WO2022224187A1 - High concentration bispecific antibody formulations - Google Patents

High concentration bispecific antibody formulations Download PDF

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Publication number
WO2022224187A1
WO2022224187A1 PCT/IB2022/053733 IB2022053733W WO2022224187A1 WO 2022224187 A1 WO2022224187 A1 WO 2022224187A1 IB 2022053733 W IB2022053733 W IB 2022053733W WO 2022224187 A1 WO2022224187 A1 WO 2022224187A1
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Prior art keywords
seq
pharmaceutical composition
amino acid
storage
temperature
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PCT/IB2022/053733
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English (en)
French (fr)
Inventor
Roland Knoblauch
Satyen Torne
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Janssen Biotech Inc
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Janssen Biotech Inc
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Priority to PE2023002909A priority Critical patent/PE20240805A1/es
Priority to AU2022260814A priority patent/AU2022260814A1/en
Priority to BR112023021549A priority patent/BR112023021549A2/pt
Priority to EP22720780.0A priority patent/EP4326242A1/en
Priority to CA3217191A priority patent/CA3217191A1/en
Priority to KR1020237039536A priority patent/KR20230174239A/ko
Priority to CN202280029655.4A priority patent/CN117177740A/zh
Priority to MX2023012508A priority patent/MX2023012508A/es
Priority to CR20230497A priority patent/CR20230497A/es
Priority to IL307879A priority patent/IL307879A/en
Application filed by Janssen Biotech Inc filed Critical Janssen Biotech Inc
Priority to JP2023564087A priority patent/JP2024514344A/ja
Priority to PH1/2023/552883A priority patent/PH12023552883A1/en
Publication of WO2022224187A1 publication Critical patent/WO2022224187A1/en
Priority to JOJO/P/2023/0263A priority patent/JOP20230263A1/ar
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • 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
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07K16/2863—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/24—Hydrolases (3) acting on glycosyl compounds (3.2)
    • C12N9/2402—Hydrolases (3) acting on glycosyl compounds (3.2) hydrolysing O- and S- glycosyl compounds (3.2.1)
    • C12N9/2474—Hyaluronoglucosaminidase (3.2.1.35), i.e. hyaluronidase
    • 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
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • 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
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

  • stable aqueous pharmaceutical compositions comprising specific formulations of a bispecific antibody.
  • the antibody comprises: a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1) comprising the amino acid sequence of SEQ ID NO:13; a first light chain (LC1) comprising a light chain variable region 1 (VL1) comprising the amino acid sequence of SEQ ID NO:14; a second heavy chain (HC2) comprising a HC2 variable region 2 (VH2) comprising the amino acid sequence of SEQ ID NO:15; a second light chain (LC2) comprising a light chain variable region 2 (VL2) comprising the amino acid sequence of SEQ ID NO:16; and wherein the composition comprises about
  • the composition comprises about 1,050 mg of the bispecific EGFR/c-Met antibody. [0004] In some embodiments, the composition comprises about 1,400 mg of the bispecific EGFR/c-Met antibody. [0005] In some embodiments, the composition comprises about 1,575 mg of the bispecific EGFR/c-Met antibody. [0006] In some embodiments, the composition comprises about 1,600 mg of the bispecific EGFR/c-Met antibody. [0007] In some embodiments, the composition comprises about 2,100 mg of the bispecific EGFR/c-Met antibody. [0008] In some embodiments, the composition comprises about 2,240 mg of the bispecific EGFR/c-Met antibody.
  • aqueous pharmaceutical compositions comprising: a) about 144 mg/mL to about 176 mg/mL of a bispecific epidermal growth factor receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody, the bispecific antibody comprising: a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1); a first light chain (LC1) comprising a light chain variable region 1 (VL1); a second heavy chain (HC2) comprising a HC2 variable region 2 (VH2); and a second light chain (LC2) comprising a light chain variable region 2 (VL2), wherein the VH1 comprises a heavy chain complementarity determining region 1 (HCDR1), a HCDR2 and a HCDR3 amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; the VL1 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2 and a LCDR3 amino acid
  • the stable aqueous pharmaceutical composition comprises about 160 mg/mL of the bispecific EGFR-cMet antibody, about 30 mM acetate and/or pharmaceutically acceptable acetate salt, about 8.5% sucrose, and about 1 mg/mL L-methionine with polysorbate 80 to a final concentration of about 0.06% (w/v) and EDTA to a final concentration of about 20 ⁇ g/mL, wherein the stable aqueous pharmaceutical composition has pH about 5.7, and wherein the bispecific EGFR-cMet antibody comprises a heavy chain 1 (HC1) comprising the amino acid sequence of SEQ ID NO:17, HC2 comprising the amino acid sequence of SEQ ID NO:19, a light chain 1 (LC1) comprising the amino acid sequence of SEQ ID NO:18, and a LC2 comprising the amino acid sequence of SEQ ID NO:20.
  • HC1 heavy chain 1
  • LC1 light chain 1
  • the stable aqueous pharmaceutical composition comprises about 160 mg/mL of the bispecific EGFR-cMet antibody, about 30 mM acetate and/or pharmaceutically acceptable acetate salt, about 8.5% sucrose, about 1 mg/mL L-methionine with polysorbate 80 to a final concentration of about 0.06% (w/v) and EDTA to a final concentration of about 20 ⁇ g/mL, and rHuPH20 to a final concentration of about 2,000 U/mL, wherein the stable aqueous pharmaceutical composition has pH about 5.7, and wherein the bispecific EGFR- cMet antibody comprises a heavy chain 1 (HC1) comprising the amino acid sequence of SEQ ID NO:17, HC2 comprising the amino acid sequence of SEQ ID NO:19, a light chain 1 (LC1) comprising the amino acid sequence of SEQ ID NO:18, and a LC2 comprising the amino acid sequence of SEQ ID NO:20.
  • HC1 heavy chain 1
  • LC1 light chain 1
  • kits for treating cancer in a subject in need thereof comprise administering to the subject the stable aqueous pharmaceutical compositions as disclosed herein.
  • methods of reducing infusion-related reactions in a subject treated with amivantamab comprising subcutaneously administering to the subject the stable aqueous pharmaceutical formulation as disclosed herein.
  • a bispecific antibody targeting EGFR and cMet comprising a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1); a first light chain (LC1) comprising a light chain variable region 1 (VL1); a second heavy chain (HC2) comprising a HC2 variable region 2 (VH2); and a second light chain (LC2) comprising a light chain variable region 2 (VL2)
  • the VH1 comprises a heavy chain complementarity determining region 1 (HCDR1), a HCDR2 and a HCDR3 comprising amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively
  • the VL1 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2 and a LCDR3 comprising amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively
  • the VH2 comprises HCDR1
  • the methods comprise combining a composition comprising about 160 mg/mL of the bispecific antibody, about 30 mM acetate and/or pharmaceutically acceptable acetate salt, about 8.5% sucrose, and about 1 mg/mL L-methionine with polysorbate 80 to a final concentration of about 0.06% (w/v) and EDTA to a final concentration of about 20 ⁇ g/mL, optionally rHuPH20 to a final concentration of about 2,000 U/mL, wherein the stable aqueous pharmaceutical composition has about pH 5.7.
  • kits comprising the stable pharmaceutical aqueous formulations as disclosed herein and instructions for use thereof.
  • FIG.1 shows the serum concentration-time profile of amivantamab doses.
  • FIG.2 shows the saturation of soluble free EGFR and MET after first SC amivantamab dose.
  • DETAILED DESCRIPTION OF THE INVENTION [0017] The disclosed 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.
  • 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 that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.
  • singular forms “a,” “an,” and “the” include the plural.
  • Various terms relating to aspects of the description are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definitions provided herein.
  • “about” when used in reference to numerical ranges, cutoffs, or specific values is used to indicate that the recited values may vary by up to as much as 10% from the listed value.
  • 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.
  • 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 IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. Antibody light chains of any vertebrate species can be assigned to one of two clearly distinct types, namely kappa ( ⁇ ) and lambda ( ⁇ ), based on the amino acid sequences of their constant domains. [0028] “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) CH1 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.
  • dAb domain antibody
  • 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. WO1998/44001, WO1988/01649, WO1994/13804, and WO1992/01047.
  • scFv single chain Fv
  • WO1998/44001 WO1988/01649
  • WO1994/13804 WO1992/01047.
  • 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
  • H1, H2, H3 three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3) refer to the regions of the antibody variable domains which are hypervariable in structure as defined by Chothia and Lesk (Chothia and Lesk Mol Biol 196:901-17, 1987).
  • Other terms include “IMGT-CDRs” (Lefranc et al., Dev Comparat Immunol 27:55-77, 2003) and “Specificity Determining Residue Usage” (SDRU) (Almagro Mol Recognit 17:132-43, 2004).
  • IMGT International ImMunoGeneTics
  • 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. A bispecific antibody is included in the term monoclonal antibody.
  • biosimilar refers to a biological product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components with no clinically meaningful differences between the biosimilar and the reference product in terms of safety, purity and potency, based upon data derived from (a) analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; (b) animal studies (including the assessment of toxicity); and/or (c) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biosimilar.
  • the biosimilar may be an interchangeable product that may be substituted for the reference product at the pharmacy without the intervention of the prescribing healthcare professional.
  • the biosimilar is to be expected to produce the same clinical result as the reference product in any given patient and, if the biosimilar is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biosimilar and the reference product is not greater than the risk of using the reference product without such alternation or switch.
  • the biosimilar utilizes the same mechanisms of action for the proposed conditions of use to the extent the mechanisms are known for the reference product.
  • the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biosimilar have been previously approved for the reference product.
  • the route of administration, the dosage form, and/or the strength of the biosimilar are the same as those of the reference product and the biosimilar is manufactured, processed, packed or held in a facility that meets standards designed to assure that the biosimilar continues to be safe, pure and potent.
  • the biosimilar may include minor modifications in the amino acid sequence when compared to the reference product, such as N- or C-terminal truncations that are not expected to change the biosimilar performance.
  • Epipe 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.
  • “Hyaluronidase” refers to an enzyme that breaks down hyaluronic acid.
  • This enzyme is often used to increase the dispersion and absorption of other co-administered drugs into tissue (e.g., subcutaneous injections, subcutaneous infusion such as hypodermoclysis). More specifically, human recombinant DNA-derived hyaluronidase enzyme PH20 (rHuPH20) is often used for increasing subcutaneous drug infusion particularly when large volumes are injected.
  • rHuPH20 human recombinant DNA-derived hyaluronidase enzyme PH20
  • 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.
  • 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 combination therapy 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.
  • 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.
  • various cancers include but are not limited to, solid malignancies such as breast cancer (BC), prostate cancer, ovarian cancer (OC), cervical cancer, skin cancer, pancreatic cancer, gastroesophageal cancer (GEC), colorectal cancer (CRC), renal cell cancer (RCC), liver cancer, hepatocellular cancer (HCC), brain cancer, squamous cell carcinoma of the head and neck (SCCHN)), lymphoma, leukemia, lung cancer (e.g. non-small cell lung cancer (NSCL) or small cell lung cancer (SCLC)), medullary thyroid cancer (MTC), and mesothelioma.
  • BC breast cancer
  • OC ovarian cancer
  • CEC gastroesophageal cancer
  • CRCC colorectal cancer
  • RRCC renal cell cancer
  • HCC hepatocellular cancer
  • SCCHN squamous cell carcinoma of the head and neck
  • the solid malignancy may be metastatic or unresectable.
  • the solid malignancy may be histologically or cytologically confirmed.
  • Reference Material (RM) as used herein refers to a vial that contains about 0.2mL aliquot of amivantamab, or biosimilar thereof, and is used in good manufacturing practices (GMP) for clinical drug substance.
  • the RM is stored at at least -60 o C and is thawed and used as a control in amivantamab analytical assays.
  • 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.
  • IRRs Infusion-related reactions” or “IRRs” may occur in some patients to whom the bi-specific EGFR/c-Met antibody, such as amivantamab, is administered. Signs and symptoms of IRRs may include include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and/or vomiting. Systemic IRRs, including severe reactions, upon the introduction of a new protein therapeutic infusion may also occur.
  • the bispecific anti-EGFR/c-Met antibody may be provided in suitable pharmaceutical compositions comprising the bispecific anti-EGFR/c-Met antibody and a pharmaceutically acceptable carrier.
  • the stable, aqueous pharmaceutical compositions may include one or more diluents, adjuvants, excipients, or vehicles with which the bispecific anti- EGFR/c-Met antibody is administered subcutaneously.
  • Exemplary excipients include one or more of buffering agents, stabilizers, chelating agents, surfactants, and enzymes.
  • the stable, aqueous pharmaceutical compositions comprising a bispecific EGFR/ c-Met antibody further comprise a buffering agent, a stabilizer, a chelating agent, a surfactant, and, optionally, a hyaluronidase.
  • the stable, aqueous pharmaceutical compositions comprising a bispecific EGFR/ c-Met antibody provided herein are also referred to as drug product or DP.
  • the bispecific EGFR/c-Met antibody comprises a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1); a first light chain (LC1) comprising a light chain variable region 1 (VL1); a second heavy chain (HC2) comprising a HC2 variable region 2 (VH2); and a second light chain (LC2) comprising a light chain variable region 2 (VL2)
  • the VH1 comprises a heavy chain complementarity determining region 1 (HCDR1), a HCDR2 and a HCDR3 amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively
  • the VL1 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2 and a LCDR3 amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively
  • the VH2 comprises the HCDR1, the HCDR2 and the HCDR3 amino acid sequences of SEQ ID NOs: 7, 8 and 9, respectively
  • the VL1 comprises a heavy chain
  • the first heavy chain (HC1) of the bispecific EGFR-cMet antibody comprises a HC1 constant domain 3 (HC1 CH3) and a HC1 variable region 1 (VH1).
  • the second heavy chain (HC2) of the bispecific EGFR-cMet antibody comprises a HC2 constant domain 3 (HC2 CH3) and a HC2 variable region 2 (VH2).
  • the first heavy chain (HC1) of the bispecific EGFR-cMet antibody comprises a HC1 constant domain 3 (HC1 CH3) and a HC1 variable region 1 (VH1 and the second heavy chain (HC2) of the bispecific EGFR-cMet antibody comprises a HC2 constant domain 3 (HC2 CH3) and a HC2 variable region 2 (VH2).
  • the first heavy chain (HC1) of the bispecific EGFR-cMet antibody comprises a HC1 constant domain 2 and constant domain 3 (HC1 CH2-CH3) and a HC1 variable region 1 (VH1).
  • the second heavy chain (HC2) of the bispecific EGFR-cMet antibody comprises a HC2 constant domain 2 and constant domain 3 (HC2 CH2- CH3) and a HC2 variable region 2 (VH2).
  • the first heavy chain (HC1) of the bispecific EGFR-cMet antibody comprises a HC1 constant domain 2 and constant domain 3 (HC1 CH2-CH3) and a HC1 variable region 1 (VH1)
  • the second heavy chain (HC2) of the bispecific EGFR-cMet antibody comprises a HC2 constant domain 2 and constant domain 3 (HC2 CH2- CH3) and a HC2 variable region 2 (VH2).
  • the bispecific antibody comprises asymmetric stabilizing mutations in the HC1 CH2-CH3 region, in the HC2 CH2-CH3 region, or both.
  • “Asymmetric stabilizing mutations” refers to mutations in a first CH2-CH3 region and in a second CH2-CH3 region which are at different positions in the first and in the second CH2-CH3 region and favor (e.g., stabilize) heterodimer formation between the first CH2-CH3 region and the second CH2- CH3 region over homodimer formation between the first CH2-CH3 region or the second CH2- CH3 region.
  • Exemplary asymmetric stabilizing mutations in the HC1 CH2-CH3 region and the HC2 CH2-CH3 region, or in the HC2 CH2-CH3 region and the HC1 CH2-CH3 region, are (wherein residue numbering is according to the EU Index): F405L and K409R, respectively; wild-type and F405L/R409K, respectively; T366W and T366S/L368A/Y407V, respectively; T366Y/F405A and T394W/Y407T, respectively; T366W/F405W and T394S/Y407A, respectively; F405W/Y407A and T366W/T394S, respectively; L351Y/F405A/Y407V and T394W, respectively; T366I/K392M/T394W and F405A/Y407V, respectively; T366L/K392M/T394W and F405A/Y40
  • the bispecific EGFR-cMet antibody comprises an HC1 variable region comprising the amino acid sequence of SEQ ID NO:13 and a LC1 variable region comprising the amino acid sequence of SEQ ID NO:14 (see table 29).
  • the bispecific antibody comprises asymmetric stabilizing mutations in the HC1 CH2-CH3 region, in the HC2 CH2-CH3 region, or both.
  • the bispecific antibody comprises K409R in the c-Met binding arm and F405L in the EGFR binding arm.
  • the bispecific EGFR-cMet antibody comprises a HC2 variable region comprising the amino acid sequence of SEQ ID NO:15 and a LC2 variable region comprising the amino acid sequence of SEQ ID NO:16 (see table 29).
  • the heavy chain 1 (HC1) comprises the amino acid sequence of SEQ ID NO:17 and the HC2 comprises the amino acid sequence of SEQ ID NO:19 (see table 29).
  • the light chain 1 (LC1) comprises the amino acid sequence of SEQ ID NO:18 and the LC2 comprises the amino acid sequence of SEQ ID NO:20 (see table 29).
  • bispecific EGFR-cMet antibody is amivantamab or a biosimilar thereof.
  • Amivantamab (JNJ-61186372) is a low fucose, fully human IgG1-based bispecific antibody directed against EGFR and cMET tyrosine kinase receptors that is approved by the FDA for patients with EGFR Exon 20ins mutations after treatment with chemotherapy .
  • Amivantamab shows activity against tumors with primary activating EGFR mutations (Exon 19 deletion [Exon 19del], Exon 21 leucine 858 to arginine substitution ([L858R], and Exon 20ins mutations), EGFR resistance mutations (tyrosine 790 to methionine [T790M] or cysteine 797 to serine [C797S] mutations), overexpressed wild type EGFR, and activation of the cMet pathway.
  • EGFR mutations Exon 19 deletion [Exon 19del], Exon 21 leucine 858 to arginine substitution ([L858R], and Exon 20ins mutations
  • EGFR resistance mutations tyrosine 790 to methionine [T790M] or cysteine 797 to serine [C797S] mutations
  • T790M methionine
  • C797S serine
  • Lazertinib is an oral, highly potent, mutant-selective, and irreversible third- generation EGFR TKI that targets both the Exon 19del and the Exon 21 L858R EGFR activating mutations, as well as the T790M resistance mutation.
  • Lazertinib has demonstrated efficacy in participants with EGFR-mutated NSCLC, with activity observed in both systemic and central nervous system lesions, demonstrating its ability to cross the blood-brain barrier.
  • the stable aqueous pharmaceutical composition comprises the bispecific EGFR-cMet antibody at a concentration of about: 100 mg/mL, 110 mg/mL, 120 mg/mL, 121 mg/mL, 122 mg/mL, 123 mg/mL, 124 mg/mL, 125 mg/mL, 126 mg/mL, 127 mg/mL, 128 mg/mL, 129 mg/mL, 130 mg/mL, 131 mg/mL, 132 mg/mL, 133 mg/mL, 134 mg/mL, 135 mg/mL, 136 mg/mL, 137 mg/mL, 138 mg/mL, 139 mg/mL, 140 mg/mL, 141 mg/mL, 142 mg/mL, 143 mg/mL, 144 mg/mL, 145 mg/mL, 146 mg/mL, 147 mg/mL, 148 mg/mL, 150 mg/mL, 151
  • the bispecific EGFR-cMet antibody has a concentration of about 160 mg/mL. [0057] In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of between about 140 mg to about 1750 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of between about 140 mg to about 2100 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of between about 1050 mg to about 2240 mg.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg,
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 350 mg, about 700 mg, about 1050 mg, about 1400 mg, about 1575 mg, or about 2100 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 350 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 700 mg. In some embodiments, the bispecific anti- EGFR/c-Met antibody is administered at a dose of about 750 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 800 mg.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 850 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 900 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 950 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1000 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1050 mg. In some embodiments, the bispecific anti- EGFR/c-Met antibody is administered at a dose of about 1100 mg.
  • the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1150 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1200 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1250 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1300 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1350 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1400 mg.
  • the bispecific anti- EGFR/c-Met antibody is administered at a dose of about 1575 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1600 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 2100 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 2240 mg. [0060] In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered once a week. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered about 1050 mg once a week.
  • the bispecific anti-EGFR/c-Met antibody is administered about 1400 mg once a week. In some embodiments, the bispecific anti-EGFR/c- Met antibody is administered about 1575 mg once a week. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered about 1600 mg once a week. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered about 2100 mg once a week. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered about 2240 mg once a week. [0061] In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered once in two weeks.
  • the bispecific anti-EGFR/c-Met antibody is administered about 1050 mg once in two weeks. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered about 1400 mg once in two weeks. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered about 1575 mg once in two weeks. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered about 1600 mg once in two weeks. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered about 2100 mg once in two weeks. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered about 2240 mg once in two weeks.
  • the bispecific anti-EGFR/c-Met antibody is administered twice a week. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered once a week. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered once in two weeks. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered once in three weeks. In some embodiments, the bispecific anti- EGFR/c-Met antibody is administered once in four weeks. [0063] For combination therapies, the one or more anti-cancer agents may be administered using recommended dosages of the anti-cancer agent. [0064] The buffering agent is suitable to adjust the pH to about 5.0 to 6.2, such as pH 5.1 to 5.7.
  • an exemplary buffer is a histidine buffer or acetate buffer.
  • the stable aqueous pharmaceutical composition comprises histidine and/or pharmaceutically acceptable histidine salt at a concentration of about: 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM, 25 mM, 26 mM, 27 mM, 28 mM, 29 mM, 30 mM, 31 mM, 32 mM, 33 mM, 34 mM, 35 mM, 36 mM, 37 mM, 38 mM, 39 mM, 40 mM, 41 mM, 42 mM, 43 mM, 44 mM, 45 mM, 46 mM, 47 mM, 48 mM
  • the histidine and/or pharmaceutically acceptable histidine salts has a concentration of about 10 mM. In some embodiments, the histidine and/or pharmaceutically acceptable histidine salts has a concentration of about 50 mM. In a further embodiment, the histidine and/or pharmaceutically acceptable histidine salt comprises L-histidine and L-histidine hydrochloride monohydrate.
  • the stable aqueous pharmaceutical composition comprises acetate and/or pharmaceutically acceptable acetate salt at a concentration of about: 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM, 25 mM, 26 mM, 27 mM, 28 mM, 29 mM, 30 mM, 31 mM, 32 mM, 33 mM, 34 mM, 35 mM, 36 mM, 37 mM, 38 mM, 39 mM, 40 mM, 41 mM, 42 mM, 43 mM, 44 mM, 45 mM, 46 mM, 47 mM, 48 mM, 49 mM, or 50 mM.
  • the acetate and/or pharmaceutically acceptable acetate salts has a concentration of about 30 mM.
  • the acetate and/or pharmaceutically acceptable acetate salt comprises glacial acetic acid and/or sodium acetate trihydrate.
  • the stabilizer may comprise sucrose and optionally methionine.
  • the stable aqueous pharmaceutical composition comprises sucrose at a concentration (percentage of weight to volume (% w/v)) of about: 6.0%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7% 6.8%, 6.9%, 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7% 7.8%, 7.9%, 8.0%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7% 8.8%, 9.9%, 10.0%, 10.1%, 10.2%, 10.3%, 10.4%, 10.5%, 10.6%, 10.7% 10.8%, 10.9%, or 11.0%.
  • the stable aqueous pharmaceutical composition comprises about 8.5% (w/v) sucrose.
  • the stable aqueous pharmaceutical composition comprises methionine (e.g. L- methionine) at a concentration of about: 0.1 mg/mL, 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL, 0.5 mg/mL, 0.6 mg/mL, 0.7 mg/mL, 0.8 mg/mL, 0.9 mg/mL, 1.0 mg/mL, 1.1 mg/mL, 1.2 mg/mL, 1.3 mg/mL, 1.4 mg/mL, 1.5 mg/mL, 1.6 mg/mL, 1.7 mg/mL, 1.8 mg/mL, 1.9 mg/mL, or 2.0 mg/mL.
  • methionine e.g. L- methionine
  • the methionine comprises L-methionine and has a concentration of about 1.0 mg/mL.
  • a preferred surfactant is polysorbate 80 (PS80).
  • the stable aqueous pharmaceutical composition comprises polysorbate 80 (PS80) at a concentration (% w/v) of about: 0.005%, 0.01%, 0.015%, 0.020%, 0.025%, 0.030%, 0.035%, 0.036%, 0.037%, 0.038%, 0.039%, 0.040%, 0.041%, 0.042%, 0.043% 0.044%, 0.045%, 0.046%, 0.047%, 0.048%, 0.049%, 0.050%, 0.051%, 0.052%, 0.053%, 0.054%, 0.055%, 0.056%, 0.057%, 0.058% 0.059%, 0.060%, 0.061%, 0.062%, 0.063%, 0.064%, 0.065%, 0.066%, 0.067%, 0.068% 0.069%, 0.070%, 0.071%, 0.071%, 0.07
  • the stable aqueous pharmaceutical composition comprises about 0.06% (w/v) PS80.
  • a preferred chelating agent is ethylenediaminetetraacetic acid (EDTA).
  • the stable aqueous pharmaceutical composition comprises EDTA at a concentration of about: 10 ⁇ g /mL, 11 ⁇ g/mL, 12 ⁇ g/mL, 13 ⁇ g/mL, 14 ⁇ g/mL, 15 ⁇ g/mL, 16 ⁇ g/mL, 17 ⁇ g/mL, 18 ⁇ g/mL, 19 ⁇ g/mL, 20 ⁇ g/mL, 21 ⁇ g/mL, 22 ⁇ g/mL, 23 ⁇ g/mL, 24 ⁇ g/mL, 25 ⁇ g/mL, 26 ⁇ g/mL, 27 ⁇ g/mL, 28 ⁇ g/mL, 29 ⁇ g/mL, or 30 ⁇ g/mL.
  • the EDTA has a concentration of about 20 ⁇ g/mL.
  • the stable aqueous pharmaceutical composition comprising a bispecific EGFR/ c-Met antibody comprises a hyaluronidase enzyme in an amount sufficient to result in an increase in the dispersion of the antibody during subcutaneous administration.
  • the hyaluronidase enzyme excipient in accordance with the formulation of the present invention is characterized by having no adverse effect on the molecular integrity of the bispecific EGFR/ c-Met antibody in the stable pharmaceutical compositions described herein.
  • the hyaluronidase enzyme merely modifies the delivery of the bispecific EGFR/ c- Met antibody to the systemic circulation but does not possess any properties that could provide or contribute to the therapeutic effects of systemically absorbed bispecific EGFR/ c-Met antibody.
  • the hyaluronidase enzyme is not systemically bioavailable and does not adversely affect the molecular integrity of the bispecific EGFR/ c-Met antibody at the recommended storage conditions of the stable pharmaceutical composition in accordance with the invention.
  • a number of suitable hyaluronidase enzymes in accordance with the present invention are known.
  • the preferred enzyme is a human hyaluronidase enzyme, such as a soluble human PH20 hyaluronidase, preferably the recombinant human hyaluronidase enzyme product known as rHuPH20.
  • the amino acid sequence of soluble human PH20 hyaluronidases include the soluble human PH20 known as rHuPH20 and available under CAS Registry No.757971-58-7. Soluble human PH20 hyaluronidiases are described in Int. Pat. Publ. No. WO2004/078140 and U.S. Pat. No.7,767,429 incorporated herein by reference, in its entirety.
  • soluble hyaluronidases include those whose sequence are set forth in any of SEQ ID NOs: 21-25. Soluble PH20 hyaluronidase, when expressed in a cell, include a signal sequence for trafficking in the cell.
  • the amino acid sequence of a soluble PH20 hyaluronidase comprises SEQ ID NO: 26.
  • the amino acid sequence of sequence of a soluble PH20 hyaluronidase SEQ ID NO: 22, namely residues 36-482 of wild type human hyaluronidase.
  • the amino acid sequence of a soluble PH20 hyaluronidase comprises SEQ ID NO: 23.
  • the amino acid sequence of a soluble PH20 hyaluronidase comprises SEQ ID NO: 24. In some embodiments, the amino acid sequence a soluble PH20 hyaluronidase rHuPH20 comprises SEQ ID NO: 25. In some embodiments, the amino acid sequence of a soluble PH20 hyaluronidase comprises SEQ ID NO: 21. In some embodiments, the soluble PH20 hyaluronidases, when expressed in a cell, comprise a mixture of species that can include any one or more of SEQ ID NO: 21 to SEQ ID NO: 25 in various abundance. The average molecular weight is 61 kDa.
  • rHuPH20 refers to the composition produced upon expression in a cell, such as CHO cell, of nucleic acid encoding residues 36-482 of SEQ ID NO: 26, generally linked to the native or a heterologous signal sequence (residues 1-35 of SEQ ID NO: 26).
  • rHuPH20 is produced by expression of a nucleic acid molecule, such as encoding amino acids 1-482 (set forth in SEQ ID NO: 26) in a mammalian cell. Translational processing removes the 35 amino acid signal sequence.
  • rHuPH20 As produced in the culture medium there is heterogeneity at the C-terminus such that the product, designated rHuPH20, includes a mixture of species that can include any one or more of the polypeptides 36-480, 36-481, and 36-482 of SEQ ID NO: 26, and some shorter polypeptides, in various abundance.
  • rHuPH20 is produced in cells, such as CHO cells, for example DG44 CHO cells) that facilitate correct N-glycosylation to retain activity.
  • the stable aqueous pharmaceutical composition comprises rHuPH20 at a concentration of about 500 U/mL, about 750 U/mL, about 1,000 U/mL, about 1,250 U/mL, about 1,500 U/mL, about 1,750 U/mL, about 2,000 U/mL, about 2,250 U/mL, about 2,500 U/mL, about 2,750 U/mL, about 3,000 U/mL, about 3,250 U/mL, about 3,500 U/mL, about 3,750 U/mL, or about 4,000 U/mL.
  • the stable aqueous pharmaceutical composition comprises rHuPH20 at a concentration of about 2,000 U/mL.
  • the stable aqueous pharmaceutical composition comprises rHuPH20 at a concentration of about 1,500 U/mL.
  • the stable aqueous pharmaceutical composition comprises rHuPH20 at a concentration of about 0.005 mg/mL, about 0.0075 mg/mL, about 0.01 mg/mL, about 0.0125 mg/mL, about 0.015 mg/mL, about 0.0175 mg/mL, about 0.02 mg/mL, about 0.0225 mg/mL, about 0.025 mg/mL, about 0.0275 mg/mL, about 0.03 mg/mL, about 0.0325 mg/mL, about 0.035 mg/mL, about 0.0375 mg/mL, or about 0.04 mg/mL.
  • the stable aqueous pharmaceutical composition comprises rHuPH20 at a concentration of about 0.02 mg/ml.
  • the stable aqueous pharmaceutical composition comprises rHuPH20 at a dose of about 10,000 U, about 11,000 U, about 12,000 U, about 13,000 U, about 13,200 U, about 14,000 U, about 15,000 U, about 16,000 U, about 17,000 U, about 17,500 U, about 18,000 U, about 19,000 U, about 19,500 U, about 19,600 U, about 19,680 U, about 19,700 U, about 20,000 U, about 21,000 U, about 22,000 U, about 23,000 U, about 24,000 U, about 25,000 U, about 26,000 U, about 26,260 U, about 26,500 U, about 26,600 U, about 26,680 U, about 26,700 U, about 27,000 U, 28,000 U, about 29,000 U, about 30,000 U or any value in between.
  • the stable aqueous pharmaceutical composition comprises rHuPH20 at a dose of about 13,000 U. In some embodiments, the stable aqueous pharmaceutical composition comprises rHuPH20 at a dose of about 13,200 U. In some embodiments, the stable aqueous pharmaceutical composition comprises rHuPH20 at a dose of about 14,000 U. In some embodiments, the stable aqueous pharmaceutical composition comprises rHuPH20 at a dose of about 17,500 U. In some embodiments, the stable aqueous pharmaceutical composition comprises rHuPH20 at a dose of about 18,000 U. In some embodiments, the stable aqueous pharmaceutical composition comprises rHuPH20 at a dose of about 19,680 U.
  • the stable aqueous pharmaceutical composition comprises rHuPH20 at a dose of about 20,000 U. In some embodiments, the stable aqueous pharmaceutical composition comprises rHuPH20 at a dose of about 26,000 U. In some embodiments, the stable aqueous pharmaceutical composition comprises rHuPH20 at a dose of about 26,260 U. In some embodiments, the stable aqueous pharmaceutical composition comprises rHuPH20 at a dose of about 26,300 U. In some embodiments, the stable aqueous pharmaceutical composition comprises rHuPH20 at a dose of about 26,400 U. In some embodiments, the stable aqueous pharmaceutical composition comprises rHuPH20 at a dose of about 26,500 U.
  • the stable aqueous pharmaceutical composition comprises rHuPH20 at a dose of about 26,600 U. In some embodiments, the stable aqueous pharmaceutical composition comprises rHuPH20 at a dose of about 27,000 U. In some embodiments, the stable aqueous pharmaceutical composition comprises rHuPH20 at a dose of about 27,500 U. In some embodiments, the stable aqueous pharmaceutical composition comprises rHuPH20 at a dose of about 28,000 U. In some embodiments, the stable aqueous pharmaceutical composition comprises rHuPH20 at a dose of about 28,500 U. In some embodiments, the stable aqueous pharmaceutical composition comprises rHuPH20 at a dose of about 29,000 U.
  • the stable aqueous pharmaceutical composition comprises rHuPH20 at a dose of about 30,000 U.
  • the stable aqueous pharmaceutical compositions of the bispecific EGFR/c-Met antibody comprise a histidine and/or a pharmaceutically acceptable histidine salt, sucrose, polysorbate 80 (PS80), methionine, EDTA, a pH from about 5.2 to about 6.2, and, optionally, a hyaluronidase.
  • the stable aqueous pharmaceutical compositions may comprise about 128 mg/mL to about 192 mg/mL of the bispecific EGFR-cMet antibody, about 10mM to about 50 mM of histidine and/or a pharmaceutically acceptable histidine salt, about 6.8% (w/v) to about 10.2% (w/v) of sucrose, about 0.036% (w/v) to about 0.084% (w/v) of polysorbate 80 (PS80), about to 0.8 mg/mL to about 1.2 mg/mL of methionine, about 16 ⁇ g/mL to about 24 ⁇ g/mL of EDTA, and a pH from about 5.2 to about 6.2.
  • the stable aqueous pharmaceutical compositions may optionally comprise about 1,000 U/mL to about 3,000 U/mL hyaluronidase.
  • the stable aqueous pharmaceutical compositions comprise about 160 mg/mL of the bispecific EGFR-cMet antibody, about 10mM of histidine and/or a pharmaceutically acceptable histidine salt, about 8.5% (w/v) of sucrose, about 0.06% (w/v) of polysorbate 80 (PS80), about 1 mg/mL of methionine, about 20 ⁇ g/mL of EDTA, and a pH of about 5.7, and optionally about 2,000 U/mL hyaluronidase.
  • the stable aqueous pharmaceutical compositions of the bispecific EGFR/c-Met antibody comprise acetate and/or a pharmaceutically acceptable acetate salt, sucrose, polysorbate 80 (PS80), methionine, EDTA, a pH from about 5.2 to about 6.2, and, optionally, a hyaluronidase.
  • the stable aqueous pharmaceutical compositions may comprise about 128 mg/mL to about 192 mg/mL of the bispecific EGFR-cMet antibody, about 10mM to about 50 mM of acetate and/or a pharmaceutically acceptable acetate salt, about 6.8% (w/v) to about 10.2% (w/v) of sucrose, about 0.036% (w/v) to about 0.084% (w/v) of polysorbate 80 (PS80), about to 0.8 mg/mL to about 1.2 mg/mL of methionine, about 16 ⁇ g/mL to about 24 ⁇ g/mL of EDTA, and a pH from about 5.2 to about 6.2.
  • the stable aqueous pharmaceutical compositions may optionally comprise about 1,000 U/mL to about 3,000 U/mL hyaluronidase.
  • the stable aqueous pharmaceutical compositions comprise about 160 mg/mL of the bispecific EGFR-cMet antibody, about 30mM of acetate and/or a pharmaceutically acceptable acetate salt, about 8.5% (w/v) of sucrose, about 0.06% (w/v) of polysorbate 80 (PS80), about 1 mg/mL of methionine, about 20 ⁇ g/mL of EDTA, and a pH of about 5.7, and optionally about 2,000 U/mL hyaluronidase.
  • the cancer may be a solid malignancy such as breast cancer (BC), prostate cancer, ovarian cancer (OC), cervical cancer, skin cancer, pancreatic cancer, gastroesophageal cancer (GEC), colorectal cancer (CRC), renal cell cancer (RCC), liver cancer, hepatocellular cancer (HCC), brain cancer, squamous cell carcinoma of the head and neck (SCCHN)), lymphoma, leukemia, lung cancer (e.g.
  • the solid malignancy may be metastatic or unresectable. In some embodiments, the solid malignancy is histologically or cytologically confirmed.
  • the disclosed stable aqueous pharmaceutical compositions may be subcutaneously administered, for example, through a subcutaneous injection. The subcutaneous injection can be performed at various locations of the subject’s body such as but not limited to the upper arm, the thigh, the abdomen or the lower back.
  • the cancer is a lung cancer.
  • the cancer is a non-small cell lung cancer (NSCLC)..
  • the cancer is treatment-na ⁇ ve locally advanced or metastatic NSCLC. In one embodiment the cancer has been treated previously by IV amivantamab. In one embodiment the cancer is harboring an EGFR exon 19del mutation. In one embodiment the cancer is harboring exon 21 L858R mutation. In one embodiment the cancer is harboring an EGFR exon20ins mutation. In one embodiment the cancer has experienced disease progression on or after treatment with a third-generation EGFR tyrosine kinase inhibitor (TKI).
  • TKI third-generation EGFR tyrosine kinase inhibitor
  • the subject is in need of treatment for a cancer as disclosed herein.
  • the article of manufacture is a single-use glass vial equipped with a stopper, which contains the stable, aqueous pharmaceutical composition to be administered.
  • the stopper is pierceable by a syringe.
  • the vial is sealed.
  • the single-use vial is a 10mL single-use glass vial with a 20 mm stopper, covered by a 20 mm aluminum seal.
  • the vial size is 2R, 4R, 6R, 8R, 10R, 15R, 20R, 25R, 30R, or 50R ISO format with a capacity of about: 4mL, 6mL, 10mL, 12mL, 14mL, 20ml, 26mL, 33mL, 38mL, or 62mL respectively.
  • the total volume of the stable aqueous pharmaceutical composition (also referred to herein as drug product or DP) ranges from about 5mL to about 10mL.
  • the total volume of the stable aqueous pharmaceutical composition ranges from about 0.5mL to about 20mL, from about 1mL to about 15mL, from about 5mL to about 10mL, 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, 1mL, 2mL, 3mL, 4mL, 5mL, 6mL, 6.5mL, 6.6mL, 6.7mL, 7 mL, 7.1 mL, 8mL, 8.5mL, 8.6mL, 8.7mL, 8.75mL, 8.8mL, 9mL, 10mL, 11mL, 12mL, 13mL, 14mL, 15mL, 16mL, 18mL, 19mL, 20mL, 25mL, or 30mL or any ranges there in between.
  • the DP stability is determined following storage for a specified period of time.
  • DP is stored for about 3 months or more, about 6 months or more, about 12 months or more, about 1.5 years or more, about 2 years or more, about 2.5 years or more, about 3 years or more, about 3.5 years or more, about 4 years or more, about 4.5 years or more, about 5 years or more, about 6 years or more, about 7 years or more, about 8 years or more, about 9 years or more, or about 10 years or more.
  • DP is stored for about 12 months or more, about 1.5 years or more, about 2 years or more, about 2.5 years or more, or about 3 years or more.
  • DP is stored for about 2 years or more.
  • Temperature [0081] In some embodiments, the DP is stable following storage at a specific temperature for a specified period of time. In some embodiments, the temperature ranges between about: -10 to 50°C, 0 to 25°C, 1 to 20°C, 1 to 15°C, 2 to 10°C, or 2 to 5°C. In some embodiments, the temperature ranges between about: 2 to 8°C.
  • the temperature is about: -10°C, -9°C, -8°C, -7°C, -6°C, -5°C, -4°C, -3°C, -2°C, -1°C, 0°C, 1°C, 2°C, 3°C, 4°C, 5 °C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48
  • the DP is stable following storage for about 12 months or more, or for about 2 years or more and at a temperature ranging from about 2°C to about 8°C. In some embodiments, the DP is stable following storage for about 12 months or more or for about 2 years or more and at a temperature of about 5°C. In some embodiments, the DP is stable following storage for about 12 months or more and at a temperature of about 25°C.
  • the stability of the presently disclosed aqueous pharmaceutical compositions is determined based on specific amount or proportion of the bispecific EGFR-cMet antibody and other constituents of the DP as provided herein (such as, but not limited to, buffering agents, stabilizers, chelating agents, surfactants, and enzymes), 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. In some embodiments, the stable DP exhibits the following results for all the factors listed in detail below herein. [0085] Color of solution [0086] 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.
  • pH Measuring the pH of the DP solution allows confirmation that it is consistent with previous DP batches at release and over the shelf life.
  • the stability of the DP is defined when its pH is about 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, or 6.4.
  • the pH of the DP is 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 as having a pH range from about 5.0 to about 6.4 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 5.2 to about 6.2 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.
  • the stability of the DP is defined when its pH ranges from about 5.4 to about 6.0 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.
  • 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. Test results are reported in nephelometric turbidity units (NTU).
  • the stability of the DP is defined when its turbidity value is about: 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 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.
  • the stability of the DP is defined when as 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.
  • the stability of the DP 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 [0093] The stability of the DP is set to a specific threshold of particles contamination based on the average number of sub-visible particles.
  • the DP stability is defined based upon various results of cSDS variables (e.g. percent purity, aglycosylated heavy chain (AGHC), 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 Reduced results consistent with stability.
  • stability is defined as having a percent purity greater than or equal to 88.0%, AGHC less than or equal to 11.0%, and no new peak greater than 1.5% compared to a validated stock of amivantamab 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 a percent purity about or more than 91.0%, AGHC less than or about 8.0%, 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.
  • stability is defined as having a percent purity about or more than 94.0%, AG HC less than or about 5.0%, 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. [0098] cSDS Non-Reduced results consistent with stability.
  • stability is defined as having a percent purity of about 88.0% 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 percent purity of about 90.0% 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.
  • stability is defined as having a percent purity of about 94.0% 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.
  • 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 there in between.
  • the DP stability is defined as having an AGHC of about: 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or any range there in between. [00101] In one embodiment, 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.
  • SE-HPLC Size-Exclusion HPLC
  • 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.
  • 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 Capillary isoelectric focusing
  • the cIEF like isoelectric gel electrophoresis (IEF) methods, separates proteins on the basis of overall charge or isoelectric point (pI). 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 DP stability is defined as having a cIEF with a MP of about: 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% or any range there 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 ranging from about 30% to about 90% 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 one embodiment, stability is defined as having a Main Peak of 37-87% 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 of 47-87% aafter 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 of 57-87% 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 DP stability is defined as having a cIEF with a with a sum of acidic peaks totaling to about: 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70% or any range there 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.
  • stability is defined as having a Sum of acidic peaks totaling 10-60% 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 Sum of acidic peaks totaling 10-50% 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 10-40% 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.
  • 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% or 15% or any range there 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.
  • stability is defined as having a Sum of basic peaks totaling about 12.0% 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 Sum of basic peaks totaling 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 Sum of basic peaks totaling about 8.0% 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.
  • Protein concentration by A280 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). [00117] Protein concentration results consistent with stability of DP.
  • the DP stability is defined as having a protein concentration of 128 to 192 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.
  • DP stability is defined as having a protein concentration of 144 to 176 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.
  • DP stability is defined as having a protein concentration of 150 mg/mL to 170 mg/mL 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.
  • Drug Product potency [00118] In vitro binding of the DP to EGFR and/or c-Met allows assessing the level of DP stability. This binding can be assessed by using, but not limited to, a homogeneous competitive time resolved fluorescence resonance energy transfer (TR-FRET) assay.
  • TR-FRET homogeneous competitive time resolved fluorescence resonance energy transfer
  • the DP stability is defined as having an EGFR binding activity, relative to a reference, of about: 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160% or 170% or any range there 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 EGFR binding 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. In a preferred embodiment, the DP stability is defined as having an EGFR binding 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 EGFR binding 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.
  • cMet Binding Activity results consistent with stability.
  • the DP stability is defined as having a cMet binding activity, relative to a reference, of about: 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, or 140% or any range there 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 cMet binding 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 a cMet binding 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. In a most preferred embodiment, the DP stability is defined as having a cMet binding 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.
  • rHuPH20 hyaluronidase enzymatic activity is determined by measuring turbidity when hyaluronic acid (HA), a substrate of rHuPH20, binds with acidified serum. The determination of hyaluronidase activity is based on the formation of a precipitate when hyaluronic acid (HA) binds with acidified serum. The activity is measured by incubating hyaluronidase with HA for 30 minutes in a 96-well plate format at 37°C and then precipitating the undigested HA with the addition of acidified serum.
  • HA hyaluronic acid
  • rHuPH20 activity results consistent with stability.
  • stability is defined as having rHuPH20 activity of about: 800U/mL, 900U/mL, 1000U/mL, 1100U/mL, 1200U/mL, 1300U/mL, 1400U/mL, 1500U/mL, 1600U/mL, 1700U/mL, 1800U/mL, 1900U/mL, 2000U/mL, 2100U/mL, 2200U/mL, 2300U/mL, 2400U/mL, 2500U/mL, 2600U/mL, 2700U/mL, 2800U/mL, 2900U/mL, 3000U/mL, 3100U/mL, 3200U/mL, 3300U/mL, 3400U/mL or 3500U/mL or any range there in between 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
  • stability is defined as having rHuPH20 activity of 1000U/mL to 3000U/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 rHuPH20 activity of 1500U/mL to 2500U/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 rHuPH20 activity of 1800U/mL to 2200U/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.
  • Analytical Tests- Surfactant [00129] Polysorbate-80 Quantification [00130] Polysorbate 80 is quantitatively determined by mixed-mode ion- exchange/hydrophobic HPLC.
  • the DP stability is defined by a PS80 concentration in percentage weight to volume of about: 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.08%, 0.09% or 0.1% or any range there 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.
  • DP stability is defined as a PS80 concentration of 0.03-0.08% 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.
  • DP stability is defined as a PS 80 concentration of 0.04-0.08% 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.
  • DP stability is defined as a PS 80 concentration of 0.05-0.08% 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.
  • Viscosity A potential problem with using high concentration protein formulations, recognized by those skilled in the art, is that the viscosity of the solution usually increases with the increase of the protein concentration. Viscous antibody solutions are difficult to process (e.g. fill vials and/or syringes) and to administer to patients.
  • the present invention provides a high concentration amivantamab composition with a viscosity that is between about 9 cP and about 11 cP at room temperature.
  • the high concentration amivantamab composition has an absolute viscosity of about 22 cP or less, 16 cP or less, 13 cP or less, 11 cP or less, 9 cP or less, 8 cP or less, 7 cP or less, 6 cP. In some embodiments, the high concentration amivantamab composition has a viscosity of about 21.9 cP as measured at 4 o C. In some embodiments, the high concentration amivantamab composition has a viscosity of about 16 cP as measured at 10 o C. In some embodiments, the high concentration amivantamab composition has a viscosity of about 13.3 cP as measured at 15 o C.
  • the high concentration amivantamab composition has a viscosity of about 11 cP as measured at 20 o C. In some embodiments, the high concentration amivantamab composition has a viscosity of about 9.3 cP as measured at 25 o C. In some embodiments, the high concentration amivantamab composition has a viscosity of about 7.9 cP as measured at 30 o C. In some embodiments, the high concentration amivantamab composition has a viscosity of about 6.7 cP as measured at 35 o C. In some embodiments, the high concentration amivantamab composition has a viscosity of about 5.8 cP as measured at 40 o C.
  • a stable aqueous pharmaceutical composition comprising a bispecific epidermal growth factor receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody and a hyaluronidase, wherein the antibody comprises: a. a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1) comprising the amino acid sequence of SEQ ID NO:13; b.
  • EGFR epidermal growth factor receptor
  • c-Met hepatocyte growth factor receptor
  • a first light chain (LC1) comprising a light chain variable region 1 (VL1) comprising the amino acid sequence of SEQ ID NO:14; c. a second heavy chain (HC2) comprising a HC2 variable region 2 (VH2) comprising the amino acid sequence of SEQ ID NO:15; d. a second light chain (LC2) comprising a light chain variable region 2 (VL2) comprising the amino acid sequence of SEQ ID NO:16; and wherein the composition comprises about 1,050 mg to about 2,240 mg of the bispecific EGFR/c-Met antibody and about 13,000 U to about 28,000 U of the hyaluronidase. 2. The stable composition of embodiment 1 wherein the composition comprises about 1,050 mg of the bispecific EGFR/c-Met antibody. 3.
  • the stable composition of embodiment 1 wherein the composition comprises about 1,400 mg of the bispecific EGFR/c-Met antibody. 4. The stable composition of embodiment 1 wherein the composition comprises about 1,575 mg of the bispecific EGFR/c-Met antibody. 4a. The stable composition of embodiment 1 wherein the composition comprises about 1,600 mg of the bispecific EGFR/c-Met antibody. 5. The stable composition of embodiment 1 wherein the composition comprises about 2,100 mg of the bispecific EGFR/c-Met antibody. 5a. The stable composition of embodiment 1 wherein the composition comprises about 2,240 mg of the bispecific EGFR/c-Met antibody. 6.
  • a stable aqueous pharmaceutical composition comprising: a) about 144 mg/mL to about 176 mg/mL of a bispecific epidermal growth factor receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody, the bispecific antibody comprising: a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1); a first light chain (LC1) comprising a light chain variable region 1 (VL1); a second heavy chain (HC2) comprising a HC2 variable region 2 (VH2); and a second light chain (LC2) comprising a light chain variable region 2 (VL2), wherein the VH1 comprises a heavy chain complementarity determining region 1 (HCDR1), a HCDR2 and a HCDR3 amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; the VL1 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2 and a LCDR3 amino acid sequences of SEQ ID NOs: 4, 5
  • the bispecific EGFR-cMet antibody comprises a HC2 variable region comprising the amino acid sequence of SEQ ID NO:15 and a LC2 variable region comprising the amino acid sequence of SEQ ID NO:16.
  • the stable aqueous pharmaceutical composition of any one of embodiments 6-11, wherein the bispecific EGFR-cMet antibody has a concentration of about 160 mg/mL.
  • the stable aqueous pharmaceutical composition of any one of embodiments 6-12, wherein the acetate and/or pharmaceutically acceptable acetate salt has a concentration of about 30 mM.
  • the stable aqueous pharmaceutical composition of any one of embodiments 6-13, wherein the acetate and/or pharmaceutically acceptable acetate salt comprises glacial acetic acid and/or sodium acetate trihydrate.
  • the stable aqueous pharmaceutical composition of any one of embodiments 6-14 comprising about 8.5% (w/v) sucrose.
  • the stable aqueous pharmaceutical composition of any one of embodiments 6-22 wherein stability is defined based on color of solution, pH, turbidity, number of subvisible particles, percentage of aglycosylated heavy chain (AGHC), percentage of new peak(s), percentage of high molecular weight species (HMWS), percentage of low molecular weight species (LMWS), percentage of sum of acidic peaks, percentage of sum of basic peaks, protein concentration, percentage of EGFR binding activity, percentage of cMet binding activity, percentage of PS80, optionally, percentage of rHuPH20 activity, or any combination thereof.
  • Aglycosylated heavy chain Aglycosylated heavy chain
  • HMWS high molecular weight species
  • LMWS low molecular weight species
  • percentage of sum of acidic peaks percentage of sum of basic peaks
  • protein concentration percentage of EGFR binding activity
  • percentage of cMet binding activity percentage of PS80
  • percentage of rHuPH20 activity or any combination thereof.
  • the stable aqueous pharmaceutical composition of embodiment 24, wherein the total volume of the composition is about 7.1mL. 26.
  • the stable aqueous pharmaceutical composition of embodiment 24, wherein the total volume of the composition is about 6.6mL. 27.
  • the stable aqueous pharmaceutical composition of embodiment 24, wherein the total volume of the composition is about 8.75mL. 28.
  • the stable aqueous pharmaceutical composition of any one of embodiments 1-27 comprising about 160 mg/mL of the bispecific EGFR-cMet antibody, about 30 mM acetate and/or pharmaceutically acceptable acetate salt, about 8.5% sucrose, and about 1 mg/mL L- methionine with polysorbate 80 to a final concentration of about 0.06% (w/v) and EDTA to a final concentration of about 20 ⁇ g/mL, wherein the stable aqueous pharmaceutical composition has pH about 5.7, and wherein the bispecific EGFR-cMet antibody comprises a heavy chain 1 (HC1) comprising the amino acid sequence of SEQ ID NO:17, HC2 comprising the amino acid sequence of SEQ ID NO:19, a light chain 1 (LC1) comprising the amino acid sequence of SEQ ID NO:18, and a LC2 comprising the amino acid sequence of SEQ ID NO:20.
  • HC1 heavy chain 1
  • LC1 light chain 1
  • LC1 comprising the amino acid sequence of SEQ
  • the stable aqueous pharmaceutical composition of any one of embodiments 1-27 comprising about 160 mg/mL of the bispecific EGFR-cMet antibody, about 30 mM acetate and/or pharmaceutically acceptable acetate salt, about 8.5% sucrose, about 1 mg/mL L-methionine with polysorbate 80 to a final concentration of about 0.06% (w/v) and EDTA to a final concentration of about 20 ⁇ g/mL, and rHuPH20 to a final concentration of about 2,000 U/mL, wherein the stable aqueous pharmaceutical composition has pH about 5.7, and wherein the bispecific EGFR-cMet antibody comprises a heavy chain 1 (HC1) comprising the amino acid sequence of SEQ ID NO:17, HC2 comprising the amino acid sequence of SEQ ID NO:19, a light chain 1 (LC1) comprising the amino acid sequence of SEQ ID NO:18, and a LC2 comprising the amino acid sequence of SEQ ID NO:20.
  • HC1 heavy chain 1
  • a method of treating cancer in a subject in need thereof comprising administering to the subject the pharmaceutical composition of any one of embodiments 1- 29. 31.
  • the method of embodiment 30, wherein the administration is subcutaneous.
  • 32. The method of embodiments 30-31, wherein the cancer comprises lung cancer, squamous cell carcinoma of the head and neck (SCCHN), hepatocellular cancer (HCC), colorectal cancer (CRC), renal cell cancer (RCC), medullary thyroid cancer (MTC), gastroesophageal cancer (GEC), mesothelioma, breast cancer (BC) or ovarian cancer (OC).
  • SCCHN squamous cell carcinoma of the head and neck
  • HCC hepatocellular cancer
  • CRCC colorectal cancer
  • MTC renal cell cancer
  • MTC medullary thyroid cancer
  • GEC gastroesophageal cancer
  • mesothelioma breast cancer (BC) or ovarian cancer (OC).
  • OC gastroesophageal cancer
  • a method for preparing a stable aqueous pharmaceutical composition of a bispecific antibody targeting EGFR and cMet comprising a first heavy chain (HC1) comprising a HC1 variable region 1 (VH1); a first light chain (LC1) comprising a light chain variable region 1 (VL1); a second heavy chain (HC2) comprising a HC2 variable region 2 (VH2); and a second light chain (LC2) comprising a light chain variable region 2 (VL2)
  • the VH1 comprises a heavy chain complementarity determining region 1 (HCDR1), a HCDR2 and a HCDR3 comprising amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively
  • the VL1 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2 and a LCDR3 comprising amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively
  • the VH2 comprises HCDR1, HCDR2 and HC
  • the bispecific EGFR-cMet antibody comprises an HC1 variable region comprising the amino acid sequence of SEQ ID NO:13 and a LC1 variable region comprising the amino acid sequence of SEQ ID NO:14.
  • the bispecific EGFR-cMet antibody comprises a HC2 variable region comprising the amino acid sequence of SEQ ID NO:15 and a LC2 variable region comprising the amino acid sequence of SEQ ID NO:16. 37.
  • any one of embodiments 34-36 wherein the antibody comprises a heavy chain 1 (HC1) comprising the amino acid sequence of SEQ ID NO:17 and a light chain 1 (LC1) comprising the amino acid sequence of SEQ ID NO:18. 38.
  • 39. The method of any one of embodiments 34-38, wherein the antibody is amivantamab or a biosimilar thereof.
  • a kit comprising the stable aqueous pharmaceutical composition of any one of embodiments 1-29 and instructions for use thereof. 41.
  • An article of manufacture comprising a container holding a stable aqueous pharmaceutical composition in accordance with any one of embodiments 1-29. 42.
  • 44. A pharmaceutical composition of any one of embodiments 1-29 for use in the treatment of cancer.
  • the pharmaceutical composition of embodiment 44, wherein the cancer comprises lung cancer.
  • the pharmaceutical composition of embodiment 44, wherein the cancer comprises non-small cell lung cancer (NSCLC). 47.
  • Color of solution may be an indicator of product stability.
  • 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.
  • Color of Solution Material and Methods Materials and methods are as described in European Pharmacopoeia 2.2.2, Degree of Coloration of Liquids European Pharmacopoeia (Ph. Eur.) 10th Edition monograph number 20202, July 2019.
  • stability of DP 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 of DP 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 of DP 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 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.
  • stability of DP is defined as having a pH range of 5.0 to 6.4 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 of DP is defined as a pH range of 5.2 to 6.2 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 .
  • stability of DP is defined as having a pH range of 5.4 to 6.0 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.
  • 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 [00156] Test results are reported in nephelometric turbidity units (NTU).
  • stability of DP 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 of DP 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 of DP 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.
  • Analytical Tests- Particulate Matter [00158] Particulate Matter (Sub-visible) Materials and Methods- All materials and methods are compliant with United States Pharmacopeia ⁇ 788> Particulate Matter. A Compendial compliant Liquid Particle Counter instrument equipped with a compendial volume sampler set-up is used.
  • Test articles are equilibrated to room temperature for at least 60 minutes, but no longer than 10 hours, prior to testing.
  • Test article vials are pooled in manner compliant with United States Pharmacopeia ⁇ 788> Particulate Matter.
  • United States Pharmacopeia ⁇ 788> Particulate Matter four portions of pooled test article, each of appropriate volume, are removed and the number of particles equal to or greater than 10 ⁇ m and 25 ⁇ m are counted per portion. Results obtained for the first portion are disregarded and the remaining three results are used to calculate the mean number of particles for the preparation examined.
  • 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 ⁇ m or greater and should not exceed 600 particles per container for particles size equal to 25 ⁇ m or greater.
  • cSDS Capillary electrophoresis sodium dodecyl sulfate
  • cSDS Capillary electrophoresis sodium dodecyl sulfate
  • cSDS Reduced Materials and Methods- Analysis employs a commercial capillary electrophoresis system with a bare fused silica capillary, 50 ⁇ m 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 s 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) is mixed with SDS and 2-mercaptoethanol and then heated for a defined time and temperature to fully denature and reduce the protein.
  • the reduced sample is injected electro- kinetically 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.
  • stability of DP is defined as having a percent purity ⁇ 88.0%, AG HC ⁇ 11.0%, and no new peak >1.5% compared to a validated stock of amivantamab 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 of DP is defined a percent purity about or more than 91.0%, AG HC less than or about 8.0%, 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.
  • stability of DP is defined as having a percent purity about or more than 94.0%, AG HC less than or about 5.0%, 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 Capillary electrophoresis sodium dodecyl sulfate
  • cSDS Non-reduced Materials and Methods- Analysis employs a commercial capillary electrophoresis system with a bare fused silica capillary, 50 ⁇ m 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 amivantamab Reference Material sample.
  • the instrument s 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 is mixed with SDS and 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 artefact 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 amivantamab Reference Material. Percent purity is defined as percent heavy chain + percent light chain. [00166] cSDS Non-Reduced results consistent with stability.
  • stability of DP is defined as having a percent purity of about 88.0% 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 of DP is defined as percent purity of about 90.0% 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.
  • stability of DP is defined as having a percent purity of about 94.0% 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
  • a 20 ⁇ l volume of analyte is injected onto a 7.8 mm x 30 cm size exclusion column with 5 ⁇ m particle size silica base, with a fractionation range of 10 to 500 kDa.
  • Aqueous phosphate buffer is used as the mobile phase at a flow rate of 0.7mL/minute and the absorbance of the eluate is monitored continuously at 280 nm.
  • Monomer main component or main peak
  • aggregates high molecular weight species, or HMWS
  • fragments low molecular weight species, or LMWS
  • stability of DP 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 of DP 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 of DP 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 .
  • stability of DP 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 of DP 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 of DP 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.
  • stability of DP 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 of DP 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 Capillary isoelectric focusing
  • 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- ⁇ m 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.
  • CPB carboxypeptidase B
  • stability of DP is defined as having a Main Peak of 37-87% 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 of DP is defined as having a Main Peak of 47-87% 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 of DP is defined as having a Main Peak of 57-87% 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 of DP is defined as having a Sum of acidic peaks totaling 10-60% 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 of DP is defined as having a Sum of acidic peaks totaling 10- 50% 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 of DP is defined as having a Sum of acidic peaks totaling 10-40% 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.
  • Sum of basic peaks- stability of DP is defined as having a Sum of basic peaks totaling about 12.0% 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 of DP is defined as having a Sum of basic peaks totaling 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 of DP is defined as having a Sum of basic peaks totaling about 8.0% 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.
  • Protein concentration of the drug product is determined by quantification of the absorbance at 280 nm (A280).
  • Protein Concentration by A280 Materials and Methods [00181] 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 (1.4mL) with a 1 cm 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.
  • 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 an amivantamab’s Absorptivity Constant of 1.40 (mg/mL) ⁇ 1 cm ⁇ 1 and instrument’s path length of 1 cm).
  • stability of DP is defined as having a protein concentration of 128 to 192 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 of DP is defined as having a protein concentration of 144 to 176 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 of DP is defined as having a protein concentration of 150 mg/mL to 170 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.
  • Analytical Tests- Potency [00185] Potency (Epidermal growth factor receptor (EGFR) Binding) [00186] The in vitro binding of drug product to EGFR is demonstrated using a homogeneous competitive time resolved fluorescence resonance energy transfer (TR-FRET) assay format.
  • TR-FRET competitive time resolved fluorescence resonance energy transfer
  • Cy5-EGFR is then similarly added, the assay plate again gentle shaken, and incubated in the dark for 4 ⁇ 1 hours. Fluorescence is then measured by spectrophotometry at 665 nm, plotted against antibody concentration and analyzed by a four- parameter logistic model. The antibody concentration required to obtain half of the maximum fluorescence response (EC50) is determined for RM, assay control and samples. The potencies of assay control and samples are calculated based on the ratio of the sample (or control) and RM EC50 values and reported as a percentage activity relative to the RM. [00188] EGFR Binding Activity results consistent with stability.
  • stability of DP is defined as 50% - 150% binding activity 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 of DP is defined as 60% - 140% binding activity 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 of DP is defined as ranging between about 80% to 120% binding activity 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.
  • TR-FRET competitive time resolved fluorescence resonance energy transfer
  • Cy5-c-MET is then similarly added, the assay plate again gently shaken, and incubated in the dark for 4 ⁇ 1 hours. Fluorescence is then measured by spectrophotometry at 665 nm, plotted against antibody concentration and analyzed by a four-parameter logistic model. The antibody concentration required to obtain half of the maximum fluorescence response (EC50) is determined for RM, assay control and samples. The potencies of assay control and samples are calculated based on the ratio of the sample (or control) and RM EC50 values and reported as a percentage activity relative to the RM. [00192] cMet Binding Activity results consistent with stability.
  • stability of DP is defined as ranging between about 50% to about 150% binding activity 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 of DP is defined as ranging between about 60% to 140% binding activity 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 of DP is defined as ranging about 80% to about 120% binding activity 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.
  • Potency rHuPH20 Activity is determined by measuring turbidity when hyaluronic acid (HA), a substrate of rHuPH20, binds with acidified serum.
  • hyaluronidase activity is based on the formation of a precipitate when hyaluronic acid (HA) binds with acidified serum.
  • the activity is measured by incubating hyaluronidase with HA for 30 minutes in a 96-well plate format at 37°C and then precipitating the undigested HA with the addition of acidified serum.
  • the resulting turbidity is measured at 640 nm and the decrease in turbidity resulting from enzymatic cleavage of the HA substrate is a measure of the hyaluronidase activity.
  • rHuPH20 Activity Materials and Methods are based on the United Stated Pharmacopeia Monograph USP29–NF24 Hyaluronidase for Injection. Standard reagents include 500mM acetate buffer (pH 3.1), 100mM acetate buffer (pH 3.1), Sterile Water for Irrigation (SWFI), Human Serum Albumin (HSA) 25% (NDC # 68209-643-02), Horse Serum, 50 mg/mL sodium hyaluronate, and rHuPH20. Assay specific reagents are listed in table 1 below.
  • the enzyme diluent, Horse Serum Working solution (2.8%), and 0.7mg/mL HA Substrate are prepared on the day of the assay.
  • the HA substrate tube is stored at 2-8°C until ready for use.
  • Assay and Sample Preparation Prior to start of assay, an empty 96-well Reaction Plate is placed in an Eppendorf Thermo-mixer and set to 15°C and allowed to equilibrate for a minimum of 30 minutes. Also, a heat block is placed in a 37°C incubator and allowed to equilibrate at the appropriate temperature for at least 2 hours prior to starting the enzyme reaction.
  • Test samples with an expected rHuPH20 activity of 2,000 U/mL are diluted with Enzyme Diluent to 9.3 U/mL. Aliquots of rHuPH20 controls and diluted test samples and are loaded into a 96-well Transfer Plate. In separate Dilution Plate, designated volumes of Enzyme Diluent are aliquoted into designated wells. WRS is aliquoted in triplicate into designated wells and then serially diluted in designated wells containing enzyme diluent. The data from these wells will be used to generate a six-point calibration curve. Fixed volumes of rHuPH20 controls and diluted samples are transferred in duplicate from the transfer plate into designated wells in the Dilution Plate.
  • Enzyme Reaction [00202] The HA substrate solution is removed from 2-8°C storage and gently mixed by 3-4 inversions. While maintaining the 15°C equilibrated 96-well Reaction Plate in the Thermo- mixer, a fixed volume of HA substrate solution is aliquoted into the corresponding well locations of the Dilution Plate. The standards, controls and samples from the Dilution Plate are then transferred to their corresponding well locations of the Dilution Plate. The 15°C Thermo-mixer is then used to mix the Reaction Plate at 900 rpm for 10 seconds.
  • the Reaction Plate is removed from the Thermo-mixer, a plate lid placed on the reaction plate, and immediately transferred into the pre-incubated heat block inside the 37°C incubator.
  • the Reaction Plate is incubated for 30 ⁇ 5 minutes at 37°C.
  • Stop Reaction and Development [00204] Once the 37°C incubation is complete, remove the covered Reaction Plate from the incubator and immediately press the covered plate into freshly dispensed ice in an ice bucket and start timer for 2 minutes. Leave plate untouched during the 2-minute incubation. After 2 minutes, wipe the bottom of the plate (e.g. Kimwipes) to remove any condensation or water and transfer the reaction plate to the 15°C Thermo-mixer.
  • Thermo-mixer lid Place the Thermo-mixer lid on and incubate at 15°C for 10 minutes. [00205] After 10 minutes, immediately remove the Thermo-mixer lid and, a fixed volume of horse serum working solution is aliquoted to each well. The plate is then covered with the Thermo-mixer lid and start a timer for 20 ⁇ 5 minutes at 15°C. After the 20 ⁇ 5 minutes incubation, the reaction plate is transferred from the 15°C Thermo-mixer to a 96-well Plate reader. The optical density of the samples is then measured at 640nm.
  • stability of DP is defined as having rHuPH20 activity of 1000U/mL to 3000U/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 of DP is defined as having rHuPH20 activity of 1500U/mL to 2500U/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 of DP is defined as having rHuPH20 activity of 1800U/mL to 2200U/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.
  • Analytical Tests- Surfactant [00210] Polysorbate-80 Quantification [00211] Polysorbate 80 is quantitatively determined by mixed-mode ion- exchange/hydrophobic HPLC. [00212] PS 80 Materials and Methods.
  • stability of DP is defined as a PS80 concentration of 0.03-0.08% 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 of DP is defined as a PS 80 concentration of 0.04-0.08% 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 of DP is defined as a PS 80 concentration of 0.05-0.08% 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.
  • Analytical Tests- Routine Characterization [00215] Peptide Map [00216] 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.
  • 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.
  • UPLC-MS Ultra High-Performance Liquid Chromatography Mass Spectroscopy
  • the denatured samples are reduced with 1 M Dithiothreitol (DTT), followed by alkylation with 1 M sodium Iodoacetate, and further treated with DTT to quench the reaction.
  • DTT Dithiothreitol
  • the reaction mixture is exchanged into digestion buffer (50 mM Tris pH 7.0, with 1 mM CaCl2) via Sephadex G-25 columns with separate columns used for blanks, Reference Material, and test articles.
  • An aliquot of 1mg/mL Trypsin stock solution is added to the sample in digestion buffer yielding a 20 ⁇ L/mL trypsin concentration.
  • the solution is incubated at 37°C for 2 hours ⁇ 30 minutes.
  • the trypsinized solution is allowed to cool to room temperature and the enzyme is inactivated with Trifluoroacetic acid.
  • the treated samples are evaluated by Ultra High-Performance Liquid Chromatography Mass Spectroscopy (UPLC-MS) equipped with a Waters Acquity BEH (Ethylene Bridged Hybrid) C18, 2.1 x 100 mm, 1.7 ⁇ m, 130 ⁇ column and an attached auto sampler.
  • 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 500 ⁇ L/minute.
  • Eluted peptides were subject to electrospray ionization and detected using a calibrated on-line mass spectrometry.
  • Example 1 Formulation screening studies [00219] Two formulation screening studies were conducted to evaluate stability trends for high concentration (175mg/mL) amivantamab formulated with varied pH values, formulation buffer species, and buffer concentrations. [00220] Study 1 [00221] The first study evaluated test formulations consisting of a range of pH values and corresponding buffer species with all other formulation components held at a fixed value. (Table 2). [00222] [00223] The test formulations were held under normal (5°C) and stress (40°C) stability conditions for three weeks. Test formulations were then assayed by SEC to evaluate the percent of aggregate, monomer, and fragment observed per test formulation.
  • Example 2 High concentration stability study
  • a stability study was conducted to evaluate three high protein concentration formulations with varied buffer concentrations and species (see Table 6 below) The test formulations were held at recommended (5°C), accelerated (25°C), and stressed (40°C) conditions up to 6-months.
  • the three test formulations were prepared from a 50mg/mL stock formulation of amivantamab. The stock formulation was concentrated by Tangential Flow Filtration (TFF) and the buffers exchanged by Ultrafiltration/Diafiltration (UF/DF). Test formulations were aliquoted into 30R vials at a fill volume of 15.6mL. The vials were stoppered, capped, and crimp sealed.
  • Formulation 1 showed a rapid increase in color scoring over time with the 6-month sample receiving the maximum B, BY, and Y color scores.
  • No changes in pH were observed for Formulations 2 and 3 over six months. However, Formulation 1 showed a marked decrease in pH between three and six months.
  • Discussion and Conclusion [00253] Throughout the study Formulation 1 showed decreased stability attributes versus Formulations 2 and 3. The change in pH at accelerated temperatures suggested that Formulation 1 (10mM Histidine) had a poor buffer capacity for amivantamab at high (160 mg/mL) concentration.
  • Formulations 2 and 3 showed similar stability profiles over the course of the study. However, at all study time points and temperatures, Formulation 2 appeared as a slightly opalescent liquid whereas Formulation 3 appeared as a clear liquid. Similarly, Formulation 3 showed lower turbidity values than Formulation 2 throughout the study.
  • Example 3 Polysorbate Concentration Range Shaking and Freeze Thaw
  • test formulation vials Multiple, identical sets of test formulation vials are created. Each set contains two vials each of test formulations containing polysorbate 80 at concentrations below, at, and above the target (0.06% w/v) PS80 value. The set will also include test formulation control vials that do not contain PS80. All other formulation components are held constant (160 mg/mL amivantamab, 30mM Acetate, 8.5% sucrose, 1 mg/mL methionine, 20 pg/mL ethylenediaminetetraacetic acid (EDTA) at pH 5.7). The formulations are dispensed to a fill volume of 7.1mL into 8R vials, stoppered, capped, and crimp sealed.
  • Methionine, 20 ⁇ g/mL EDTA, 0.06% PS-80, pH 5.1 was aliquoted into mutliple replicate 30R vials at a fill volume of 15.6mL per vial.
  • the vials were stoppered, capped, and crimp sealed.
  • the remaining replicate vials were placed on stability at accelerated (25°C) conditions for six months.
  • an aged replicate vial was placed horizontally on an orbital shaker and shaken at approximately 250 rpm for up to 72 hours under ambient room temperature (+ shaking).
  • an aged replicate vial was subjected to five (5) freeze/thaw cycles (5xFT) with one cycle defined as freezing to -70°C for 24 hours followed by passive thawing at ambient room temperature for 24 hours.
  • 5xFT freeze/thaw cycles
  • Example 4 Polysorbate Concentration Range Shaking & Freeze Thaw in rHuPH20 containing formulations
  • a study is performed to examine the effects of multi-factorial varying of formulation component concentration levels of bispecific EGFR-cMet antibody drug product held at recommended (5°C) and accelerated (25°C) conditions.
  • the formulation components evaluated are protein concentration, acetate concentration, sucrose concentration, polysorbate 80 concentration, EDTA/methionine concentration, and pH level.
  • the lowest and highest test factor concentration values tested are approximately 10 to 40% lower or higher than the target test factor concentration value respectively (see Table 12).
  • Test formulations are prepared and aliquoted into 8R vials at a fill volume of 7. lmL.
  • the vials are stoppered, capped, and crimp sealed.
  • the vials are placed on stability at recommended (5°C) and accelerated (25°C) conditions. At designated time points, samples are pulled and assayed.
  • test results for each attribute of the test formulations at study initiation (time zero), after 12 months at the recommended storage condition (5 °C), and after 6 months at accelerated temperature (25 °C) will be presented in tabular form reporting the range, mean, and standard deviation of the test formulations for each of the following attributes: cIEF (% area Main Peak, % Sum of Acidic peaks, % Sum of Basic peaks), cSDS (% Purity (non reduced), % Purity (reduced)), SE-HPLC (% Aggregate, % Monomer, % Fragment), Particulate Matter (sub- vis) (Parti cles/container >10 mhi, Particles/container >25 mhi), and Turbidity (NTU).
  • cIEF % area Main Peak, % Sum of Acidic peaks, % Sum of Basic peaks
  • cSDS % Purity (non reduced), % Purity (reduced)
  • SE-HPLC % Aggreg
  • Example 6 Formulation robustness development with rHuPH20 [00295] Study Design
  • a study is performed to examine the effects of multi-factorial varying of formulation component concentration levels of bispecific EGFR-cMet antibody drug product with rHuPH20 held at recommended (5°C) and accelerated (25°C) conditions.
  • the formulation components evaluated are protein concentration, acetate concentration, sucrose concentration, polysorbate 80 concentration, EDTA/methionine concentration, rHuPH20 concentration and pH.
  • the lowest and highest test factor concentration values tested are approximately 10 to 50% lower rHuPH20 (U/mL) 1000 2000 3000
  • Test formulations are prepared and aliquoted into 8R vials at a fill volume of 7.5mL.
  • the vials are stoppered, capped, and crimp sealed.
  • the vials are placed on stability at recommended (5°C) and accelerated (25°C) conditions. At designated time points, samples are pulled and assayed.
  • Study Results The test results for each attribute of the test formulations at study initiation (time zero), after 12 months at the recommended storage condition (5 °C), and after 6 months at accelerated temperature (25 °C) will be presented in tabular form reporting the the range, mean, and standard deviation of the test formulations for each of the following attributes: cIEF (% area Main Peak, % Sum of Acidic peaks, % Sum of Basic peaks), cSDS (% Purity (non reduced), % Purity (reduced)), SE-HPLC (% Aggregate, % Monomer, % Fragment), Particulate Matter (sub- vis) (Parti cles/container >10 ⁇ m , Particles/container >25 ⁇ m ), Turbidity (NTU), and rHuPH20 Activity (U/mL).
  • cIEF % area Main Peak, % Sum of Acidic peaks, % Sum of Basic peaks
  • cSDS % Purity (non reduced), % Pur
  • Example 7 Formulated drug bulk production
  • Ultrafiltration/diafiltration is performed to re-formulate the amivantamab Virus Retentive filtrate intermediate manufacturing solution to a pre-formulated bulk (pFB) solution consisting of 160 mg/mL amivantamab, 30 mM Acetate, 8.5% sucrose, 1 mg/mL L-methionine, pH 5.7.
  • pFB pre-formulated bulk
  • Polysorbate 80 (6.0 % w/v) and EDTA (2 mg/mL) stock solution is added to the pFB at a 1 : 100 dilution to obtain a final concentration of 0.06% (w/v) Polysorbate 80, and 20 pg/mL EDTA yielding the Formulated Bulk (FB) consisting of 160 mg/mL amivantamab in 30 mM Acetate, 8.5% (w/v) sucrose, 1 mg/mL L-methionine, 0.06% Polysorbate 80, 20 pg/mL EDTA, pH 5.7.
  • the FB solution is then mixed uniformly. Final filtration of the Formulated Bulk is achieved using a sterile 0.45/0.22pm filter immediately followed with a subsequent, in-line 0.22 pm filter.
  • the FB is filled into polycarbonate Biotainer(s).
  • the fill volume is 20% to 90% of the biotainer’s stated volume.
  • Example 8 Drug formulation with rHuPh20 production
  • rHuPH20 Formulated Bulk is added to the Amivantamab Formulated Bulk solution to obtain a final concentration of 2,000 IU/mL rHuPH20 yielding the Drug Formulation with rHuPH20 consisting of 160 mg/mL amivantamab in 30 mM Acetate, 8.5% (w/v) sucrose, 1 mg/mL L-methionine, 0.06% Polysorbate 80, 20 pg/mL EDTA, rHuPH202000IU, pH 5.7.
  • the Histidine and sodium chloride contribution from rHuPH20 Formulated Bulk is considered minimal and therefore not listed in the Amivantamab with rHuPH20 Drug Formulation composition.
  • Drug Formulation solution is then mixed uniformly. Initial filtration of the Drug Formulation is achieved using a sterile 0.22pm filter. Final filtration of the Drug Formulation is achieved using a sterile 0.22pm filter immediately followed with a subsequent, in-line 0.22 pm filter.
  • Example 9 Drug product: composition and components of primary packaging
  • Amivantamab drug product (DP) primary packaging consists of a glass vial, a polymer vial stopper, and an aluminum seal. Table 17 lists specific components for the primary packaging material p
  • Example 10 Drug product with rHuPH20: composition and components of primary packaging
  • Amivantamab with rHuPH20 drug product (DP) primary packaging consists of a glass vial, a polymer vial stopper, and an aluminum seal. Table 19 lists specific components for the primary packaging material Seals 20 mm aluminum seal with Flip-Off button
  • Example 11 Description of Drug Product stability study [00326] This study was conducted to monitor amivantamab DP attributes placed on stability under various environmental conditions and lengths of time. Study test articles were prepared by aliquoting Formulated Bulk into 8R vials at a fill volume of 7. lmL. The vials were stoppered, capped, and crimp sealed.
  • Example 12 Description of Drug Product stability study with rHuPH20
  • Example 13 Subcutaneous delivery of amivantamab in patients with advanced solid malignancies.
  • SC subcutaneous
  • SPECT MET-directed therapy
  • Eligible tumor types included non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), hepatocellular cancer (HCC), colorectal cancer (CRC), renal cell cancer (RCC), medullary thyroid cancer (MTC), gastroesophageal cancer (GEC), mesothelioma, breast cancer (BC) and ovarian cancer (OC).
  • NSCLC non-small cell lung cancer
  • SCCHN squamous cell carcinoma of the head and neck
  • HCC hepatocellular cancer
  • CRCC colorectal cancer
  • MTC renal cell cancer
  • GEC gastroesophageal cancer
  • mesothelioma breast cancer
  • BC breast cancer
  • OC ovarian cancer
  • the study objectives were to evaluate the feasibility of administration, safety, and pharmacokinetics (PK) of a low concentration formulation, 50 mg/mL of amivantamab ⁇ rHuPH20 (Part 1) and a high concentration formulation, 160 mg/mL of amivantamab ⁇ rHuPH20 (Part 2).
  • the low concentration formulation (50 mg/mL) amivantamab was administered either with (Ami-LC-MD [mix and deliver]) or without (Ami-LC) rHuPH20 (Part 1, Cohorts la and lb, respectively).
  • the high concentration formulation (160 mg/mL) amivantamab was administered either with (Ami-HC-CF [coformulated]) or without (Ami-HC) rHuPH20 (Part 2, Cohorts 2a and 2b, respectively).
  • Patients in Part 1 and Part 2 received a dosage of amivantamab at 1050 mg and 2,000 Units/mL rHuPH20 (1400 mg and 2000 Units/mL rHuPH20 for bodyweight >80 kg) SC (weekly for the first 4 weeks and every other week thereafter).
  • This study also evaluated administering the full dose of amivantamab on the first day.
  • Example 14 Amivantamab and lazertinib in patients with EGFR-mutant non-small cell lung (NSCLC) after progression on osimertinib and platinum-based chemotherapy.
  • NSCLC non-small cell lung
  • Patients received 1050 mg IV amivantamab (1400 mg, >80 kg) + 240 mg oral lazertinib. Response was assessed per RECIST vl.l (European Journal of Cancer, vol. 45, pp. 228-247 (2009)) and is reported for efficacy-evaluable patients, defined as those who had a >6 mo of follow-up for response durability.
  • Results 162 patients were enrolled in the cohort (median 62 y, 65% women, 61% Asian, median of 3 [range, 2-14] prior lines of therapy). Median time between last osimertinib treatment to first dose of amivantamab + lazertinib was 6.3 mo and 2.0 mo for the target and heavily pretreated populations, respectively. Of 50 efficacy-evaluable patients in the target population, the ORR was 36% (95% Cl, 23-51), with 1 complete response (CR) and 17 partial responses (PRs), and the clinical benefit rate (CBR) was 58% (95% Cl, 43-72). Median duration of response (mDOR) was not reached.
  • IRR Infusion-related reaction
  • AE adverse event
  • rash 41%
  • stomatitis 39%
  • Most common grade >3 treatment-related AEs were infusion-related reactions (7%), acneiform dermatitis (5%), and hypoalbuminemia (4%).
  • Example 15 Subcutaneous delivery of amivantamab, co-formulated with rHuPH20.
  • the proposed preliminary recommended phase 2 dose (RP2D) for once every two weeks (Q2W) amivantamab dosing regimens is 1600 mg for patients with a BW ⁇ 80 kg and 2240 mg for participants with a BW >80 kg.
  • This preliminary subcutaneous dose comprises amivantamab at the concentration of 160 mg/mL coformulated with rHuPH20 (amivantamab SC-CF).
  • the proposed recommended dosing regimens for amivantamab SC-CF are selected to ensure that the resulting exposures are similar to those observed with the IV RP2D regimens. Bioavailability was estimated by comparing the observed AUC following SC dosing (cohorts with and without rHuPH20 formulations) to the corresponding observed AUC following IV dosing.
  • the SC cohorts were dosed at the IV RP2D (1050 mg for participants with a BW ⁇ 80 kg and 1400 mg for participants with a BW >80 kg). At this dose, saturation of soluble free EGFR and cMet was achieved after the first SC dose. Moreover, all 33 participants were negative for anti-amivantamab antibodies.
  • the mean (CV%, n) area under the concentration time curves (AUQC2D1- C2D15 were 95,416 pgxh/mL (45.4%, 7) and 75,378 pgxh/mL (27.0%, 5) for cohorts from 160mg/ml with and without rHuPH20, respectively.
  • Co formulation of amivantamab with rHuPH20 (ie, amivantamab SC- CF) provided improved bioavailability (65% vs 51%), compared to formulations without rHuPH20, in addition to shortening the needed for injection time by approximately eightfold. Based on the estimated bioavailability, a preliminary RP2D of 1,600 mg for participants with a BW ⁇ 80 kg and 2,240 mg for participants with a BW >80 kg was proposed.
  • amivantamab SC-CF will be administered at the preliminary RP2D of 1,600 mg for participants ⁇ 80 kg body weight and 2,240 mg for participants >80 kg body weight.
  • Cohort 1 will assess the combination of amivantamab SC-CF (Q2W) and lazertinib in subjects with treatment-naive locally advanced or metastatic NSCLC harboring an EGFR exon 19del or exon 21 L858R mutation. Participants will receive amivantamab on Cycle 1 Days 1, 8, 15, and 22 and on Day 1 and 15 of each subsequent 28-day cycle, starting with Cycle 2. Amivantamab SC-CF will be administered SC by manual injection at 1,600 mg (2,240 mg if body weight >80 kg). Lazertinib will be given 240 mg orally once daily.
  • Cohort 4 will assess the feasibility of amivantamab SC-CF (Q2W) as a switch therapy in subjects who received >3 months of amivantamab IV as per standard of care. Participants will receive amivantamab on Cycle 1 Days 1, 8, 15, and 22 and on Day 1 and 15 of each subsequent 28-day cycle, starting with Cycle 2. Amivantamab SC-CF will be administered by manual injection at 1,600 mg (2,240 mg if body weight >80 kg ).
  • VL2 c-Met binding arm YAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYY

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