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WO2025166234A1 - Procédés d'administration d'anticorps qui se lient au récepteur alpha de l'interleukine 4 - Google Patents

Procédés d'administration d'anticorps qui se lient au récepteur alpha de l'interleukine 4

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Publication number
WO2025166234A1
WO2025166234A1 PCT/US2025/014129 US2025014129W WO2025166234A1 WO 2025166234 A1 WO2025166234 A1 WO 2025166234A1 US 2025014129 W US2025014129 W US 2025014129W WO 2025166234 A1 WO2025166234 A1 WO 2025166234A1
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WIPO (PCT)
Prior art keywords
seq
cdr
set forth
antibody
nos
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Pending
Application number
PCT/US2025/014129
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English (en)
Inventor
Eric Franklin Zhu
Shawn Michael RUSSELL
Jason Z. OH
Kenneth Evan Thompson
Hussam Hisham Shaheen
Peter Evan Harwin
Tomas KISELAK
Carl DAMBKOWSKI
Michael Henderson
Amol KAMBOJ
Erica WINTER
Kristine NOGRALES
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Apogee Therapeutics Inc
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Apogee Therapeutics Inc
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Publication of WO2025166234A1 publication Critical patent/WO2025166234A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • 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
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • 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

  • Interleukin 4 and interleukin 13 share a common receptor component, the Interleukin-4 Receptor Alpha (IL-4R ⁇ ) chain, that pairs with distinct subunits (Nelms, K., et al. (1999) Annu. Rev. Immunol.17:701–738) and (Jensen, P.L. (2000) Stem Cells.18:61–62).
  • IL-4R ⁇ pairs with the common ⁇ c chain to form a type I IL-4R complex that is found predominantly in hematopoietic cells and is exclusive for IL-4.
  • IL-4R ⁇ also pairs with the Interleukin-13 Receptor alpha 1 (IL-13R ⁇ 1) subunit to form a type II IL-4R that binds both IL-4 and IL-13.
  • the type II receptor is expressed on both hematopoietic and nonhematopoietic cells.
  • IL-4 (also known as B cell stimulating factor or BSF-1) was originally characterized by its ability to stimulate the proliferation of B cells in response to low concentrations of antibodies directed to surface immunoglobulin. IL-4 has been shown to possess a broad spectrum of biological activities, including growth stimulation of T cells, mast cells, granulocytes, megakaryocytes, and erythrocytes.
  • IL-4 induces the expression of class II major histocompatibility complex molecules in resting B cells and enhances the secretion of IgE and IgG1 isotypes by stimulated B cells.
  • the biological and immunological functions of B-lymphocytes, monocytes, dendritic cells, and fibroblasts are all affected by IL-4 and IL-13.
  • These cytokines interact Goodwin Ref: AOE-103WO with IL-4R to initiate the type 2 inflammatory pathway, which results in Th2 cell differentiation, inflammation, and mucus production.
  • the type-2 inflammatory pathway is first activated in allergic illnesses by aberrant cytokine release resulting from an imbalance of Th1 and Th2 differentiation.
  • Mast cells and basophils are then called upon to degranulate and release inflammatory substances.
  • the secreted IL-4 and IL-13 continue to bind to their respective receptors, such as IL-4R ⁇ , that repeatedly promotes TH2 differentiation and subsequent inflammation.
  • IL-4R ⁇ The important role of IL-4 and IL-13 in the type-2 inflammation pathway identifies IL-4R ⁇ as a potential target for individuals who exhibit aberrant type-2 inflammatory responses. Unlike medications that target IL-4 and IL-13 exclusively, targeting IL-4R ⁇ would target both IL-4 and IL-13.
  • antibodies that bind IL-4R ⁇ that modify type-2 inflammation and methods of administering such antibodies to treat immune disorders, such as asthma are needed.
  • hIL-4R ⁇ human interleukin-4 receptor alpha
  • the antibodies are characterized by binding to hIL-4R ⁇ with high affinity and by the ability to neutralize hIL-4R ⁇ activity.
  • the human antibodies are capable of blocking hIL-13/hIL-13R1 complex binding to hIL-4R ⁇ , and thus inhibiting signaling by hIL-13.
  • the antibodies can be full-length (e.g., an IgG1 or IgG4 antibody) or may comprise only an antigen-binding portion (e.g., a Fab, F(ab′)2, or scFv fragment), and may be modified to effect functionality, e.g., to abrogate residual effector functions (Reddy et al. (2000) J. Immunol.164:1925-1933) and/or extend half-life. Described herein are methods of inhibiting IL-4R ⁇ biological activity. In certain aspects, the antibodies and methods described herein are used for treatment of an inflammatory disease or disorder associated with elevated levels of IL-4 and/or IgE.
  • described herein are methods of treating asthma by administering anti-IL4R ⁇ antibodies.
  • the method comprises administering to the patient a first dose of an anti-Interleukin (IL)-4 Receptor alpha (IL-4R ⁇ ) antibody, wherein the first dose is between about 100 mg and about Goodwin Ref: AOE-103WO 1,500 mg (e.g., selected from about 150 mg, about 200 mg, about 300 mg, about 350 mg, about 600 mg, about 650 mg, about 1,200 mg, and about 1,300 mg)
  • the anti-IL-4R ⁇ antibody comprises: a) a variable heavy (VH) chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a variable light (VL) chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein: CDR- H1 comprises a sequence selected from the
  • the patient is administered a second dose between about 100 mg and about 1,500 mg (e.g., selected from about 150 mg, about 200 mg, about 300 mg, about 350 mg, about 600 mg, about 650 mg, about 1,200 mg, and about 1,300) of the anti-IL- 4R ⁇ antibody.
  • the patient is administered a first dose of 150 mg and a second dose of 150 mg; a first dose of 300 mg and a second dose of 300 mg; a first dose of 600 mg and a second dose of 600 mg; or a first dose of 1,200 mg and a second dose of 1,200 mg.
  • the patient is administered the second dose about 2 weeks to about 14 weeks after the first dose of the anti-IL-4R ⁇ antibody. In some embodiments, the patient is administered the second dose about 3 weeks after the first dose of the anti-IL-4R ⁇ antibody. In some embodiments, the patient is administered the second dose about 4 weeks after the first dose of the anti-IL-4R ⁇ antibody. In some embodiments, the patient is administered the second dose about 5 weeks after the first dose of the anti-IL-4R ⁇ antibody. In some embodiments, the patient is administered the second dose about 6 weeks after the first dose of the anti-IL-4R ⁇ antibody. In some embodiments, the patient is administered the second dose about 7 weeks after the first dose of the anti-IL-4R ⁇ antibody.
  • the patient is administered the second dose about 8 weeks after the first dose of the anti-IL-4R ⁇ antibody. In some embodiments, the patient is administered the second dose about 9 weeks after the first dose of the anti-IL-4R ⁇ antibody. In some embodiments, the Goodwin Ref: AOE-103WO patient is administered the second dose about 10 weeks after the first dose of the anti-IL-4R ⁇ antibody. In some embodiments, the patient is administered the second dose about 11 weeks after the first dose of the anti-IL-4R ⁇ antibody. In some embodiments, the patient is administered the second dose about 12 weeks after the first dose of the anti-IL-4R ⁇ antibody. In some embodiments, the patient is administered the second dose about 13 weeks after the first dose of the anti-IL-4R ⁇ antibody.
  • the patient is administered the second dose 25, 26, 27, 28, 29, 30, 31, or 32 days after the first dose of the anti-IL-4R ⁇ antibody. In some embodiments, the patient is administered the second dose 28, 29, or 30 days after the first dose of the anti- IL-4R ⁇ antibody. In some embodiments, the patient is administered the second dose 29 days after the first dose of the anti-IL-4R ⁇ antibody. [0012] In certain embodiments, the patient is administered a first dose and a second dose of the anti- IL-4R ⁇ antibody, wherein the first dose is 600 mg, and wherein the second dose is 600 mg. In some embodiments, the second dose is administered 29 days after the first dose.
  • the patient is administered a third, fourth, and/or fifth dose between about 100 mg and about 1,500 mg (e.g., selected from about 150 mg, about 200 mg, about 300 mg, about 350 mg, about 600 mg, about 650 mg, about 1,200 mg, and about 1,300 mg) of the anti-IL-4R ⁇ antibody.
  • the third, fourth, and/or fifth dose is administered the second about 2 weeks to about 14 weeks after the previously administered dose of the anti-IL-4R ⁇ antibody.
  • the antibody does not comprise: a.
  • the antibody does not comprise any combination of: a. a CDR-H1 set forth in any of SEQ ID NOs: 1, 67, or 187; b. a CDR-H2 set forth in any of SEQ ID NOs: 5, 71, or 79; c.
  • the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 10, 71, or 84; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 24 or 98; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 36 or 102; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 45 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 30 or 102; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 47 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • the antibody comprises a VH sequence selected from the sequences set forth in SEQ ID NOs: 113-145. [0020] In some embodiments, the antibody comprises a VL sequence selected from the sequences set forth in SEQ ID NOs: 146-186. [0021] In some embodiments, the antibody comprises a VH sequence selected from the sequences set forth in SEQ ID NOs: 113-145 and a VL sequence selected from the sequences set forth in SEQ ID NOs: 146-186. In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 121 and a VL sequence set forth in SEQ ID NO: 158.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 130 and a VL sequence set forth in SEQ ID NO: 166. In some embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 134 and a VL sequence set forth in SEQ ID NO: 178. Goodwin Ref: AOE-103WO [0022] In some embodiments, the antibody is a humanized, fully human, or chimeric antibody. In some embodiments, the antibody is a fully human antibody. [0023] In some embodiments, the antibody comprises a heavy chain human constant region of a class selected from IgG, IgA, IgD, IgE, and IgM.
  • the antibody comprises a human heavy chain constant region of the class IgG and a subclass selected from IgG1, IgG2, IgG3, and IgG4. In some embodiments, the antibody comprises an Fc region. In some embodiments, the antibody comprises a human IgG1 Fc region. [0024] In some embodiments, the antibody comprises a constant heavy chain sequence selected from the sequences set forth in SEQ ID NOs: 192-235 and 251-408. In some embodiments, the antibody comprises a constant light chain sequence comprising a sequence set forth in SEQ ID NO: 236.
  • the antibody comprises an Fc region comprising one or more amino acid substitutions, wherein the one or more amino acid substitutions results in an increase in one or more of antibody half-life, ADCC activity, ADCP activity, or CDC activity compared with the Fc without the one or more substitutions.
  • the antibody comprises an Fc region comprising one or more amino acid substitutions, wherein the one or more amino acid substitutions results in a decrease in one or more of ADCC activity, ADCP activity, or CDC activity 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, L234A, L235A,L242A, L243A M252Y, S254T, T256E, M260Y, S262T, T264E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311V, A378V, E380A, M428L, N434A, and N434S; optionally, wherein the one or more amino acid substitutions comprises a plurality of amino acid substitutions selected from the group consisting of i) M428L/N434S; ii) M252Y/S254T/T256E (YTE) or M260Y/S262T/T264E (YTE) using direct numbering; iii) T250Q/M428L; iv) T307A
  • the patient has a diagnosis of mild or moderate asthma as defined by Global Initiative for Asthma. Goodwin Ref: AOE-103WO
  • the patient has a fractional exhaled nitric oxide (FeNO) of at least 25 parts per billion (ppb) prior to administration of the antibody.
  • FeNO fractional exhaled nitric oxide
  • the FeNO is reduced by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, or by at least 50% following administration of the anti-IL-4R ⁇ antibody.
  • the FeNO is reduced by at least 5, 10, or 15 ppb following administration of the anti-IL-4R ⁇ antibody.
  • the patient has pre-bronchodilator forced expiratory volume in 1 second (FEV1) that is at least 60% of the predicted normal value prior to administration of the antibody.
  • FEV1 is increased by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, or by at least 50% following administration of the anti-IL-4R ⁇ antibody.
  • the forced vital capacity (FVC) is increased by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, or by at least 50% following administration of the anti-IL-4R ⁇ antibody.
  • the peak expiratory flow (PEF) is increased by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, or by at least 50% following administration of the anti-IL4R ⁇ antibody.
  • the antibody is administered in a pharmaceutical composition.
  • the composition is a unit dose with an extractable volume of 2 mL.
  • the composition is administered via a pre-filled syringe or auto-injector.
  • disclosed herein are methods of using recombinant human antibodies that specifically bind human interleukin-4 receptor alpha (hIL-4R ⁇ ) to treat asthma.
  • the antibodies can be full-length (for example, an IgG1 or IgG4 antibody) or may comprise only an antigen-binding portion (for example, a Fab, F(ab′)2 or scFv fragment), and may be modified to effect functionality, e.g., to abrogate residual effector functions (Reddy et al. (2000) J. Immunol.164:1925-1933) and/or extend half-life.
  • the disclosure relates to a method for treating asthma or COPD in a human subject, wherein the method comprises administering an antibody that binds IL- 4R ⁇ , comprising: a) a VH sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a VL sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein: CDR-H1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 1-4, 66-70, and 187-191; CDR-H2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 5-16 and 71-90; CDR-H3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 17-25 and 92-99, CDR-L1 comprises a sequence selected from the sequences set forth in SEQ ID NOs:
  • the disclosure relates to a method for treating asthma or COPD in a human subject, wherein the method comprises (a) administering an antibody that binds Interleukin (IL)-4 Receptor alpha (IL-4R ⁇ ), comprising: a) a variable heavy (VH) chain sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a variable light (VL) chain sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein CDR-H1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 1-4, 66-70, and 187-191; CDR-H2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 5-16 and 71-90; CDR-H3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 17-25 and 92-99, CDR-L1 comprises a sequence
  • the disclosure relates to a method of reducing a fractional nitric oxide concentration in exhaled breath (FeNO) of a human subject, wherein the method comprises administering an antibody that binds IL-4R ⁇ , comprising: a) a VH sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a VL sequence having three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3; wherein Goodwin Ref: AOE-103WO CDR-H1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 1-4, 66-70, and 187-191; CDR-H2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 5-16 and 71-90; CDR-H3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 17-25 and 92-99, CDR-L1 comprises a
  • the disclosure relates to a method for treating asthma or COPD in a human subject comprising (a) selecting a patient with an elevated level of fractional exhaled nitric oxide (FeNO) and (b) administering to the patient a therapeutically effective amount of an antibody that binds IL-4R ⁇ , wherein the antibody comprises: a) a VH sequence having three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3; and b) a VL sequence having 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 SEQ ID NOs: 1-4, 66-70, and 187-191; (ii) CDR-H2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 5-16 and 71-90; (iii) CDR-H3 comprises a sequence selected from the sequences
  • the antibody does not comprise a. CDR-H1 set forth in SEQ ID NO: 1; CDR-H2 set forth in SEQ ID NO: 5; CDR-H3 set forth in SEQ ID NO: 17; CDR-L1 set forth in SEQ ID NO: 26; CDR-L2 set forth in SEQ ID NO: 41; and CDR-L3 set forth in SEQ ID NO: 53; or b.
  • the antibody does not comprise any combination of a. a CDR-H1 set forth in any of SEQ ID NOs: 1, 67, or 187; b. a CDR-H2 set forth in any of SEQ Goodwin Ref: AOE-103WO ID NOs: 5, 71, or 79; c. a CDR-H3 set forth in any of SEQ ID NOs: 17 or 91; d. a CDR-L1 set forth in any of SEQ ID NOs: 26 or 100; e. a CDR-L2 set forth in SEQ ID NO: 41 or the amino acid sequence LG; and f. a CDR-L3 set forth in SEQ ID NO: 53.
  • the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 10, 71, or 84; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 24 or 98; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 36 or 102; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 45 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 30 or 102; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 47 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • the antibody comprises a VH sequence selected from the sequences set forth in SEQ ID NOs: 113-145. [0049] In certain embodiments, the antibody comprises a VL sequence selected from the sequences set forth in SEQ ID NOs: 146-186. [0050] In certain embodiments, the antibody comprises a VH sequence selected from the sequences set forth in SEQ ID NOs: 113-145 and a VL sequence selected from the sequences set forth in SEQ ID NOs: 146-186. [0051] In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 121 and a VL sequence set forth in SEQ ID NO: 158.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 130 and a VL sequence set forth in SEQ ID NO: 166. Goodwin Ref: AOE-103WO [0053] In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 134 and a VL sequence set forth in SEQ ID NO: 178. [0054] In certain embodiments, the antibody is a humanized, fully human, or chimeric antibody. In certain embodiments, the antibody is a fully human antibody. [0055] In certain embodiments, the antibody comprises a heavy chain human constant region of a class selected from IgG, IgA, IgD, IgE, and IgM.
  • the antibody comprises a human heavy chain constant region of the class IgG and a subclass selected from IgG1, IgG2, IgG3, and IgG4. [0056] In certain embodiments, the antibody comprises an Fc region. In certain embodiments, the antibody comprises a human IgG1 Fc region. [0057] In certain embodiments, the antibody comprises a constant heavy chain sequence selected from the sequences set forth in SEQ ID NOs: 192-235 and 251-408. [0058] In certain embodiments, the antibody comprises a constant light chain sequence comprising a sequence set forth in SEQ ID NO: 236.
  • the antibody comprises an Fc region comprising one or more amino acid substitutions, wherein the one or more amino acid substitutions results in an increase in one or more of antibody half-life, ADCC activity, ADCP activity, or CDC activity compared with the Fc without the one or more substitutions.
  • the antibody comprises an Fc region comprising one or more amino acid substitutions, wherein the one or more substitutions results in a decrease in one or more of ADCC activity, ADCP activity, or CDC activity 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, L234A, L235A,L242A, L243A M252Y, S254T, T256E, M260Y, S262T, T264E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311V, A378V, E380A, M428L, N434A, and N434S; optionally, wherein the one or more amino acid substitutions comprises a plurality of amino acid substitutions selected from the group consisting of i) M428L/N434S; ii) M252Y/S254T/T256E (YTE) or M260Y/S262T/T264E (YTE) using direct numbering; iii) T250Q/M428L; iv) T307A
  • the FeNO is reduced by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, or by at least 50% following administration of the antibody.
  • FIG.1A and FIG.1B are a set of graphs showing the ability of exemplary antibodies and dupilumab to inhibit IL-4 and IL-13 binding.
  • FIG.2A and FIG.2B are a set of graphs showing the ability of exemplary antibodies and dupilumab to inhibit IL-4-induced and IL-13-induced STAT6 phosphorylation (pSTAT6).
  • FIG.3A and FIG.3B are a set of graphs showing the ability of exemplary antibodies and dupilumab to inhibit IL-4-induced and/or IL-13-induced TARC secretion.
  • FIG.4A and FIG.4B are a set of graphs showing the ability of exemplary antibodies and dupilumab to inhibit IL-4-induced and IL-13-induced proliferation of TF-1 cells.
  • FIG.5A and FIG.5B are a set of graphs showing the serum concentration of exemplary antibodies (Construct 13 (mAb422), Construct 38 (mAb471)) and dupilumab over time after a single intravenous (FIG.5A) or subcutaneous (FIG.5B) administration of 25 mg/kg in non-human primates.
  • FIG.6 is a graph showing the ability of different doses of Construct 38 (mAb471) to inhibit pSTAT6 in humans over time.
  • FIG.7 is a graph showing the ability of different doses of Construct 38 (mAb471) to inhibit TARC secretion in humans over time.
  • FIG.8 is a set of graphs showing the ability of a 600 mg dose of Construct 38 (mAb471) to inhibit TARC secretion in humans over time (left panel) as compared to Dupixent ® (right panel).
  • FIG.9 is a graph showing the ability of Construct 38 (mAb471) doses to inhibit IgE levels in humans over time.
  • FIG.10 is a graph showing the effect of Construct 38 (mAb471) doses on periostin levels in humans over time.
  • FIG.11 is a graph showing the mean serum concentration of Construct 38 (mAb471) over time, following administration of a single dose of 150, 300, 600, or 1200 mg.
  • FIG.12 is a graph showing the modeled median concentration of Construct 38 (mAb471) over time when administered every 2 months. The speckled shaded area depicts the 90% prediction interval.
  • 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 Goodwin Ref: AOE-103WO 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.
  • composition when a composition is described as ‘consisting essentially of’ a component, the composition may additionally contain any amount of pharmaceutically acceptable carriers, vehicles, or diluents and other such components which do not substantially affect the condition being treated.
  • vehicle refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked.
  • the term includes the vector as a self- replicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked.
  • host cell Such vectors are referred to herein as “expression vectors.”
  • host cell refers to cells into which an exogenous nucleic acid has been introduced, and the progeny of such cells.
  • Host cells include “transformants” (or “transformed cells”) and “transfectants” (or “transfected cells”), which each include the primary transformed or transfected cell and progeny derived therefrom.
  • Such progeny may not be completely identical in nucleic acid content to a parent cell and may contain mutations.
  • a “recombinant host cell” or “host cell” refers to a cell that includes an exogenous polynucleotide, regardless of the method used for insertion, for example, direct uptake, transduction, f-mating, or other methods known in the art to create recombinant host cells.
  • the term “eukaryote” refers to organisms belonging to the phylogenetic domain Eucarya such as animals (including but not limited to, mammals, insects, reptiles, birds, etc.), ciliates, plants (including but not limited to, monocots, dicots, algae, etc.), fungi, yeasts, flagellates, microsporidia, protists, etc.
  • prokaryote refers to prokaryotic organisms.
  • a non-eukaryotic organism can belong to the Eubacteria (including but not limited to, Escherichia coli, Thermus thermophilus, Bacillus stearothermophilus, Pseudomonas fluorescens, Pseudomonas aeruginosa, Pseudomonas putida, etc.) phylogenetic domain, or the Archaea (including but not limited to, Methanococcus jannaschii, Methanobacterium Goodwin Ref: AOE-103WO thermoautotrophicum, Halobacterium such as Haloferax volcanii and Halobacterium species NRC-1, Archaeoglobus fulgidus, Pyrococcus furiosus, Pyrococcus horikoshii, Aeuropyrum pernix, etc.) phylogenetic domain.
  • Eubacteria including but not limited to, Escherichia
  • an “effective amount” or “therapeutically effective amount” as used herein refers to an amount of therapeutic compound, such as an anti-IL-4R ⁇ 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 are reducing an aberrant immune response; slowing or delaying disease development; stabilization of disease; and amelioration of one or more symptoms. An effective amount may be given in one or more dosages.
  • the term “treating” (and variations thereof such as “treat” or “treatment”) 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, 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” or “individual” mean a mammalian subject. Exemplary subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, and sheep.
  • the subject is a human.
  • the subject has a disease or condition that can be treated with an antibody provided herein.
  • the disease or condition is an inflammatory or immunological disease.
  • the disease or condition is asthma or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • kits therapeutic or diagnostic products
  • pharmaceutical 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.
  • co-administration include the administration of two or more therapeutic agents either simultaneously, concurrently, or sequentially within no specific time limits.
  • the agents are present in the cell or in the subject’s body at the same time or exert their biological or therapeutic effect at the same time.
  • the therapeutic agents are in the same composition or unit dosage form. In other embodiments, the therapeutic agents are in separate compositions or unit dosage forms.
  • a first agent can be administered prior to the administration of a second therapeutic agent.
  • 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.
  • the term “about” indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term “about” indicates the designated value ⁇ 10%, ⁇ 5%, or ⁇ 1%. In certain embodiments, where applicable, the term “about” indicates the designated value(s) ⁇ one standard deviation of that value(s).
  • the term “agonize” refers to the activation of receptor signaling to induce a biological response associated with activation of the receptor.
  • An “agonist” is an entity that binds to and agonizes a receptor.
  • the term “antagonize” refers to the inhibition of receptor signaling to inhibit a biological response associated with activation of the receptor.
  • an “antagonist” is an entity that binds to and antagonizes a receptor. Goodwin Ref: AOE-103WO [0096] For any of the structural and functional characteristics described herein, methods of determining these characteristics are known in the art. [0097] The term “optionally” is meant, when used sequentially, to include from one to all of the enumerated combinations and contemplates all sub-combinations. [0098] The term “amino acid” refers to, for example, the twenty common naturally occurring amino acids.
  • 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), 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).
  • 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). Unless indicated otherwise, as used herein, “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 (sec-1), as used herein, refers to the dissociation rate constant of a particular antibody-antigen interaction. This value is also referred to as the koff value.
  • ka M-1 ⁇ sec-1
  • KD Kd/ka.
  • affinity of an antibody is described in terms of the KD for an interaction between such antibody and its antigen. For clarity, as known in the art, a smaller KD value indicates a higher affinity interaction, while a larger KD value indicates a lower affinity interaction.
  • 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-4R ⁇ antibody,” “IL-4R ⁇ antibody,” or “IL-4R ⁇ specific antibody” is an antibody, as provided herein, which specifically binds to the antigen IL-4R ⁇ .
  • epitope means a portion of an antigen that specifically binds to an antibody.
  • epitope means a portion of an antigen that specifically binds to an antibody.
  • 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”).
  • 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 or “fully 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.
  • 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. For further details, see Jones et al.
  • 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 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
  • single-chain refers to a molecule comprising amino acid monomers linearly linked by peptide bonds.
  • the C-terminus of the Fab light chain is connected to the N-terminus of the Fab heavy chain in the single-chain Fab molecule.
  • an scFv has the variable domain of its light chain (VL) connected from its C-terminus to the N-terminal end of the variable domain of its heavy chain (VH) by a polypeptide chain.
  • the scFv comprises a polypeptide chain wherein the C-terminal end of the VH is connected to the N-terminal end of VL by a polypeptide chain.
  • a “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, Goodwin Ref: AOE-103WO also referred to as hypervariable region (HVR)) that are involved in antigen-binding.
  • 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. [00118] “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain. [00119] “Single-chain Fv,” “sFv,” or “scFv” include 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.
  • the Fc domain may follow the VH 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. In some cases, 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 and fragments thereof are described in Arabi Ghahroudi et al., (1998) FEBS Letters 414:521-526 and Muyldermans et al.
  • 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).
  • the terms “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.
  • the term “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.
  • substantially purified refers to a construct described herein or variant thereof that may be substantially or essentially free of components that normally accompany or interact with the protein as found in its naturally occurring environment, i.e.
  • a native cell or host cell in the case of recombinantly produced antibody that, in certain embodiments, is substantially free of cellular material includes preparations of protein having less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% (by dry weight) of contaminating protein.
  • 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
  • test and Goodwin Ref AOE-103WO reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then 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, (1981) Adv. Appl. Math.2:482, by the homology alignment algorithm of Needleman & Wunsch, (1970) J. Mol. Biol.48:443, by the search for similarity method of Pearson & Lipman, (1988) Proc. Nat’l. Acad.
  • Ranges recited herein are understood to be shorthand for all of the values within the range, inclusive of the recited endpoints.
  • 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.
  • the present application provides antibodies and compositions comprising an antibody which binds IL-4 Receptor alpha (IL-4R ⁇ ).
  • the recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda.
  • the “class” of an antibody or immunoglobulin refers to the type of constant domain or constant region Goodwin Ref: AOE-103WO possessed by its heavy chain.
  • IgA immunoglobulin
  • IgD immunoglobulin
  • IgE immunoglobulin
  • IgG immunoglobulin
  • IgM immunoglobulin M
  • the heavy chain constant domains that correspond to the different classes of immunoglobulins are called ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
  • An exemplary immunoglobulin (antibody) structural unit is composed of two pairs of polypeptide chains, each pair having one “light” (about 25 kD) and one “heavy” chain (about 50-70 kD).
  • the N-terminal domain of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
  • VL variable light chain
  • VH variable heavy chain
  • the IgG1 heavy chain comprises the VH, CH1, CH2, and CH3 domains, respectively from the N-to-C terminus.
  • the light chain comprises the VL and CL domains from N-to-C terminus.
  • the IgG1 heavy chain comprises a hinge between the CH1 and CH2 domains.
  • the immunoglobulin constructs comprise at least one immunoglobulin domain selected from IgG, IgM, IgA, IgD, or IgE connected to a therapeutic polypeptide.
  • the immunoglobulin domain found in an antibody provided herein is from or is derived from an immunoglobulin-based construct such as a diabody or a nanobody.
  • the immunoglobulin constructs described herein comprise at least one immunoglobulin domain from a heavy chain antibody such as a camelid antibody.
  • the immunoglobulin constructs provided herein comprise at least one immunoglobulin domain from a mammalian antibody, such as a bovine antibody, a human antibody, a camelid antibody, a mouse antibody, or any chimeric antibody.
  • the antibodies provided herein comprise a heavy chain.
  • the heavy chain is an IgA.
  • the heavy chain is an IgD. In one embodiment, the heavy chain is an IgE. In one embodiment, the heavy chain is an IgG. In one embodiment, the heavy chain is an IgM. In one embodiment, the heavy chain is an IgG1. In one embodiment, the heavy chain is an IgG2. In one embodiment, the heavy chain is an IgG3. In one embodiment, the heavy chain is an IgG4. In one embodiment, the heavy chain is an IgA1. In one embodiment, the heavy chain is an IgA2. [00136] In some embodiments, an antibody is an IgG1 antibody. In some embodiments, an antibody is an IgG3 antibody. In some embodiments, an antibody is an IgG2 antibody.
  • an antibody is an IgG4 antibody.
  • Goodwin Ref: AOE-103WO AOE-103WO
  • native four-chain antibodies comprise six HVRs; three in the VH (H1, H2, and H3), and three in the VL (L1, L2, and L3).
  • HVRs generally comprise amino acid residues from the hypervariable loops and/or from the complementarity determining regions (CDRs), the latter being of highest sequence variability and/or involved in antigen recognition. With the exception of CDR1 in VH, CDRs generally comprise the amino acid residues that form the hypervariable loops.
  • Hypervariable regions are also referred to as “complementarity determining regions” (CDRs), and these terms are used herein interchangeably in reference to portions of the variable region that form the antigen-binding regions.
  • CDRs complementarity determining regions
  • This particular region has been described by Kabat et al., U.S. Dept. of Health and Human Services, Sequences of Proteins of Immunological Interest (1983) and by Chothia et al. (1987) J Mol Biol 196:901-917, where the definitions include overlapping or subsets of amino acid residues when compared against each other. Nevertheless, application of either definition to refer to a CDR of an antibody or variants thereof is intended to be within the scope of the term as defined and used herein.
  • residue numbers which encompass a particular CDR will vary depending on the sequence and size of the CDR. Those skilled in the art can routinely determine which residues comprise a particular CDR given the variable region amino acid sequence of the antibody.
  • the 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.
  • 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-4R ⁇ variants with different point-mutations or to chimeric IL-4 R ⁇ variants.
  • an epitope on a target antigen bound by an antibody of interest e.g., IL-4R ⁇
  • a routine cross-blocking assay such as that described in Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1988)
  • epitope mapping can be performed by methods known in the art.
  • the two or more different epitopes may be epitopes on the same antigen (e.g., a single IL-4R ⁇ ) or on different antigens (e.g., different IL-4R ⁇ molecules, or a IL-4R ⁇ Goodwin Ref: AOE-103WO molecule and a non-IL-4R ⁇ molecule).
  • a multi-specific antibody binds two different epitopes (i.e., a “bispecific antibody”). In some aspects, a multi-specific antibody binds three different epitopes (i.e., a “trispecific antibody”).
  • Anti-IL-4R ⁇ antibodies can include those described herein such as the clones set forth in the drawings and/or tables.
  • the antibody comprises an alternative scaffold. In some embodiments, the antibody consists of an alternative scaffold. In some embodiments, the antibody consists essentially of an alternative scaffold. In some embodiments, the antibody comprises an antibody fragment. In some embodiments, the antibody consists of an antibody fragment. In some embodiments, the antibody consists essentially of an antibody fragment.
  • the antibodies are monoclonal antibodies. [00148] In some embodiments, the antibodies are polyclonal antibodies. [00149] In some embodiments, the antibodies are produced by hybridomas. In other embodiments, the antibodies are produced by recombinant cells engineered to express the desired variable and constant domains. [00150] In some embodiments, the antibodies may be single chain antibodies or other antibody derivatives retaining the antigen specificity and the lower hinge region or a variant thereof. [00151] In some embodiments, the antibodies may be polyfunctional antibodies, recombinant antibodies, fully human antibodies, humanized antibodies, or fragments or variants thereof.
  • the antibody fragment or a variant thereof is selected from a Fab fragment, a Fab′2 fragment, a CDR ,and scFv. TABLE 2. Sequences of IL-4R ⁇ antibody constructs – VH, VL, and associated CDRs Identifier VH and Heavy chain CDRs VL and Light chain CDRs Du ilumab VH (SEQ ID NO: 113) VL (SEQ ID NO: 146) Goodwin Ref: AOE-103WO Identifier VH and Heavy chain CDRs VL and Light chain CDRs mAb410 VH (SEQ ID NO: 114) VL (SEQ ID NO: 147) Goodwin Ref: AOE-103WO Identifier VH and Heavy chain CDRs VL and Light chain CDRs CDR3 Kbt (SEQ ID NO 18) CDR3 Kbt (SEQ ID NO 55) Goodwin Ref: AOE-103WO Identifier VH and Heavy chain CDRs VL and Light chain CDRs CDRs CDR3
  • 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 illustrative VH sequence provided in SEQ ID NOs: 113-145.
  • an antibody provided herein comprises a VH sequence provided in SEQ ID NOs: 113-145, 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 Goodwin Ref: AOE-103WO example, be isolated de novo according to the methods provided herein for obtaining antibodies.
  • VL Domains [00154]
  • an antibody provided herein comprises a VL sequence selected from SEQ ID NOs: 146-186.
  • 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 illustrative VL sequence provided in SEQ ID NOs: 146-186.
  • an antibody provided herein comprises a VL sequence provided in SEQ ID NOs: 146-186, 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 selected from SEQ ID NOs: 113-145; and a VL sequence selected from SEQ ID NOs: 146- 186.
  • any of SEQ ID NOs: 113-145 can be combined with any of SEQ ID NOs: 146-186.
  • an antibody provided herein comprises a VH sequence and a VL sequence of a construct provided in TABLE 2.
  • 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 a VH sequence provided in SEQ ID NOs: 113-145; and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a VL sequence provided in SEQ ID NOs: 146-186.
  • an antibody provided herein comprises a VH sequence provided in SEQ ID NOs: 113-145, 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 Goodwin Ref: AOE-103WO sequence provided in SEQ ID NOs: 146-186, 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.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 114 and a VL sequence set forth in SEQ ID NO: 147.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 114 and a VL sequence set forth in SEQ ID NO: 148. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 115 and a VL sequence set forth in SEQ ID NO: 149. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 114 and a VL sequence set forth in SEQ ID NO: 150. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 116 and a VL sequence set forth in SEQ ID NO: 151.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 117 and a VL sequence set forth in SEQ ID NO: 152. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 118 and a VL sequence set forth in SEQ ID NO: 153. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 117 and a VL sequence set forth in SEQ ID NO: 154. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 119 and a VL sequence set forth in SEQ ID NO: 155.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 120 and a VL sequence set forth in SEQ ID NO: 156. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 120 and a VL sequence set forth in SEQ ID NO: 157. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 114 and a VL sequence set forth in SEQ ID NO: 158. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 121 and a VL sequence set forth in SEQ ID NO: 158.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 122 and a VL sequence set forth in SEQ ID NO: 158. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 114 and a VL sequence set forth in SEQ ID NO: 159. In certain embodiments, the Goodwin Ref: AOE-103WO antibody comprises a VH sequence set forth in SEQ ID NO: 123 and a VL sequence set forth in SEQ ID NO: 159. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 124 and a VL sequence set forth in SEQ ID NO: 160.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 125 and a VL sequence set forth in SEQ ID NO: 161. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 126, and a VL sequence set forth in SEQ ID NO: 162. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 127 and a VL sequence set forth in SEQ ID NO: 163. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 128 and a VL sequence set forth in SEQ ID NO: 164.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 124 and a VL sequence set forth in SEQ ID NO: 158. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 129 and a VL sequence set forth in SEQ ID NO: 165. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 130, and a VL sequence set forth in SEQ ID NO: 166. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 131 and a VL sequence set forth in SEQ ID NO: 167.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 132 and a VL sequence set forth in SEQ ID NO: 159. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 133 and a VL sequence set forth in SEQ ID NO: 159. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 121 and a VL sequence set forth in SEQ ID NO: 168. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 134 and a VL sequence set forth in SEQ ID NO: 169.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 113 and a VL sequence set forth in SEQ ID NO: 170. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 134 and a VL sequence set forth in SEQ ID NO: 171. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 135 and a VL sequence set forth in SEQ ID NO: 172. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 136 and a VL sequence set forth in SEQ ID NO: 173.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 131 and a VL sequence set forth in SEQ ID NO: 174. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 137 and a VL sequence set forth in SEQ ID NO: 175. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 114 and a VL sequence set forth in SEQ ID NO: 176. In certain embodiments, the Goodwin Ref: AOE-103WO antibody comprises a VH sequence set forth in SEQ ID NO: 138 and a VL sequence set forth in SEQ ID NO: 177.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 134 and a VL sequence set forth in SEQ ID NO: 178. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 139 and a VL sequence set forth in SEQ ID NO: 179. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 140 and a VL sequence set forth in SEQ ID NO: 180. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 141 and a VL sequence set forth in SEQ ID NO: 181.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 142 and a VL sequence set forth in SEQ ID NO: 182. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 143 and a VL sequence set forth in SEQ ID NO: 183. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 114 and a VL sequence set forth in SEQ ID NO: 184. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 144 and a VL sequence set forth in SEQ ID NO: 185.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 145 and a VL sequence set forth in SEQ ID NO: 186.
  • any of the antibodies described above further comprises a heavy chain comprising a human IgG sequence selected from a sequence set forth in SEQ ID NOs: 192-235 and 251-408.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 113; a VL sequence set forth in SEQ ID NO: 146; and the antibody further comprises a heavy chain comprising a human IgG sequence selected from a sequence set forth in SEQ ID NOs: 192-235 and 251-408.
  • the antibody further comprises a constant light chain sequence comprising a sequence set forth in SEQ ID NO: 236.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 134, a VL sequence set forth in SEQ ID NO: 178, a heavy chain constant region comprising LALA/YTE substitutions, and a human kappa light chain constant region.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 134, a VL sequence set forth in SEQ ID NO: 178, a heavy chain constant region comprising a sequence set forth in SEQ ID NO: 205 or SEQ ID NO: 321, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 236.
  • the antibody comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, Goodwin Ref: AOE-103WO 97%, 98%, or 99% identity to a VH sequence provided in SEQ ID NO: 134; and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a VL sequence provided in SEQ ID NO: 178, a heavy chain constant region comprising LALA/YTE substitutions, and a human kappa light chain constant region.
  • the antibody comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a VH sequence provided in SEQ ID NO: 134; and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a VL sequence provided in SEQ ID NO: 178, a heavy chain constant region comprising a sequence set forth in SEQ ID NO: 205 or SEQ ID NO: 321 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 205 or SEQ ID NO: 321, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 236 or a sequence having at least about 80%, 90%, 91%, 92%, 93%,
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 121, a VL sequence set forth in SEQ ID NO: 158, a heavy chain constant region comprising a sequence set forth in SEQ ID NO: 205 or SEQ ID NO: 321, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 236.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 130, a VL sequence set forth in SEQ ID NO: 166, a heavy chain constant region comprising LALA/YTE substitutions, and a human kappa light chain constant region.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 130, a VL sequence set forth in SEQ ID NO: 166, a heavy chain constant region comprising a sequence set forth in SEQ ID NO: 205 or SEQ ID NO: 321, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 236.
  • the antibody comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a VH sequence provided in SEQ ID NO: 130; and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a VL sequence provided in SEQ ID NO: 166, a heavy chain constant region comprising LALA/YTE substitutions, and a human kappa light chain constant region.
  • the antibody comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a VH sequence provided in SEQ ID NO: 130; and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, Goodwin Ref: AOE-103WO 95%, 96%, 97%, 98%, or 99% identity to a VL sequence provided in SEQ ID NO: 166, a heavy chain constant region comprising a sequence set forth in SEQ ID NO: 205 or SEQ ID NO: 321 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 205 or SEQ ID NO: 321, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 236 or a sequence having at least about 80%, 90%,
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 121, a VL sequence set forth in SEQ ID NO: 158, a heavy chain constant region comprising LALA/YTE substitutions, and a human kappa light chain constant region.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 121, a VL sequence set forth in SEQ ID NO: 158, a heavy chain constant region comprising a sequence set forth in SEQ ID NO: 205 or SEQ ID NO: 321, and a light chain constant region comprising a sequence set forth in SEQ ID NO: 236.
  • the antibody comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a VH sequence provided in SEQ ID NO: 121; and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a VL sequence provided in SEQ ID NO: 158, a heavy chain constant region comprising LALA/YTE substitutions, and a human kappa light chain constant region.
  • the antibody comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to a VH sequence provided in SEQ ID NO: 121; and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%. or 99% identity to a VL sequence provided in SEQ ID NO: 158, a heavy chain constant region comprising a sequence set forth in SEQ ID NO: 205 or SEQ ID NO: 321 or a sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%.
  • CDRs [00167]
  • an antibody comprising 1, 2, 3, 4, 5, or 6 of the CDRs of TABLE 2.
  • an antibody Goodwin Ref: AOE-103WO comprising 6 of the Kabat CDRs of TABLE 2, 6 of the Chothia CDRs of TABLE 2, or 6 of the IMGT CDRs of TABLE 2.
  • an antibody provided herein comprises one to three CDRs of a VH domain selected from SEQ ID NOs: 113-145. In some embodiments, an antibody provided herein comprises two to three CDRs of a VH domain selected from SEQ ID NOs: 113-145. In some embodiments, an antibody provided herein comprises three CDRs of a VH domain selected from SEQ ID NOs: 113-145. In some aspects, the CDRs are Exemplary CDRs. In some aspects, the CDRs are Kabat CDRs. In some aspects, the CDRs are Chothia CDRs. In some aspects, the CDRs are IMGT CDRs. In some aspects, the CDRs are AbM CDRs.
  • 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-H1, CDR-H2, or CDR-H3 of SEQ ID NOs: 1-107 and 187-191 or the amino acid sequences LG, KG, EG, SA, and LS.
  • the CDR-H1 is a CDR-H1 of a VH domain selected from SEQ ID NOs: 113-145, 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: 113-145, 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: 113-145, 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: 146-186. In some embodiments, an antibody provided herein comprises two to three CDRs of a VL domain of SEQ ID NOs: 146-186.
  • an antibody provided herein comprises three CDRs of a VL domain of SEQ ID NOs: 146-186.
  • the CDRs are Exemplary CDRs.
  • the CDRs are Kabat CDRs.
  • the CDRs are Chothia CDRs.
  • the CDRs Goodwin Ref: AOE-103WO are IMGT CDRs.
  • the CDRs are AbM CDRs.
  • 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: 26-65 and 100-107 or the amino acid sequences LG, KG, EG, SA, and LS.
  • the CDR-L1 is a CDR-L1 of a VL domain of SEQ ID NOs: 146-186, 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: 41-52 and the amino acid sequences LG, KG, EG, SA, and LS, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions.
  • the CDR-L3 is a CDR-L3 of a VL domain of SEQ ID NOs: 146-186, 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 VH domain selected from SEQ ID NOs: 113-145 and one to three CDRs of a VL domain selected from SEQ ID NOs: 146-186.
  • an antibody provided herein comprises two to three CDRs of a VH domain selected from SEQ ID NOs: 113-145 and two to three CDRs of a VL domain selected from SEQ ID NOs: 146-186. In some embodiments, an antibody provided herein comprises three CDRs of a VH domain selected from SEQ ID NOs: 113-145 and three CDRs of a VL domain selected from SEQ ID NOs: 146-186. In some aspects, the CDRs are Exemplary CDRs. In some aspects, the CDRs are Kabat CDRs. In some aspects, the CDRs are Chothia CDRs. In some aspects, the CDRs are IMGT CDRs.
  • the CDRs are AbM CDRs. In some aspects, the CDRs are Contact CDRs.
  • an antibody provided herein comprises a CDR-H3 selected from SEQ ID NOs: 17-25 and 92-99. In some aspects, 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: 17-25 and 92-99.
  • the CDR-H3 is a CDR-H3 selected from SEQ ID NOs: 17-25 and 92-99, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid Goodwin Ref: AOE-103WO 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 a CDR-H1 selected from SEQ ID NOs: 1-4, 66-70, and 187-191.
  • 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: 1-4, 66-70, and 187-191.
  • the CDR-H1 is a CDR-H1 selected from SEQ ID NO: 1-4, 66-70, and 187-191, 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 selected from SEQ ID NOs: 5-16 and 71-90.
  • the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with a CDR-H2 selected from SEQ ID NOs: 5-16 and 71-90.
  • the CDR-H2 is a CDR-H2 selected from SEQ ID NOs: 5-16 and 71-90, 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 Goodwin Ref: AOE-103WO 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: 53-65.
  • 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: 53- 65.
  • the CDR-L3 is a CDR-L3 selected from SEQ ID NOs: 53-65, 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-L2 selected from SEQ ID NOs: 41-52 and the amino acid sequences LG, KG, EG, SA, and LS.
  • 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: 41-52 and the amino acid sequences LG, KG, EG, SA, and LS.
  • the CDR-L2 is a CDR-L2 selected from SEQ ID NOs: 41-52 and the amino acid sequences LG, KG, EG, SA, and LS, 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: 26-40 and 100-107.
  • 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: 26-40 and 100-107.
  • the CDR-L1 is a CDR-L1 selected from SEQ ID NOs: 26-40 and 100-107, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid Goodwin Ref: AOE-103WO 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: 17-25 and 92-99, a CDR-H2 of SEQ ID NOs: 5-16 and 71-90, a CDR-H1 selected from SEQ ID NOs: 1-4, 66-70, and 187-191, a CDR-L3 selected from SEQ ID NOs: 53-65, a CDR-L2 selected from SEQ ID NOs: 41-52 and the amino acid sequences LG, KG, EG, SA, and LS, and a CDR-L1 selected from SEQ ID NOs: 26-40 and 100-107.
  • 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: 17-25 and 92-99
  • 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: 5-16 and 71-90
  • 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: 1-4, 66-70, and 187-191
  • the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with
  • the CDR-H3 is a CDR-H3 selected from SEQ ID NOs: 17-25 and 92-99, 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: 5-16 and 71-90, 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: 1-4, 66-70, and 187-191, with up to 1, 2, 3, 4, or 5 amino acid substitutions;
  • the CDR-L3 is a CDR-L3 selected from SEQ ID NOs: 53-65, with up to 1, 2, 3, 4, or 5 amino acid substitutions;
  • the CDR-L2 is a CDR-L2 selected from SEQ ID NOs: 41-52 and the amino acid sequences LG, KG, EG, SA, and LS, with up to 1, 2, 3, or 4 amino acid Goodwin Ref: AOE-103
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 1, 67, or 187; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 5, 71, or 79; a CDR-H3 comprising the sequence set forth in SEQ ID NOs: 17 or 91; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 26 or 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 41 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 53.
  • 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: 17 or 91
  • 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: 5, 71, or 79
  • 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: 1, 67, or 187
  • 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: 17 or 91, 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: 5, 71, or 79, 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: 1, 67, or 187, with up to 1, 2, 3, 4, or 5 amino acid substitutions
  • the CDR-L3 is a CDR-L3 of SEQ ID NO: 53 with up to 1, 2, 3, 4, or 5 amino acid substitutions
  • the CDR-L2 is a CDR-L2 of SEQ ID NO: 41 or the amino acid sequence LG, with up to 1, 2, 3, or 4 amino acid substitutions
  • the CDR-L1 is a CDR-L1 of SEQ ID NOs: 26 or 100, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 42 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 54.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 62, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 42 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 55.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 7, 72, or 81; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 22 or 93; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 29 or 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 55.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71 or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 45 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 55.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 8, 73, or 82; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 19 or 94; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 30 or 102; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 56.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 8, 73, or 82; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 31 or 103; a CDR-L2 comprising the sequence set forth in Goodwin Ref: AOE-103WO SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 57.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 17 or 91; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 32 or 102; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 46 or the amino acid sequence KG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 58.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 8, 73, or 82; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 32 or 102; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 45 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 59.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 68, or 189; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 32 or 102; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 45 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 9, 77, or 83; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 29 or 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 9, 77, or 83; a CDR-H3 comprising Goodwin Ref: AOE-103WO the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 57.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 10, 71, or 84; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 3, 69, or 190; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 8, 73, or 82; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 21 or 96; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 7, 72, or 81; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 42 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 62.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 11, 73, or 85; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 33 or 102; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 23, 69, or 190; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 11, 73, or 85; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 19 or 94; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 34 or 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 11, 73, or 85; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 22 or 93; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 34 or 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 56.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 3, 69, or 190; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 23 or 97; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in Goodwin Ref: AOE-103WO SEQ ID NO: 42 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 7, 72, or 81; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20, 18, or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 7, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 24 or 98; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 36 or 102; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 45 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 8, 73, or 82; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 37 or 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 47 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 12, 74, or 86; a CDR-H3 Goodwin Ref: AOE-103WO comprising the sequence set forth in any of SEQ ID NOs: 24, or 98; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 189; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 13, 71, or 87; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 10, 71, or 84; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 34 or 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 57.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 34 or 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 1, 66, or 187; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 5, 71, or 79; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 17 or 91; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 38 or 105; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 48 or the amino acid sequence SA; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 63.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 39 or 106; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 41 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 64.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 14, 75, or 88; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 39 or 106; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 49 or the amino acid sequence LS; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 63.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 19 or 94; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 42 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 8, 73, or 82; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 31 or 103; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 58.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 3, 69, or 190; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 5, 71, or 79; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 19 or 94; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 33 or 102; a CDR-L2 comprising the sequence set forth in Goodwin Ref: AOE-103WO SEQ ID NO: 50 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 30 or 101; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 51 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 3, 67, or 190; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 15, 67, or 89; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 40 or 107; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 52 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 30 or 102; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 47 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 4, 70, or 191; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 11, 73, or 85; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 22, 18, or 93; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 30 or 102; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 60.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 14, 75, or 88; a CDR-H3 Goodwin Ref: AOE-103WO comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 65.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 15, 76, or 89; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 19 or 94; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 62.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 3, 69, or 190; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 9, 77, or 83; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 19 or 94; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 55.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 15, 76, or 89; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 24 or 98; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 34 or 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 42 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 18 or 92; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 32 or 102; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 51 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 16, 78, or 90; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 19 or 94; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 28 or 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 45 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 57.
  • an antibody provided herein comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 4, 70, or 191; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 16, 78, or 90; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 25 or 99; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 34 or 100; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 53.
  • 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 TABLE 2;
  • 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 TABLE 2
  • 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 TABLE 2
  • 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 TABLE 2
  • the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 9
  • the CDR-H3 is a CDR-H3 of TABLE 2, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions
  • the CDR-H2 is a CDR- H2 of TABLE 2, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions
  • the CDR-H1 is a CDR-H1 of TABLE 2, with up to 1, 2, 3, 4, or 5 amino acid substitutions
  • the CDR-L3 is a CDR-L3 of TABLE 2 with up to 1, 2, 3, 4, or 5 amino acid substitutions
  • the CDR-L2 is a CDR-L2 of TABLE 2, with up to 1, 2, 3, or 4 amino acid substitutions
  • the CDR-L1 is a CDR-L1 of TABLE 2, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.
  • the antibody further comprises a heavy chain comprising a human IgG sequence selected from a sequence set forth in SEQ ID NOs: 192-235 and 251-408.
  • the antibody further comprises a constant light chain sequence comprising a sequence set forth in SEQ ID NO: 236.
  • the antibody further comprises a heavy chain comprising a human IgG sequence selected from SEQ ID NO: 205 and SEQ ID NO: 321 and a constant light chain sequence comprising a sequence set forth in SEQ ID NO: 236.
  • the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 10, 71, or 84; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 27 or 101; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 43 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • the antibody further comprises a heavy chain constant region (e.g., an IgG1 constant region) comprising LALA/YTE substitutions.
  • the antibody comprises a heavy chain comprising a heavy chain constant region selected from SEQ ID NO: 205 and SEQ ID NO: 321.
  • the antibody comprises a human kappa light chain constant region.
  • the antibody comprises a constant light chain sequence comprising a sequence set forth in SEQ ID NO: 236.
  • the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in any of SEQ ID NOs: 24 or 98; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 36 or 102; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 45 or the amino acid sequence LG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • the antibody further comprises a heavy chain constant region (e.g., an IgG1 constant region) comprising LALA/YTE substitutions.
  • the antibody comprises a heavy chain comprising a heavy chain constant region selected from SEQ ID NO: 205 and SEQ ID NO: 321.
  • the antibody comprises a human kappa light chain constant region.
  • the antibody comprises a constant light chain sequence comprising a sequence set forth in SEQ ID NO: 236.
  • the antibody comprises a CDR-H1 comprising the sequence set forth in any of SEQ ID NOs: 2, 67, or 188; a CDR-H2 comprising the sequence set forth in any of SEQ ID NOs: 6, 71, or 80; a CDR-H3 comprising the sequence set forth in Goodwin Ref: AOE-103WO any of SEQ ID NOs: 20 or 95; a CDR-L1 comprising the sequence set forth in any of SEQ ID NOs: 30 or 102; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 47 or the amino acid sequence EG; and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 61.
  • the antibody further comprises a heavy chain constant region (e.g., an IgG1 constant region) comprising LALA/YTE substitutions.
  • the antibody comprises a heavy chain comprising a heavy chain constant region selected from SEQ ID NO: 205 and SEQ ID NO: 321.
  • the antibody comprises a human kappa light chain constant region.
  • the antibody comprises a constant light chain sequence comprising a sequence set forth in SEQ ID NO: 236.
  • 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.
  • Fc Region [00232] 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. (2010) Allergy Clin. Immunol.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. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.
  • 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.
  • 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 FcR
  • FcRn neonatal receptor
  • Fc amino acid modifications in the Fc region are known in the art for selectively altering the affinity of the Fc for different Fc-gamma 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: S298A/E333A/K334A, S298A/E333A/K334A/K326A (Lu et al.
  • an antibody described herein includes modifications 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. The following TABLE 3 summarizes various designs reported in the literature for effector function engineering.
  • Patent No.8,409,572 which teaches selecting cell lines for antibody production for their ability to yield lower levels of fucosylation on antibodies can be fully afucosylated (meaning they contain no detectable fucose) or they can be partially afucosylated, meaning that the isolated 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 described herein can include a dimeric Fc that comprises one or more amino acid modifications as noted in TABLE 3 that confer improved effector function.
  • the antibody can be afucosylated to improve effector function.
  • Fc modifications reducing FcgR, complement binding, and/or effector function are known in the art. Recent publications describe strategies that have been used to engineer antibodies with reduced or silenced effector activity (see Strohl, WR (2009), Curr Opin Biotech 20:685-691, and Strohl, WR and Strohl LM, “Antibody Fc engineering for optimal antibody performance” In Therapeutic Antibody Engineering, Cambridge: Woodhead Publishing (2012), pp 225-249).
  • 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.
  • RMD bacterial oxidoreductase GDP-6-deoxy-D-lyxo-4-hexylose reductase
  • Patent No.8,409,572 which teaches selecting cell lines for antibody production for their ability to yield lower levels of fucosylation on antibodies.
  • 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.
  • RMD bacterial oxidoreductase GDP-6-deoxy-D-lyxo-4- hexylose reductase
  • Antibodies can be fully afucosylated (meaning they contain no detectable fucose) or they can be partially afucosylated, meaning that the isolated 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.
  • 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, and 2004/0109865; International Pat. Pub.
  • 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.
  • the heavy chain comprises a constant heavy chain sequence selected from the sequences set forth in SEQ ID NOs: 192-235 and 251-408.
  • the constant heavy chain sequence (e.g., a constant heavy chain sequence selected from SEQ ID NOs: 192-235 and 251-306) further comprises a C-terminal lysine (SEQ ID NOs: 307-408).
  • a C-terminal lysine may be present in the corresponding coding sequence of the constant heavy chain region, it tends to be cleaved off during manufacture or after administration. Accordingly, sequences of heavy chain constant regions with and without the C-terminal lysine are provided herein.
  • an antibody provided herein comprises a VH sequence and a VL sequence provided in TABLE 2, together with a heavy chain constant region selected from a sequence set forth in SEQ ID NOs: 192-235 and 251-408.
  • an antibody provided herein comprises a VH sequence and a VL sequence provided in TABLE 2, together with a light chain constant region set forth in SEQ ID NO: 146.
  • the antibody comprises a VH sequence set forth in SEQ ID NO: 113 and a VL sequence set forth in SEQ ID NO: 146; and wherein the constant heavy chain comprises a human IgG sequence selected from a sequence set forth in SEQ ID NOs: 192-235 and 251-408.
  • the constant heavy chain comprises a human IgG sequence selected from a sequence set forth in SEQ ID NOs: 251-408.
  • the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions result in an increase in one or more of antibody half-life, ADCC activity, ADCP activity, or 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 antibody has an increased half-life that is about 10,000-fold, 1,000-fold, 500-fold, 100-fold, 50-fold, 20-fold, 10-fold, 9- fold, 8-fold, 7-fold, 6-fold, 5-fold, 4.5-fold, 4-fold, 3.5-fold, 3-fold, 2.5-fold, 2-fold, 1.95- fold, 1.9-fold, 1.85-fold, 1.8-fold, 1.75-fold, 1.7-fold, 1.65-fold, 1.6-fold, 1.55-fold, 1.50-fold, 1.45-fold, 1.4-fold, 1.35-fold, 1.3-fold, 1.25-fold, 1.2-fold, 1.15-fold, 1.1-fold, or 1.05-fold longer compared to an antibody comprising a wild-type Fc region.
  • the antibody has an increased half-life that is about 10,000-fold, 1,000-fold, 500-fold, 100- fold, 50-fold, 20-fold, 10-fold, 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4.5-fold, 4-fold, 3.5-fold, 3-fold, 2.5-fold, 2-fold, 1.95-fold, 1.9-fold, 1.85-fold, 1.8-fold, 1.75-fold, 1.7-fold, 1.65-fold, 1.6-fold, 1.55-fold, 1.50-fold, 1.45-fold, 1.4-fold, 1.35-fold, 1.3-fold, 1.25-fold, 1.2-fold, 1.15-fold, 1.1-fold, or 1.05-fold longer compared to dupilumab.
  • the antibody has an increased half-life that is about 2.5-fold, 2.4-fold, 2.3-fold, 2.2-fold, 2.1-fold, 2.0-fold, 1.9-fold, or 1.8-fold longer compared to dupilumab.
  • the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions result in a decrease in one or more of ADCC activity, ADCP activity, or CDC activity compared with the Fc without the one or more substitutions.
  • the one or more amino acid substitutions is selected from the group consisting of S228P (SP), M252Y, S254T, T256E, M260Y, S262T, T264E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311V, A378V, E380A, M428L, N434A, N434S, N297A, D265A, L234A, L235A, L242A, L243A, and N434W.
  • the one or more amino acid substitutions comprises a specific combination of amino acid substitutions selected from the group consisting of M428L/N434S (LS); M252Y/S254T/T256E (YTE) or M260Y/S262T/T264E (YTE) using direct numbering; 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 (LALA) or L242A/L243A (LALA) using direct numbering, M428L/N434S (LS);
  • an antibody described herein comprises an Fc region with YTE mutations at positions 260/262/264, respectively.
  • an antibody described herein comprises an Fc region with LALA mutations at positions 242/243, respectively.
  • an antibody described herein comprises an Fc region with YTE mutations at positions 260/262/264, respectively, and with LALA mutations at positions 242/243, respectively.
  • an antibody described herein Goodwin Ref: AOE-103WO comprises the VH and VL of Construct 38 (mAb471) and an Fc region comprising YTE mutations at positions 260/262/264, respectively, and with LALA mutations at positions 242/243, respectively.
  • the human Fc region comprises a human IgG1 Fc with LALA mutations.
  • the human Fc region comprises a human IgG1 Fc with YTE mutations.
  • the human Fc region comprises a human IgG1 Fc with LALA and YTE mutations.
  • YTE and “LALA” mutations can be located at different amino acid position numbers.
  • a human Fc region can comprise a human IgG1 Fc with LALA mutations at L42A/L243A and/or YTE mutations at M260Y/S262T/T264E.
  • 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.
  • Binding [00259]
  • 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-4R ⁇ ) 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 anti-IL-4R ⁇ antibody for a non-target molecule is less than about 50% of the affinity for IL-4R ⁇ . In some embodiments, the affinity of an anti-IL-4R ⁇ antibody for a non-target molecule is less than about 40% of Goodwin Ref: AOE-103WO the affinity for IL-4R ⁇ . In some embodiments, the affinity of an anti-IL-4R ⁇ antibody for a non-target molecule is less than about 30% of the affinity for IL-4R ⁇ .
  • the affinity of an anti-IL-4R ⁇ antibody for a non-target molecule is less than about 20% of the affinity for IL-4R ⁇ . In some embodiments, the affinity of an anti-IL-4R ⁇ antibody for a non-target molecule is less than about 10% of the affinity for IL-4R ⁇ . In some embodiments, the affinity of an anti-IL-4R ⁇ antibody for a non-target molecule is less than about 1% of the affinity for IL-4R ⁇ . In some embodiments, the affinity of an anti-IL-4R ⁇ antibody for a non- target molecule is less than about 0.1% of the affinity for IL-4R ⁇ .
  • the term “competes with” or “cross-competes with” indicates that the two or more antibodies compete for binding to an antigen (e.g., IL-4R ⁇ ).
  • an antigen e.g., IL-4R ⁇
  • IL-4R ⁇ is coated on a surface and contacted with a first anti-IL-4R ⁇ antibody, after which a second anti-IL-4R ⁇ antibody is added.
  • a first anti-IL-4R ⁇ antibody is coated on a surface and contacted with IL-4R ⁇ and then a second anti-IL-4R ⁇ antibody is added.
  • 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.
  • a skilled artisan can select the concentrations of the antibodies used in the competition assays based on the affinities of the antibodies for IL-4 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.
  • a 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 Goodwin Ref: AOE-103WO 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
  • Goodwin Ref: AOE-103WO by, e.g., at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as measured in a competitive binding assay.
  • 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 hindrance to occur.
  • a second, competing antibody can be identified that competes for binding to IL-4R ⁇ 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-4R ⁇ sequence set forth in SEQ ID NOs: 237-240.
  • the antibody binds to an IL-4R ⁇ sequence set forth in SEQ ID NOs: 237-240 with a KD 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-4R ⁇ sequence set forth in SEQ ID NOs: 237-240 with a KD of less than or equal to about 1 x 10 -10 M, as measured by surface plasmon resonance (SPR).
  • the antibody binds to human IL-4R ⁇ with a KD of less than or equal to about 1 x 10 -9 M, as measured by surface plasmon resonance (SPR).
  • SPR surface plasmon resonance
  • an antibody provided herein binds IL-4R ⁇ 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-4R ⁇ 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 -9 M, as measured by ELISA or any other suitable method known in the art.
  • the KD of the antibody provided herein for the binding of IL-4R ⁇ 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 Goodwin Ref: AOE-103WO provided herein binds IL-4R ⁇ 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.
  • the antibody provided herein binds IL-4R ⁇ with a KD 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 .
  • the antibody provided herein binds IL-4R ⁇ 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.
  • the antibody provided herein binds FcRn with an affinity at pH 7.4 compared to pH 6.0 at a ratio (pH 7.4/pH 6.0) of about 10,000, 1,000, 500, 100, 50, 20, 10, 9, 8, 7, 6, 5, 4.5, 4, 3.5, 3, 2.5, 2, 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, or 1.05, as measured by ELISA or any other suitable method known in the art.
  • the antibody provided herein binds FcRn with an affinity at pH 6.0 compared to pH 7.4 at a ratio (pH 6.0/pH 7.4) of about 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.
  • Function [00269] “Effector functions” refer to those biological activities mediated by the Fc region of an antibody, which activities may vary depending on the antibody isotype.
  • compositions comprising the antibodies including pharmaceutical compositions comprising any one or more of the antibodies described herein with one or more pharmaceutically acceptable excipients.
  • the composition is sterile.
  • compositions generally comprise an effective amount of an antibody.
  • compositions can comprise, in addition to one or more of the antibodies disclosed herein, a pharmaceutically acceptable excipient, carrier, buffer, stabilizer, or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material can depend on the route of administration, e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, and intraperitoneal routes.
  • Pharmaceutical compositions for oral administration can be in tablet, capsule, powder, or liquid form.
  • a tablet can include a solid carrier such as gelatin or an adjuvant.
  • Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil, or synthetic oil.
  • a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil, or synthetic oil.
  • Physiological saline solution, dextrose, or other saccharide solution or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol can be included.
  • glycols such as ethylene glycol, propylene glycol, or polyethylene glycol
  • the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity, and stability.
  • Suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer’s Injection, and Lactated Ringer’s Injection. Preservatives, stabilizers, buffers, antioxidants, and/or other additives can be included, as required.
  • administration is preferably in a “therapeutically effective amount” or “prophylactically effective amount” (as the case can be, although prophylaxis can be considered therapy), this being sufficient to show benefit to the individual.
  • the actual amount administered and rate and time-course of administration will depend on the nature and severity of disease being treated. Prescription of treatment, e.g.
  • a composition can be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated. Methods Methods of Preparation [00276] Antibodies described herein can be produced using recombinant methods and compositions, e.g., as described in U.S. Pat. No.4,816,567.
  • an isolated nucleic acid encoding an antibody described herein is provided.
  • Such a nucleic acid may encode an amino acid sequence comprising the VL and/or an amino acid sequence comprising the VH of the antibody (e.g., the light and/or heavy chains of the antibody) or an amino acid sequence comprising the VHH of a single domain antibody.
  • one or more vectors e.g., expression vectors
  • the nucleic acid is provided in a multicistronic vector.
  • a host cell comprising such nucleic acid(s) is provided.
  • a host cell comprises (e.g., has been transformed with): (1) a vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of the antigen-binding polypeptide construct, or (2) a first vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antigen-binding polypeptide construct and a second vector comprising a nucleic acid that encodes an amino acid sequence comprising the VH of the antigen-binding polypeptide construct.
  • the host cell is eukaryotic, e.g.
  • a method of making an antibody comprises culturing a host cell comprising nucleic acid encoding the antibody, as provided above, under conditions suitable for expression of the antibody, and optionally recovering the antibody from the host cell (or host cell culture medium).
  • nucleic acid encoding an antibody e.g., as described above, is isolated and inserted into one or more vectors for further cloning and/or expression in a host cell.
  • nucleic acid may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody).
  • the protein in certain embodiments is present at about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, about 4%, about 3%, about 2%, or about 1%, or less of the dry Goodwin Ref: AOE-103WO weight of the cells.
  • the protein in certain embodiments, is present in the culture medium at about 5 g/L, about 4 g/L, about 3 g/L, about 2 g/L, about 1 g/L, about 750 mg/L, about 500 mg/L, about 250 mg/L, about 100 mg/L, about 50 mg/L, about 10 mg/L, or about 1 mg/L or less of the dry weight of the cells.
  • substantially purified antibody produced by the methods described herein has a purity level of at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, specifically, a purity level of at least about 75%, 80%, 85%, and more specifically, a purity level of at least about 90%, a purity level of at least about 95%, a purity level of at least about 99%, or greater as determined by appropriate methods such as SDS/PAGE analysis, RP-HPLC, SEC, and capillary electrophoresis.
  • Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells described herein.
  • Recombinant host cells or host cells are cells that include an exogenous polynucleotide, regardless of the method used for insertion, for example, direct uptake, transduction, f-mating, or other methods known in the art to create recombinant host cells.
  • the exogenous polynucleotide may be maintained as a nonintegrated vector, for example, a plasmid, or alternatively, may be integrated into the host genome.
  • Host cells can include CHO, derivatives of CHO, NS0, Sp2O, CV-1, VERO-76, HeLa, HepG2, Per.C6, or BHK.
  • the antibody may be produced in bacteria, in particular when glycosylation and Fc effector function are not needed.
  • expression of antibody fragments and polypeptides in bacteria see, e.g., U.S. Pat. Nos.5,648,237, 5,789,199, and 5,840,523. See also Charlton, Methods in Molecular Biology, Vol.248 (B.K.C. Lo, ed., Humana Press, Totowa, N.J., 2003), pp.245-254, describing expression of antibody fragments in E.
  • eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for antibody-encoding vectors, including fungi and yeast strains whose glycosylation pathways have been “humanized,” resulting in the production of an antibody with a partially or fully human glycosylation pattern. See Gerngross, Nat. Biotech.22:1409-1414 (2004), and Li et al., Nat. Biotech.24:210-215 (2006).
  • Suitable host cells for the expression of glycosylated antibodies are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Numerous baculoviral strains have been identified which may be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells. [00284] Plant cell cultures can also be utilized as hosts. See, e.g., U.S. Pat. Nos.5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing PLANTIBODIESTM technology for producing antibodies in transgenic plants).
  • Vertebrate cells may also be used as hosts.
  • mammalian cell lines that are adapted to grow in suspension may be useful.
  • useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney line (293 cells as described, e.g., in Graham et al., J. Gen Virol.36:59 (1977)); baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells as described, e.g., in Mather, Biol.
  • monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., in Mather et al., Annals N.Y. Acad. Sci.383:44-68 (1982); MRC 5 cells; and FS4 cells.
  • Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR ⁇ CHO cells (Urlaub et al., Proc. Natl. Acad. Sci.
  • the antibodies described herein are produced in stable mammalian cells, by a method comprising: transfecting at least one stable mammalian cell with a nucleic acid encoding the antibody, in a predetermined ratio; and expressing the nucleic acid in the at least one mammalian cell.
  • the predetermined ratio of nucleic acid is determined in transient transfection experiments to determine the relative ratio of input nucleic acids that results in the highest percentage of the antibody in the expressed product.
  • the method of producing a glycosylated antibody in stable mammalian cells described herein said method comprising identifying and purifying the desired glycosylated antibody.
  • the said identification is by one or both of liquid chromatography and mass spectrometry.
  • the antibodies can be purified or isolated after expression.
  • Proteins may be isolated or purified in a variety of ways known to those skilled in the art.
  • Standard purification methods include chromatographic techniques, including ion exchange, hydrophobic interaction, affinity, sizing or gel filtration, and reversed-phase, carried out at atmospheric pressure or at high pressure using systems such as FPLC and HPLC.
  • Purification methods also include electrophoretic, immunological, precipitation, dialysis, and chromatofocusing techniques. Ultrafiltration and diafiltration techniques, in conjunction with protein concentration, are also useful.
  • a variety of natural proteins bind Fc and antibodies, and these proteins can find use in the present invention for purification of antibodies.
  • the bacterial proteins A and G bind to the Fc region.
  • the bacterial protein L binds to the Fab region of some antibodies.
  • Purification can often be enabled by a particular fusion partner.
  • antibodies may be purified using glutathione resin if a GST fusion is employed, Ni +2 affinity chromatography if a His-tag is employed or immobilized anti-flag antibody if a flag-tag is used.
  • suitable purification techniques see, e.g. incorporated entirely by reference Protein Purification: Principles and Practice, 3rd Ed., Scopes, Springer-Verlag, NY, 1994, incorporated entirely by reference. The degree of purification necessary will vary depending on the use of the antibodies. In some instances, no purification is necessary.
  • the antibodies are purified using Anion Exchange Chromatography including, but not limited to, chromatography on Q-sepharose, DEAE sepharose, poros HQ, poros DEAF, Toyopearl Q, Toyopearl QAE, Toyopearl DEAE, Resource/Source Q and DEAE, Fractogel Q, and DEAE columns.
  • Anion Exchange Chromatography including, but not limited to, chromatography on Q-sepharose, DEAE sepharose, poros HQ, poros DEAF, Toyopearl Q, Toyopearl QAE, Toyopearl DEAE, Resource/Source Q and DEAE, Fractogel Q, and DEAE columns.
  • the proteins described herein are purified using Cation Exchange Chromatography including, but not limited to, SP-sepharose, CM sepharose, poros HS, poros CM, Toyopearl SP, Toyopearl CM, Resource/Source S and CM, Fractogel S, and CM columns and their equivalents and comparables. Goodwin Ref: AOE-103WO [00292]
  • antibodies described herein can be chemically synthesized using techniques known in the art (e.g., see Creighton, 1983, Proteins: Structures and Molecular Principles, W. H.
  • polypeptide corresponding to a fragment of a polypeptide can be synthesized by use of a peptide synthesizer.
  • nonclassical amino acids or chemical amino acid analogs can be introduced as a substitution or addition into the polypeptide sequence.
  • Non-classical amino acids include, but are not limited to, to the D-isomers of the common amino acids, 2,4diaminobutyric acid, alpha-amino isobutyric acid, 4aminobutyric acid, Abu, 2-amino butyric acid, g-Abu, e-Ahx, 6amino hexanoic acid, Aib, 2-amino isobutyric acid, 3-amino propionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, alanine, fluoro-amino acids, designer amino acids such as methyl amino acids, C-methyl amino acids, N-methyl amino acids, and amino acid analogs in general.
  • the amino acid can be D (dextrorotary) or L (levorotary).
  • described herein is a method for treating a subject in need thereof with an anti-IL-4R ⁇ antibody, the method comprising administering to a mammalian subject a therapeutically effective amount of an anti-IL-4R ⁇ antibody or pharmaceutical composition comprising an anti-IL-4R ⁇ antibody described herein.
  • the present application provides methods of treating a disorder or disease associated with elevated levels of IL-4 and/or IgE in a subject.
  • described herein are methods for treating a pathology associated with IL-4, IL-13, and/or IL-4R ⁇ activity, the method comprising administering to a mammalian subject a therapeutically effective amount an isolated anti-IL-4R ⁇ antibody or a pharmaceutical composition comprising an isolated anti-IL-4R ⁇ antibody described herein.
  • the antibodies and antibody fragments disclosed herein are useful for treating diseases and disorders which are improved, inhibited, or ameliorated by reducing IL-4, IL-13, and/or IL-4R ⁇ activity.
  • IL-4 and IL-13 related disorders which are treated by the antibodies or antibody fragments of the disclosure include an inflammatory disorder or disease.
  • Non- limiting examples of disorders which are treated by the antibodies or antibody fragments of the disclosure include, atopic dermatitis (AD), asthma (mild, moderate or severe), 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), Chronic Spontaneous Urticaria (CSU), Chronic Pruritis of Unknown Origin (CPUO), Bullous Pemphigoid (BP), Cold Inducible Urtic
  • described herein are 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 the antibody of or a pharmaceutical composition described herein.
  • the inflammatory disorder or disease is atopic dermatitis.
  • the inflammatory disorder or disease is asthma.
  • the inflammatory disorder or disease is nasal polyps.
  • described herein are methods for treating a pathology associated with elevated levels of IL-4 and/or IL-13 in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount an antibody or a pharmaceutical composition described herein.
  • described herein are methods of reducing biological activity of IL-4, IL13, and/or IL-4R ⁇ in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount an antibody or a pharmaceutical composition described herein.
  • described herein are methods of preventing an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising Goodwin Ref: AOE-103WO administering to the mammalian subject a therapeutically effective amount an antibody or a pharmaceutical composition described herein.
  • a first dose of an anti- IL-4R ⁇ antibody comprising administering to the patient a first dose of an anti- IL-4R ⁇ antibody, wherein the first dose is between about 100 mg and about 1,500 mg (e.g., selected from about 150 mg, about 200 mg, about 300 mg, about 350 mg, about 600 mg, about 650 mg, about 1,200 mg, or about 1,300 mg) wherein the anti-IL-4R ⁇ antibody comprises an anti- IL-4R ⁇ antibody disclosed herein.
  • the method comprises administering to the patient a second dose of an anti- IL-4R ⁇ antibody, wherein the second dose is between about 100 mg and about 1,500 mg (e.g., selected from about 150 mg, about 200 mg, about 300 mg, about 350 mg, about 600 mg, about 650 mg, about 1,200 mg, and about 1,300).
  • the method comprises administering to the patient a first dose and a second dose of an anti- IL-4R ⁇ antibody, wherein the first dose is 600 mg, and wherein the second dose is 600 mg.
  • the second dose is administered 29 days after the first dose.
  • the patient has a diagnosis of mild or moderate asthma as defined by Global Initiative for Asthma.
  • the patient has a fractioned exhaled nitric oxide (FeNO) of at least 25 parts per billion (ppb) prior to administration of the antibody.
  • FeNO fractioned exhaled nitric oxide
  • the FeNO is reduced by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, or by at least 50% following administration of the anti-IL-4R ⁇ antibody.
  • the FeNO is reduced by at least 5, 10, or 15 ppb following administration of the anti-IL-4R ⁇ antibody.
  • the patient has a pre-bronchodilator forced expiratory volume in 1 second (FEV1) that is at least 60% of the predicted normal value (e.g., between 3.0 and 5.0 mL).
  • the FEV1 is increased by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, or by at least 50% following administration of the anti-IL-4R ⁇ antibody.
  • the forced vital capacity (FVC) is increased by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, or by at least 50% following administration of the anti-IL-4R ⁇ antibody.
  • the peak expiratory flow (PEF) is increased by at least 10%, by at least 15%, Goodwin Ref: AOE-103WO by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, or by at least 50% following administration of the anti-IL4R ⁇ antibody.
  • FeNO is a biomarker of bronchial or airway inflammation. FeNO is produced by airway epithelial cells in response to inflammatory cytokines including IL-4 and IL-13 (Alwing et al. (1993), Eur. Respir. J.6: 1368-1370). FeNO levels in healthy adults range from 2 to 30 ppb. FeNO levels are correlated to severity in both asthma and COPD.
  • the disclosure includes methods comprising administering an IL-4R ⁇ antibody to a human subject with elevated levels of FeNO, such as more than about 30 ppb, more than about 31 ppb, more than about 32 ppb, more than about 33 ppb, more than about 34 ppb, or more than about 35 ppb.
  • FeNO may be used as a marker to determine the effectiveness of the IL-4R ⁇ antibody in treating asthma.
  • the person skilled in the art would readily be able to measure FeNO using known techniques, for example a FeNO test is done by the patients breathing out slowly and steadily into the mouthpiece attached to a hand-held monitor (e.g., a NIOX instrument by Aerocrine AB, Soina, Sweden).
  • the reading shows up on the monitor, with the result of the FeNO test showing how inflamed the airways are.
  • a commonly used FeNO test is the American Thoracic Society (ATS) 2005 test.
  • the percentage reduction of FeNO by the IL-4R ⁇ antibody may, for example, be determined relative to a control subject who has not been administered an IL-4R ⁇ antibody. This may be the same subject (with FeNO being assessed prior to administration of a IL-4R ⁇ antibody) or in a different subject who has not been administered an IL-4R ⁇ antibody. A placebo may have been administered to this different subject.
  • the disclosure also includes methods for treating asthma or COPD in a human subject comprising administering an IL-4R ⁇ antibody as disclosed herein wherein FeNO is reduced following administration of the antibody.
  • the FeNO is reduced by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, or by at least 50% following administration of the antibody.
  • the disclosure relates to a method for treating asthma or COPD in a human subject comprising (a) administering an IL-4R ⁇ antibody and (b) measuring FeNO of the human subject.
  • the disclosure relates to a method reducing FeNO of a human subject comprising administering an IL-4R ⁇ antibody as disclosed herein.
  • the FeNO is reduced by at least 10%, by at least 15%, by at least 20%, by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, or by at least 50% following administration of the antibody.
  • the disclosure relates to a method for treating asthma or COPD in a human subject comprising (a) selecting a patient with an elevated level of FeNO and (b) administering to the patient a therapeutically effective amount of an IL-4R ⁇ antibody as disclosure herein.
  • the human subject has an elevated level of FeNO that is more than about 30 ppb, more than about 31 ppb, more than about 32 ppb, more than about 33 ppb, more than about 34 ppb, or more than about 35 ppb.
  • the subject’s lung function is improved (e.g., as measured by an improvement in forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, FEV1 percent predicted, FVC percent predicted, FEV1/FVC percent predicted, and/or peak expiratory flow (PEF)) following administration of the antibody.
  • FEV1 forced expiratory volume in 1 second
  • FVC forced vital capacity
  • FEV1/FVC forced vital capacity
  • FEV1 percent predicted FVC percent predicted
  • FEV1/FVC percent predicted FEV1/FVC percent predicted
  • PEF peak expiratory flow
  • an antibody is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.
  • An effective amount of an anti-IL-4R ⁇ antibody may be administered for the treatment of a disease or disorder.
  • the appropriate dosage of the anti-IL-4R ⁇ antibody may be determined based on the type of disease or disorder to be treated, the type of the anti-IL-4R ⁇ antibody, the severity and course of the disease or disorder, the clinical condition of the individual, the individual’s clinical history and response to the treatment, and the discretion of the attending physician.
  • the anti-IL-4R ⁇ antibody is administered in an amount of about 50 mg to about 1500 mg, for example, in an amount of about 150 mg, about 300 mg, about 600 mg, or about 1200 mg.
  • the anti-IL-4R ⁇ antibody is Goodwin Ref: AOE-103WO administered weekly, every two weeks, every three weeks, every four weeks, every six weeks, every two months, or every three months.
  • the patient is administered the anti-IL-4R ⁇ antibody about every 3 weeks. In some embodiments, the patient is administered the anti-IL-4R ⁇ antibody about every 4 weeks. In some embodiments, the patient is administered the anti-IL-4R ⁇ antibody about every 5 weeks.
  • the patient is administered the anti-IL- 4R ⁇ antibody about every 6 weeks. In some embodiments, the patient is administered the anti-IL-4R ⁇ antibody about every 7 weeks. In some embodiments, the patient is administered the anti-IL-4R ⁇ antibody about every 8 weeks. In some embodiments, the patient is administered the anti-IL-4R ⁇ antibody about every 9 weeks. In some embodiments, the patient is administered the anti-IL-4R ⁇ antibody about every 10 weeks. In some embodiments, the patient is administered the anti-IL-4R ⁇ antibody about every 11 weeks. In some embodiments, the patient is administered the anti-IL-4R ⁇ antibody about every 12 weeks. In some embodiments, the patient is administered the anti-IL-4R ⁇ antibody about every 13 weeks.
  • the patient is administered the anti-IL-4R ⁇ antibody about every two months. In some embodiments, the patient is administered the anti-IL-4R ⁇ antibody about every three months. [00317] In some embodiments, the patient is administered a first dose and a second dose of the anti- IL-4R ⁇ antibody, wherein the first dose is 600 mg, and wherein the second dose is 600 mg. In some embodiments, the second dose is administered 29 days after the first dose. [00318] In some embodiments, an antibody provided herein is administered with at least one additional therapeutic agent. Any suitable additional therapeutic or immunotherapeutic agent may be administered with an antibody provided herein.
  • Additional therapeutic agents include agents that are used to treat or prevent a disease or disorder such as, but not limited to, an inflammatory disease or disorder associated with elevated levels of IL-4, IL-13, and/or IgE.
  • the additional therapeutic agent can be administered by any suitable means.
  • an antibody provided herein and the additional therapeutic agent are included in the same pharmaceutical composition.
  • an antibody provided herein and the additional therapeutic agent are included in different pharmaceutical compositions.
  • administration of the antibody can occur prior to, simultaneously, and/or following administration of the additional therapeutic agent.
  • administration of an antibody provided herein and the additional therapeutic agent occur within about one month of each other. In some embodiments, administration of an antibody provided herein and the additional therapeutic agent occur within about one week of each other. In some embodiments, administration of an antibody provided herein and the additional therapeutic agent occur within about one day of each other. In some embodiments, administration of an antibody provided herein and the additional therapeutic agent occur within about twelve hours of each other. In some embodiments, administration of an antibody provided herein and the additional therapeutic agent occur within about one hour of each other. Kits and Articles of Manufacture [00321] The present application provides kits comprising any one or more of the antibody compositions described herein and instructions for use.
  • kits further contain a component selected from any of secondary antibodies, reagents for immunohistochemistry analysis, pharmaceutically acceptable excipient, package insert, instruction manual, and any combination thereof.
  • the kit comprises a pharmaceutical composition comprising any one or more of the antibody compositions described herein with one or more pharmaceutically acceptable excipients.
  • the present application also provides articles of manufacture comprising any one of the antibody compositions or kits described herein. Examples of an article of manufacture include vials (including sealed vials).
  • the harvested supernatants were loaded to a column of MabselectTM SuReTM (GE Healthcare). After washing column with Buffer A (PBS, PH 7.4), the protein was eluted with Buffer B (1 M Glycine, pH 2.7), and immediately neutralized with 1/10 volume of Buffer D (1 M sodium citrate, pH 6.0). The affinity purified antibody was then buffer exchanged into 20 mM sodium acetate pH 5.5.
  • Buffer A PBS, PH 7.4
  • Buffer B 1 M Glycine, pH 2.7
  • Buffer D 1 M sodium citrate, pH 6.0
  • a BIACORE® 8K SPR system (GE HealthCare) equipped with Series S Sensor Chip Protein G (Cytiva, Cat.29179315) was used to determine the binding kinetic rate and affinity constants at 25 ⁇ C and in a running buffer of HBS-EP+ (10 mM HEPES pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.05% Surfactant P20). Following a stabilization period in running buffer, the anti-IL13 mAb constructs (diluted to 1 ⁇ g/mL were captured onto flow cell 2 (active) for 60 sec at a flow rate of 10 uL/min.
  • Recombinant Human IL-4 Protein, His Tag (Acro Cat. IL3-H52H4) was prepared at concentrations of 0, 0.39, 0.78, 1.56, 3.13, 6.25, 12.5 and 0 nM and injected over flow cell 1 (reference) and flow cell 2 (active) for 180 sec at a flow rate of 30 ⁇ L/min.
  • Recombinant Cynomolgus IL-4 Protein, His Tag (SINO Goodwin Ref: AOE-103WO BIOLOGICAL, Cat.11057-C07H) was prepared at concentrations of 0, 0.39, 0.78, 1.56, 3.13, 6.25, 12.5, 25 and 0 nM and injected over flow cell 1 (reference) and flow cell 2 (active) for 180 sec at a flow rate of 30 ⁇ L/min. Samples were injected in a multi-cycle manner over freshly captured mAb, by regenerating the capture surfaces with injection of glycine pH 1.5 for 30 sec at a flow rate of 30 ⁇ L/min. The data was processed and analyzed with BIACORE® Insight Evaluation Software Version 2.0.15.12933 (GE Healthcare) as follows.
  • the first round of selection consisted of 1 nM biotinylated hIL-4R ⁇ and the output of that round was subsequently split into four distinct secondary rounds of parallel selection consisting of A) 1 nM biotinylated hIL-4R ⁇ while also being washed for 4 hours at room temperature in buffer containing 100 nM of unlabeled hIL-4R ⁇ , B) 0.1 nM biotinylated hIL-4R ⁇ while also being washed for 4 hours at room temperature in buffer containing 10 nM of unlabeled hIL-4R ⁇ , C) 50 nM biotinylated cyIL-4R ⁇ with no wash, and D) 5 nM biotinylated cyIL-4R ⁇ with no wash.
  • Mutant clones from the output of each arm of secondary selection were analyzed for koff as a proxy for binding affinity by using periplasmic extracts of each mutant clone using surface plasmon resonance (SPR) and comparing to dupilumab, as well as bioinformatic analyses of sequences to identify patterns of enrichment.
  • Mutants that exhibited no loss or improved binding relative to dupilumab as well as population enrichment Goodwin Ref: AOE-103WO throughout the selection were combined into a single library comprising all mutants in both the heavy and light chain.
  • Fabs containing a random combinatorial mix of these individual CDR mutants were again screened in a phage display system, with multiple combinations of selection strategies outlined in TABLE 5.
  • an HC30M sensor chip that was previously functionalized with a polyclonal mixture of goat anti-human Fc antibody and used to capture purified antibodies at a level between 100-1000 RLU. Subsequently, concentrations of antigen ranging from 200 nM to 0.13 nM were injected over the surface at a rate of 2 mL/min. Regeneration of the chip between different concentrations of antigen was performed with 200 mM phosphoric acid and antibody was captured again as previously described. Association and dissociation rate constants were subsequently determined through fitting to a 1:1 Langmuir binding model using the Kinetics Software from Carterra from which a K D value was derived. Results are summarized in TABLE 6.
  • KD of purified antibodies to FcRn, Fc ⁇ R, and C1q was determined through surface plasmon resonance (SPR) using a BIACORE® 8K. Briefly, an SPR chip functionalized with Protein G was used to capture purified antibodies normalized to 0.5 mg/mL, at a flow rate of 10 uL/min for 60 seconds. A paired channel with only buffer was used as reference. Subsequently, concentrations of human or cyno FcRn ranging from 25 nM to 0.39 nM were injected over the surface with captured purified antibody as well as the reference channel. Regeneration of the chip between different concentrations of IL-13 was performed with 10 mM Glycine HCl, pH 1.5 and antibody was again captured as previously described.
  • Affinity measurement as described was done at both pH 7.4 and pH 6.0. Association and dissociation rate constants were subsequently determined through fitting to a 1:1 Langmuir binding model using the BIACORE® Insight Evaluation Software from which a KD value was derived.
  • the tested antibody showed enhanced binding to FcRn at pH 6.0 relative to an IgG4 positive control (TABLE 7), which is a strong indicator that such antibody would have increased half-life in vivo. This was further confirmed in a pharmacokinetics study in cynomolgus monkey. The tested antibody also had decreased affinity to Fc ⁇ R and C1q (TABLE 7).
  • IC50 values were determined as the concentration of antibody required to inhibit 50% of the maximum MFI of biotinylated hIL-13 OR biotinylated hIL-4 surface detected with incubation of 0.05 ug/mL of hIL-13 OR 0.04 ug/mL hIL-4 alone. Results are summarized in TABLE 8, TABLE 9, FIG.1A, and FIG.1B.
  • Cells were collected and seeded at 50,000 cells per well in 100 ⁇ L. Concurrently, a 100 ⁇ L mixture of hIL-13 OR hIL-4 and purified antibody (1:1 by volume) was added to the same well, resulting in a final concentration of 10 ng/mL of hIL-13 OR 5 ng/mL of hIL-4 and 0-50 nM of purified antibody. Cells were incubated at 37 °C for 1 hour and subsequently fixed, permeabilized, and stained with a PE-conjugated anti-pSTAT6 antibody. The MFI of cells in each well were recorded by FACS using a BD FACSCanto II and subsequent data were analyzed using GraphPad Prism.
  • IC50 values were determined as the concentration of antibody required to inhibit 50% of the maximum MFI of pSTAT6 detected with incubation of 10 ng/mL of hIL- 13 OR 5 ng/mL of hIL-4 alone. Results are summarized in TABLE 10, TABLE 11, FIG. 2A, and FIG.2B. [00337] As shown in TABLE 10, clones were identified that demonstrated more effective inhibition of IL-13 and/or IL-4 induced phosphorylation of STAT6 as compared to dupilumab by up to about 2-fold (such as, for example: construct 15, construct 18, construct 21, construct 23, construct 24, construct 27 and construct 28).
  • A549 cells were seeded at 20,000 cells in 100 ⁇ L of DMEM + 10% FBS and cultured overnight at 37 °C. The next day, the cell culture media was discarded and cells were gently washed with fresh media.
  • a 150 ⁇ L mixture of hIL-13, purified antibody, and hTNFa (1:1:1 by volume) were added to the wells, resulting in a final concentration of 20 ng/mL hIL-13, 0- 100 nM purified antibody, and 200 ng/mL hTNFa OR 1.5 ng/mL hIL-4, 0-100 nM purified antibody, and 50 ng/mL TNFa. Cells were incubated in this mixture at 37 °C for 20-24 hour.
  • TARC ELISA kit R&D Systems
  • concentrations of TARC in each well were analyzed using GraphPad Prism.
  • IC50 values were determined as the concentration of antibody required to inhibit 50% of the maximum TARC concentration detected with Goodwin Ref: AOE-103WO incubation of only 20 ng/mL of hIL-13 and 200 ng/mL hTNFa OR 1.5 ng/mL hIL-4 and 50 ng/mL hTNFa. Results are summarized in Table 10A, Table 10B, FIG.3A, and FIG.3B.
  • TF-1 cells were harvested and starved in RPMI1640 +10% FBS without additional cytokine for 4 hours. During this time, a mixture of hIL-13 OR hIL-4 and purified antibody (1:1 by volume) was prepared 50 ⁇ L was added per well. Following starvation, TF-1 cells were again harvested and seeded at 15,000 cells in 50 ⁇ L per well, resulting in a final concentration of 4 ng/mL of hIL-13 OR 0.5 ng/mL of hIL-4 and 0-5 nM purified antibody.
  • ELISA was used to assess non-specificity. Briefly, ELISA plates were coated with a 0.15% baculovirus particle (BVP) suspension and incubated at 4 °C, overnight.
  • BVP baculovirus particle
  • Purified antibodies are analyzed for their maximum solubility and corresponding viscosity. Briefly, for maximum solubility, purified antibodies are formulated into a buffer of 20 mM Histidine, 4% sucrose, 0.04% PS80 and pH X, Y, and Z and are concentrated. Concentration at antibody at this point is evaluated and is determined to be the maximum solubility of the antibody at that pH. Subsequently, viscosity of the antibody at that concentration and pH are determined.
  • Binding affinity (KD) of exemplary antibodies to human IL-4R ⁇ was determined using the Kinetic Exclusion Assay (KinExA). Briefly, antibody and recombinant human IL- 4R ⁇ were equilibrated in solution.
  • equilibration samples were done with a fixed concentration of the antibody ranging from 2.27 pm to 100 pM and a titration of recombinant human IL-4R ⁇ generated from a starting concentration ranging from 9.78 pM to 1.00 nM with 2-fold dilutions for a total set of dilutions ranging from 11 to 13 concentrations. Samples were incubated for a time period ranging from 3.5 hours to 340 hours, to fully reach equilibrium. Once samples reached equilibrium, azlactone beads previously coated with recombinant human IL-4R ⁇ were used to capture any free antibody from the equilibrated solution.
  • PK Pharmacokinetic Analysis of Anti-IL-4R ⁇ Antibodies
  • PK parameters were determined from cynomolgus serum samples up to day 91.
  • the PK analysis demonstrated that, with IV administration, Construct 13 (mAb422) and Construct 38 (mAb471) had a half-life of 17.62 and 25.60 days, respectively, compared with 10.88 days for dupilumab (25 mg/kg IV).
  • the results are summarized in TABLE 17 and TABLE 19 (SC results shown). Similar results were seen with SC administration.
  • the PK analysis demonstrated that the exemplary antibodies, Construct 13 (mAb422) and Construct 38 (mAb471), had improved half-life and reduction in serum clearance rates compared to those of dupilumab as reported in TABLE 17, TABLE 18, FIG.5A, and FIG.5B.
  • Construct 13 mAb422
  • Construct 38 mAb471
  • TABLE 20 Antibody Bioavailability (%) Dupilumab 100% Example 12.
  • Epitope binning is a technique used to cluster different mAbs based on the specific region of the antigen (in this case IL-4R ⁇ ) that is recognized by the antibody.
  • TMDD This is a receptor-mediated endocytosis process, meaning that the interactions of the antibody with its receptor results in the internalization of the antibody- receptor complex and subsequent degradation via lysosomes, specialized organelles, or areas within the cell that degrade molecules and other biomaterial. TMDD is commonly observed for mAbs with receptor targets, such as dupilumab, which targets IL-4R ⁇ .
  • Receptor-mediated endocytosis Binding of antibodies to Fc-gamma-receptors, present on many immune cells, can also trigger an elimination process similar to TMDD.
  • CDX-0159 is an antibody targeting KIT (c-KIT/CD117) receptor tyrosine kinase with YTE amino acid substitutions for half-life extension currently in clinical development.
  • CDX-0159 In NHPs, half-life was shown to be 22 days for CDX-0159 compared to 4.8 days for CDX-0158, a non-half-life extended antibody directed at the same target. Clinically, CDX-0159 showed a 32-day half-life, suggesting an approximately one-and-a-half times increase over NHP data. Further, CDX-0159 has shown a human half-life that is approximately five times greater than CDX-0158, the non-half-life extended antibody directed at the same target (half-life of CDX-0159 was 32 days versus 6 days for CDX-0158).
  • VRDN-002 is an antibody targeting anti-IGF-1 receptor with recycling-based FC modifications for half-life extension (i.e., YTE or LS or similar amino acid substitutions) currently in clinical development.
  • half-life extension i.e., YTE or LS or similar amino acid substitutions
  • YTE or LS or similar amino acid substitutions i.e., YTE or LS or similar amino acid substitutions
  • teprotumumab a non-half-life extended antibody directed at the same target.
  • VRDN-002 showed an approximately 30- to 40-day half-life in an interim analysis, suggesting an approximately two to three times increase over NHP data.
  • VRDN-002 has shown a human half-life that is approximately three to four times greater than teprotumumab, the non-half-life extended antibody directed at the same target (half-life of VRDN-002 was approximately 30 to 40 days compared to approximately 10 to 11 days for teprotumumab).
  • the antibodies disclosed herein may have a human half-life of approximately 30 to 60 days, based on a one-and-a-half to three times factor going from NHPs to humans, or of approximately 45 to 70 days, based on a three to five times factor going from non-half-life extended antibodies to half-life extended antibodies directed at the same receptor target.
  • a Ctrough for the disclosed antibodies was targeted to be equal to dupilumab’s Ctrough in maintenance with every two weeks dosing, which was approximately 75 mg/L.
  • AOE-103WO overlapping epitopes of dupilumab and the antibodies disclosed herein that bin with dupilumab, and the similarity each in potency across multiple in vitro assays necessary exposures for potential clinical activity of the antibodies disclosed herein can be predicted.
  • the antibodies disclosed herein can be administered every six weeks if they demonstrate a half-life of at least 42 days and every two months if they demonstrate a half-life of at least 59 days.
  • Example 14 A Phase 1, Randomized, Blinded, Placebo-controlled, Single Ascending Dose, First-in-human, Study of the Safety, Tolerability, and Pharmacokinetics of Construct 38 (mAb471) in Healthy Participants [00366]
  • This study evaluated single ascending doses (SAD; FIG.13) of Construct 38 (mAb471) administered subcutaneously (SC) in healthy participants (administered within 4 hours of drawing the dosage into the syringe). It consisted of a maximum of 4 cohorts and each cohort consisted of up to 8 healthy participants.
  • Clinical safety laboratory findings serum chemistry (including liver function tests, electrolytes, and kidney function tests), full blood count, and coagulation tests) were assessed using whole blood samples. Urinalysis was assessed using urine samples. Vital signs included heart rate, blood pressure, body temperature, and respiratory rate.
  • PK pharmacokinetics
  • Cmax maximum observed serum concentration
  • tmax time to Cmax
  • tmax terminal elimination rate constant
  • t1/2 terminal elimination half-life
  • AUC area under the serum concentration- time curve
  • AUC0–last AUC from time 0 extrapolated to infinity
  • CL/F apparent clearance
  • Vz/F apparent volume of distribution
  • ADA samples were performed using a validated ADA assay in a 3-tier format (screen, confirm, and titer) and NAb assay in samples that have positive titers for ADA.
  • Secondary outcomes also included PK parameters: ratio of Cmax in participants with or without ADA and the ratio of AUC in participants with or without ADA.
  • Immunogenicity data summaries included incidence of samples screened positive for ADA, incidence of samples confirmed positive for ADA, and summaries of ADA titers and NAb (neutralizing antibody), as applicable.
  • ADA data presence and potential impact on PK or safety was summarized by dose and time.
  • FEV1/FVC is a ratio that provides additional information about the type of lung disease a patient has, e.g., obstructive or restrictive, and aids in the diagnosis of certain respiratory diseases such as asthma.
  • Percent predicted values are calculated by taking a patient’s absolute measurements of FEV1, FVC, and/or FEV1/FVC and dividing those by what the patient’s measurements should be or are expected to be for those tests based on the patient’s demographics and then multiplying that ratio by 100. Percent predicted values are commonly used to classify the severity of the respiratory disease, such as asthma, and to help clinicians track how a patient’s lungs are functioning over time. [00376] Key inclusion criteria included: 1.
  • Liver function tests i.e., alanine aminotransferase and aspartate aminotransferase
  • elevated bilirubin was not allowed unless due to Gilbert’s syndrome.
  • Impaired renal function defined as an estimated glomerular filtration rate ⁇ 60 mL/min/1.73 m 2 (milliliter per minute per square meter) at screening. j.
  • any other laboratory vital sign (e.g., hypertension that could be unsafe for study drug administration per Investigator assessment), ECG abnormality (e.g., QTcF prolongation), clinically significant medical condition (e.g., cardiac failure), or finding that, in the Investigator’s opinion, was likely to unfavorably alter the risk of study participation, confound study results, or interfere with the study conduct or compliance; participants were rescreened and tests were repeated at the Investigator’s discretion.
  • vital sign e.g., hypertension that could be unsafe for study drug administration per Investigator assessment
  • ECG abnormality e.g., QTcF prolongation
  • clinically significant medical condition e.g., cardiac failure
  • Phase 1 Single Ascending Dose By Cohort 4 g Goodwin Ref: AOE-103WO TABLE 22* Phase 1 Single Ascending Dose: By Cohort Overall c TABLE 23** Phase 1 Single Ascending Dose: By Cohort Overall t ) Goodwin Ref: AOE-103WO Phase 1 Single Ascending Dose: By Cohort Overall * * ) intervention.
  • Non-cardiac chest pain was deemed as not related to study drug and likely related to dyspepsia or musculoskeletal causes.
  • FIG.6 shows the median percent pSTAT over time post-dose.
  • FIG.7 shows the median percent change from baseline in TARC over time post- dose. TARC suppression was observed in all cohorts.
  • FIG.8 shows the median percent change from baseline in TARC over time following a single 600 mg dose of mAb471 and a single 600 mg dose of DUPIXENT.
  • a single dose of 600 mg of mAb471 resulted in deeper TARC reduction compared to Dupixent ® .
  • Goodwin Ref AOE-103WO Total IgE Levels in SAD Cohorts
  • FIG.9 shows the median percent change from baseline of IgE levels following single doses of mAb471. Results showed trends toward reduced total IgE levels at later timepoints (e.g., generally beginning around Day 29).
  • Periostin Levels in SAD Cohorts [00386]
  • FIG.10 shows the percent change from median baseline levels of serum periostin.
  • PK modeling was performed based on the mean observed Ctrough at steady state for dupilumab in adults with asthma (69.0 ⁇ g/mL) and COPD (61.8 ⁇ g/mL) in two clinical trials
  • Goodwin Ref AOE-103WO reported in Dupixent ® European Public Assessment Report (EMEA/H/C/004390/II/0079).
  • EMEA/H/C/004390/II/0079 Modeled exposures using a 760 mg dose supported potential up to 8-week dosing, as shown in FIG.12.
  • Example 15 A Phase 1, Randomized, Blinded, Placebo-controlled, Multiple-Dose Study of Construct 38 (mAb471) in Participants with Mild-to-Moderate Asthma [00390] This study will evaluate multiple dose (MD) administration of Construct 38 (mAb471) administered subcutaneously (SC) in participants (FIG.13). It will consist of approximately 20 patients with mild to moderate asthma, who will be randomized 3:1 mAb471 (600 mg per dose) to placebo.
  • MD multiple dose
  • SC subcutaneously
  • the patients that receive mAb471 will receive a dose on Days 1 and 29.
  • the study will be conducted at multiple sites in Australia. The anticipated duration of the study is approximately 238 days.
  • Placebo solution will be administered via SC injection.
  • the primary outcomes will be safety, including incidence of clinically significant laboratory findings, incidence of clinically significant vital signs, incidence of clinically significant abnormal electrocardiogram (ECG) values, and incidence of clinically significant physical exam findings.
  • ECG electrocardiogram
  • Treatment-emergent adverse events (including those leading to discontinuation of study drug) will be monitored via interviews, physical examinations and review of clinical safety laboratory test results and ECG reports.
  • Clinical safety laboratory findings will be assessed using whole blood samples.
  • Urinalysis will be assessed using urine samples.
  • Vital signs include heart rate, blood pressure, body temperature, and respiratory rate. Resting vital signs will be obtained after the participant has been in a sitting or supine position for at least 5 minutes.
  • Electrocardiogram parameters will be measured. Standard 12-lead ECGs will be obtained in triplicate (1 to 3 minutes apart) after the participant has been resting for at least 5 minutes in a seated or supine position.
  • CRU clinical research unit
  • Timepoints will be taken on days 1 and 29: 0, 4, 8, 24, 48, and 72 hours post-dose, and on Days 8, 15, 22, 36, 43, 50, 57, 85, 113, 141, 169, and 197 post-dose.
  • Secondary outcomes include pharmacokinetics (PK) parameters: maximum observed serum concentration (Cmax), time to Cmax (tmax), terminal elimination rate constant (lambda z), terminal elimination half-life (t1/2), area under the serum concentration- time curve (AUC) from time 0 to the last quantifiable time point (AUC0–last), AUC from time 0 extrapolated to infinity (AUC0-inf), apparent clearance (CL/F), apparent volume of distribution (Vz/F) and AUC0-672.
  • PK pharmacokinetics
  • ADA samples will be performed using a validated ADA assay in a 3-tier format (screen, confirm, titer) and NAb assay in samples that have positive titers for ADA.
  • Secondary outcomes also include PK parameters: ratio of Cmax in participants with or without ADA and the ratio of AUC in participants with or without ADA.
  • Immunogenicity data summaries will include incidence of samples screened positive for ADA, incidence of samples confirmed positive for ADA, and summaries of ADA titers and NAb (neutralizing antibody), as applicable.
  • ADA data presence and potential impact on PK or safety
  • dose and time may be summarized by dose and time.
  • Fractional Exhaled Nitric Oxide is a biomarker of bronchial or airway inflammation. FeNO is produced by airway epithelial cells in response to inflammatory cytokines including IL-4 and IL-13 (Alwing et al. (1993), Eur. Respir.
  • FeNO levels in healthy adults range from 2 to 30 parts per billion (ppb). FeNO is measured prior to the start of the study and at regular intervals throughout using a NIOX instrument by Aerocrine AB, Soina, Sweden. The assessment is conducted prior to spirometry and following a fast of at least an hour.
  • Other exploratory outcomes include: Goodwin Ref: AOE-103WO - measuring changes from baseline over time in forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, FEV1 percent predicted, FVC percent predicted, FEV1/FVC percent predicted, and peak expiratory flow (PEF) in patients with mild-to-moderate asthma.
  • FEV1/FVC is a ratio that provides additional information about the type of lung disease a patient has, e.g., obstructive or restrictive, and aids in the diagnosis of certain respiratory diseases such as asthma.
  • Percent predicted values are calculated by taking a patient’s absolute measurements of FEV1, FVC, and/or FEV1/FVC and dividing those by what the patient’s measurements should be or are expected to be for those tests based on the patient’s demographics and then multiplying that ratio by 100. Percent predicted values are commonly used to classify the severity of the respiratory disease, such as asthma, and to help clinicians track how a patient’s lungs are functioning over time.
  • Respiratory Infection Suspected or confirmed bacterial or viral infection of the upper or lower respiratory tract, sinus, or middle ear that occurred within and/or has not resolved within 4 weeks of screening that a) led to a change in asthma management or b) in the opinion of the Investigator, is expected to affect the patient’s asthma status or the patient’s ability to participate in the study. Note that patients may be rescreened once to allow for an adequate time period between resolution of the infection and screening. 6. Evidence of clinically significant abnormalities or disease other than as previously described. a. Hemoglobin A1c ⁇ 6.5% and/or diagnosis of diabetes mellitus. b. Positive test for human immunodeficiency virus antibody. c.
  • Impaired renal function defined as an estimated glomerular filtration rate ⁇ 60 mL/min/1.73 m 2 (milliliter per minute per square meter) at screening.
  • Any other laboratory, vital sign e.g., hypertension that could be unsafe for study drug administration per Investigator assessment
  • ECG abnormality e.g., QTcF Goodwin Ref: AOE-103WO prolongation
  • clinically significant medical condition e.g., cardiac failure
  • participants may be rescreened and tests may be repeated at the Investigator’s discretion.

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Abstract

L'invention concerne des anticorps qui se lient au récepteur alpha de l'interleukine 4 (IL-4Rα) et leurs procédés d'utilisation. Dans certains aspects, l'invention concerne des procédés d'inhibition de l'activité biologique IL-4Rα. Dans certains aspects, les anticorps et les procédés décrits ici sont utilisés pour le traitement d'une maladie ou d'un trouble inflammatoire associé à des niveaux élevés d'IL-4 et/ou d'IgE. Dans certains aspects, l'invention concerne des méthodes de traitement de l'asthme par administration d'anticorps anti-IL4Rα.
PCT/US2025/014129 2024-01-31 2025-01-31 Procédés d'administration d'anticorps qui se lient au récepteur alpha de l'interleukine 4 Pending WO2025166234A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010053751A1 (fr) * 2008-10-29 2010-05-14 Regeneron Pharmaceuticals, Inc. Anticorps humains à forte affinité dirigés contre le récepteur de l’il-4 humaine
US8980273B1 (en) * 2014-07-15 2015-03-17 Kymab Limited Method of treating atopic dermatitis or asthma using antibody to IL4RA
US20170281769A1 (en) * 2014-09-03 2017-10-05 Medimmune Limited STABLE ANTI-IL-4Ra FORMULATION

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010053751A1 (fr) * 2008-10-29 2010-05-14 Regeneron Pharmaceuticals, Inc. Anticorps humains à forte affinité dirigés contre le récepteur de l’il-4 humaine
US8980273B1 (en) * 2014-07-15 2015-03-17 Kymab Limited Method of treating atopic dermatitis or asthma using antibody to IL4RA
US20170281769A1 (en) * 2014-09-03 2017-10-05 Medimmune Limited STABLE ANTI-IL-4Ra FORMULATION

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