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WO2025137523A2 - Formulations pharmaceutiques d'anticorps se liant à l'interleukine 13 - Google Patents

Formulations pharmaceutiques d'anticorps se liant à l'interleukine 13 Download PDF

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Publication number
WO2025137523A2
WO2025137523A2 PCT/US2024/061395 US2024061395W WO2025137523A2 WO 2025137523 A2 WO2025137523 A2 WO 2025137523A2 US 2024061395 W US2024061395 W US 2024061395W WO 2025137523 A2 WO2025137523 A2 WO 2025137523A2
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seq
cdr
set forth
formulation
antibody
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WO2025137523A3 (fr
Inventor
Holly Prentice
Gayathri Ratnaswamy
Rebecca Lucille DABORA
Aaron Noyes
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Apogee Therapeutics Inc
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Apogee Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • 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
    • 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

  • CDR-H1 comprises the sequence set forth in SEQ ID NO: 58 or 67; b. CDR-H2 comprises the sequence set forth in SEQ ID NO: 100 or 104; c. CDR-H3 comprises the sequence set forth in SEQ ID NO: 112; d. CDR-L1 comprises the sequence set forth in SEQ ID NO: 141 or 149; e. CDR-L2 comprises the sequence set forth in SEQ ID NO: 153 or 596; and f. CDR-L3 comprises the sequence set forth in SEQ ID NO: 165.
  • the formulation further comprises a metal ion chelator.
  • the metal ion chelator is EDTA or salt thereof.
  • the antibody is at a concentration of about 160-200 mg/mL.
  • the histidine buffer, acetate buffer, or succinate buffer is at a concentration between 5 mM and 20 mM. In certain embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 10 mM.
  • the histidine buffer comprises a histidine and a histidine salt. In certain embodiments, the histidine is L-histidine. In certain embodiments, the histidine salt is L-histidine HCl monohydrate.
  • the formulation comprises methionine, and wherein the methionine is L-methionine. In certain embodiments, the L-methionine is at a concentration between 1 mM and 20 mM. In certain embodiments, the L-methionine is at a concentration of about 10 mM. [0015] In certain embodiments, the formulation comprises arginine, and wherein the arginine is L-arginine. In certain embodiments, the formulation comprises an L-arginine salt solution. In certain embodiments, the L-arginine salt solution salt solution comprises HCl monohydrate. In certain embodiments, wherein the L-arginine salt solution is at a concentration between 40 mM and 250 mM.
  • the L-arginine salt solution is at a concentration of about 80 mM. In certain embodiments, the L-arginine salt solution is at a concentration of about 120 mM. [0016] In certain embodiments, the formulation further comprises a surfactant. [0017] In certain embodiments, the formulation comprises a polysorbate. In certain embodiments the polysorbate is at a concentration between 0.005% w/v and 0.15% w/v, e.g., 0.01% w/v-0.10% w/v. In certain embodiments, the polysorbate is at a concentration of about 0.05% w/v. In certain embodiments, the polysorbate is polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.
  • the pH is between 5.5 and 6.5, such as at about 6.0. In certain embodiments, the pH is 5.8. In certain embodiments, the pH is 6.0.
  • a formulation comprising: (a) an IL-13 antibody at a concentration of about 180 mg/mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HCl monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L- methionine at a concentration of about 10 mM; and (e) polysorbate 80 at a concentration of about 0.05% w/v, at pH of about 5.8.
  • a formulation comprising: (a) an IL-13 antibody present at a concentration of about 180 mg/mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L- histidine HCl monohydrate; (c) an L-arginine salt solution at a concentration of about 80 mM; (d) L-methionine at a concentration of about 10 mM; and (e) polysorbate 80 at a concentration of about 0.05% w/v, at pH of about 5.8.
  • a formulation comprising: (a) an IL-13 antibody present at a concentration of about 200 mg/mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L- histidine HCl monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; and (e) polysorbate 80 at a concentration of about 0.05% w/v, at pH of about 5.8.
  • a formulation comprising: (a) an IL-13 antibody at a concentration of about 180-200 mg/mL (e.g., at 180 mg/mL or 200 mg/mL); (b) a histidine buffer at a concentration of about 10 mM (e.g., at 10 mM), wherein the histidine buffer comprises L-histidine and L-histidine HCl monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM (e.g., at 120 mM); (d) L-methionine at a concentration of about 10 mM (e.g., at 10 mM); (e) polysorbate 80 at a concentration of about 0.05% w/v Attorney Docket No.: AOJ-017PC AOE-003WO (e.g., at 0.05% polysorbate 80), (f) EDTA or a salt thereof (e.g., EDTA-2Na
  • a formulation comprising: (a) an IL-13 antibody at a concentration of about 180-200 mg/mL (e.g., at 180 mg/mL or 200 mg/mL); (b) a histidine buffer at a concentration of about 10 mM (e.g., at 10 mM), wherein the histidine buffer comprises L-histidine and L-histidine HCl monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM (e.g., at 120 mM); (d) L-methionine at a concentration of about 10 mM (e.g., at 10 mM); and (e) poloxamer 188 at a concentration of about 0.5 mg/ml (e.g., at 0.5 mg/ml), at pH of about 5.8-6.0 (e.g., at a pH of 5.8 or a pH of 6.0).
  • an IL-13 antibody at a concentration of about 180-200 mg/mL (e.
  • the formulation further comprises: (f) a sugar or sugar alcohol.
  • the sugar or sugar alcohol is at a concentration between 1% w/v and 8% w/v. In certain embodiments, the sugar or sugar alcohol is at a concentration of about 3% w/v.
  • the sugar or sugar alcohol is a disaccharide. In certain embodiments, the disaccharide is sucrose.
  • the IL-13 antibody comprises: (a) a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR- H3; and (b) a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein: (i) CDR-H1 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 58-99 and 121; (ii) CDR- H2 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 100-111; (iii) CDR-H3 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 112-120 and 130-140, (iv) CDR-L1 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 141-144 and 149-152, (v) CDR
  • the (a) CDR-H1 comprises a sequence selected from the sequences set forth in any one of SEQ ID NO: 58, SEQ ID NO: 68, and SEQ ID NO: 85;
  • CDR-H2 comprises a sequence selected from the sequences set forth in any one of SEQ ID NO: 100, SEQ ID NO: 104, and SEQ ID NO: 108;
  • CDR-H3 comprises a sequence selected from the sequences set forth in any one of SEQ ID NO: 112 and SEQ ID NO: 130,
  • CDR-L1 comprises a sequence selected from the sequences set forth in any one of SEQ Attorney Docket No.: AOJ-017PC AOE-003WO ID NO: 141 and SEQ ID NO: 149,
  • CDR-L2 comprises a sequence selected from the sequences set forth in any one of SEQ ID NO: 153 and SEQ ID NO: 164;
  • CDR-L3 comprises the sequence set forth in SEQ ID NO:
  • the IL-13 antibody comprises: (a) CDR-H1 comprising a sequence selected from the sequences set forth in any one of SEQ ID NOs: 58-66; (b) CDR- H2 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 100-103; (c) CDR-H3 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 112-120, (d) CDR-L1 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 141-144, (e) CDR-L2 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 153-158; and (f) CDR-L3 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 165-172.
  • the IL-13 antibody comprises: (a) CDR-H1 comprising a sequence selected from the sequences set forth in any one of SEQ ID NOs: 67-83; (b) CDR- H2 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 104-107; (c) CDR-H3 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 112-120, (d) CDR-L1 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 141-144, (e) CDR-L2 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 153-158; and (f) CDR-L3 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 165-172.
  • CDR-L1 comprises a sequence selected from the sequences set forth in any one of SEQ ID NO: 141 and SEQ ID NO: 149, e.
  • CDR-L2 comprises a sequence selected from the sequences set forth in any one of SEQ ID NO: 153 and SEQ ID NO: 164; and f.
  • CDR-L3 comprises the sequence set forth in SEQ ID NO: 165.
  • the IL-13 antibody comprises: (i) a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and (ii) a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein: a. CDR-H1 comprises the sequence set forth in SEQ ID NO: 58 or 67; b. CDR-H2 comprises the sequence set forth in SEQ ID NO: 100 or 104; c.
  • the IL-13 antibody comprises a means for extending the half-life of the IL-13 antibody.
  • the means comprises at least one amino acid modification in the IL-13 antibody, as described further herein.
  • the formulation further comprises a sugar or sugar alcohol.
  • FIG.2 is a graph depicting the average gliding force in Newtons (N) (y-axis) at room temperature of a formulation with varied concentrations of an IL-13 antibody (x-axis) and including 150 mM Arg-HCl, 80 mM Arg-HCl and 3% w/v sucrose, or 120 mM Arg-HCl injected through a pre-filled syringe (PFS).
  • N Newtons
  • x-axis concentrations of an IL-13 antibody
  • PFS pre-filled syringe
  • FIG.7A-7B show bar graphs of CE-SDS-NR (FIG.7A) and CE-SDS-R (FIG.7B) results in samples tested with different combinations of syringes (C and D) and plungers (A and B).
  • FIG.8 shows a bar graph of ELISA results for container closure compatibility for samples tested with different combinations of syringes (C and D) and plungers (A and B).
  • compositions described herein can either comprise the listed components or steps, or can “consist essentially of” the listed components or steps.
  • composition when a composition is described as “consisting essentially of” the listed components, the composition contains the components listed, and may contain other components which do not substantially affect the condition being treated, but do not contain any other components which substantially affect the condition being treated other than those components expressly listed; or, if the composition does contain extra components other than those listed which substantially affect the condition being treated, the composition does not contain a sufficient concentration or amount of the extra components to substantially affect the condition being treated.
  • a method is described as “consisting essentially of” the listed steps, the method contains the steps listed, and may contain other steps that do not substantially affect the condition being treated, but the method does not contain any other steps which substantially affect the condition being treated other than those steps expressly listed.
  • an “effective amount” or “therapeutically effective amount” as used herein refers to an amount of therapeutic compound, such as an IL-13 antibody, administered to an individual, either as a single dose or as part of a series of doses, which is effective to produce or contribute to a desired therapeutic effect, either alone or in combination with another therapeutic modality. Examples of a desired therapeutic effect is enhancing an immune response, slowing or delaying tumor development; stabilization of disease; amelioration of one or more symptoms.
  • treating refers to clinical intervention in an attempt to alter the natural course of a disease or condition in a subject in need thereof. Treatment can be performed during the course of clinical pathology. Desirable effects of treatment include preventing recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, Attorney Docket No.: AOJ-017PC AOE-003WO preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
  • the term “sufficient amount” means an amount sufficient to produce a desired effect, e.g., an amount sufficient to modulate an immune response in a subject.
  • the terms “subject”, “patient”, and “individual” are used interchangeably herein.
  • the term “subject”, “patient”, or “individual” means a mammalian subject. Exemplary subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, and sheep. In certain embodiments, the subject is a human. In certain embodiments the subject has a disease or condition that can be treated with an antibody provided herein.
  • composition refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective in treating a subject, and which contains no additional components which are unacceptably toxic to the subject in the amounts provided in the pharmaceutical composition.
  • modulate and “modulation” refer to reducing or inhibiting or, alternatively, activating or increasing, a recited variable.
  • the terms “increase” and “activate” refer to an increase of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or greater in a recited variable.
  • the terms “reduce” and “inhibit” refer to a decrease of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or greater in a recited variable.
  • Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C); glutamic acid (Glu; E), Attorney Docket No.: AOJ-017PC AOE-003WO glutamine (Gln; Q), Glycine (Gly; G); histidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V).
  • an amino acid described herein may refer to its L-isomer form.
  • methionine may refer to L-methionine
  • proline may refer to L-proline
  • arginine may refer to L-arginine.
  • affinity refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen or epitope).
  • affinity refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen or epitope).
  • KD Kd/ka. In certain embodiments, the affinity of an antibody is described in terms of the KD for an interaction between such antibody and its antigen.
  • KA ka/kd.
  • antibody is used herein in its broadest sense and includes certain types of immunoglobulin molecules comprising one or more antigen-binding domains that specifically bind to an antigen or epitope. An antibody specifically includes intact antibodies (e.g., intact immunoglobulins), antibody fragments, and multi-specific antibodies.
  • a “anti-IL-13 antibody,” “IL-13 antibody,” or “IL-13 specific antibody” is an antibody, as provided herein, which specifically binds to the antigen IL-13.
  • the term “epitope” means a portion of an antigen that specifically binds to an antibody.
  • the term “hypervariable region” or “HVR,” as used herein, refers to each of the regions of an antibody variable domain which are hypervariable in sequence and/or form structurally defined loops (“hypervariable loops”). Attorney Docket No.: AOJ-017PC AOE-003WO [00106]
  • the term “antigen-binding domain” means the portion of an antibody that is capable of specifically binding to an antigen or epitope.
  • chimeric antibody refers to an antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species.
  • human antibody refers to an antibody which possesses an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies.
  • humanized antibody refers to a protein having a sequence that differs from the sequence of an antibody derived from a non-human species by one or more amino acid substitutions, deletions, and/or additions, such that the humanized antibody is less likely to induce an immune response, and/or induces a less severe immune response, as compared to the non-human species antibody, when it is administered to a human subject.
  • multispecific antibody refers to an antibody that comprises two or more different antigen-binding domains that collectively specifically bind two or more different epitopes.
  • a “monospecific antibody” is an antibody that comprises one or more binding sites that specifically bind to a single epitope.
  • a monospecific antibody is a naturally occurring IgG molecule which, while divalent (i.e., having two antigen-binding domains), recognizes the same epitope at each of the two antigen-binding domains.
  • the binding specificity may be present in any suitable valency.
  • the term “monoclonal antibody” refers to an antibody from a population of substantially homogeneous antibodies.
  • a population of substantially homogeneous antibodies comprises antibodies that are substantially similar and that bind the same epitope(s), except for variants that may normally arise during production of the monoclonal antibody. Such variants are generally present in only minor amounts.
  • a monoclonal antibody is typically obtained by a process that includes the selection of a single antibody from a plurality of antibodies.
  • the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones.
  • the selected antibody can be further altered, for Attorney Docket No.: AOJ-017PC AOE-003WO example, to improve affinity for the target (“affinity maturation”), to humanize the antibody, to improve its production in cell culture, and/or to reduce its immunogenicity in a subject.
  • affinity maturation affinity for the target
  • the term “single-chain” refers to a molecule comprising amino acid monomers linearly linked by peptide bonds.
  • an scFv has a variable domain of light chain (VL) connected from its C-terminus to the N-terminal end of a variable domain of heavy chain (VH) by a polypeptide chain.
  • VL variable domain of light chain
  • VH variable domain of heavy chain
  • the scFv comprises of polypeptide chain where in the C-terminal end of the VH is connected to the N-terminal end of VL by a polypeptide chain.
  • the “Fab fragment” (also referred to as fragment antigen-binding) contains the constant domain (CL) of the light chain and the first constant domain (CH1) of the heavy chain along with the variable domains VL and VH on the light and heavy chains respectively.
  • the variable domains comprise the complementarity determining loops (CDR, also referred to as hypervariable region) that are involved in antigen-binding.
  • CDR complementarity determining loops
  • Fab′ fragments differ from Fab fragments by the addition of a few residues at the carboxy terminus of the heavy chain CH1 domain including one or more cysteines from the antibody hinge region.
  • “F(ab’)2” fragments contain two Fab’ fragments joined, near the hinge region, by disulfide bonds.
  • F(ab’)2 fragments may be generated, for example, by recombinant methods or by pepsin digestion of an intact antibody.
  • the F(ab’) fragments can be dissociated, for example, by treatment with ß-mercaptoethanol.
  • “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.
  • Single-chain Fv or “sFv” or “scFv” includes the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain.
  • the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen-binding.
  • a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen-binding.
  • an Fc domain may be attached to the C-terminal of the scFv.
  • the Fc domain may follow the VH Attorney Docket No.: AOJ-017PC AOE-003WO or VL, depending on the orientation of the variable domains in the scFv (i.e., VH -VL or VL - VH). Any suitable Fc domain known in the art or described herein may be used.
  • the Fc domain comprises an IgG4 Fc domain.
  • the term “single domain antibody” or “sdAb” refers to a molecule in which one variable domain of an antibody specifically binds to an antigen without the presence of the other variable domain.
  • Single domain antibodies are described in Arabi Ghahroudi et al., FEBS Letters, 1998, 414:521-526 and Muyldermans et al., Trends in Biochem. Sci., 2001, 26:230-245, each of which is incorporated by reference in its entirety.
  • Single domain antibodies are also known as sdAbs or nanobodies. Sdabs are fairly stable and easy to express as fusion partner with the Fc chain of an antibody (Harmsen MM, De Haard HJ (2007). “Properties, production, and applications of camelid single-domain antibody fragments”. Appl. Microbiol Biotechnol.77(1): 13-22).
  • full length antibody “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a naturally occurring antibody structure and having heavy chains that comprise an Fc region.
  • a “full length antibody” is an antibody that comprises two heavy chains and two light chains.
  • antibody fragment refers to an antibody that comprises a portion of an intact antibody, such as the antigen-binding or variable region of an intact antibody.
  • Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab’)2 fragments, Fab’ fragments, scFv (sFv) fragments, and scFv-Fc fragments.
  • Fc domain or “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions.
  • percent “identity,” in the context of two or more nucleic acid or polypeptide sequences, refer to two or more sequences or subsequences that have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned for maximum correspondence, as measured using one of the sequence comparison algorithms described below (e.g., using publicly available computer software such as BLAST, BLASTP, BLASTN, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE software or other algorithms available to persons of skill) or by visual inspection.
  • sequence comparison algorithms e.g., using publicly available computer software such as BLAST, BLASTP, BLASTN, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE software or other algorithms available to persons of skill
  • sequence comparison typically one sequence acts as a reference sequence to which test sequences are compared.
  • test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated.
  • sequence comparison algorithm calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.
  • Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math.2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol.48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat'l. Acad. Sci.
  • a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50.
  • stable formulation refers to a formulation in which the protein of interest (here an antibody or an antigen binding fragment thereof) essentially retains its physical, chemical and/or biological properties upon storage.
  • the protein of interest here an antibody or an antigen binding fragment thereof
  • various analytical methods are well within the knowledge of the skilled person (see some examples in the Example section). Stability is typically assessed at a selected temperature (for instance ⁇ 70 °C, -40° C, -20° C, 2-8 °C, 25 °C, 35 °C, or more) for a selected time period (e.g., 3 months, 6 months, 12 months, or more).
  • an antibody once formulated, it may be stored frozen (-20 °C to -70 °C) , under refrigerated conditions (typically 2-8° C), or at room temperature (typically 20-26° C) before being prepared for administration to a patient. It is important that the formulated antibody is stable over time at least at 2-25° C or under frozen conditions (-20 to -70° C), as shown for example at 2-8° C, 25° C, -20° C, -40° C, and -70° C.
  • Various values can be used to conclude about stability over a given time period (in comparison of the initial data), such as (and not limited to): 1) no more than 10% of alteration of the monomeric form of the antibody, 2) no more than 10% of increase in High Molecular Weight Species (HMW; also herein referred to as aggregates), 3) no more than 10% of increase in Low Molecular Weight species (LMW), 4) no more than +1-0.3 unit variation of the pH, 5) changes in charge variation, 6) changes in potency, or 7) changes in particulates, the relevant changed ranges of which one of skill in the art could determine.
  • HMW High Molecular Weight Species
  • LMW Low Molecular Weight species
  • amino acid sequence boundaries of a CDR can be determined by one of skill in the art using any of a number of known numbering schemes, including those described by Kabat et al., supra (“Kabat” numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948 (“Chothia” numbering scheme); MacCallum et al., 1996, J. Mol. Biol.262:732- 745 (“Contact” numbering scheme); Lefranc et al., Dev. Comp. Immunol., 2003, 27:55-77 (“IMGT” numbering scheme); and Honegge and Plückthun, J. Mol.
  • Table 1 provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR- H2, and CDR-H3 as identified by the Kabat and Chothia schemes.
  • residue numbering is provided using both the Kabat and Chothia numbering schemes.
  • CDRs may be assigned, for example, using antibody numbering software, such as Abnum, available at www.bioinf.org.uk/abs/abnum/, and described in Abhinandan and Martin, Immunology, 2008, 45:3832-3839, incorporated by reference in its entirety. Table 1.
  • an antigen-binding domain is an antigen-binding domain formed by a VH-VL dimer of an antibody.
  • Another example of an antigen-binding domain is an antigen-binding domain formed by diversification of certain loops from the tenth fibronectin type III domain of an Adnectin.
  • An antigen-binding domain can include CDRs 1, 2, and 3 from a heavy chain in that order; and CDRs 1, 2, and 3 from a light chain in that order.
  • Epitopes frequently consist of surface-accessible amino acid residues and/or sugar side chains and may have specific three-dimensional structural characteristics, as well as specific charge characteristics.
  • Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter may be lost in the presence of denaturing solvents.
  • An epitope may comprise amino acid residues that are directly involved in the binding and other amino acid residues, which are not directly involved in the binding.
  • the epitope to which an antibody binds can be determined using known techniques for epitope determination such as, for example, testing for antibody binding to IL-13 variants with different point-mutations or to chimeric IL-13 variants.
  • a routine cross-blocking assay such as that described in Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1988), can be performed.
  • epitope mapping can be performed by methods known in the art.
  • AOJ-017PC AOE-003WO [00151] Chimeric antibodies are antibodies in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species.
  • Human antibodies are antibodies which possess an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies.
  • a humanized antibody has a sequence that differs from the sequence of an antibody derived from a non-human species by one or more amino acid substitutions, deletions, and/or additions, such that the humanized antibody is less likely to induce an immune response, and/or induces a less severe immune response, as compared to the non- human species antibody, when it is administered to a human subject.
  • certain amino acids in the framework and constant domains of the heavy and/or light chains of the non-human species antibody are mutated to produce the humanized antibody.
  • the constant domain(s) from a human antibody are fused to the variable domain(s) of a non-human species.
  • one or more amino acid residues in one or more CDR sequences of a non-human antibody are changed to reduce the likely immunogenicity of the non-human antibody when it is administered to a human subject, wherein the changed amino acid residues either are not critical for immunospecific binding of the antibody to its antigen, or the changes to the amino acid sequence that are made are conservative changes, such that the binding of the humanized antibody to the antigen is not significantly worse than the binding of the non-human antibody to the antigen. Examples of how to make humanized antibodies can be found in U.S. Pat. Nos.6,054,297, 5,886,152 and 5,877,293.
  • the two or more different epitopes may be epitopes on the same antigen (e.g., a single IL-13) or on different antigens (e.g., different IL-13 molecules, or a IL-13 molecule and a non- IL-13 molecule).
  • a multi-specific antibody binds two different epitopes (i.e., a “bispecific antibody”).
  • a multi-specific antibody binds three different epitopes (i.e., a “trispecific antibody”).
  • a trispecific antibody can include those described herein such as the clones set forth in the drawings and/or tables.
  • the antibody comprises an alternative scaffold.
  • the antibody consists of an alternative scaffold.
  • the antibody consists essentially of an alternative scaffold.
  • the antibody comprises an antibody fragment.
  • the antibody consists of an antibody fragment.
  • the antibody consists essentially of an antibody fragment.
  • the antibodies are monoclonal antibodies.
  • the antibodies are polyclonal antibodies.
  • the antibodies are produced by hybridomas.
  • the antibodies are produced by recombinant cells engineered to express the desired variable and constant domains.
  • the antibodies may be single chain antibodies or other antibody derivatives retaining the antigen specificity and the lower hinge region or a variant thereof.
  • the antibodies may be polyfunctional antibodies, recombinant antibodies, human antibodies, humanized antibodies, fragments or variants thereof.
  • the antibody fragment or a derivative thereof is selected from a Fab fragment, a Fab′2 fragment, a CDR, and ScFv.
  • the antibodies are capable of forming an immune complex.
  • an immune complex can be a tumor cell covered by antibodies.
  • Sequences of IL-13 Antibodies VH Domains [00162]
  • the present disclosure further provides formulations comprising: (a) an IL-13 antibody present at a concentration between 140 mg/mL and 290 mg/mL; (b) a histidine buffer (e.g., combination L-histidine and L-histidine HCl buffer), an acetate buffer (e.g., combination acetic acid and sodium acetate trihydrate), or a succinate buffer (e.g., combination succinic acid and sodium succinate hexahydrate); (c) arginine and/or methionine (e.g., L-arginine and/or L-methionine) or a salt solution thereof; and (d) a polysorbate or a poloxamer, at pH 5.0 to 7.0.
  • a histidine buffer e.g., combination L-hist
  • the IL-13 antibody comprises: (i) a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and (ii) a variable light (VL) chain sequence Attorney Docket No.: AOJ-017PC AOE-003WO comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein: (a) CDR-H1 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 58-99 and 121; (b) CDR-H2 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 100-111; (c) CDR-H3 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 112-120 and 130-140, (d) CDR-L1 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 141-
  • the present disclosure further provides formulations comprising: (a) an IL-13 antibody present at a concentration, e.g., between 140 mg/mL and 290 mg/mL; (b) a histidine buffer (e.g., combination L-histidine and L-histidine HCl buffer), an acetate buffer (e.g., combination acetic acid and sodium acetate trihydrate), or a succinate buffer (e.g., combination succinic acid and sodium succinate hexahydrate); (c) arginine and/or methionine (e.g., L-arginine and/or L-methionine) or a salt solution thereof; and (d) a polysorbate or a poloxamer, at pH 5.0 to 7.0.
  • a histidine buffer e.g., combination L-histidine and L-histidine HCl buffer
  • an acetate buffer e.g., combination acetic acid and sodium acetate trihydrate
  • succinate buffer
  • the IL-13 antibody comprises: (i) a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and (ii) a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein: (a) CDR-H1 comprises a sequence selected from the sequences set forth in any one of SEQ ID NO: 58, SEQ ID NO: 68, and SEQ ID NO: 85; (b) CDR-H2 comprises a sequence selected from the sequences set forth in any one of SEQ ID NO: 100, SEQ ID NO: 104, and SEQ ID NO: 108; (c) CDR-H3 comprises a sequence selected from the sequences set forth in any one of SEQ ID NO: 112 and SEQ ID NO: 130, (d) CDR-L1 comprises a sequence selected from the sequences set forth in any one of SEQ ID
  • an antibody provided herein comprises a VH sequence selected from SEQ ID NOs: 1-32.
  • an antibody provided herein comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to an VH sequence provided in SEQ ID NOs: 1-32.
  • an antibody provided herein comprises a VH sequence provided in SEQ ID NOs: 1-32, with up Attorney Docket No.: AOJ-017PC AOE-003WO to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the antibodies described in this paragraph are referred to herein as “variants.”
  • such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein.
  • such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.
  • VL Domains [00166]
  • an antibody provided herein comprises a VL sequence selected from SEQ ID NOs: 33-57.
  • an antibody provided herein comprises a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to an VL sequence provided in SEQ ID NOs: 33-57.
  • an antibody provided herein comprises a VL sequence provided in SEQ ID NOs: 33-57 with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the antibodies described in this paragraph are referred to herein as “variants.”
  • such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein.
  • such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.
  • an antibody provided herein comprises a VH sequence selected from SEQ ID NOs: 1-32; and a VL sequence selected from SEQ ID NOs: 33-57, such as any of the VH-VL combinations set forth for Constructs 3-127 and 132-144 in Table 2, below. [00169] In certain aspects, any of SEQ ID NOs: 1-32 can be combined with any of SEQ ID NOs: 33-57. [00170] In certain embodiments, the antibody comprises a VH sequence selected from the sequences set forth in SEQ ID NOs: 1-32 and a VL sequence set forth in SEQ ID NO: 39.
  • the antibody comprises the VH sequence set forth in SEQ ID NO: 3 and the VL sequence set forth in SEQ ID NO: 39. [00172] In certain embodiments, the antibody comprises a VH sequence selected from the sequences set forth in SEQ ID NOs: 1-32 and a VL sequence set forth in SEQ ID NO: 51.
  • an antibody provided herein comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to an VH sequence provided in SEQ ID NOs: 1-32; and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to an VL sequence provided in SEQ ID NOs: 33-57.
  • an antibody provided herein comprises a VH sequence provided in SEQ ID NOs: 1-32, with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions; and a VL sequence provided in SEQ ID NOs: 33-57, with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • an antibody provided herein comprises a VH sequence and a VL sequence selected from combinations set forth for Constructs 3-127 and 132-144 in Table 2, below.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 1 and a VL sequence set forth in SEQ ID NO: 33. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 2 and a VL sequence set forth in SEQ ID NO: 33. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 3 and a VL sequence set forth in SEQ ID NO: 35. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 4 and a VL sequence set forth in SEQ ID NO: 35. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 5 and a VL sequence set forth in SEQ ID NO: 35.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 6 and a VL sequence set forth in SEQ ID NO: 35. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 35. In certain embodiments, the Attorney Docket No.: AOJ-017PC AOE-003WO antibody comprises a VH sequence set forth in SEQ ID NO: 3 and a VL sequence set forth in SEQ ID NO: 36. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 4 and a VL sequence set forth in SEQ ID NO: 36.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 5 and a VL sequence set forth in SEQ ID NO: 36. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 6 and a VL sequence set forth in SEQ ID NO: 36. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 36. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 3 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 4 and a VL sequence set forth in SEQ ID NO: 39.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 5 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 6 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 3 and a VL sequence set forth in SEQ ID NO: 40. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 4 and a VL sequence set forth in SEQ ID NO: 40.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 5 and a VL sequence set forth in SEQ ID NO: 40. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 6 and a VL sequence set forth in SEQ ID NO: 40. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 40. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 8 and a VL sequence set forth in SEQ ID NO: 42. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 9 and a VL sequence set forth in SEQ ID NO: 43.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 44. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 45. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 46. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 47.
  • the Attorney Docket No.: AOJ-017PC AOE-003WO antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 48. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 49. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 50. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 51.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 52. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 53. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 54. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 55. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 56.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 57. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 10 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 11 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 12 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 13 and a VL sequence set forth in SEQ ID NO: 39.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 14 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 15 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 16 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 17 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 18 and a VL sequence set forth in SEQ ID NO: 39.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 19 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 20 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 21 and a VL sequence set forth in SEQ ID NO: 39. In Attorney Docket No.: AOJ-017PC AOE-003WO certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 22 and a VL sequence set forth in SEQ ID NO: 39.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 23 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 24 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 25 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 26 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 27 and a VL sequence set forth in SEQ ID NO: 39.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 28 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 28 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 29 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 30 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 31 and a VL sequence set forth in SEQ ID NO: 39.
  • the IL-13 antibody comprises a heavy chain variable domain comprising a framework region sequence selected from a sequence set forth in SEQ ID NOs: 198-229, 255-256, 258-259, 261-285, 311-315, 317-342, 368-369, 371-399, and 540-580.
  • the IL-13 antibody comprises a heavy chain variable domain comprising 1, 2, 3, or 4 framework region sequences selected from a sequence set forth in SEQ ID NOs: 198-229, 255-256, 258-259, 261-285, 311-315, 317-342, 368-369, 371-399, and 540-580.
  • the IL-13 antibody comprises a light chain variable domain comprising a framework region sequence selected from a sequence set forth in SEQ ID NOs: 230-231, 233-235, 239, 241-254, 286, 288, 290-291, 293, 296-310, 343-345, 347, Attorney Docket No.: AOJ-017PC AOE-003WO 400-424, and 581-609.
  • the IL-13 antibody comprises a light chain variable domain comprising 1, 2, 3, or 4 framework region sequences selected from a sequence set forth in SEQ ID NOs: 230-231, 233-235, 239, 241-254, 286, 288, 290-291, 293, 296-310, 343-345, 347, 400-424, and 581-609.
  • the IL-13 antibody comprises a heavy chain variable domain comprising 1, 2, 3, or 4 framework region sequences selected from a sequence set forth in SEQ ID NOs: 198-229, 255-256, 258-259, 261-285, 311-315, 317-342, 368-369, 371-399, and 540-580, and comprises a light chain variable domain comprising 1, 2, 3, or 4 framework region sequences selected from a sequence set forth in SEQ ID NOs: 230-231, 233-235, 239, 241-254, 286, 288, 290-291, 293, 296-310, 343-345, 347, 400-424, and 581- 609. Table 2.
  • Anti-interleukin (IL)-13 antibody VH-VL sequences Construc VH; VL; HC VH sequence VL sequence t ID t t R F Y S T R F Y S Attorney Docket No.: AOJ-017PC AOE-003WO Human kappa CAGDGYYPYAMDNW YYCQQNNEDPRTFGGGT LC GQGSLVTVSS (SEQ ID KVEIK (SEQ ID NO: 471) R F Y S S T R F Y S S T F Y Y K F Y Attorney Docket No.: AOJ-017PC AOE-003WO YTE; Human WLGMIWGDGKIVYNS LASNLESGVPSRFSGSGS kappa LC ALKSRLTITKDSSTSTV RTDFTLTISSLQPEDFATY K F Y Y K F Y Y K F Y Y K Attorney Docket No.: AOJ-017PC AOE-003WO HC
  • an IL-13 antibody comprises a VH domain selected from any one the VH domains of Constructs 3-127 and 132-144 in Table 2 or a VH domain having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, and a HC domain comprising a sequence selected from any one of SEQ ID NOs: 425-468, 484-539, and 610-709 or an HC domain having at least about 80%, 90%, 91%, 92%, 93%, Attorney Docket No.: AOJ-017PC AOE-003WO 94%, 95%, 96%, 97%, 98% or 99% identity thereto.
  • a VH domain listed for any one of Constructs 3-127 and 132-144 in Table 2 can be combined with a heavy chain constant (HC) domain provided herein.
  • an IL-13 antibody comprises a VH domain selected from any one the VH domains of Constructs 3-127 and 132- 144 in Table 2 or a VH domain having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, and a HC domain comprising a sequence selected from any one of SEQ ID NOs: 610, 615-641, and 654-709 or an HC domain having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto.
  • the HC domain is an IgG1 HC domain.
  • the HC domain includes IgG4-SP, hIgG1-LALA-YTE, hIgG1-LAGA YTE, hIgG1-LALA-LS, IgG4-YTE HC, and IgG4-LS.
  • such an IgG4-SP HC constant domain has the sequence: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS RLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 427).
  • such a hIgG1-LALA-YTE HC constant domain has the sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP EAAGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSPG (SEQ ID NO: 439).
  • such a hIgG1-LAGA YTE HC constant domain has the sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP ELAGAPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT Attorney Docket No.: AOJ-017PC AOE-003WO KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSPG (SEQ ID NO: 440).
  • such a hIgG1-LALA-LS HC constant domain has the sequence: [00184] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSPG (SEQ ID NO: 446).
  • such an IgG4-LS HC constant domain has the sequence: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS RLTVDKSRWQEGNVFSCSVLHEALHSYTQKSLSLSLGK (SEQ ID NO: 460).
  • such a hIgG1-LALA-YTE HC C-terminal lysine variant constant domain has the sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP EAAGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG Attorney Docket No.: AOJ-017PC AOE-003WO SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS
  • such a hIgG1-LAGA YTE HC C-terminal lysine variant constant domain has the sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP ELAGAPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSPGK (SEQ ID NO: 625).
  • such a hIgG1-LALA-LS HC C-terminal lysine variant constant domain has the sequence: [00190] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSPGK (SEQ ID NO: 631).
  • a VL domain listed for Constructs 3-127 and 132-144 in Table 2 can be combined with a light chain constant (LC) domain provided herein.
  • the LC domain is a human kappa LC constant domain.
  • such a human kappa LC constant domain has the sequence: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 469).
  • an antibody provided herein comprises one to three CDRs of a VH domain selected from SEQ ID NOs: 1-32, such as any of the CDRs listed in Table 3, Table 4, or Table 5, below. In some embodiments, an antibody provided herein comprises two to three CDRs of a VH domain selected from SEQ ID NOs: 1-32. In some embodiments, an antibody provided herein comprises three CDRs of a VH domain selected from SEQ ID NOs: 1-32. In some embodiments, the CDRs are Exemplary CDRs. In some embodiments, Attorney Docket No.: AOJ-017PC AOE-003WO the CDRs are Kabat CDRs.
  • the CDRs are Chothia CDRs. In some embodiments, the CDRs are IMGT CDRs. In some embodiments, the CDRs are AbM CDRs. In some embodiments, the CDRs are Contact CDRs. [00193] In some embodiments, the CDRs are CDRs having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with a CDR-H1, CDR-H2, or CDR-H3 of SEQ ID NOs: 58-140.
  • the CDR-H1 is a CDR-H1 of a VH domain selected from SEQ ID NOs: 1-32, with up to 1, 2, 3, 4, or 5 amino acid substitutions.
  • the CDR-H2 is a CDR-H2 of a VH domain of SEQ ID NO: 1-32, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions.
  • the CDR-H3 is a CDR-H3 of a VH domain selected from SEQ ID NOs: 1-32, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • an antibody provided herein comprises one to three CDRs of a VL domain of SEQ ID NOs: 33-57, such as any of the CDRs listed in Table 6, Table 7, or Table 8, below.
  • an antibody provided herein comprises two to three CDRs of a VL domain of SEQ ID NOs: 33-57. In some embodiments, an antibody provided herein comprises three CDRs of a VL domain of SEQ ID NOs: 33-57. In some embodiments, the CDRs are Exemplary CDRs. In some embodiments, the CDRs are Kabat CDRs. In some embodiments, the CDRs are Chothia CDRs. In some embodiments, the CDRs are IMGT CDRs. In some embodiments, the CDRs are AbM CDRs. In some embodiments, the CDRs are Contact CDRs.
  • the CDRs are CDRs having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with a CDR-L1, CDR-L2, or CDR-L3 of SEQ ID NOs: 141-188.
  • the CDR-L1 is a CDR-L1 of a VL domain of SEQ ID NOs: 33-57, with up to 1, 2, 3, 4, or 5 amino acid substitutions.
  • the CDR-L2 is a CDR-L2 of a VL domain of SEQ ID NOs: 33-57 , with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions.
  • the CDR-L3 is a CDR- Attorney Docket No.: AOJ-017PC AOE-003WO L3 of a VL domain of SEQ ID NOs: 33-57, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein.
  • an antibody provided herein comprises one to three CDRs of a VH domain selected from SEQ ID NOs: 1-32 and one to three CDRs of a VL domain of SEQ ID NOs: 33-57. In some embodiments, an antibody provided herein comprises two to three CDRs of a VH domain selected from SEQ ID NOs: 1-32 and two to three CDRs of a VL domain of SEQ ID NOs: 33-57.
  • an antibody provided herein comprises three CDRs of a VH domain selected from SEQ ID NOs: 1-32 and three CDRs of a VL domain of SEQ ID NOs: 33-57.
  • the CDRs are Exemplary CDRs.
  • the CDRs are Kabat CDRs.
  • the CDRs are Chothia CDRs.
  • the CDRs are IMGT CDRs.
  • the CDRs are AbM CDRs.
  • the CDRs are Contact CDRs.
  • an antibody provided herein comprises a CDR-H3 selected of SEQ ID NOs: 112-120 and 130-40.
  • the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H3 of SEQ ID NOs: 112-120 or 130-40.
  • the CDR-H3 is a CDR-H3 selected of SEQ ID NOs: 112-120 and 130-40, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the antibodies described in this paragraph are referred to herein as “variants.”
  • such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein.
  • such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.
  • an antibody provided herein comprises a CDR-H1 of SEQ ID NOs: 58-99 and 121.
  • the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 of SEQ ID NOs: 58-99 or 121.
  • the CDR-H1 is a CDR-H1 of SEQ ID NOs: 58-99 or 121, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the antibodies described in this paragraph are referred to herein as “variants.”
  • such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein.
  • such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.
  • an antibody provided herein comprises a CDR-H2 of any one of SEQ ID NOs: 100-111.
  • the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of any one of SEQ ID NOs: 100-111.
  • the CDR-H2 is a CDR-H2 of any one of SEQ ID NOs: 100-111, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the antibodies described in this paragraph are referred to herein as “variants.”
  • such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein.
  • such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.
  • an antibody provided herein comprises a CDR-L3 selected from SEQ ID NOs: 165-172.
  • the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L3 of SEQ ID NOs: 165-172.
  • the CDR-L3 is a CDR-L3 of SEQ ID NOs: 165- 172, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the antibodies described in this paragraph are referred to herein as “variants.”
  • such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method Attorney Docket No.: AOJ-017PC AOE-003WO known in the art or described herein.
  • such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.
  • an antibody provided herein comprises a CDR-L2 selected from SEQ ID NOs: 153-158 and the amino acid sequence LAS.
  • the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L2 selected from SEQ ID NOs: 153-158 and the amino acid sequence LAS.
  • the CDR-L2 is a CDR-L2 selected from SEQ ID NOs: 153-158 and the amino acid sequence LAS, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the antibodies described in this paragraph are referred to herein as “variants.”
  • such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein.
  • such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.
  • an antibody provided herein comprises a CDR-L1 selected from SEQ ID NOs: 141-144 and 149-152.
  • the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR- L1 selected from SEQ ID NOs: 141-144 and 149-152.
  • the CDR-L1 is a CDR-L1 selected from SEQ ID NOs: 141-144 and 149-152, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the antibodies described in this paragraph are referred to herein as “variants.”
  • such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein.
  • such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.
  • an antibody provided herein comprises a CDR-H3 selected from SEQ ID NOs: 112-120 and 130-140, a CDR-H2 of SEQ ID NOs: 100-111, a CDR-H1 selected from SEQ ID NOs: 58-99 and 121, a CDR-L3 selected from SEQ ID NOs: 165-172, a CDR-L2 selected from SEQ ID NOs: 153-158 and the amino acid sequence LAS, and a Attorney Docket No.: AOJ-017PC AOE-003WO CDR-L1 selected from SEQ ID NOs: 141-144 and 149-152.
  • the CDR- H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H3 selected from SEQ ID NOs: 112-120 and 130-140
  • the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of SEQ ID NOs: 100-111
  • the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 selected from SEQ ID NOs: 58-99 and 121
  • the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L3 selected from SEQ ID NOs
  • the CDR-H3 is a CDR-H3 selected from SEQ ID NOs: 112-120 and 130-140, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions;
  • the CDR-H2 is a CDR- H2 of SEQ ID NOs: 100-111, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions;
  • the CDR-H1 is a CDR-H1 selected from SEQ ID NOs: 58-99 and 121, with up to 1, 2, 3, 4, or 5 amino acid substitutions;
  • the CDR-L3 is a CDR-L3 selected from SEQ ID NOs: 165-172, with up to 1, 2, 3, 4, or 5 amino acid substitutions;
  • the CDR-L2 is a CDR-L2 selected from SEQ ID NOs: 153-158 and the amino acid sequence LAS, with up to 1, 2, 3, or 4 amino acid substitutions;
  • the CDR-L1 is a CDR-L1 selected from SEQ ID NOs:
  • an antibody provided herein comprises a CDR-H3 of SEQ ID NOs: 112, 121, and 130, a CDR-H2 of SEQ ID NOs: 100, 104, and 108, a CDR-H1 of SEQ ID NOs: 58, 68, and 85, a CDR-L3 of SEQ ID NOs: 168, 173, and 181, a CDR-L2 of SEQ ID NOs: 153 and the amino acid sequence LAS, and a CDR-L1 of SEQ ID NOs: 141 and 149.
  • the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H3 of SEQ ID NOs: 112 or 130
  • the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of SEQ ID NOs: 100, 104 or 108
  • the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 of SEQ ID NOs: 58, 68 or 85
  • the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L3 of SEQ ID NO: 168
  • the CDR-H3 is a CDR-H3 of SEQ ID NOs: 112 or 130, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions
  • the CDR-H2 is a CDR-H2 of SEQ ID NOs: 100, 104 or 108, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions
  • the CDR-H1 is a CDR-H1 of SEQ ID NOs: 58, 68 or 85, with up to 1, 2, 3, 4, or 5 amino acid substitutions
  • the CDR-L3 is a CDR-L3 of SEQ ID NO: 168 with up to 1, 2, 3, 4, or 5 amino acid substitutions
  • the CDR-L2 is a CDR-L2 of SEQ ID NOs: 153 or the amino acid sequence LAS, with up to 1, 2, 3, or 4 amino acid substitutions
  • the CDR-L1 is a CDR-L1 of SEQ ID NOs: 141 or 149, with up to 1, 2, 3, 4, 5, or 6
  • an antibody provided herein comprises a CDR-H3 of SEQ ID NOs: 112, 121 or 130, a CDR-H2 of SEQ ID NOs: 100, 104 or 108, a CDR-H1 of SEQ ID NOs: 58, 68, or 85, a CDR-L3 of SEQ ID NO: 165, a CDR-L2 of SEQ ID NOs: 153 or the amino acid sequence LAS, and a CDR-L1 of SEQ ID NOs: 141 or 149.
  • the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H3 of SEQ ID NOs: 112 or 130
  • the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of SEQ ID NOs: 100, 104 or 108
  • the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 of SEQ ID NOs: 58, 68 or 85
  • the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L3 of SEQ ID NO: 165
  • the CDR-H3 is a CDR-H3 of SEQ ID NOs: 112 or 130, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions
  • the CDR-H2 is a CDR-H2 of SEQ ID NOs: 100, 104 or 108, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions
  • the CDR-H1 is a CDR-H1 of SEQ ID NOs: 58, 68 or 85, with up to 1, 2, 3, 4, or 5 amino acid substitutions
  • the CDR-L3 is a CDR-L3 of SEQ ID NO: 165, with up to 1, 2, 3, 4, or 5 amino acid substitutions
  • the CDR-L2 is a CDR-L2 of SEQ ID NO: 153 or the amino acid sequence LAS, with up to 1, 2, 3, or 4 amino acid substitutions
  • the CDR-L1 is a CDR-L1 of SEQ ID NOs: 141 or 149, with up to 1, 2, 3, 4, 5, or 6
  • an antibody provided herein comprises a CDR-H3 of SEQ ID NOs: 112 or 130, a CDR-H2 of SEQ ID NOs: 100, 104, or 108, a CDR-H1 of SEQ ID NOs: 58, 68, or 85, a CDR-L3 of SEQ ID NO: 165, a CDR-L2 of SEQ ID NO: 158 or the amino acid sequence LAS, and a CDR-L1 of SEQ ID NOs: 141 or 149.
  • the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H3 of SEQ ID NOs: 112 or 130
  • the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of SEQ ID NOs: 100, 104, or108
  • the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 of SEQ ID NOs: 58, 68 or 85
  • the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L3 of SEQ ID NO: 165
  • the CDR-H3 is a CDR-H3 of SEQ ID NOs: 112 or 130, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions
  • the CDR-H2 is a CDR-H2 of SEQ ID NOs: 100, 104, or 108, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions
  • the CDR-H1 is a CDR-H1 of SEQ ID NOs: 58, 68, or 85, with up to 1, 2, 3, 4, or 5 amino acid substitutions
  • the CDR-L3 is a CDR-L3 of SEQ ID NO: 165, with up to 1, 2, 3, 4, or 5 amino acid substitutions
  • the CDR-L2 is a CDR-L2 of SEQ ID NO: 158 or the amino acid sequence LAS, with up to 1, 2, 3, or 4 amino acid substitutions
  • the CDR-L1 is a CDR- L1 of SEQ ID NOs: 141 or 149, with up to 1, 2, 3, 4, 5,
  • an antibody provided herein comprises a CDR-H3 of SEQ ID NOs: 112, 121 or 130, a CDR-H2 of SEQ ID NOs: 100, 104 or 108, a CDR-H1 of SEQ ID NOs: 58, 67, or 84, a CDR-L3 of SEQ ID NO: 165, a CDR-L2 of SEQ ID NOs: 153 or the amino acid sequence LAS, and a CDR-L1 of SEQ ID NOs: 141 or 149.
  • the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H3 of SEQ ID NOs: 112 or 130
  • the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of SEQ ID NOs: 100, 104 or 108
  • the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 of SEQ ID NOs: 58, 67 or 84
  • the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L3 of SEQ ID NO:
  • the CDR-H3 is a CDR-H3 of SEQ ID NOs: 112 or 130, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions
  • the CDR-H2 is a CDR-H2 of SEQ ID NOs: 100, 104 or 108, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions
  • the CDR-H1 is a CDR-H1 of SEQ ID NOs: 58, 67 or 84, with up to 1, 2, 3, 4, or 5 amino acid substitutions
  • the CDR-L3 is a CDR-L3 of SEQ ID NO: 165, with up to 1, 2, 3, 4, or 5 amino acid substitutions
  • the CDR-L2 is a CDR-L2 of SEQ ID NO: 153 or the amino acid sequence LAS, with up to 1, 2, 3, or 4 amino acid substitutions
  • the CDR-L1 is a CDR-L1 of SEQ ID NOs: 141 or 149, with up to 1, 2, 3, 4, 5, or
  • an antibody provided herein comprises a CDR-H3 of SEQ ID NOs: 112 or 130, a CDR-H2 of SEQ ID NOs: 100, 104, or 108, a CDR-H1 of SEQ ID NOs: 58, 67, or 84, a CDR-L3 of SEQ ID NO: 165, a CDR-L2 of SEQ ID NO: 158 or the amino acid sequence LAS, and a CDR-L1 of SEQ ID NOs: 141 or 149.
  • the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H3 of SEQ ID NOs: 112 or 130
  • the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of SEQ ID NOs: 100, 104, or108
  • the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 of SEQ ID NOs: 58, 67 or 84
  • the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L3 of SEQ ID NO:
  • the CDR-H3 is a CDR-H3 of SEQ ID NOs: 112 or 130, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions
  • the CDR-H2 is a CDR-H2 of SEQ ID NOs: 100, 104, or 108, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions
  • the CDR-H1 is a CDR-H1 of SEQ ID NOs: 58, 67, or 84, with up to 1, 2, 3, 4, or 5 amino acid substitutions
  • the CDR-L3 is a CDR-L3 of SEQ ID NO: 165, with up to 1, 2, 3, 4, or 5 amino acid substitutions
  • the CDR-L2 is a CDR-L2 of SEQ ID NO: 158 or the amino acid sequence LAS, with up to 1, 2, 3, or 4 amino acid substitutions
  • the CDR-L1 is a CDR- L1 of SEQ ID NOs: 141 or 149, with up to 1, 2, 3, 4,
  • the amino acid substitutions are conservative amino acid substitutions.
  • the antibodies described in this disclosure are referred to herein as “variants” or “clones”.
  • such variants or clones are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein.
  • such variants or cones are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.
  • the antibodies disclosed herein do not include antibodies disclosed in US Patent number 9,067,994.
  • IL-13 antibody does not comprise any combination of: (a) a CDR-H1 set forth in any of SEQ ID NOs: 58, 67, or 84; (b) a CDR-H2 set forth in any of SEQ ID NOs: 100, 104, or 108; (c) a CDR-H3 set forth in any of SEQ ID NOs: 112 or 130; (d) a CDR-L1 set forth in any of SEQ ID NOs: 141 or 149; (e) a CDR-L2 set forth in any of SEQ ID NOs: 153 or 154; and (f) a CDR-L3 set forth in SEQ ID NO: 165.
  • Fc Region [00213] The structures of the Fc regions of various immunoglobulins, and the glycosylation sites contained therein, are known in the art. See Schroeder and Cavacini, J. Allergy Clin. Immunol., 2010, 125:S41-52, incorporated by reference in its entirety.
  • the Fc region may be a naturally occurring Fc region, or an Fc region modified as described in the art or elsewhere in this disclosure.
  • numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed.
  • an “Fc polypeptide” of a dimeric Fc as used herein refers to one of the two polypeptides forming the dimeric Fc domain, i.e., a polypeptide comprising C-terminal constant regions of an immunoglobulin heavy chain, capable of stable self-association.
  • an Fc polypeptide of a dimeric IgG Fc comprises an IgG CH2 and an IgG CH3 constant domain sequence.
  • An Fc can be of the class IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.
  • 125 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR [00215]
  • the terms “Fc receptor” and “FcR” are used to describe a receptor that binds to the Fc region of an antibody.
  • an FcR can be a native sequence human FcR.
  • an FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII subclasses, including allelic variants and alternatively spliced forms of these receptors.
  • Fc ⁇ RII receptors include Fc ⁇ RIIA (an “activating receptor”) and Fc ⁇ RIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof.
  • Immunoglobulins of other isotypes can also be bound by certain FcRs (see, e.g., Janeway et al., Immuno Biology: the immune system in health and disease, (Elsevier Science Ltd., NY) (4th ed., 1999)).
  • Activating receptor Fc ⁇ RIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain.
  • Inhibiting receptor Fc ⁇ RIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain (reviewed in Da ⁇ ron, Annu. Rev. Immunol. 15:203-234 (1997)).
  • FcRs are reviewed in Ravetch and Kinet, Annu. Rev.
  • FcR neonatal receptor
  • Modifications in the CH2 domain can affect the binding of FcRs to the Fc.
  • a number of amino acid modifications in the Fc region are known in the art for selectively altering the affinity of the Fc for different Fcgamma receptors.
  • the Fc comprises one or more modifications to promote selective binding of Fc-gamma receptors.
  • Exemplary mutations that alter the binding of FcRs to the Fc are listed below: [00218] S298A/E333A/K334A, S298A/E333A/K334A/K326A (Lu Y, Vernes JM, Chiang N, et al. J Immunol Methods.
  • an antibody described herein includes modifications designed to improve its ability to mediate effector function. Such modifications are known in the art and include afucosylation, or engineering of the affinity of the Fc towards an activating receptor, mainly FCGR3a for ADCC, and towards C1q for CDC.
  • FCGR3a for ADCC
  • C1q for CDC
  • an antibody described herein can include a dimeric Fc that comprises one or more amino acid modifications as noted in Table 9 that confer improved 127 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR effector function.
  • the antibody can be afucosylated to improve effector function.
  • Table 9. CH2 domains and effector function engineering Reference Mutations Effect C C C C C C C C C C C C C C C C C [00227] Fc modifications designed to reduce FcgR and/or complement binding and/or effector function are known in the art.
  • Examples of cell lines capable of producing defucosylated antibody include CHO-DG44 with stable overexpression of the bacterial oxidoreductase GDP-6-deoxy-D- lyxo-4-hexylose reductase (RMD) (see Henning von Horsten et al., Glycobiol 2010, 20:1607- 1618) or Lec13 CHO cells, which are deficient in protein fucosylation (see Ripka et al., Arch. Biochem. Biophys., 1986, 249:533-545; U.S. Pat. Pub. No.
  • Examples of cell lines capable of producing defucosylated antibody include CHO- DG44 with stable overexpression of the bacterial oxidoreductase GDP-6-deoxy-D-lyxo-4- hexylose reductase (RMD) (see Henning von Horsten et al., Glycobiol 2010, 20:1607-1618) or Lec13 CHO cells, which are deficient in protein fucosylation (see Ripka et al., Arch. Biochem. Biophys., 1986, 249:533-545; U.S. Pat. Pub. No.
  • knockout cell lines such as alpha-1,6- fucosyltransferase gene or FUT8 knockout CHO cells (see Yamane-Ohnuki et al., Biotech. Bioeng., 2004, 87: 614-622; Kanda et al., Biotechnol. Bioeng., 2006, 94:680-688; and WO 2003/085107; each of which is incorporated by reference in its entirety).
  • Antibodies can be fully afucosylated (meaning they contain no detectable fucose) or they can be partially afucosylated, meaning that the antibody contains less than 95%, less than 85%, less than 75%, less than 65%, less than 55%, less than 45%, less than 35%, less than 25%, less than 15% or less than 5% of the amount of fucose normally detected for a similar antibody produced by a mammalian expression system.
  • an antibody provided herein comprises an IgG1 domain with reduced fucose content at position Asn 297 compared to a naturally occurring IgG1 domain. Such Fc domains are known to have improved ADCC. See Shields et al., J.
  • an antibody provided herein comprises an Fc region with one or more amino acid substitutions which improve ADCC, such as a substitution at one or more of positions 298, 333, and 334 of the Fc region.
  • an antibody provided herein comprises an Fc region with one or more amino acid substitutions at positions 239, 332, and 330, as described in Lazar et al., Proc. Natl. Acad. Sci. USA, 2006,103:4005-4010, incorporated by reference in its entirety.
  • Other illustrative glycosylation variants which may be incorporated into the antibodies provided herein are described, for example, in U.S. Pat. Pub. Nos. 2003/0157108, 2004/0093621, 2003/0157108, 2003/0115614, 2002/0164328, 2004/0093621, 2004/0132140, 2004/0110704, 2004/0110282, 2004/0109865; International Pat. Pub. Nos.
  • an antibody provided herein comprises an Fc region with at least one galactose residue in the oligosaccharide attached to the Fc region.
  • Such antibody variants may have improved CDC function.
  • an antibody provided herein comprises one or more alterations that improves or diminishes C1q binding and/or CDC. See U.S. Pat. No. 6,194,551; WO 99/51642; and Idusogie et al., J. Immunol., 2000, 164:4178-4184; each of which is incorporated by reference in its entirety.
  • an antibody provided herein comprises a heavy chain comprising a constant heavy chain (HC) region comprising an amino acid sequence set forth in SEQ ID NO: 439 or SEQ ID NO: 624.
  • an antibody provided herein comprises a constant light chain (LC) region comprising an amino acid sequence set forth in SEQ ID NO: 469.
  • an antibody provided herein comprises (1) a constant heavy chain (HC) region comprising an amino acid sequence set forth in SEQ ID NO: 439 or SEQ ID NO: 624 or a HC region comprising sequence comprising an amino acid sequence having at least 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 439 or SEQ ID NO: 624 (2) a constant light chain (LC) region comprising an amino acid sequence set forth in SEQ ID NO: 469, or a LC region comprising sequence comprising an amino acid sequence having at least 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 469 (3) a VH comprising an amino acid sequence set forth in SEQ ID NO: 3 or a VH having at least 95%, 96%, 97%, 98%, 99% or 100% sequence
  • the isolated antibody comprises a heavy chain constant (HC) region comprising an amino acid sequence set forth in SEQ ID NO: 439 or 624 and a light chain constant (LC) region comprising an amino acid sequence set forth in SEQ ID NO: 469, wherein the antibody further comprises a VH comprising an amino acid sequence having at least 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3 and a VL comprising an amino acid sequence at least 95% 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 39, wherein the VH comprises a HCDR1 comprising SEQ ID NO: 58, SEQ ID NO: 68, or SEQ ID NO: 85; a HCDR2 comprising SEQ ID NO: 100, SEQ ID NO: 104, or SEQ ID NO: 108; and a HCDR3 comprising SEQ ID NO: 112 or SEQ ID NO: 130; and the VL comprises a LCDR1 comprising SEQ ID NO: 58
  • the isolated antibody comprises a HCDR1 comprising SEQ ID NO: 58, a HCDR2 comprising SEQ ID NO: 100, a HCDR3 comprising SEQ ID NO: 112, a LCDR1 comprising SEQ ID NO: 141, a LCDR2 comprising SEQ ID NO: 153, and a LCDR3 comprising SEQ ID NO: 165.
  • the isolated antibody comprises a VH comprising an amino acid sequence set forth in SEQ ID NO:3.
  • the isolated antibody comprises a VL comprising an amino acid sequence set forth in SEQ ID NO:39.
  • the isolated antibody comprises a VH comprising an amino acid sequence set forth in SEQ ID NO:3 and a VL comprising an amino acid sequence set forth in SEQ ID NO:39.
  • the isolated antibody comprises a heavy chain 132 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR constant (HC) region comprising an amino acid sequence set forth in SEQ ID NO: 439.
  • the isolated antibody comprises a heavy chain constant (HC) region comprising an amino acid sequence set forth in SEQ ID NO: 624.
  • the isolated antibody comprises a constant light chain (LC) region comprising an amino acid sequence set forth in SEQ ID NO: 469.
  • the isolated antibody comprises a heavy chain constant (HC) region comprising an amino acid sequence set forth in SEQ ID NO: 439 or 624 and a constant light chain (LC) region comprising an amino acid sequence set forth in SEQ ID NO: 469.
  • the isolated antibody comprises the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of Construct 133.
  • the isolated antibody comprises the VH of Construct 133.
  • the isolated antibody comprises the VL of Construct 133.
  • the isolated antibody comprises the VH and VL of Construct 133.
  • the isolated antibody comprises the heavy chain constant (HC) region of Construct 133.
  • the isolated antibody comprises the constant light chain (LC) region of Construct 133. In certain embodiments, the isolated antibody comprises the heavy chain constant (HC) region and constant light chain (LC) region of Construct 133. [00243] In certain embodiments, the isolated antibody comprises Construct 133, i.e., comprising a HCDR1 comprising SEQ ID NO: 58, a HCDR2 comprising SEQ ID NO: 100, a HCDR3 comprising SEQ ID NO: 112, a LCDR1 comprising SEQ ID NO: 141, a LCDR2 comprising SEQ ID NO: 153, a LCDR3 comprising SEQ ID NO: 165, a VH comprising SEQ ID NO:3, a VL comprising SEQ ID NO:39, a heavy chain constant (HC) region comprising an amino acid sequence set forth in SEQ ID NO: 439 or 624 and a constant light chain (LC) region comprising an amino acid sequence set forth in SEQ ID NO: 469.
  • Construct 133 i
  • the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions result in increased antibody half-life, increased ADCC activity, increased ADCP activity, or increased CDC activity compared with the Fc without the one or more substitutions.
  • the one or more amino acid substitutions results in increased antibody half-life at pH 6.0 compared to an antibody comprising a wild-type Fc region.
  • the one or more amino acid substitutions is selected from the group consisting of S228P (SP); M252Y, S254T, T256E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311V, A378V, E380A, M428L, N434A, N434S, N297A, D265A, L234A, L235A, and N434W.
  • SP S228P
  • the one or more amino acid substitutions comprises a plurality of amino acid substitutions selected from the group consisting of M428L/N434S (LS); M252Y/S254T/T256E (YTE); T250Q/M428L; T307A/E380A/N434A; T256D/T307Q (DQ); T256D/T307W (DW); M252Y/T256D (YD); T307Q/Q311V/A378V (QVV); T256D/H285D/T307R/Q311V/A378V (DDRVV); L309D/Q311H/N434S (DHS); S228P/L235E (SPLE); L234A/L235A (LA), M428L/N434A L234A/G237A (LALA), L234A/L235A/G237A, L234A/L235A/P329G
  • the antibodies described herein comprise an Fc region with YTE mutations at positions 253, 255, and 257. In certain embodiments, the antibodies described herein comprise an Fc region with LALA mutations at positions 235 and 236, respectively. In certain embodiments, the antibodies described herein comprise an Fc region with YTE mutations at positions 253, 255 and 257 and with LALA mutations at positions 235 and 236. In certain embodiments, the antibodies described herein comprise the heavy and light chain variable regions (VH and VL) as set forth in SEQ ID NOs: 3 and 39, respectively, and an Fc region comprising YTE mutations at positions 253, 255 and 257, respectively and with LALA mutations at positions 235 and 236, respectively.
  • VH and VL heavy and light chain variable regions
  • the antibodies described herein comprise a human IgG1 Fc with LALA mutations. In certain embodiments, the antibodies described herein comprise a human IgG1 Fc with YTE mutations. In certain embodiments, the antibodies described herein comprise a human IgG1 Fc with LALA and YTE mutations. In certain embodiments, when direct numbering is used these “YTE” and “LALA” mutations can be located at different amino acid position numbers.
  • the human Fc region comprises a human IgG1 Fc with LALA mutations at L235A/L236A and/or YTE mutations at M253Y/S255T/T257E.
  • the Fc region binds an Fc ⁇ Receptor selected from the group consisting of: Fc ⁇ RI, Fc ⁇ RIIa, Fc ⁇ RIIb, Fc ⁇ RIIc, Fc ⁇ RIIIa, and Fc ⁇ RIIIb.
  • the Fc region binds an Fc ⁇ Receptor with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.
  • the fragment crystallizable region (Fc region) of the IL-13 antibody described herein carries a triple substitution M252Y/S254T/T256E (YTE) designed to increase the half-life of the IgG.
  • the Fc region of the anti-IL-13 antibody described herein carries a triple substitution M253Y/S255T/T257E (YTE) designed to increase the half-life of the IgG.
  • YTE substitutions increase the binding of the modified IgG to the human neonatal Fc receptor (FcRn). FcRn-bound IgG is recycled via lysosomal salvage, resulting in the IgG returning to the circulation.
  • the YTE substitutions confer greater FcRn-IgG binding, prolonging the IgG serum half-life compared to an unmodified IgG.
  • LALA Modification [00250]
  • the IL-13 antibodies described herein additionally carries Fc region amino acid modifications L234A/L235A or L235A/L236A in the IgG1 heavy chain, commonly called LALA mutations. These changes can impair Fc receptor binding to IgG and prevent undesired effector cell activation.
  • an IL-13 antibody described herein is a high-affinity IgG1 humanized monoclonal antibody (mAb) that binds IL-13.
  • the IL-13 antibody described herein contains YTE and LALA modifications and is built on an IgG1 backbone.
  • the binding of the IL-13 antibodies described herein to IL-13 prevent the formation of the IL-13R ⁇ 1/IL-4R ⁇ active receptor heterodimer and subsequent IL-13-mediated signaling.
  • the direct consequences of IL-13 signaling in atopic dermatitis (AD) pathology include dermal thickening, increased CD4 + T cell infiltration, and dermal barrier disruption. Consequently, preventing receptor heterodimer formation is believed to decrease the clinical severity of AD.
  • the affinity of a molecule X for its partner Y can be represented by the dissociation equilibrium constant (KD).
  • KD dissociation equilibrium constant
  • the kinetic components that contribute to the dissociation equilibrium constant are described in more detail below.
  • Affinity can be measured by common methods known in the art, including those described herein, such as surface plasmon resonance (SPR) technology (e.g., BIACORE®) or biolayer interferometry (e.g., FORTEBIO®).
  • the terms “bind,” “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction (e.g., with a non- target molecule).
  • Specific binding can be measured, for example, by measuring binding to a target molecule (i.e., IL-13) and comparing it to binding to a non-target molecule.
  • Specific binding can also be determined by competition with a control molecule that mimics the epitope recognized on the target molecule. In that case, specific binding is indicated if the binding of the antibody to the target molecule is competitively inhibited by the control molecule.
  • the affinity of an IL-13 antibody for a non-target molecule is less than about 50% of the affinity for IL-13. In certain embodiments, the affinity of an IL-13 antibody for a non- target molecule is less than about 40% of the affinity for IL-13. In certain embodiments, the affinity of an IL-13 antibody for a non-target molecule is less than about 30% of the affinity for IL-13.
  • the affinity of an IL-13 antibody for a non-target molecule is less than about 20% of the affinity for IL-13. In certain embodiments, the affinity of an IL-13 136 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR antibody for a non-target molecule is less than about 10% of the affinity for IL-13. In certain embodiments, the affinity of an IL-13 antibody for a non-target molecule is less than about 1% of the affinity for IL-13. In certain embodiments, the affinity of an IL-13 antibody for a non- target molecule is less than about 0.1% of the affinity for IL-13.
  • the term “competes with” or “cross-competes with” indicates that the two or more antibodies compete for binding to an antigen (e.g., IL-13).
  • an antigen e.g., IL-13
  • IL-13 is coated on a surface and contacted with a first IL-13 antibody, after which a second IL-13 antibody is added.
  • a first IL-13 antibody is coated on a surface and contacted with IL-13, and then a second IL-13 antibody is added. If the presence of the first IL-13 antibody reduces binding of the second IL-13 antibody, in either assay, then the antibodies compete with each other.
  • the term “competes with” also includes combinations of antibodies where one antibody reduces binding of another antibody, but where no competition is observed when the antibodies are added in the reverse order.
  • the first and second antibodies inhibit binding of each other, regardless of the order in which they are added.
  • one antibody reduces binding of another antibody to its antigen by at least 25%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% as measured in a competitive binding assay.
  • concentrations of the antibodies used in the competition assays based on the affinities of the antibodies for IL-13 and the valency of the antibodies.
  • the assays described in this definition are illustrative, and a skilled artisan can utilize any suitable assay to determine if antibodies compete with each other. Suitable assays are described, for example, in Cox et al., “Immunoassay Methods,” in Assay Guidance Manual [Internet], Updated December 24, 2014 (ncbi.nlm.nih.gov/books/NBK92434/; accessed September 29, 2015); Silman et al., Cytometry, 2001, 44:30-37; and Finco et al., J. Pharm. Biomed. Anal., 2011, 54:351-358; each of which is incorporated by reference in its entirety.
  • test antibody competes with a reference antibody if an excess of a test antibody (e.g., at least 2x, 5x, 10x, 20x, or 100x) inhibits or blocks binding of the reference antibody by, e.g., at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as measured in a competitive binding assay.
  • a test antibody e.g., at least 2x, 5x, 10x, 20x, or 100x
  • Antibodies identified by competition assay include antibodies binding to the same epitope as the reference antibody and antibodies binding to an adjacent epitope sufficiently proximal to the epitope bound by the reference antibody for steric 137 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR hindrance to occur.
  • a second, competing antibody can be identified that competes for binding to IL-13 with a first antibody described herein.
  • the second antibody can block or inhibit binding of the first antibody by, e.g., at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as measured in a competitive binding assay.
  • the second antibody can displace the first antibody by greater than 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.
  • the antibody binds an IL-13 sequence set forth in SEQ ID NOs: 472-475.
  • the antibody binds to an IL-13 sequence set forth in SEQ ID NOs: 472-475 with a K D of less than or equal to about 1, 2, 3, 4, 5, 6, 7, 8, 9 x 10 -9 M, as measured by surface plasmon resonance (SPR).
  • the antibody binds to an IL-13 sequence set forth in SEQ ID NOs: 472-475 with a KD of less than or equal to about 1 x 10 -10 M, as measured by surface plasmon resonance (SPR). In certain embodiments, the antibody binds to human IL-13 with a K D of less than or equal to about 1 x 10 -9 M, as measured by surface plasmon resonance (SPR).
  • an antibody provided herein binds IL-13 with a KD of less than or equal to about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.95, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 x 10 -8 M, as measured by ELISA or any other suitable method known in the art.
  • an antibody provided herein binds IL-13 with a K D of less than or equal to about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.95, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 x 10 -9 M, as measured by ELISA or any other suitable method known in the art.
  • the K D of an antibody provided herein for the binding of IL- 13 is between about 0.001-0.01, 0.01-0.1, 0.01-0.05, 0.05-0.1, 0.1-0.5, 0.5-1, 0.25-0.75, 0.25-0.5, 0.5-0.75, 0.75-1, 0.75-2, 1.1-1.2, 1.2-1.3, 1.3-1.4, 1.4-1.5, 1.5-1.6, 1.6-1.7, 1.7-1.8, 1.8-1.9, 1.9-2, 1-2, 1-5, 2-7, 3-8, 3-5, 4-6, 5-7, 6-8, 7-9, 7-10, or 5-10 x 10 -8 M, as measured by ELISA or any other suitable method known in the art.
  • an antibody provided herein binds IL-13 with a KD of less than or equal to about 1 x 10 -8 M, or less than or equal to above 1 x 10 -9 M as measured by ELISA or any other suitable method known in the art.
  • an antibody provided herein binds IL-13 with a K D of less than or equal to about 10, 9, 8, 7, 6, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.98, 1.95, 1.9, 1.85, 1.8, 1.75, 1.7, 1.65, 1.6, 1.55, 1.50, 1.45, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.05, 0.01, 0.005, 0.001, 0.0005, or 0.0001 x 10 -8 M, or less, as measured by ELISA or any other suitable method known in the art .
  • an antibody provided herein binds IL-13 with a KD between 5-3, 4-2, 3-1, 1.9-1.8, 1.8-1.7, 1.7-1.6, 1.6-1.5, 1.9-1.5, 1.5-1, 1-0.8, 1-0.5, 0.9-0.6, 0.7-0.4, 0.6-0.2, 0.5-0.3, 0.3-0.2, 0.2-0.1, 0.1-0.01, 0.01-0.001, or 0.001-0.0001 x 10 -8 M as measured by ELISA or any other suitable method known in the art.
  • Pharmaceutical Formulations and Methods of Manufacture Thereof [00262]
  • the present disclosure provides pharmaceutical formulations that comprise a therapeutically effective amount of an IL-13 antibody disclosed herein.
  • the pharmaceutical formulation comprises one or more excipients and/or surfactants and is maintained at a certain pH.
  • excipient include any non-therapeutic agent added to the formulation to provide a desired physical or chemical property, for example, pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption, or penetration.
  • Methods of manufacturing pharmaceutical formulations of the disclosure are also contemplated.
  • the method can include adjusting the matrix of an intermediate preparation of the disclosure (e.g., changing the buffer composition and/or the concentration of a purified preparation of an IL-13 antibody), such as by Ultrafiltration and Diafiltration (UFDF), to increase a concentration of an IL-13 antibody.
  • a method of manufacturing an intermediate preparation of an interleukin 13 (IL-13) antibody comprising: (a) obtaining a purified preparation of the IL-13 antibody; and (b) adjusting the matrix of the purified preparation of step (a), wherein adjusting the matrix of comprises performing Ultrafiltration and Diafiltration (UFDF) with the diafiltration buffer of the above described aspect or any one of the embodiments thereof, thereby obtaining the intermediate preparation of the IL-13 antibody.
  • the intermediate preparation (e.g., a UFDF intermediate preparation) can be used to prepare a final preparation through the addition of excipients and/or dilution.
  • 139 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR
  • the intermediate preparation of the IL-13 antibody has a higher concentration of the IL-13 antibody relative to the purified preparation.
  • the method of manufacturing further comprises: (c) formulating the intermediate preparation to obtain a formulation of the IL-13 antibody.
  • the formulation of the IL-13 antibody comprises a formulation described herein.
  • a diafiltration buffer comprising: (a) a histidine buffer; and (b) arginine or a salt solution thereof, at pH of from 5.4 to 7.0, e.g., from 5.5-6.5. In some embodiments, the pH is from about 5.7 to about 6.5. In some embodiments, the pH is about 5.8 or about 6.0.
  • the histidine buffer comprises a histidine and a histidine salt. In some embodiments, the histidine is L-histidine. In some embodiments, the histidine salt is L- histidine HCl monohydrate.
  • Histidine buffer can be present in an amount of about 15-20 mM, for example, at about 18 mM.
  • the diafiltration buffer comprises arginine, and wherein the arginine is L-arginine.
  • the diafiltration buffer comprises an L-arginine salt solution.
  • the L-arginine salt solution salt solution comprises HCl monohydrate.
  • the L-arginine salt solution is at a concentration between 40 mM and 200 mM.
  • the L-arginine salt solution is at a concentration of about 50 mM.
  • the L-arginine salt solution is at a concentration of about 100 mM.
  • the L-arginine salt solution is at a concentration of about 120 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 170 mM.
  • Excipients, Surfactants, and pH may be selected for their suitability for intravenous or subcutaneous administration, providing the necessary stabilizing, buffering capacity, viscosity, and tonicity. The formulation can improve the stability of the IL-13 antibody and can provide a sterile solution suitable for subcutaneous or intravenous administration.
  • the excipients and/or surfactants contained in the formulation are pharmacopoeial grade excipients.
  • the excipients in the formulation comprise a histidine buffer (also referred 140 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR to as a His buffer) (e.g., a combination L-histidine and L-histidine HCl buffer, also referred to as L-His and L-His HCl), an acetate buffer, or a succinate buffer; arginine (Arg) and/or methionine (Met) (e.g., L-arginine (L-Arg) and/or L-methionine (L-Met)) or a salt solution thereof; and a polysorbate or a poloxamer.
  • a histidine buffer also referred 140 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Dock
  • the formulation further comprises a sugar or sugar alcohol.
  • the one or more excipients in the pharmaceutical formulation of the present invention can comprise a buffering agent.
  • buffering agent refers to one or more components that when added to an aqueous solution is able to protect the solution against variations in pH when adding acid or alkali, or upon dilution with a solvent.
  • histidine buffers, acetate buffers, and succinate buffers in certain embodiments, phosphate buffers, glycinate buffers, carbonate buffers, citrate buffers and the like can be used.
  • sodium, potassium or ammonium ions can serve as counterion.
  • the buffer or buffer system such as a histidine buffer (e.g., a combination L-histidine and L-histidine HCl buffer), acetate buffer, or succinate buffer, comprises at least one buffer that has a buffering range that overlaps fully or in part with the range of between 5.5 and 7.0 (e.g., between 5.6 and 6.5, and 5.7 and 6.2).
  • the pH is between 5.6 and 6.5.
  • the pH is between 5.8 and 6.0.
  • the buffer has a pH of about 5.5.
  • the buffer has a pH of about 5.6.
  • the buffer has a pH of about 5.7.
  • the buffer has a pH of about 5.8. In some embodiments, the buffer has a pH of about 5.9. In some embodiments, the buffer has a pH of about 6.0. In some embodiments, the buffer has a pH of about 6.1. In some embodiments, the buffer has a pH of about 6.2. In some embodiments, the buffer has a pH of about 6.3. In some embodiments, the buffer has a pH of about 6.4. In some embodiments, the buffer has a pH of about 6.5. In some embodiments, the buffer has a pH of about 5.9-6.3. In some embodiments, the buffer has a pH of about 6.0.
  • the histidine buffer e.g., a combination L-histidine and L- histidine HCl buffer
  • acetate buffer e.g., acetate buffer
  • succinate buffer is at a concentration between 5 mM and 20 mM (e.g., between 6 mM and 19 mM, 7 mM and 18 mM, 8 mM and 17 mM, 9 mM and 16 mM, and 10 mM and 15 mM).
  • the histidine buffer, acetate buffer, or 141 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR succinate buffer is at a concentration between 6 mM and 19 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration between 7 mM and 18 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration between 8 mM and 17 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration between 9 mM and 16 mM.
  • the histidine buffer, acetate buffer, or succinate buffer is at a concentration between 10 mM and 15 mM.
  • the histidine buffer e.g., a combination L-histidine and L- histidine HCl buffer
  • acetate buffer, or succinate buffer is at a concentration of about 1 mM.
  • the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 2 mM.
  • the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 3 mM.
  • the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 4 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 5 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 6 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 7 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 8 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 9 mM.
  • the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 10 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 11 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 12 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 13 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 14 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 15 mM.
  • the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 16 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 17 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 18 mM. In some embodiments, the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 19 mM.
  • the histidine buffer, acetate buffer, or succinate buffer is at a concentration of about 20 mM.
  • the formulation comprises a histidine buffer (e.g., a combination L-histidine and L-histidine HCl buffer), acetate buffer, or succinate buffer.
  • the formulation comprises a histidine buffer.
  • the histidine buffer comprises L-histidine and L-histidine HCl.
  • the formulation comprises an acetate buffer.
  • the formulation comprises a succinate buffer.
  • a histidine buffer acts as a buffering agent.
  • the histidine buffer comprises a histidine and a histidine salt.
  • the histidine is L-histidine.
  • the histidine salt is L-histidine HCl monohydrate.
  • the formulation comprises methionine. In some embodiments, the methionine is L-methionine.
  • the methionine (e.g., L-methionine) is at a concentration between 1 mM and 20 mM (e.g., between 2 mM and 19 mM, 3 mM and 18 mM, 4 mM and 17 mM, 5 mM and 16 mM, and 5 mM and 15 mM).
  • the L-methionine is at a concentration between 1 mM and 19 mM.
  • the L-methionine is at a concentration between 2 mM and 18 mM.
  • the L-methionine is at a concentration between 3 mM and 17 mM.
  • the L-methionine is at a concentration between 4 mM and 16 mM. In some embodiments, the L-methionine is at a concentration between 5 mM and 15 mM. [00281] In some embodiments, the methionine (e.g., L-methionine) is at a concentration of about 1 mM. In some embodiments, the L-methionine is at a concentration of about 2 mM. In some embodiments, the L-methionine is at a concentration of about 3 mM. In some embodiments, the L-methionine is at a concentration of about 4 mM. In some embodiments, the L-methionine is at a concentration of about 5 mM.
  • the methionine e.g., L-methionine
  • the methionine is at a concentration of about 1 mM. In some embodiments, the L-methionine is at a concentration of about 2 mM. In some embodiments,
  • the L-methionine is at a concentration of about 6 mM. In some embodiments, the L-methionine is at a concentration of about 7 mM. In some embodiments, the L-methionine is at a concentration of about 8 mM. In some embodiments, the L-methionine is at a concentration of about 9 mM. In some embodiments, the L-methionine is at a concentration of about 10 mM. In some embodiments, the L-methionine is at a concentration of about 11 mM.
  • the L-methionine is 143 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR at a concentration of about 12 mM. In some embodiments, the L-methionine is at a concentration of about 13 mM. In some embodiments, the L-methionine is at a concentration of about 14 mM. In some embodiments, the L-methionine is at a concentration of about 15 mM. In some embodiments, the L-methionine is at a concentration of about 16 mM. In some embodiments, the L-methionine is at a concentration of about 17 mM.
  • the L-methionine is at a concentration of about 18 mM. In some embodiments, the L-methionine is at a concentration of about 19 mM. In some embodiments, the L-methionine is at a concentration of about 20 mM.
  • the formulation comprises arginine. In some embodiments, the arginine is L-arginine. In some embodiments, the formulation comprises an L-arginine salt solution. In some embodiments, the L-arginine or L-arginine salt solution acts as a viscosity modulator. In some embodiments, the L-arginine salt solution salt solution comprises HCl monohydrate.
  • the arginine (e.g., L-arginine) salt solution is at a concentration between 40 mM and 250 mM (e.g., between 50 mM and 200 mM, 60 mM and 150 mM, 70 mM and 125 mM, 80 mM and 100 mM, and about 90 mM).
  • the arginine (e.g., L-arginine) salt solution is at a concentration between 70 mM and 130 mM.
  • the L-arginine salt solution is at a concentration of about 40 mM.
  • the L-arginine salt solution is at a concentration of about 50 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 60 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 70 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 80 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 90 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 100 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 120 mM.
  • the L-arginine salt solution is at a concentration of about 125 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 150 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 170 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 200 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 250 mM. 144 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR [00285]
  • the one or more excipients in the pharmaceutical formulation disclosed herein further comprises a surfactant.
  • surfactant refers to a surface active molecule containing both a hydrophobic portion (e.g., alkyl chain) and a hydrophilic portion (e.g., carboxyl and carboxylate groups). Surfactants are useful in pharmaceutical formulations for reducing aggregation of a therapeutic protein.
  • Surfactants suitable for use in the pharmaceutical formulations are generally non-ionic surfactants and include, but are not limited to, polysorbates (e.g., polysorbates 20 or 80); poloxamers (e.g., poloxamer 188); sorbitan esters and derivatives; Triton; sodium laurel sulfate; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl- sulfobetadine; lauryl-, myristyl-, linoleyl- or stearyl-sarcosine; linoleyl-, myristyl-, or cetyl- betaine; lauramidopropyl-cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropylbetaine (e.g.
  • the surfactant is a polysorbate. In certain embodiments, the surfactant is polysorbate 80. In certain embodiments, the surfactant is a poloxamer. In certain embodiments, the surfactant is poloxamer 188. [00286] In some embodiments, a polysorbate or poloxamer acts as a stabilizer. In some embodiments, the polysorbate or poloxamer is at a concentration between 0.005% w/v and 0.15% w/v or between 0.01% w/v and 0.15% w/v (e.g., between 0.02% and 0.14%, 0.03% and 0.13%, 0.04% and 0.12%, 0.05% and 0.11%, or about 0.1%).
  • the polysorbate or poloxamer is at a concentration between 0.02% and 0.14%. In some embodiments, the polysorbate or poloxamer is at a concentration between 0.03% and 0.13%. In some embodiments, the polysorbate or poloxamer is at a concentration between 0.04% and 0.12%. In some embodiments, the polysorbate or poloxamer is at a concentration between 0.05% and 0.11%.
  • the polysorbate or poloxamer is at a concentration between 0.005% w/v and 0.10% w/v, or between 0.005% w/v and 0.05% w/v or between 0.05% w/v and 0.10 w/v, or at about 0.05% w/v or at 0.05% w/v. [00287] In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.005% w/v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.01% w/v.
  • the polysorbate or poloxamer is at a concentration of about 145 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR 0.02% w/v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.03% w/v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.04% w/v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.05% w/v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.06% w/v.
  • the polysorbate or poloxamer is at a concentration of about 0.07% w/v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.08% w/v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.09% w/v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.1% w/v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.11% w/v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.12% w/v.
  • the polysorbate or poloxamer is at a concentration of about 0.13% w/v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.14% w/v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.15% w/v. [00288] In some embodiments, the polysorbate is polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80. In some embodiments, the polysorbate is polysorbate 20. In some embodiments, the polysorbate is polysorbate 40. In some embodiments, the polysorbate is polysorbate 60. In some embodiments, the polysorbate is polysorbate 80.
  • the poloxamer is poloxamer 188, also referred to herein as P188.
  • P188 is included in the formulation at a concentration in a range of, for example 0.1-2.0 mg/ml, 0.25-1.5 mg/ml or 0.5-1.0 mg/ml, or at a concentration of 0.25 mg/ml, 0.5 mg/ml, 0.75 mg/ml or 1.0 mg/ml.
  • the formulation comprises P188 at a concentration of 0.5 mg/ml.
  • the one or more excipients in the pharmaceutical formulation of the present invention can further comprise a metal ion chelator.
  • Metal ion chelators also known as chelating agents, bind metal ions to form water soluble complexes and thus can be used to remove metal ions from a formulation.
  • the metal ion chelator is ethylenediaminetetraacetic acid (EDTA), or a salt thereof (e.g., disodium EDTA, sodium calcium edetate, tetrasodium EDTA).
  • the metal ion chelator is EDTA disodium salt (EDTA-2Na).
  • the metal ion chelator is EDTA-2Na, which is included in the formulation at a concentration in a range of, for example, 0.001-1 mM or 0.01-1mM or 0.001-0.5 mM or 0.01-0.5 mM or at a 146 4925-0461-2873 v.1 4925-0461-2873 v.1
  • the formulation comprises EDTA (e.g., EDTA-2Na) at a concentration of 0.05 mM.
  • EDTA e.g., EDTA-2Na
  • Other metal ion chelators are known in the art, non-limiting examples of which include ethylenediamine (1,2-diaminoethane), diethylenetriaminepentaacetic acid (DTPA), ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), succimer (dimercaptonol), dimercaprol (BAL), nitrilotriacetic acid (NTA), iminodisuccinic acid (IDS), polyaspartic acid, S,S-ethylenediamine-N,N′-disuccinic acid (EDDS), methylglycinediacetic acid (MGDA), L-Glutamic acid N,N-diacetic acid, t
  • the one or more excipients in the pharmaceutical formulation of the present invention can further comprise a sugar or sugar alcohol.
  • Sugars and sugar alcohols are useful in pharmaceutical formulations as a thermal stabilizer.
  • the pharmaceutical formulation comprises a sugar, for example, a monosaccharide (glucose, xylose, or erythritol), a disaccharide (e.g., sucrose, trehalose, maltose, or galactose), or an oligosaccharide (e.g., stachyose).
  • the pharmaceutical formulation comprises sucrose.
  • the pharmaceutical composition comprises a sugar alcohol, for example, a sugar alcohol derived from a monosaccharide (e.g., mannitol, sorbitol, or xylitol), a sugar alcohol derived from a disaccharide (e.g., lactitol or maltitol), or a sugar alcohol derived from an oligosaccharide.
  • the pharmaceutical formulation comprises sucrose.
  • a sugar or sugar alcohol acts as a stabilizer.
  • the sugar or sugar alcohol is at a concentration between 1% w/v and 5% w/v (e.g., between 2% w/v and 4% w/v, or about 3% w/v). In some embodiments, the sugar or sugar alcohol is at a concentration between 2% w/v and 4% w/v. [00294] In some embodiments, the sugar or sugar alcohol is at a concentration of about 1% w/v. In some embodiments, the sugar or sugar alcohol is at a concentration of about 2% w/v. In some embodiments, the sugar or sugar alcohol is at a concentration of about 3% w/v. In some embodiments, the sugar or sugar alcohol is at a concentration of about 4% w/v.
  • the sugar or sugar alcohol is at a concentration of about 5% w/v. 147 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR
  • the sugar or sugar alcohol is a disaccharide.
  • the disaccharide is sucrose.
  • the formulation is adjusted to final volume in water for injection (WFI).
  • WFI water for injection
  • the drug product is diluted in an aqueous carrier suitable for the route of administration, e.g., intravenous administration.
  • Exemplary carriers include sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), a pH buffered solution (e.g., phosphate-buffered saline), sterile saline solution, Ringer's solution, or dextrose solution.
  • SWFI sterile water for injection
  • BWFI bacteriostatic water for injection
  • a pH buffered solution e.g., phosphate-buffered saline
  • sterile saline solution e.g., Ringer's solution
  • Ringer's solution e.g., Ringer's solution
  • dextrose solution e.g., sterile saline solution
  • D5W 5% dextrose solution
  • the pharmaceutical formulation of the present invention comprises: (a) an IL-13 antibody present at a concentration between 140 mg/mL and 290 mg/mL; (b) a histidine buffer (e.g., combination L-histidine and L-histidine HCl buffer), an acetate buffer (e.g., combination acetic acid and sodium acetate trihydrate), or a succinate buffer (e.g., combination succinic acid and sodium succinate hexahydrate); (c) arginine and/or methionine (e.g., L-arginine and/or L-methionine) or a salt solution thereof; and (d) a polysorbate or a poloxamer, at pH 5.0 to 7.0.
  • a histidine buffer e.g., combination L-histidine and L-histidine HCl buffer
  • an acetate buffer e.g., combination acetic acid and sodium acetate trihydrate
  • a succinate buffer e.g.,
  • the pharmaceutical formulation of the present invention comprises: (a) IL-13 antibody present at a concentration between 140 mg/mL and 290 mg/mL; (b) a histidine buffer (e.g., combination L-histidine and L-histidine HCl buffer), an acetate buffer (e.g., combination acetic acid and sodium acetate trihydrate), or a succinate buffer (e.g., combination succinic acid and sodium succinate hexahydrate); (c) arginine and/or methionine (e.g., L-arginine and/or L-methionine) or a salt solution thereof; and (d) a polysorbate or a poloxamer, at pH 5.0 to 7.0.
  • a histidine buffer e.g., combination L-histidine and L-histidine HCl buffer
  • an acetate buffer e.g., combination acetic acid and sodium acetate trihydrate
  • a succinate buffer e.g., combination
  • the IL-13 antibody comprises: (i) a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and (ii) a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein: (a) CDR-H1 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 58-99 and 121; (b) CDR-H2 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 100-111; 148 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR (c) CDR-H3 comprises a sequence selected from the sequences set forth in any one of SEQ ID NOs: 112-120 and 130-140, (d) CDR-L1 comprises a sequence selected from
  • the pharmaceutical formulation of the present invention comprises: (a) an IL-13 antibody at a concentration, e.g., between 140 mg/mL and 290 mg/mL; (b) a histidine buffer (e.g., a combination L-histidine and L-histidine HCl buffer), an acetate buffer, or a succinate buffer; (c) arginine and/or methionine (e.g., L-arginine and/or L- methionine) or a salt solution thereof; and (d) a polysorbate or a poloxamer, at pH 5.0 to 7.0.
  • a histidine buffer e.g., a combination L-histidine and L-histidine HCl buffer
  • an acetate buffer e.g., acetate buffer, or a succinate buffer
  • arginine and/or methionine e.g., L-arginine and/or L- methionine
  • a salt solution thereof e
  • the IL-13 antibody comprises: (i) a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and (ii) a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR- L2, and CDR-L3; wherein: (a) CDR-H1 comprises a sequence selected from the sequences set forth in any one of SEQ ID NO: 58, SEQ ID NO: 68, and SEQ ID NO: 85; (b) CDR-H2 comprises a sequence selected from the sequences set forth in any one of SEQ ID NO: 100, SEQ ID NO: 104, and SEQ ID NO: 108; (c) CDR-H3 comprises a sequence selected from the sequences set forth in any one of SEQ ID NO: 112 and SEQ ID NO: 130, (d) CDR-L1 comprises a sequence selected from the sequences set forth in any one of SEQ ID
  • the pharmaceutical formulation of the present invention comprises: (a) an IL-13 present at a concentration of, e.g., about 180 mg/mL; (b) a histidine buffer (e.g., a combination L-histidine and L-histidine HCl buffer) at a concentration of about 10 mM; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; and (e) polysorbate 80 at a concentration of about 0.05% w/v, at pH of about 5.8.
  • a histidine buffer e.g., a combination L-histidine and L-histidine HCl buffer
  • an L-arginine salt solution at a concentration of about 120 mM
  • L-methionine at a concentration of about 10 mM
  • polysorbate 80 at a concentration of about 0.05% w/v, at pH of about 5.8.
  • the pharmaceutical formulation of the present invention comprises: (a) IL-13 antibody present at a concentration of, e.g., about 180 mg/mL; (b) a 149 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR histidine buffer (e.g.,, a combination L-histidine and L-histidine HCl buffer) at a concentration of about 10 mM; (c) an L-arginine salt solution at a concentration of about 80 mM; (d) L- methionine at a concentration of about 10 mM; and (e) polysorbate 80 at a concentration of about 0.05% w/v, at pH of about 5.8.
  • AOE-003PR histidine buffer e.g.,, a combination L-histidine and L-histidine HCl buffer
  • an L-arginine salt solution at a concentration of about 80 mM
  • the pharmaceutical formulation of the present invention comprises: (a) IL-13 antibody present at a concentration of, e.g., about 200 mg/mL; (b) a histidine buffer (e.g., a combination L-histidine and L-histidine HCl buffer) at a concentration of about 10 mM; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L- methionine at a concentration of about 10 mM; and (e) polysorbate 80 at a concentration of about 0.05% w/v, at pH of about 5.8.
  • a histidine buffer e.g., a combination L-histidine and L-histidine HCl buffer
  • an L-arginine salt solution at a concentration of about 120 mM
  • L- methionine at a concentration of about 10 mM
  • polysorbate 80 at a concentration of about 0.05% w/v, at pH of about 5.8.
  • the pharmaceutical formulation of the present invention comprises: (a) an IL-13 antibody present at a concentration of, e.g., about 180 mg/mL (e.g., at 180 mg/ml); (b) a histidine buffer (e.g., a combination L-histidine and L-histidine HCl buffer) at a concentration of about 10 mM (e.g., at 10 mM); (c) an L-arginine salt solution at a concentration of about 120 mM (e.g., at 120 mM); (d) L-methionine at a concentration of about 10 mM (e.g., at 10 mM); (e) polysorbate 80 at a concentration of about 0.05% w/v (e.g., at 0.05% w/v); and (f) EDTA or a salt thereof (e.g., EDTA-2Na) at a concentration of about 0.05 mM (e.g.,
  • the pharmaceutical formulation of the present invention comprises: (a) an IL-13 antibody present at a concentration of, e.g., about 180 mg/mL (e.g., at 180 mg/ml); (b) a histidine buffer (e.g., a combination L-histidine and L-histidine HCl buffer) at a concentration of about 10 mM (e.g., at 10 mM); (c) an L-arginine salt solution at a concentration of about 120 mM (e.g., at 120 mM); (d) L-methionine at a concentration of about 10 mM (e.g., at 10 mM); (e) poloxamer 188 at a concentration of about 0.5 mg/ml (e.g., at 0.5 mg/ml), at pH of about 5.8-6.0 (e.g., at pH 5.8 or pH 6.0).
  • a histidine buffer e.g., a combination L-histidine and L-hist
  • the formulation comprises a sugar, for example, sucrose at a concentration between about 2% w/v and 8% w/v, such as a concentration of about 3% w/v or about 5% w/v.
  • a sugar for example, sucrose at a concentration between about 2% w/v and 8% w/v, such as a concentration of about 3% w/v or about 5% w/v.
  • the pharmaceutical formulations of the present invention exhibit high levels of stability.
  • a pharmaceutical formulation is stable when the IL-13 antibody within the formulation retains an acceptable degree of physical property, chemical structure, and/or biological function after storage under defined conditions.
  • the pharmaceutical formulation can be prepared and stored as a liquid formulation.
  • the pharmaceutical formulation is a liquid formulation for storage frozen (-20 to -70° C), under refrigerated conditions (typically 2-8° C), or at room temperature (typically 20-26° C) before preparation for administration.
  • the pharmaceutical formulation is a liquid formulation for storage at a suitable temperature and protected from light.
  • Antibody 180 mg/mL or 200 mg/mL concentrate for injection is suitable for subcutaneous administration with disposable syringes, without dilution or with dilution in a carrier buffer.
  • Materials found to be compatible with an antibody herein comprise injection syringes composed of polypropylene or polycarbonate, and needles for injection composed of stainless steel. Compatibility of antibody concentrate for solution for injection has been demonstrated with pre- filled syringes for an antibody concentration of from 160 mg/mL and 250 mg/mL.
  • the pharmaceutical formulation Prior to pharmaceutical use, can be diluted in an aqueous carrier if suitable for the route of administration.
  • a IL-13 antibody is fully formulated for subcutaneous administration (i.e., no diluents are added), and thus is identical in composition to the formulation described herein.
  • the IL-13 antibody may be further diluted in an appropriate carrier prior to pharmaceutical use.
  • suitable carriers include sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), a pH buffered solution (e.g., phosphate- buffered saline), sterile saline solution, Ringer’s solution, or dextrose solution.
  • SWFI sterile water for injection
  • BWFI bacteriostatic water for injection
  • a pH buffered solution e.g., phosphate- buffered saline
  • sterile saline solution e.g., Ringer’s solution
  • dextrose solution e.g., phosphate- buffered saline
  • Ringer’s solution e.g., Ringer’s solution
  • dextrose solution e.g., sterile saline solution
  • Ringer sterile saline solution
  • dextrose solution e.g., phosphate- buffered saline
  • Ringer sterile saline solution
  • the diluted pharmaceutical formulation is isotonic and suitable for administration by intravenous infusion, e.g., D5W.
  • the formulation is diluted in about 50 mL D5W, 100 mL D5W, 150 mL D5W, 200 mL D5W, 250 mL D5W, 300 mL D5W, 350 mL D5W, 400 mL D5W, 450 mL D5W, 500 mL D5W, or 1 L D5W.
  • the pharmaceutical formulation comprises the IL-13 antibody at a concentration suitable for storage.
  • the pharmaceutical formulation comprises the IL-13 antibody at a concentration between 160 mg/mL and 250 mg/mL (e.g., between 170 mg/mL and 210 mg/mL, 180 mg/mL and 200 mg/mL, or about 190 mg/mL).
  • the IL- 13 antibody is at a concentration between 170 mg/mL and 210 mg/mL.
  • the IL-13 antibody is at a concentration between 180 mg/mL and 200 mg/mL.
  • the IL-13 antibody is at a concentration of about 160 mg/mL.
  • the IL-13 antibody is at a concentration of about 170 mg/mL.
  • the IL-13 antibody is at a concentration of about 180 mg/mL. In some embodiments, the IL-13 antibody is at a concentration of about 190 mg/mL. In some embodiments, the IL-13 antibody is at a concentration of about 200 mg/mL. In some embodiments, the IL-13 antibody is at a concentration of about 210 mg/mL. In some embodiments, the IL-13 antibody is at a concentration of about 220 mg/mL. In some embodiments, the IL-13 antibody is at a concentration of about 230 mg/mL. In some embodiments, the IL-13 antibody is at a concentration of about 240 mg/mL. In some embodiments, the IL-13 antibody is at a concentration of about 250 mg/mL.
  • the IL-13 antibody is at a concentration of 160 mg/mL. In some embodiments, the IL-13 antibody is at a concentration of 170 mg/mL. In some embodiments, the IL-13 antibody is at a concentration of 180 mg/mL. In some embodiments, the IL-13 antibody is at a concentration of 190 mg/mL. In some embodiments, the IL-13 antibody is at a concentration of 200 mg/mL. In some embodiments, the IL-13 antibody is at a concentration of 210 mg/mL. In some embodiments, the IL-13 antibody is at a concentration of 220 mg/mL.
  • the IL-13 antibody is at a concentration of 230 mg/mL. In some embodiments, the IL-13 antibody is at a concentration of 240 mg/mL. In some embodiments, the IL-13 antibody is at a concentration of 250 mg/mL.
  • Formulations described herein may be included in e.g., a vial, bag, bottle or on-body device. In some embodiments, the vial is a syringe. In some embodiments, the vial is a glass syringe.
  • the syringe is a prefilled syringe. In some embodiments, the prefilled syringe is a prefilled glass syringe. Additionally, formulations herein may be included in and administered by pens, autoinjectors, including autoinjector syringes and cartridges, and on-body devices. In some embodiments, when an on-body device is used for administration, up to 5 mL of the formulation may be present in the device.
  • an extractable volume of the vial is between 1.0 mL and 10.0 mL, e.g., between 1.0 mL and 3.0 mL or between 3.0 mL and 10.0 mL. In some embodiments, the extractable volume of the vial is about 1.0, 2.0 mL, 3.0 mL, 4.0 mL, 5.0 mL, 6.0 mL, 7.0 mL, 8.0 mL, 9.0 mL or 10.0 mL. As used herein, the “extractable volume” of the vial is the amount that can be withdrawn from the receptacle.
  • the pharmaceutical formulation is packaged in a vial (e.g., a pen or syringe).
  • the vial comprises an overfill to allow for complete removal of the intended dose.
  • the vial comprises an overfill of 5 to 35%, 10 to 30%, 15 to 25%, or 10 to 20%.
  • the vial comprises an overfill of about 20%.
  • the formulation may be a liquid formulation.
  • the amount of IL-13 antibody in the container is suitable for administration as a single dose.
  • the amount of IL-13 antibody in the container is suitable for administration in multiple doses.
  • the pharmaceutical formulation comprises the IL-13 antibody in an amount of 0.1 to 200 mg.
  • the pharmaceutical formulation comprises the IL-13 antibody in an amount of 1 to 200 mg, 10 to 200 mg, 20 to 200 mg, 50 to 200 mg, 100 to 200 mg, 200 to 500 mg, 500 to 2000 mg, 1000 to 2000 mg, 0.1 to 1000 mg, 1 to 1000 mg, 10 to 1000 mg, 20 to 1000 mg, 50 to 1000 mg, 100 to 1000 mg, 200 to 1000 mg, 500 to 1000 mg, 0.1 to 500 mg, 1 to 500 mg, 10 to 500 mg, 20 to 500 mg, 50 to 500 mg, 100 to 500 mg, 200 to 500 mg, 0.1 to 200 mg, 1 to 200 mg, 10 to 200 mg, 20 153 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR to 200 mg, 50 to 200 mg, 100 to 200 mg, 0.1 to 100
  • the pharmaceutical formulation comprises the IL-13 antibody in an amount of about 0.1 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1500 mg, or about 2000 mg.
  • Methods of Use [00320] The present application provides compositions comprising a formulation or vial described herein for use in the treatment of an inflammatory disorder or disease.
  • the present application also provides compositions comprising a formulation or vial (e.g., pre-filled syringe) described herein for use in methods of treating inflammatory, allergic, and immunologic diseases, such as atopic dermatitis, in a patient in need thereof.
  • a formulation or vial e.g., pre-filled syringe
  • the patient has been diagnosed with moderate-to-severe atopic dermatitis.
  • the patient has had moderate-to-severe atopic dermatitis for at least one year.
  • the patient is a pediatric patient.
  • the patient has one or more of: (a) an Eczema Area and Severity Index Score (EASI) of ⁇ 10 (e.g., an EASI of ⁇ 16 or an EASI ⁇ 10 and ⁇ 16), (b) an Investigator Global Assessment (IGA) score of ⁇ 3 and (c) a body surface area (BSA) of ⁇ 10%.
  • EASI Eczema Area and Severity Index Score
  • ASI Eczema Area and Severity Index Score
  • the patient has an Eczema Area and Severity Index Score (EASI) of ⁇ 16.
  • the patient has an Eczema Area and Severity Index Score (EASI) of ⁇ 10 and less than 16.
  • EASI Eczema Area and Severity Index Score
  • the patient has an Investigator Global Assessment (IGA) score of ⁇ 3.
  • the patient has a body surface area (BSA) of ⁇ 10%.
  • the “Investigator Global Assessment” or “IGA” is an assessment measure used globally to rate the severity of the patient’s AD (Simpson E, et al. J Am Acad Dermatol. 2020;83(3):839-846).
  • AOE-003PR score is selected using descriptors that best describe the overall appearance of the lesions at a given time point. It is not necessary that all characteristics under Morphological Description be present.
  • the IGA can be conducted prior to conducting the EASI and BSA assessments.
  • the “Eczema Area and Severity Index” or “EASE is a measure used in clinical settings to assess the severity and extent of AD (Hanifin et al., Exp Dermatol. 2001; 10: 11-18).
  • EASI is a composite index with scores ranging from 0 to 72, with the higher values indicating more severe and or extensive disease.
  • the severity of erythema, induration/papulation, excoriation, and lichenification can be assessed by a clinician or other medical professional on a scale of 0 (absent) to 3 (severe) for each of the 4 body areas: head and neck, trunk, upper limbs, and lower limbs, with half points allowed.
  • the extent of AD involvement in each of the 4 body areas can be assessed as a percentage by body surface area of head, trunk, upper limbs, and lower limbs, and converted to a score of 0 to 6.
  • a total score (0 – 72) is assigned based on the sum of total scores for each of the four body region scores.
  • the “Scoring of Atopic Dermatitis” or “SCORAD” is a validated clinical tool for assessing the extent and intensity of AD developed by the European Task Force on Atopic Dermatitis (Consensus report of the European Task Force on Atopic Dermatitis. Dermatology. 1993; 186(l):23-31).
  • AD extent of AD is assessed as a percentage of each defined body area and reported as the sum of all areas, with a score ranging from 0 to 100 (assigned as “A” in the overall SCORAD calculation);
  • A the severity of 6 symptoms of AD: redness, swelling, oozing/crusting, excoriation, skin thickening/lichenification, dryness.
  • Each item is graded as follows: none (0), mild (1), moderate (2), or severe (3) (for a maximum of 18 total points, assigned as “B” in the overall SCORAD calculation); (iii) subjective assessment of itch and of sleeplessness is recorded for each symptom using a visual analogue scale (VAS), where 0 is no itch (or sleeplessness) and 10 is the worst imaginable itch (or sleeplessness), with a maximum possible score of 20 (assigned as “C” in the overall SCORAD calculation).
  • VAS visual analogue scale
  • the SCORAD Index formula is: A/5 + 7B/2 + C.
  • the maximal score of the SCORAD Index is 103.
  • Pruritus Numerical Rating Scale is an 11 -point scale used by patients (and if applicable, with help of parents/ caregiver if required) to rate their worst itch severity over the past 24 hours with 0 indicating “No itch” and 10 indicating “Worst itch imaginable” (Phan NQ, et al. Acta Derm Venereol 2012; 92: 502-507). Assessments are recorded by the patient daily 155 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR using an electronic diary.
  • the baseline pruritus NRS is determined based on the average of daily Pruritus NRS during the 7 days immediately preceding baseline. A minimum of 4 daily scores out of the 7 days immediately preceding baseline is required for this calculation.
  • Sleep loss scale rates patient’s sleep loss due to pruritus on a 5-point Likert scale (with scores ranging from 0 [not at all], 1 [a little], 2 [moderately], 3 [quite a bit], to 4 [unable to sleep at all]). Assessments will be recorded daily by the patient using an electronic diary.
  • the Patient-Oriented Eczema Measure is a 7-item, validated, questionnaire completed by the patient (and if applicable, with help of parents/ caregiver if required) to assess disease symptoms over the last week (Centre of Evidence Based Dermatology. POEM – Patient Oriented Eczema Measure. Available at www.nottingham.ac.uk/research/groups/cebd/resources/poem.aspx). Patients are asked to respond to 7 questions on skin dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping.
  • DLQI Dermatology Life Quality Index
  • the 10 questions cover the following topics: symptoms, embarrassment, shopping and home care, clothes, social and leisure, sport, work or study, close relationships, sex, and treatment, over the previous week.
  • Each question is scored from 0 to 3 (“not at all,” “a little,” “a lot,” and “very much”), giving a total score ranging from 0 to 30. A high score is indicative of a poor quality of life.
  • methods described herein comprise determining one or more of the following characteristics of the patient at baseline and during and after the induction period: Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Body Surface Area (BSA), Pruritus Numerical Rating Scale (NRS), Sleep loss scale, SCORing Atopic Dermatitis (SCORAD), Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI).
  • EASI Eczema Area and Severity Index
  • IGA Investigator Global Assessment
  • BSA Body Surface Area
  • NRS Pruritus Numerical Rating Scale
  • SCORing Atopic Dermatitis SCORAD
  • POEM Patient Oriented Eczema Measure
  • DLQI Dermatology Life Quality Index
  • methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: 156 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR Eczema Area and Severity Index (EASI).
  • methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Investigator Global Assessment (IGA).
  • methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Body Surface Area (BSA).
  • BSA Body Surface Area
  • methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Pruritus Numerical Rating Scale (NRS). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Sleep loss scale, SCORing Atopic Dermatitis (SCORAD). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Patient Oriented Eczema Measure (POEM). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Dermatology Life Quality Index (DLQI).
  • DLQI Dermatology Life Quality Index
  • a patient described herein is determined to have one or more of the following characteristics of the patient at baseline and during and after the induction period: Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Body Surface Area (BSA), Pruritus Numerical Rating Scale (NRS), Sleep loss scale, SCORing Atopic Dermatitis (SCORAD), Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI).
  • EASI Eczema Area and Severity Index
  • IGA Investigator Global Assessment
  • BSA Body Surface Area
  • NRS Pruritus Numerical Rating Scale
  • PES Patient Oriented Eczema Measure
  • DLQI Dermatology Life Quality Index
  • a patient herein is determined to have a characteristic Eczema Area and Severity Index (EASI) at baseline and during and after the induction period.
  • a patient herein is determined to have a characteristic Investigator Global Assessment (IGA) at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Body Surface Area (BSA) at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Pruritus Numerical Rating Scale (NRS) at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Sleep loss scale, SCORing Atopic Dermatitis (SCORAD) at baseline and during and after the induction period.
  • IGA Investigator Global Assessment
  • BSA Body Surface Area
  • NRS Pruritus Numerical Rating Scale
  • a patient herein is determined to have a characteristic Sleep loss scale, SCORing Atopic Dermatitis (SCORAD) at baseline and during and after the induction period.
  • a patient herein is determined to have a characteristic Patient Oriented Eczema Measure (POEM) at baseline and during and after the induction period. 157 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR
  • a patient herein is determined to have a characteristic Dermatology Life Quality Index (DLQI) at baseline and during and after the induction period.
  • DLQI Dermatology Life Quality Index
  • the present application provides methods of contacting IL-13 with an IL- 13 antibody, such as a human, humanized, or chimeric antibody, which results in inhibition of IL-13 binding to an IL-13 receptor expressed on a cell.
  • compositions comprising a formulation or vial described herein for use in the treatment of an inflammatory disorder or disease selected from the group consisting of asthma, idiopathic pulmonary fibrosis, alopecia areata, chronic sinusitis with nasal polyps, Chronic Rhinosinusitis without Nasal Polyps (CRSsNP), eosinophilic esophagitis (EoE), an Eosinophilic gastrointestinal disorder or disease (ENID) selected from the group consisting of Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), and Eosinophilic Gastroenteritis (EGE), Churg-Strauss syndrome/Eosinophilic granulomatosis with polyangiitis (EGPA), Prurigo Nodularis (PN), of Chronic Spontaneous Urticaria (CSU), Chronic Pruritis of an inflammatory disorder or disease selected from the group consisting
  • the present application provides methods for treating an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the formulation described herein.
  • the inflammatory disorder or disease is atopic dermatitis.
  • the inflammatory disorder or disease is selected from the group consisting of asthma, idiopathic pulmonary fibrosis, alopecia areata, chronic sinusitis with nasal polyps, Chronic Rhinosinusitis without Nasal Polyps (CRSsNP), eosinophilic esophagitis (EoE), an Eosinophilic gastrointestinal disorder or disease (ENID) selected from the group consisting of Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), and Eosinophilic Gastroenteritis (EGE), Churg-Strauss syndrome/Eosinophilic granulomatosis with polyangiitis (EGPA), Prurigo Nodularis (PN), of Chronic Spontaneous Urticaria (CSU), Chronic Pruritis of Unknown Origin (CPUO), Bullous Pemphigoid (BP), Cold In
  • the inflammatory disorder or disease is asthma. In some embodiments, the inflammatory disorder or disease is idiopathic pulmonary fibrosis. In some embodiments, the inflammatory disorder or disease is alopecia areata. In some embodiments, the inflammatory disorder or disease is chronic sinusitis with nasal polyps. In some embodiments, the inflammatory disorder or disease is Chronic Rhinosinusitis without Nasal Polyps (CRSsNP). In some embodiments, the inflammatory disorder or disease is eosinophilic esophagitis (EoE).
  • EoE eosinophilic esophagitis
  • the inflammatory disorder or disease is an Eosinophilic gastrointestinal disorder or disease (ENID) selected from the group consisting of Eosinophilic Gastritis (EoG).
  • EoG Eosinophilic Gastritis
  • the inflammatory disorder or disease is Eosinophilic Enteritis (EoN).
  • EoC Eosinophilic Colitis
  • the inflammatory disorder or disease is and Eosinophilic Gastroenteritis (EGE).
  • the inflammatory disorder or disease is Churg-Strauss syndrome/Eosinophilic granulomatosis with polyangiitis (EGPA).
  • the inflammatory disorder or disease is Prurigo Nodularis (PN).
  • the inflammatory disorder or disease is of Chronic Spontaneous Urticaria (CSU).
  • the inflammatory disorder or disease is Chronic Pruritis of Unknown Origin (CPUO).
  • the inflammatory disorder or disease is Bullous Pemphigoid (BP).
  • the inflammatory disorder or disease is Cold Inducible Urticaria (ColdU).
  • the inflammatory disorder or disease is Allergic Fungal Rhinosinusitis (AFRS).
  • the inflammatory disorder or disease is Allergic Bronchopulmonary Aspergillosis (ABPA).
  • the inflammatory disorder or disease is Chronic Obstructive Pulmonary Disease (COPD).
  • COPD Chronic Obstructive Pulmonary Disease
  • the present application provides methods for treating a pathology associated with elevated levels of IL-13 in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the formulation described herein.
  • the present application provides methods of reducing biological activity of IL-13 in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the formulation described herein.
  • the present application provides methods of inhibiting the TH2 type allergic response in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the formulation described herein.
  • the present application provides methods of reducing levels of Thymus and Activation Regulated Chemokine (TARC)/CCL17 in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the formulation described herein.
  • the present application provides methods of preventing an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the formulation described herein.
  • the formulation is administered subcutaneously or intravenously.
  • Example 1 Formulation of an Anti-Interleukin 13 Antibody: pH and Buffer Studies [00344] This Example describes formulation studies of an interleukin 13 (IL-13) antibody, Construct 133. In formulating the antibody, twelve pH/buffers were investigated under stress conditions (40 °C for up to 4 weeks) to select pH and buffer system that stabilize the antibody.
  • IL-13 interleukin 13
  • a panel of analytical methods were used to characterize the pH and buffer studies, including appearance, pH, protein concentration, size exclusion-ultra performance liquid chromatography (SE-UPLC), imaged capillary isoelectric focusing (iCIEF), chip method of sodium dodecyl sulfate-polyacrylamide capillary electrophoresis (non-reduced and reduced, Caliper-SDS-NR & R, respectively), and differential scanning calorimetry (DSC), described below.
  • SE-UPLC size exclusion-ultra performance liquid chromatography
  • iCIEF imaged capillary isoelectric focusing
  • chip method of sodium dodecyl sulfate-polyacrylamide capillary electrophoresis non-reduced and reduced, Caliper-SDS-NR & R, respectively
  • DSC differential scanning calorimetry
  • Buffers tested included a histidine buffer (i.e., combination L-histidine and L-histidine HCl buffer), an acetate buffer, a succinate buffer, and a phosphate buffer (PB). The histidine, acetate, and succinate buffers stabilized the antibody well.
  • a histidine buffer i.e., combination L-histidine and L-histidine HCl buffer
  • PB phosphate buffer
  • the spectrometer was used to measure the absorbance in two cuvettes in parallel, and the concentration value was calculated.
  • SE-UPLC The pH meter was calibrated with three different standards (pH 4.01, 7.00, and 9.21) prior to usage. The slope of calibration was between 95.0% to 105.0%. Each sample was measured twice, and an average result was reported.
  • SE-UPLC [00350] SE-UPLC was used as a purity analysis method to separate proteins based on their sizes. Size exclusion chromatography was performed on an Agilent UPLC system with a size 161 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR exclusion chromatography (SEC) column (Waters Acquity BEH 150 ⁇ 4.6 mm, 1.7 ⁇ m).
  • the sampler temperature was set to 5 ⁇ 3 °C and the column oven temperature was set as 25 ⁇ 3 °C.
  • the mobile phase was 50 mM PB, 300 mM NaCl, pH 6.8 ⁇ 0.1; and the flow rate was set as 0.4 mL/min. 10 ⁇ g of each sample was injected. Detection wavelength was set at 280 nm and the run time was 8 min. Data was analyzed by Agilent CDS Software.
  • iCIEF [00351] iCIEF was used to monitor the distribution of charged variants.
  • the isoelectric point (pI) which is an intrinsic property of a given protein, is the pH at which the protein molecule did not carry net electrical charge.
  • Antibody samples were mixed with master mixture to generate loading mixture, which contained 4.0 ⁇ L Pharmalyte 3-10, 35 ⁇ L 1% MC, 0.5 ⁇ L pI marker 4.65, 0.5 ⁇ L pI marker 9.22, 37.5 ⁇ L 8 M urea solution, and 2.5 ⁇ L ultrapure water at a final protein concentration of 1.0 mg/mL.
  • the loading mixture was loaded into a Maurice iCIEF cartridge and analyzed with Maurice Capillary Isoelectric Focusing Analyzer with whole-column detection camera. After the analysis, the raw data were processed with Empower 3.
  • Reduced Caliper SDS (Caliper-SDS-R) was performed based on a PerkinElmer Caliper automated electrophoresis that allowed protein separation by size after reduction of 162 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR sample.
  • samples were diluted to 1 mg/mL with pure water. 2 ⁇ L of diluted samples were mixed with 7 ⁇ L of the sample denaturing solution (the mixture of sample buffer, 10% SDS solution, and 1 M dithiothreitol as a reduction agent, with the volume ratio of 100:10:4).
  • Measurements were performed on MicroCalTM VP Capillary DSC for thermal transition midpoint (Tm) and onset of unfolding (T Onset ) testing. Samples were diluted to 1 mg/mL with the reference buffer. 400 ⁇ L of respective reference buffers were added into the odd-numbered wells of a 96-well plate, and 400 ⁇ L of samples were added into the even-numbered wells of the same plate. Experimental parameters were set such that the scan temperature ramped from 10 °C to 95 °C at a scan rate of 200 °C/hour. Data analysis was performed in MicroCal VP Capillary DSC automated data analysis software.
  • a total of 12 pH/buffer systems covering the pH range from 4.5 to 7.5 were designed, including 20 mM acetate buffer (pH 4.5, pH 5.0, and pH 5.5), 20 mM succinate buffer (pH 5.0, pH 5.5, and pH 6.0), 20 mM histidine buffer (pH 5.5, pH 6.0, and pH 6.5; histidine buffers refers throughout Examples to a combination of L-histidine and L-histidine HCl), and 20 mM phosphate buffer (PB) (pH 6.5, pH 7.0, and pH 7.5).
  • the antibody was buffer-exchanged into 12 buffers, then concentrated to target protein concentration (150 mg/mL), respectively.
  • Each of the 12 solutions was filtered with a 0.22 ⁇ m polyvinylidene fluoride (PVDF) filter and filled into 2 mL glass vials (1 mL per vial), then stoppered, capped, and labeled.
  • PVDF polyvinylidene fluoride
  • Each of the twelve samples was tested for appearance, protein concentration, SE-UPLC, iCIEF, Caliper-SDS-NR & R, DSC, 163 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR and pH at Day 0. Additionally, at Day 0, after testing, the twelve samples were stored at 40 °C for up to 4 weeks.
  • Caliper-SDS-NR & R For Caliper-SDS-NR, the purity of all samples decreased with the increase of incubation time at 40 °C for up to 4 weeks (up to 22.0%). Acetate at pH 4.5 (B1), PB at pH 7.0 and 7.5 (B11 and B12, respectively) showed a faster and greater decline (> 8% by 4 weeks) than the samples in the other pH/buffer systems. Samples in the succinate and histidine buffer systems, particularly succinate at pH 6.0 (B6) and histidine at pH 5.5, 6.0, and 6.5 (B7, B8 and B9, respectively) performed relatively better.
  • T Onset values were higher than 55.0 °C in all formulations except acetate buffer at pH 4.5 (B1) and succinate buffer at pH 5.0 (B4), indicating good conformational thermal stability overall.
  • the pH/buffer studies investigated twelve pH/buffer types under stress conditions (40 °C for up to 4 weeks), and the results showed that stability of the antibody was dependent upon both the pH and buffer. Taken together, the studies herein demonstrated relatively poor protein stability in acetate at pH 4.5 and 5.0 (B1 and B2, respectively), succinate at pH 5.0 and 5.5 (B4 and B5, respectively) and all PB buffer systems (pH 6.5-7.5, B10-B12, respectively).
  • Example 2 Formulation of an Anti-IL-13 Antibody: Excipients and Surfactant Strength Studies [00365] This Example describes formulation studies of an IL-13 antibody.
  • excipients e.g., sucrose, ⁇ / ⁇ -trehalose dihydrate, and L-arginine hydrochloride (Arg-HCl), L-methionine, etc.
  • concentration of a polysorbate e.g., polysorbate 80 (PS80) at 0.02% w/v, 0.04% w/v, and 0.06% w/v
  • a poloxamer e.g., poloxamer 188 (P188) at 0.05% w/v, 0.08% w/v, and 0.10% w/v
  • stress conditions 40 °C for up to 4 weeks, agitation at 300 rpm for up to 3 days, and freeze and thaw for up to 5 cycles
  • a panel of analytical methods were used to characterize the excipients and surfactant strengths, including appearance, pH, protein concentration, SE-UPLC, Caliper-SDS-NR & R, and iCIEF (the Methods of which are described in Example 1), as well as osmolality, viscosity, and amount of sub-visible particles by micro-flow imaging (MFI), described below.
  • MFI micro-flow imaging
  • Excipient L-arginine was selected for further testing based upon data that demonstrated that it improved (decreased) viscosity.
  • Table 11 Excipients Name Vendor Cat. No. 166 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR Name Vendor Cat. No. Sodium acetate trihydrate Avantor 3461-01 0 0 0 0 0 0 C 0 0 2 0 , , , , , , [00368] See Example 1.
  • Osmolality was measured using an Advanced 2020 Multi-Sample Osmometer. Before and after the tests, the testing accuracy of the osmometer was confirmed with a Clinitrol 290 mOsm/kg reference solution. The sample volume for testing was 20 ⁇ L, and only one test was performed for each sample. Viscosity [00370] A viscosity test was used to characterize the fluid properties of liquid sample. Measurements were performed by a VROC® initium one plus viscometer (Rheosense).
  • Osmolality, viscosity, and pH As shown in Table 14, the pH of all the tested formulations was reported at their target value at T0. The osmolality, which is not a stability- indicative parameter, of all samples was approximately 285 mOsm/kg to 320 mOsm/kg, which demonstrated suitability for subcutaneous administration. The viscosity of all samples was between 5.9 mPa-s to 9.3 mPa-s, where the addition of Arg-HCl (E4 and E5) reduced the viscosity compared to those of other formulations.
  • Table 14 Osmolality, pH, and Viscosity Results Osmolality H Viscosity ) 170 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR E1 (Sucrose, 0.02% PS80) 302 6.0 8.4 E2 (Sucrose Methionine 002% PS80) 295 60 82 remained relatively stable during the study.
  • Sub-visible particle Compared with T0, no substantial changes were observed in the amount of sub-visible particles ( ⁇ 2 ⁇ m, ⁇ 10 ⁇ m, or ⁇ 25 ⁇ m) after FT for 5 cycles, agitation for 3 days, or 40 °C incubation for 4 weeks in all tested formulations. By comparing samples within the same buffer system but different excipients (E1-E7), no differences of the amount of sub-visible particles were observed. Additionally, there were no obvious differences in the amount of the sub-visible particles in E1 (0.02% PS80), E8 (0.04% PS80), E9 (0.06% PS80), E10 (0.10% P188), E11 (0.08% P188), and E12 (0.05% P188).
  • SE-UPLC The data summary from the SE-UPLC testing for excipients and surfactants strength study is provided in Table 15. After freeze and thaw for 5 cycles or agitation for 3 days, the main peak % of all the test formulations remained at approximately 99.0% indicating consistent antibody freeze and thaw stability and agitation stability under the studied parameter in all studied formulations. [00381] After incubation at 40 °C for 4 weeks, the main peak % in all formulations declined by up to 2.9% compared to T0, although the differences were small. E8 and E9 (Sucrose, 0.04% and 0.06% PS80) showed slightly lower main peak levels.
  • E2 (Sucrose, Methionine, 171 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR 0.02% PS80) showed the smallest changes in main peak purity and HMW species, indicating that L-methionine helped control HMW formation.
  • Table 15 SE-UPLC Results Formulation No. Stress SE-UPLC (Main peak % 3 6 3 6 3 6 172 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR Formulation No. Stress SE-UPLC (Main peak % 3 6 3 6 .
  • Caliper-SDS-NR & R The data summary from the Caliper-SDS-NR & R testing for excipients and surfactants strength study is provided in Table A.
  • E1 Sudrose
  • E3 Sudrose, EDTA-2Na
  • E6 Tehalose dihydrate
  • E7 Sorbitol
  • Example 3 Formulation of an Anti-IL-13 Antibody: Viscosity and Osmolality Studies
  • This Example describes formulation studies of an IL-13 antibody.
  • a key parameter was viscosity.
  • Different excipients e.g., Arg-HCl, glycine, and proline
  • a panel of analytical methods were used to characterize the viscosity excipient studies, including appearance, MFI, protein concentration, SE-UPLC, pH, osmolality, and viscosity (the Methods of which are described in Example 1 and Example 2).
  • the formulations selected for this stage of testing included a pH of about 5.8 due to its favorable results in SE-UPLC experiments (see Example 1), a histidine buffer (or comparable acetate or succinate buffer, respectively) and L-methionine, which was demonstrated to help control HMW formation and antibody purity (see Example 2).
  • the excipient L-arginine was identified as useful for reducing viscosity.
  • Methods [00388] In brief, the IL-13 antibody was in a histidine buffer system at pH 6.0 with protein concentration at 257 mg/mL.
  • Arg-HCl was selected as a viscosity modulator, and further experiments were conducted to identify a suitable Arg-HCl concentration to enable a high protein concentration, yet reduce viscosity.
  • Arg-HCl and antibody protein concentrations that minimize viscosity and achieve osmolality in an acceptable range.
  • Analytical testing included measurement of protein concentration, pH, osmolality, and viscosity at 20 °C and 25 °C. The results are shown in Table 19 and Table 20, with Table 19 outlining the formulations used in the experiments of Table 20.
  • Formulation A 10 mM His buffer, 10 mM Met, 150 mM Arg-HCl, 0.05% PS80, pH 5.8
  • Formulation B 10 mM His buffer, 10 mM Met, 80 mM Arg-HCl, 3%(w/v) sucrose, 0.05% PS80, pH 5.8
  • Formulation C 10 mM His buffer, 10 mM Met, 120 mM Arg-HCl, 0.05% PS80, pH 5.8.
  • Table 21 Additional osmolality and viscosity experiments of the three formulations are shown in Table 21, which were used to characterize the formulations over a range of antibody protein concentration.
  • Arg-HCl was selected for inclusion in the final formulation as a viscosity modifier and L-Methionine was included in the formulation based on experiments described in Example 2, particularly the finding that L-methionine helped control HMW formation and antibody purity.
  • sucrose may be advantageous as a cryoprotectant, however it increased viscosity and osmolality. Based upon this, the inclusion of sucrose was further tested with a reduced concentration of L- arginine to compensate for the impact to osmolality in long term storage and stability studies described in Example 6 and Example 7.
  • Table 19 Formulations Tested in Further Viscosity Studies Target concentration (mg/mL) Final formulation 220 0, 0, Table 20: Further Viscosity Study Results [Arg- Target Measured pH Osmolality Viscosity Viscosity 186 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR [Arg- Target Measured pH Osmolality Viscosity Viscosity HCl] conc.
  • the experiment consisted of: Run 1: 904.4 g/m 2 , Run 2: 965.8 g/m 2 , and Run 3: 971.9 g/m 2 using a Millipore, PES Type D Screen, 30 kDa membrane with 2 ⁇ 0.11 m 2 for Run 1 and 3 ⁇ 88 cm 2 for Runs 2 and 3.
  • the DF buffers tested were 15 mM His-HCl, 120 mM Arg-HCl with a pH of 5.7, 5.5, and 5.9 for Runs 1-3, respectively. The results are provided in Table 23.
  • Example 5 Formulation of an Anti-IL-13 Antibody: Injectability Study [00401]
  • This Example describes injectability studies to evaluate whether the forces required for injection would be acceptable for the formulation, as described and developed in Examples 1-4, of an IL-13 antibody.
  • the formulations selected for this stage of testing included a pH of about 5.8 due to its favorable results in SE-UPLC experiments (see Example 1), a histidine buffer (or comparable acetate or succinate buffer, respectively), L-methionine, which was demonstrated to help control HMW formation and antibody purity (see Example 2), and the excipient Arg-HCl, based on its ability to reduce viscosity (see Example 3).
  • the break-loose force and glide force method quantitatively measured the forces required to complete a prefilled syringe (PFS) injection (i.e., expel the content of the PFS).
  • PFS prefilled syringe
  • Break-loose force was defined as the force required to cause a change (from a rested position) in the plunger stopper position.
  • Glide force maximum glide force was defined as the maximum force measured on the glide force profile during the course of expelling the contents of a PFS.
  • the test was conducted with an Instron materials testing machine-34TM-5 equipped with a 2000N load cell. The load cell was selected based on the sample property (the maximum force is within the 70% of the load cell range).
  • the crosshead moved at a 140 mm/min speed to apply compressive force to the PFS plunger rod.
  • the measured compression force was recorded at 60 Hz as the content of the PFS being extruded (expelled).
  • the measurement stopped when the force reached end of test criteria where the plunger stopper hits the end of syringe barrel. Data are reported numerically in 2 decimal places (N). [00403]
  • the required amounts of material, excipient stock solutions, and surfactant stock solution were calculated, weighed, and well-mixed to prepare formulations with the target protein concentration at 220 mg/mL according to the formulation recipes listed in Table 24.
  • a panel of analytical methods were used to evaluate long-term storage conditions, the Methods of which are described in Example 1 and Example 2 and in the Potency section, below.
  • formulated antibody was used to fill either a 2R glass vial and stopper (e.g.. Schott cat no 1626151 and West cat no 1970-0173) to represent a drug product configuration or a Sartorius Celsius FFT bag to represent a drug substance configuration.
  • the vial configuration was tested at 5 °C (the intended storage temperature), 25 °C, or 40 °C, as well as for photostability under dark versus light conditions.
  • the higher temperatures and photostability conditions were intended to evaluate more stressful conditions to provide an early indication of potential degradation pathways that may occur during long term storage at the intended storage 194 4925-0461-2873 v.1 4925-0461-2873 v.1 Attorney Docket No.: AOE-003PR temperature and/or manufacturing procedures.
  • the bag configuration was tested at -70 °C and for freeze thaw cycles to evaluate stability during long term storage and/or manufacturing procedures. Potency [00408]
  • the binding assay used was an enzyme-linked immunosorbent assay (ELISA).
  • IL-13 is an immunoregulatory cytokine, which regulates the function of human B cells and monocytes. In this assay, IL-13 was immobilized onto a 96-well plate.
  • WBP2546 was added and bound to the captured human IL-13.
  • the bound WBP2546 was detected by anti-human IgG (F(ab’)2 specific)-peroxidase secondary antibody.
  • 3,3',5,5' tetramethylbenzidine (TMB) substrate solution was loaded into the wells subsequently.
  • a blue color developed in proportion to the amount of bound secondary antibody. Blue color development was stopped by adding stop solution and the color changed to yellow.
  • the measured absorbance at 450 nm was subtracted from absorbance at 650 nm, producing a signal that was proportional to the concentration of the analyte in the well.
  • the vial configuration was tested at 5 °C (the intended storage temperature), 25 °C, or 40 °C as well as for photostability under dark versus light conditions, The higher temperatures and photostability conditions were intended to evaluate more stressful conditions to provide an early indication of potential degradation pathways that may occur during long term storage at the intended storage temperature and/or manufacturing procedures.
  • the bag configuration was tested at -70 °C and for freeze thaw cycles to evaluate stability during long term storage and/or manufacturing procedures. [00411] Using a fill volume of 2.7 mL per vial or bag, three formulations (F1, F2, and F3), outlined in Table 26, were tested under the various conditions.
  • the formulations selected this stage of testing included a pH of about 5.8 due to its favorable results in SE-UPLC experiments (see Example 1), a histidine buffer (or comparable acetate or succinate buffer, respectively), L-methionine, which was demonstrated to help control HMW formation and antibody purity (see Example 2), and the excipient Arg-HCl, based on its ability to reduce viscosity (see Example 3).
  • Table 26 Formulations Tested for Long-Term Storage and Stability No. Protein pH Buffer and Excipient Excipient Excipient conc.
  • surfactant 1 2 3 pH, appearance, sub-visible particles (MFI), protein concentration, SE-UPLC, iCIEF, and CE-SDS, were evaluated for the vial configuration using the Materials and Methods described throughout Examples 1-2 after 1 month of storage at 5 °C, 25 °C, or 40 °C, photostability under dark and light conditions. Storage at -70 °C and free/thaw stability was evaluated for the bag configuration. [00413] The T0 antibody, histidine, and L-arginine concentrations, osmolality, and viscosity data are presented in Table 27. Table 27: Concentrations, Osmolality, and Viscosity Results No.
  • the decreased purity may be caused by aggregates instead of fragments.
  • No substantial decreases were observed for dark control samples stored at 25°C for 7 days and 14 days (two weeks). No substantial difference between F1, F2, and F3 were observed after 1000 lux light exposure for 7 days (1 week) and 14 days (2 weeks).
  • F2, stored at -70 °C for 1 month (1M) a substantial increase in ⁇ 2 ⁇ m was observed in sub-visible particles results (Table 30).
  • F1, F2, and F3, stored at -70 °C for 1 month no substantial changes were observed in SEC/Caliper/iCIEF/PS80 test results (Table 30).
  • Example 7 12-Month Stability Study of Three Formulations
  • three formulations were tested for stability under various conditions over a 12-month period.
  • the tested formulations are shown in Table 32, referred to as F1, F2 and F3, with the control formulation referred to as F4.
  • the anti-IL-13 antibody (protein) used in this example was Construct 133.
  • Table 32 Formulations Tested Protein pH Buffer and Excipient Excipient Excipient Formulation Conc.
  • Surfactant 1 2 3 - Samples were prepared to a fill-volume of 2.7 ml/vial or 4 ml/bag. The study plan for the various conditions tested, and the sampling schedule, are shown in Table 33.
  • the quality aspects set forth in Table 33 were tested as described in previous examples. The results for the stability data at 5°C, 25°C, 40°C and -70°C storage conditions are shown in Table 34, Table 35, Table 36 and Table 37, respectively.
  • Example 8 Investigation of PS80 Degradation In the stability studies described in Example 7, degradation of PS80 was observed in certain samples under certain conditions. Accordingly, studies were performed to identify the mechanism(s) of PS80 degradation. In one study, formulation buffers were formulated with different lots of raw materials and a metal ion chelator (EDTA-2Na) was added to certain formulations, along with increasing the concentration of PS80 in certain formulations. The formulations tested in the study are shown in Table 40.
  • EDTA-2Na metal ion chelator
  • Table 40 Formulations Tested in Metal Ion Chelator Study , Attorney Docket No.: AOE-003PR 10 mM L-His/L-His-HCl, 120 mM L-Arg-HCl, 10 mM L-Met, F03 , y p p p y levels of iron (Fe), cobalt (Co), nickel (Ni), copper (Cu) and zinc (Zn) in the formulations.
  • the concentration of PS80 was also measured in the formulations at T0 and after storage at 25°C for defined periods of time (1 week, 2 weeks, 1 month). The results of the metal ion chelator study are summarized in Table 41.
  • Table 41 Metal Ion Chelator Study Results Comment Analysis Result Fe C ( /L) Ni ( /L) C ( /L) Zn ( /L) (PS80 # Attorney Docket No.: AOE-003PR 25C-1M: 0.021% Additional investigational studies were performed to evaluate the impact on PS80 degradation of clone material, formulation buffers, water, PS80 lots and the material of construction of vials (glass vs. polymer). Representative results are shown in Table 42.
  • Example 9 Formulations to Counteract PS80 Degradation
  • a panel of formulations was prepared that included either PS80 or P188 as surfactant. Additionally, a metal ion chelator was included in some formulations and omitted from others. The formulations were tested for various quality parameters, as described in previous examples. Table 43 shows results for surfactant stability (%) over time at the indicated temperatures. Table 44 and Table 45 show the SE-UPLC results over time at 25°C and 5°C, respectively. Table 46 and Table 47 show the iCIEF results over time at 25°C and 5°C, respectively.
  • Example 10 Determination of Minimum Effective Amount of PS80 to Protect Against Mechanical Shear Stress This example describes a study to establish a minimum PS80 concentration that can protect the formulation against mechanical stress induced by agitation (e.g., during shipping).
  • Formulations having PS80 concentrations of 0, 0.0005, 0.003, 0.005, 0.01, 0.03, 0.05 % (w/v) were evaluated for their resistance against agitation at 300 rpm for 3 days. Tested formulations are shown in Table 51. Table 51: Formulations with Varying PS80 Concentrations Attorney Docket No.: AOE-003PR No. Protein conc. pH/buffer Excipients Surfactant The study plan is summarized in Table 52. The formulations were tested for various quality parameters, as described in previous examples. Table 52: Study Plan Attorney Docket No.: AOE-003PR The results for sub-visible particles (MFI), SE-UPLC, iCIEF and CE-SDS are shown in Table 53, Table 54, Table 55 and Table 56, respectively.
  • MFI sub-visible particles
  • Example 11 Compatibility Studies with Glass Pre-Filled Syringes and Rubber Plunger Stoppers
  • PFS pre-filled syringe
  • C and D the syringes and plunger stoppers.
  • a and B two different plunger stoppers from two different manufacturers
  • FIG. 8 Table 57 Attorney Docket No.: AOE-003PR summarizes the overall assessment of visual appearance, turbidity, concentration, subvisible particles, pH, PS80, SEC, iCIEF, CE-SDS-NR/R, and ELISA for the samples.
  • the formulations tested were: (1) 180 mg/mL IL-13 antibody, L-10 mM His/L-His-HCl, 120 mM L-Arg-HCl, 10 mM L-Met, 0.05 mM EDTA, 0.05% PS80, pH 6.0; and (2) 180 mg/mL IL-13 antibody, 10 mM L-His/L-His-HCl, 120 mM L-Arg-HCl, 10 mM L-Met, 0.5 mg/mL P188, pH 6.0
  • Formulations were tested for various quality parameters over time and at various temperatures as described in the previous examples according to the study plan set forth in Table 58.
  • Tg viscosity, pH, osmolality and excipient concentration at time zero (T0) are shown in Table 59.
  • the 5°C data is summarized in Table 60.
  • the 25°C data is summarized in Table 61.
  • the 40°C data is summarized in Table 62.
  • the data for agitation is summarized in Table 63.
  • the -70°C data is summarized in Table 64.

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Abstract

L'invention concerne des formulations pharmaceutiques d'anticorps anti-interleukine (IL)-13. L'invention concerne également des formulations pharmaceutiques destinées à être utilisées dans le traitement d'un trouble ou d'une maladie inflammatoire.
PCT/US2024/061395 2023-12-20 2024-12-20 Formulations pharmaceutiques d'anticorps se liant à l'interleukine 13 Pending WO2025137523A2 (fr)

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