSDS (reduced and non-reduced), charge heterogeneity by cIEF, and sub- visible particulate matter by light obscuration (LO).
  • the same shaking study design was used for a second study augmented with an additional time point of 72 hours, a control sample at 0.04% (w/v) PS20 held at ambient conditions for 120 hours without shaking, and a broader, orthogonal battery of analytical assays.
  • the second study evaluated lOmg/mL and 90mg/mL teclistamab in 15 mM acetate, 8% (w/v) sucrose, 20 pg/mL EDTA at pH 5.2 supplemented with either 0.02, 0.04, or 0.06% (w/v) PS20.
  • the SEC results after shaking showed a slight trend of increases aggregation in the lowest (0.02% w/v) PS20 concentrations samples. However, these values are consistent with a preferred embodiment of DP stability.
  • Test formulations consisted of 10 mg/mL or 90 mg/mL teclistamab, 15 mM acetate, 8% sucrose, 20 pg/mL EDTA, and 0.04% PS 20 at pH 5.2 with or without the addition of Iron (Fe3+), Chromium (Cr3+), Copper (Cu2+), Nickel (Ni2+), and Molybdenum (Mo5+).
  • Iron Fe3+
  • Cr3+ Chromium
  • Cu2+ Copper
  • Nickel Ni2+
  • Molybdenum Mo5+
  • the lOmg/mL test formulations were aliquoted into 6R vials at a fill volume of 3.5mL and 90 mg/mL test formulations were aliquoted into 2mL vials at a fill volume of 2.0mL. All vials were stoppered, capped, and crimp sealed. The vials were placed on stability at recommended (5°C) and accelerated (25°C) conditions for up to 6 months. At designated time points, samples were pulled and assayed. [00261] As shown in Table 6, quality attributes for the 10 mg/mL and 90 mg/mL formulations stressed with metal ions after 6 months of storage at 2-8°C were nearly identical to their respective control formulations.
  • a stability monoclonal antibody formulation is the result of the net effect of the complex interactions between the formulation’s components.
  • Design of Experiments (DOE) methodology was used to create a multi-factorial stability study in which a statistically determined number of experimental test formulations are generated that simultaneously vary the parameters of formulation components.
  • DOE Design of Experiments
  • Statistical analysis of the study results provides a quantitative understanding of how formulation parameters interact to impact stability attributes and, in turn, demonstrate the robustness of formulation.
  • Experimental test formulations of BCMA x CD3 drug product were held at recommended (5°C) and accelerated (25°C) conditions for up to 12 months and six months, respectively.
  • the formulation components evaluated were protein concentration, acetate concentration, sucrose concentration, polysorbate 20 concentration, EDTA concentration, and pH.
  • the ranges of the factor concentrations tested are listed in Table 8 (target formulation values included in table to provide context).
  • the study encompassed both 10 mg/mL and 90 mg/mL DP formulations.
  • a typical protein concentration range for evaluation is +/- 12% of the target value. Therefore, the protein concentration values selected for the study represent the 88% of the 10 mg/mL and 111% of the of the 90 mg/mL formulations.
  • JNJ-64007957 concentration (mg/mL) 8.2 107.5 pH 4.5 5.9
  • the vials were stoppered, capped, and crimp sealed.
  • the vials were placed on stability at recommended (5°C) and accelerated (25°C) conditions. At designated time points, samples were pulled and assayed.
  • API concentration showed a statistically significant negative correlation with % monomer while also showing a corresponding, statistically significant positive correlation with % aggregate.
  • API concentration also showed a statistically significant negative correlation with % acid peak while also showing a statistically significant positive correlation with % basic peak.
  • Table 12 the range of result values for % acid peak and % basic peak are considered extremely narrow for those two attributes. Therefore, while calculated to be of statistical significance, API concentration from 8-100mg/mL is not considered to have a practical impact on the % acid and % basic peaks.
  • Formulation pH showed a statistically significant negative correlation with % monomer while also showing a corresponding, statistically significant positive correlation with % aggregate. These trends indicate that increased pH correlates with decreased stability as measured by SEC. However, within the pH range evaluated in this study (4.6 - 5.8), the range of % monomer and % aggregate assay results observed were consistent with the most preferred embodiment of stability.
  • Formulation pH showed a statistically significant positive correlation with turbidity indicating that increased pH correlates with decreased stability as measured by turbidity.
  • the r-squared (adj) value for the linear model was relatively low (54.28%). This is possibly related to the observations above in which turbidity values greater than 15 NTU were consistently observed in three test formulations formulated at high pH value (5.8) and high protein concentration (100 mg/mL). The three turbidity result values may in turn be skewing the linear model used of this analysis. However, within the pH range evaluated in this study (4.6 - 5.8), the range of turbidity results for low protein concentration test formulations observed were consistent with the most preferred embodiment of stability.
  • pH also showed a statistically significant negative correlation with % main peak and % purity by cSDS-reduced while also showing a statistically significant positive correlation with % basic peak.
  • the range of result values for % acid peak, % main peak and % purity by cSDS-reduced are considered extremely narrow for those three attributes. Therefore, while calculated to be of statistical significance, pH from 4.6 to 5.8 is not considered to have a practical impact on the % acid, % basic peak, and % purity by cSDS-reduced.
  • Acetate Formulation showed a statistically significant negative correlation with % monomer while also showing a corresponding, statistically significant positive correlation with % aggregate. These trends indicate that increased acetate concentration correlates with decreased stability as measured by SEC. However, within the acetate concentration range evaluated in this study (10 - 20 mM), the range of % monomer and % aggregate assay results observed were consistent with the most preferred embodiment of stability.
  • Example 6 Formulated drug bulk production
  • Ultrafiltration/diafiltration was performed to re-formulate the teclistamab Planova filtrate intermediate manufacturing solution to a pre-formulated bulk (pFB) solution consisting of 90mg/mL teclistamab, 10 mM Acetate, 8% (w/v) Sucrose, pH 4.9.
  • pFB pre-formulated bulk
  • the FB was filled into polycarbonate Biotainer(s).
  • the fill volume is 20% to 90% of the biotainer’s stated volume.
  • Example 7 90 mg/mL Drug Product Formulation: composition and components of primary packaging
  • the 90 mg/mL Teclistamab drug product (DP) primary packaging consists of a glass vial, a polymer vial stopper, and an aluminum seal.
  • Table 15 provides the specific components for the primary packaging material of the 90 mg/mL DP presentation.
  • Example 8 lOmg/mL DP Solution Production
  • Dilution Buffer was added to the 90 mg/mL FB yielding a lOmg/mL Drug Product solution consisting of 10 mg/mL teclistamab in 15 mM Acetate, 8% (w/v) Sucrose, 0.04% Polysorbate 20, 20 pg/mL EDTA, pH 5.2.
  • Example 9 10 mg/mL Drug Product Formulation: composition and components of primary packaging
  • Table 17 Composition of 10 mg/mL Teclistamab Drug Product
  • Glacial acetic acid 0.240 mg
  • the 10 mg/mL teclistamab drug product (DP) primary packaging consists of a glass vial, a polymer vial stopper, and an aluminum seal.
  • Table 18 lists specific components for the primary packaging material of the 30mg DP presentation.
  • Stopper 20 Stopper 4023/50 Gray with Flurotec Coating, RTS
  • Example 10 Description of 90mg/mL stability study
  • Table 21 Stability Results for 90mg/mL Teclistamab Drug Product Stored at 25 °C
  • Example 11 Description of lOmg/mL stability study

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KR20240099432A (ko) 2024-06-28
TW202328209A (zh) 2023-07-16
CA3238152A1 (en) 2023-05-19
EP4430082A1 (en) 2024-09-18
US20230279136A1 (en) 2023-09-07

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