Methods of administering antibodies that bind interleukin 13

Abstract

Described herein are methods of administration of antibodies that bind interleukin 13 (IL-13) and methods of use thereof. In certain aspects, described herein are methods of inhibiting IL‑13 biological activity. In certain aspects, the antibodies and methods described herein are used for treatment of an inflammatory disorder or disease.

Description

METHODS OF ADMINISTERING ANTIBODIES THAT BIND INTERLEUKIN 13 CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application Nos.63 / 462,832, filed April 28, 2023; 63 / 469,180, filed May 26, 2023; 63 / 471,088, filed June 5, 2023; 63 / 521,614, filed June 16, 2023; 63 / 541,581, filed September 29, 2023; 63 / 612,871, filed December 20, 2023; 63 / 621,479, filed January 16, 2024; and 63 / 561,097, filed March 4, 2024, the entire disclosure of each of which is hereby incorporated by reference in its entirety for all purposes. BACKGROUND

[0002] The interleukin (IL)-13 is a T helper cell subclass 2 (Th2) cytokine, and belongs to the family of type I cytokines. However, IL-13 is involved in the differentiation of naïve T cells into Th2 cells. IL-13 promotes B-cell proliferation and induces class switching to IgG4 and IgE in combination with CD40 / CD40L co-stimulation (IL-13 up-regulates FcεRI and thus helps in IgE priming of mast cells). In monocytes / macrophages, IL-13 up-regulates expression of CD23 and MHC class I and class II antigens; down-regulates the expression of CD14; inhibits antibody-dependent cytotoxicity IL-13; and promotes eosinophil survival, activation, and recruitment. IL-13 also manifests important functions on nonhematopoietic cells, such as smooth muscle cells, epithelial cells, endothelial cells, and fibroblast cells. IL- 13 enhances proliferation and cholinergic-induced contractions of smooth muscles. In epithelial cells, IL-13 potently induces chemokine production, alters mucociliary differentiation, decreases ciliary beat frequency of ciliated epithelial cells, and results in goblet cell metaplasia. In endothelial cells, IL-13 is a potent inducer of vascular cell adhesion molecule 1 (VCAM-1), which is important for recruitment of eosinophils. In human dermal fibroblasts, IL-13 induces type 1 collagen synthesis in human dermal fibroblasts.

[0003] The inhibition of IL-13 may be used to treat or prevent inflammatory diseases and conditions, such as those related to elevated levels of IgE, including but not limited to: asthma, allergic rhinitis, urticaria, asthma, allergic rhinitis, urticaria, and allergic or atopic dermatitis. Thus, the development of potent and specific inhibitors of IL-13, for example, inhibitors that remain active for longer terms when administered to subjects, are needed for the prevention and / or treatment IL-13 and IgE-mediated diseases or conditions.BRIEF DESCRIPTION OF THE DRAWINGS

[0004] These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description, and accompanying drawings, where:

[0005] Figure 1 is a schematic depicting the design of a single- and multiple-ascending dose (SAD and MAD, respectively) study, respectively, using an anti-IL-13 antibody described herein. Bold arrows indicate equivalent dosages between the SAD and MAD dosing schemes. Abbreviations: Q4wk every 4 weeks; SRC, safety review committee; SC, SQ, subcutaneous.

[0006] Figure 2 is a graph depicting the serum concentration (ng / mL) of Construct 133 and lebrikizumab over time (days post injection) in non-human primates (NHPs). The half- life of Construct 133 was 27.6 days, as compared to 17 to 18 days for lebrikizumab.

[0007] Figure 3 is a graph depicting normalized AUC0-∞ (Cnorm*day), or area under the curve (AUC) from dosing to infinity, among antibodies with the YTE substitution.

[0008] Figure 4 is a schematic depicting the design of a single- and multiple-ascending dose (SAD and MAD, respectively) study, respectively, using Construct 133 described herein. Abbreviations: PK, pharmacokinetics, ADA, anti-drug antibodies, pSTAT6, phosphorylated signal transducer and activator or transcription 6, TARC, thymus- and activation-regulated chemokine, SQ, subcutaneous.

[0009] Figure 5 is a set of graphs depicting the serum concentration (µg / mL) of Construct 133 over time (weeks post injection) in humans enrolled in the SAD (left panel) and MAD (right panel) studies described in Figure 4. Abbreviations: D1, day 1, 29, day 29.

[0010] Figure 6 is a graph depicting the median percent change from baseline of inhibition of IL-13-induced phosphorylation of STAT6 (pSTAT6) in humans enrolled in the SAD study described in Figure 4. At about three months (Week 12, up arrow), which was the latest follow-up, pSTAT6 remained suppressed after a single-dose of Construct 133.

[0011] Figure 7 is a set of graphs depicting the median percent change from baseline of inhibition of IL-13-induced release of thymus-and activation-regulated chemokine (TARC) in humans enrolled the SAD study described in Figure 4 (right panel) as compared to subjects receiving Dupixent (right panel).

[0012] Figure 8 is a schematic depicting the design of a Phase 2 clinical trial, using Construct 133 described herein.SUMMARY

[0013] In certain aspects, described herein is a method of treating atopic dermatitis in a patient in need thereof, the method comprising subcutaneously administering to the patient: a) one to five or more induction doses, each selected from 100 mg, 125 mg, 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 360 mg, 400 mg, 450 mg, 600 mg, 720 mg, 800 mg, 900 mg, 1080 mg, or 1200 mg or a dose listed in any one of Tables 11-13 of an anti-IL-13 antibody; and b) one or more maintenance doses administered about 4-17 weeks or more after the first induction dose; wherein the maintenance dose is 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 360 mg, 400 mg, 450 mg, 600 mg, 800 mg, 1080 mg, or 1200 mg or a dose listed in Table 14 of the anti-IL-13 antibody; and wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid set forth in SEQ ID NO: 3 and a light chain variable region (VL) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid set forth in SEQ ID NO: 39.

[0014] In certain embodiments, the method further comprises administering a loading dose prior to the one to five or more induction doses, wherein the loading dose is 2 times the induction dose.

[0015] In certain embodiments, the one or more maintenance doses are administered about 4-16 weeks or 12-16 weeks after the first induction dose.

[0016] In certain embodiments, the first induction dose is 150 mg, 300 mg, 360 mg, or 600 mg. In certain embodiments, the first induction dose is 360 mg.

[0017] In certain embodiments, the method further comprises administering a second, third, fourth, and / or fifth induction dose of 300 mg or 360 mg of the anti-IL-13 antibody. In certain embodiments, the method further comprises administering a second, third, fourth, and / or fifth induction dose of 360 mg of the anti-IL-13 antibody.

[0018] In certain embodiments, the second induction dose is administered about 2 to about 16 weeks after the first induction dose.

[0019] In certain embodiments, the second induction dose is administered about two or about eight weeks after the first induction dose. In certain embodiments, the second induction dose is administered about eight weeks after the first induction dose.

[0020] In certain embodiments, the method further comprises administering a second, third, fourth, and / or fifth induction dose of 600 mg of the anti-IL-13 antibody.

[0021] In certain embodiments, the second induction dose is administered about 2 to about 16 weeks after the first induction dose.

[0022] In certain embodiments, the second induction dose is administered about 2 to about 16 weeks after the first induction dose.

[0023] In certain embodiments, the maintenance dose is 150 mg, 200 mg, 300 mg, 360 mg, 400 mg, 600 mg, or 800 mg and is administered every 3 months, every 12 weeks, or 4 times a year.

[0024] In certain embodiments, the maintenance dose is 150 mg, 200 mg, 300 mg, 360 mg, 400 mg, 600 mg, or 800 mg and is administered every 2 months or every 8 weeks. 13.

[0025] In certain embodiments, the maintenance dose is 150 mg, 200 mg, 300 mg, 360 mg, 400 mg, 600 mg, or 800 mg and is administered every 16 weeks or three times a year.

[0026] In certain embodiments, the maintenance dose is 150 mg, 200 mg, 300 mg, 360 mg, 400 mg, 600 mg, or 800 mg and is administered every 20 weeks.

[0027] In certain embodiments, the maintenance dose is 150 mg, 200 mg, 300 mg, 360 mg, 400 mg, 600 mg, or 800 mg and is administered every 24 weeks, every 26 weeks, every 6 months, or twice a year.

[0028] In certain embodiments, the maintenance dose is 150 mg, 200 mg, 300 mg, 360 mg, 400 mg, 600 mg, or 800 mg and is administered once a year.

[0029] In certain embodiments, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered every 3 months, 12 weeks, or 4 times a year.

[0030] In certain embodiments, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered every 2 months or 8 weeks.

[0031] In certain embodiments, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered every 16 weeks or three times a year.

[0032] In certain embodiments, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered every 20 weeks.

[0033] In certain embodiments, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered every 6 months or twice a year.

[0034] In certain embodiments, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered once a year.

[0035] In certain embodiments, each unit dose is administered as composition comprising 150 mg / mL, 180 mg / mL, or 200 mg / mL of the anti-IL-13 antibody.

[0036] In certain embodiments, the unit dose has an extractable volume of about 2 mL, about 2.25 mL, or about 2.7 mL.

[0037] In certain embodiments, the anti-IL-13 antibody is administered by an autoinjector or a prefilled syringe.

[0038] In certain embodiments, the patient has been diagnosed with moderate-to-severe atopic dermatitis.

[0039] In certain embodiments, the patient has had moderate-to-severe atopic dermatitis for at least one year.

[0040] In certain embodiments, the patient has one or more of: (a) an Eczema Area and Severity Index Score (EASI) of ≥10, (b) an Investigator Global Assessment (IGA) score of ≥3 and (c) a body surface area (BSA) of ≥10%.

[0041] In certain embodiments, the method further comprises determining one or more of the following characteristics of the patient at baseline and during and after the induction period: Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Body Surface Area (BSA), Pruritus Numerical Rating Scale (NRS), Skin Pain Numerical Rating Scale (SP-NRS), Sleep loss scale, SCORing Atopic Dermatitis (SCORAD), Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), Asthma Control Questionnaire 5-item version (ACQ-5), Sino-nasal Outcome Test 22-item version (SNOT-22).

[0042] In certain aspects, described herein is a method of treating atopic dermatitis in a patient in need thereof, the method comprising: subcutaneously administering to the patient an anti-IL-13 antibody for an induction period of 4 to 17 weeks, wherein, during the induction period, the anti-IL-13 antibody is administeredonce or twice at a loading dose of from about 100 mg to about 1200 mg or a dose listed in any one of Tables 11-13, and, optionally, at least once at a dose that is at one-half or one-quarter of the loading dose; and subcutaneously administering to the patient the anti-IL-13 antibody at a dose of from about 100 mg to about 1200 mg or a dose listed in Table 14 for a maintenance period; wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) sequence identity to SEQ ID NO: 3 and a light chain variable region (VL) comprising an amino acid sequence at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%) sequence identity to SEQ ID NO: 39, wherein the VH comprises a HCDR1 comprising SEQ ID NO: 58, SEQ ID NO: 68, or SEQ ID NO: 85; a HCDR2 comprising SEQ ID NO: 100, SEQ ID NO: 104, or SEQ ID NO: 108; and a HCDR3 comprising SEQ ID NO: 112 or SEQ ID NO: 130; and the VL comprises a LCDR1 comprising SEQ ID NO: 141 or SEQ ID NO: 149; a LCDR2 comprising SEQ ID NO: 5, and a LCDR3 comprising SEQ ID NO: 6. 32.

[0043] In certain embodiments, during the induction period, the loading dose is about 100 mg, 150 mg, 180 mg, 200 mg, 300 mg, 360 mg, 400 mg, 450 mg, 600 mg, 720 mg, 800 mg, 900 mg, 1080 mg, or 1200 mg.

[0044] In certain embodiments, during the induction period, the loading dose is administered at week 0 and week 2.

[0045] In certain embodiments, during the induction period, the loading dose is administered at week 0 and week 4.

[0046] In certain embodiments, during the induction period, the loading dose is administered at week 0 and week 8.

[0047] In certain embodiments, during the induction period, the loading dose is administered at week 0 and week 12.

[0048] In certain embodiments, during the induction period, the one-half or one-quarter dose is administered at weeks 8, 12, and 16.

[0049] In certain embodiments, during the induction period, the one-half or one-quarter dose is administered at weeks 4, 8, 12, and 16.

[0050] In certain embodiments, during the induction period, the one-half or one-quarter dose is administered at weeks 4 and 12.

[0051] In certain embodiments, during the induction period, the one-half or one-quarter dose is administered at weeks 2, 4, and 12.

[0052] In certain embodiments, during the induction period, the one-half or one-quarter dose is administered at weeks 2 and 12.

[0053] In certain embodiments, during the induction period, the one-half or one-quarter dose is administered at week 12.

[0054] In certain embodiments, during the induction period, the one-half or one-quarter dose is administered at weeks 8 and 16.

[0055] In certain embodiments, during the induction period, the one-half or one-quarter dose is administered at week 16.

[0056] In certain embodiments, during the induction period, the one-half or one-quarter dose is administered at weeks 4 and 14.

[0057] In certain embodiments, during the induction period, the one-half or one-quarter dose is administered at week 14.

[0058] In certain embodiments, during the induction period, the one-half or one-quarter dose is administered at weeks 2, 4, and 14.

[0059] In certain embodiments, the maintenance dose is 100 mg, 150 mg, 180 mg, 200 mg, 300 mg, 360 mg, 400 mg, 450 mg, 600 mg, 720 mg, 800 mg, or 900 mg.

[0060] In certain embodiments, during the maintenance period, the anti-IL-13 antibody is administered every 3 months, 12 weeks, or 4 times a year.

[0061] In certain embodiments, during the maintenance period, the anti-IL-13 antibody is administered every 2 months or 8 weeks.

[0062] In certain embodiments, during the maintenance period, the anti-IL-13 antibody is administered every 16 weeks or three times a year.

[0063] In certain embodiments, during the maintenance period, the anti-IL-13 antibody is administered every 20 weeks.

[0064] In certain embodiments, during the maintenance period, the anti-IL-13 antibody is administered every 6 months or twice a year.

[0065] In certain embodiments, during the maintenance period, the anti-IL-13 antibody is administered once a year.

[0066] In certain embodiments, the anti-IL-13 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid set forth in SEQ ID NO: 3 and a light chain variable region (VL) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid set forth in SEQ ID NO: 39.

[0067] In certain aspects, described herein is a method of treating atopic dermatitis in a patient in need thereof, the method comprising subcutaneously administering to the patient: a) two loading doses of 720 mg of an anti-IL-13 antibody prior to two induction doses; b) two induction doses of 360 mg of the anti-IL-13 antibody; and c) one or more maintenance doses of 360 mg of the anti-IL-13 antibody administered starting at about 12 weeks or more after the first induction dose; and wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid set forth in SEQ ID NO: 3 and a light chain variable region (VL) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid set forth in SEQ ID NO: 39.

[0068] In certain embodiments, the second loading dose is administered about 2 weeks after the first loading dose.

[0069] In certain embodiments, the first induction dose is administered about 2 weeks after the second loading dose.

[0070] In certain embodiments, the second induction dose is administered about 8 weeks after the first induction dose.

[0071] In certain embodiments, the maintenance dose is administered every 3 months.

[0072] In certain embodiments, the maintenance dose is administered every 6 months.

[0073] In certain aspects, described herein is a method of treating atopic dermatitis in a patient in need thereof, the method comprising subcutaneously administering to the patient: a) a loading dose of 720 mg of an anti-IL-13 antibody prior to two induction doses; b) two induction doses of 360 mg of the anti-IL-13 antibody; and c) one or more maintenance doses of 360 mg of the anti-IL-13 antibody administered starting at about 12 weeks or more after the first induction dose; and wherein the anti-IL-13antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid set forth in SEQ ID NO: 3 and a light chain variable region (VL) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid set forth in SEQ ID NO: 39.

[0074] In certain embodiments, the first induction dose is administered about 4 weeks after the loading dose.

[0075] In certain embodiments, the second induction dose is administered about 8 weeks after the first induction dose.

[0076] In certain embodiments, the maintenance dose is administered every 3 months.

[0077] In certain embodiments, the maintenance dose is administered every 6 months.

[0078] In certain aspects, described herein is a method of treating atopic dermatitis in a patient in need thereof, the method comprising subcutaneously administering to the patient: a) a loading dose of 360 mg of an anti-IL-13 antibody prior to two induction doses; b) two induction doses of 180 mg of the anti-IL-13 antibody; and c) one or more maintenance doses of 180 mg of the anti-IL-13 antibody administered starting at about 12 weeks or more after the first induction dose; and wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid set forth in SEQ ID NO: 3 and a light chain variable region (VL) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid set forth in SEQ ID NO: 39.

[0079] In certain embodiments, the first induction dose is administered about 4 weeks after the loading dose.

[0080] In certain embodiments, the second induction dose is administered about 8 weeks after the first induction dose.

[0081] In certain embodiments, the maintenance dose is administered every 3 months.

[0082] In certain embodiments, the maintenance dose is administered every 6 months.

[0083] In certain embodiments, each dose is administered as composition comprising 150 mg / mL, 180 mg / mL, or 200 mg / mL of the anti-IL-13 antibody.

[0084] In certain embodiments, the composition is a unit dose with an extractable volume of 2 mL.

[0085] In certain embodiments, the patient has been diagnosed with moderate-to-severe atopic dermatitis.

[0086] In certain embodiments, the patient has had moderate-to-severe atopic dermatitis for at least one year.

[0087] In certain embodiments, the patient has one or more of: (a) an Eczema Area and Severity Index Score (EASI) of ≥10, (b) an Investigator Global Assessment (IGA) score of ≥3 and (c) a body surface area (BSA) of ≥10%.

[0088] In certain embodiments, the method further comprises determining one or more of the following characteristics of the patient at baseline and during and after the induction period Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Body Surface Area (BSA), Pruritus Numerical Rating Scale (NRS), Skin Pain Numerical Rating Scale (SP-NRS), Sleep loss scale, SCORing Atopic Dermatitis (SCORAD), Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), Asthma Control Questionnaire 5-item version (ACQ-5), Sino-nasal Outcome Test 22-item version (SNOT-22).

[0089] In certain aspects, described herein is a composition comprising 150 mg / mL, 180 mg / mL, or 200 mg / mL of an anti-IL-13 antibody, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid set forth in SEQ ID NO: 3 and a light chain variable region (VL) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid set forth in SEQ ID NO: 39.

[0090] In certain embodiments, the composition is a unit dose with an extractable volume of 2 mL, 2.25 mL, or 2.7 mL.

[0091] In certain aspects, described herein is an autoinjector configured to deliver a composition comprising 150 mg / mL, 180 mg / mL, or 200 mg / mL of an anti-IL-13 antibody, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid set forth in SEQ ID NO: 3 and a light chainvariable region (VL) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid set forth in SEQ ID NO: 39.

[0092] In certain embodiments, the composition is a unit dose with an extractable volume of 2 mL, 2.25 mL, or 2.7 mL.

[0093] In certain embodiments, the method, composition, or autoinjector described herein further comprises a heavy chain constant region of SEQ ID NO: 439 or SEQ ID NO: 624 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto.

[0094] In certain embodiments, the method, composition, or autoinjector described herein further comprises a light chain constant region of SEQ ID NO: 469 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto. DETAILED DESCRIPTION Definitions

[0095] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art, such as, for example, the widely utilized molecular cloning methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 4th ed. (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer-defined protocols and conditions unless otherwise noted.

[0096] As used herein, the singular form “a,” “an,” and “the” includes plural references unless indicated otherwise.

[0097] It is understood that aspects and embodiments of the invention described herein include “comprising” “consisting” and “consisting essentially of” aspects and embodiments

[0098] For all compositions described herein, and all methods using a composition described herein, the compositions can either comprise the listed components or steps, or can “consist essentially of” the listed components or steps. When a composition is described as “consisting essentially of” the listed components, the composition contains the components listed, and may contain other components which do not substantially affect the condition being treated, but do not contain any other components which substantially affect the condition being treated other than those components expressly listed; or, if the composition does contain extra components other than those listed which substantially affect the condition being treated, the composition does not contain a sufficient concentration or amount of the extra components to substantially affect the condition being treated. When 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. As a non-limiting specific example, 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.

[0099] The term “vector,” as used herein, 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. Such vectors are referred to herein as “expression vectors.”

[0100] The terms “host cell,” “host cell line,” and “host cell culture” are used interchangeably and refer 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.

[0101] As used herein, 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.

[0102] As used herein, the term “prokaryote” refers to prokaryotic organisms. For example, 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 thermoautotrophicum, Halobacterium such as Haloferax volcanii and Halobacterium species NRC-1, Archaeoglobus fulgidus, Pyrococcus furiosus, Pyrococcus horikoshii, Aeuropyrum pernix, etc.) phylogenetic domain.

[0103] An “effective amount” or “therapeutically effective amount” as used herein refers to an amount of therapeutic compound, such as an anti-IL-13 antibody, administered to an individual, either as a single dose or as part of a series of doses, which is effective to produce or contribute to a desired therapeutic effect, either alone or in combination with another therapeutic modality. Examples of a desired therapeutic effect is enhancing an immune response, slowing or delaying tumor development; stabilization of disease; amelioration of one or more symptoms. An effective amount may be given in one or more dosages.

[0104] 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, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.

[0105] 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.

[0106] As used herein, the terms “subject”, “patient”, and “individual” are used interchangeably herein. The term “subject”, “patient”, or “individual” means a mammalian subject. Exemplary subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, and sheep. In certain embodiments, the subject is a human. In certain embodiments the subject has a disease or condition that can be treated with an antibodyprovided herein. In some aspects, the disease or condition is a cancer. In some aspects, the disease or condition is a viral infection.

[0107] The term “in vitro” refers to processes that occur in a living cell growing separate from a living organism, e.g., growing in tissue culture.

[0108] The term “in vivo” refers to processes that occur in a living organism.

[0109] The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic or diagnostic products (e.g., kits) that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and / or warnings concerning the use of such therapeutic or diagnostic products.

[0110] The term “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.

[0111] The terms “co-administration,” “co-administer,” and “in combination with” include the administration of two or more therapeutic agents either simultaneously, concurrently or sequentially within no specific time limits. In one embodiment, 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. In one embodiment, 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. In certain embodiments, a first agent can be administered prior to the administration of a second therapeutic agent.

[0112] The terms “modulate” and “modulation” refer to reducing or inhibiting or, alternatively, activating or increasing, a recited variable.

[0113] 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.

[0114] 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.

[0115] 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 designatedvalue ± 10%, ± 5%, or ± 1%. In certain embodiments, where applicable, the term “about” indicates the designated value(s) ± one standard deviation of that value(s).

[0116] 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.

[0117] 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.

[0118] For any of the structural and functional characteristics described herein, methods of determining these characteristics are known in the art.

[0119] The term “optionally” is meant, when used sequentially, to include from one to all of the enumerated combinations and contemplates all sub-combinations.

[0120] The term “amino acid” refers to 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).

[0121] The term “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).

[0122] The term “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.

[0123] The term “ka” (M-1×sec-1), as used herein, refers to the association rate constant of a particular antibody -antigen interaction. This value is also referred to as the kon value.

[0124] The term “KD” (M), as used herein, refers to the dissociation equilibrium constant of a particular antibody -antigen interaction. KD = kd / ka. In certain embodiments, the affinity of an antibody is described in terms of the KD for an interaction between such antibody and its antigen. 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.

[0125] The term “KA” (M-1), as used herein, refers to the association equilibrium constant of a particular antibody-antigen interaction. KA = ka / kd.

[0126] The term “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.

[0127] A “anti-IL-13 antibody,” “IL-13 antibody,” or “IL-13 specific antibody” is an antibody, as provided herein, which specifically binds to the antigen IL-13.

[0128] The term “epitope” means a portion of an antigen that specifically binds to an antibody.

[0129] The term “hypervariable region” or “HVR,” as used herein, refers to each of the regions of an antibody variable domain which are hypervariable in sequence and / or form structurally defined loops (“hypervariable loops”).

[0130] The term “antigen-binding domain” means the portion of an antibody that is capable of specifically binding to an antigen or epitope.

[0131] The term “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.

[0132] The term “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.

[0133] The term “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.

[0134] The term “multispecific antibody” refers to an antibody that comprises two or more different antigen-binding domains that collectively specifically bind two or more different epitopes.

[0135] A “monospecific antibody” is an antibody that comprises one or more binding sites that specifically bind to a single epitope. An example of a monospecific antibody is anaturally 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.

[0136] 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. For example, 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.

[0137] The term “single-chain” refers to a molecule comprising amino acid monomers linearly linked by peptide bonds. In a particular such embodiment, 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. As described in more detail herein, an scFv has a variable domain of light chain (VL) connected from its C-terminus to the N-terminal end of a variable domain of heavy chain (VH) by a polypeptide chain. Alternately the scFv comprises of polypeptide chain where in the C-terminal end of the VH is connected to the N-terminal end of VL by a polypeptide chain.

[0138] The “Fab fragment” (also referred to as fragment antigen-binding) contains the constant domain (CL) of the light chain and the first constant domain (CH1) of the heavy chain along with the variable domains VL and VH on the light and heavy chains respectively. The variable domains comprise the complementarity determining loops (CDR, also referred to as hypervariable region) that are involved in antigen-binding. 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.

[0139] “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.

[0140] “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.

[0141] “Single-chain Fv” or “sFv” or “scFv” includes the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain. In one embodiment, 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. For a review of scFv see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol.113, Rosenburg and Moore eds., Springer-Verlag, New York, pp.269-315 (1994). HER2 antibody scFv fragments are described in WO93 / 16185; U.S. Pat. No.5,571,894; and U.S. Pat. No. 5,587,458.

[0142] “scFv-Fc” fragments comprise an scFv attached to an Fc domain. For example, an Fc domain may be attached to the C-terminal of the scFv. 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.

[0143] 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., FEBS Letters, 1998, 414:521-526 and Muyldermans et al., Trends in Biochem. Sci., 2001, 26:230-245, each of which is incorporated by reference in its entirety. Single domain antibodies are also known as sdAbs or nanobodies. Sdabs are fairly stable and easy to express as fusion partner with the Fc chain of an antibody (Harmsen MM, De Haard HJ (2007). “Properties, production, and applications of camelid single-domain antibody fragments”. Appl. Microbiol Biotechnol.77(1): 13-22).

[0144] 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. For example, when used to refer to an IgG molecule, a “full length antibody” is an antibody that comprises two heavy chains and two light chains.

[0145] 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.

[0146] The term “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.

[0147] The term “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.

[0148] The term 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. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (ncbi.nlm.nih.gov). Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Depending on the application, the percent “identity” can exist over a region of the sequence being compared, e.g., over a functional domain, or, alternatively, exist over the full length of the two sequences to be compared.

[0149] For sequence comparison, typically one sequence acts as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, test and 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.

[0150] Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math.2:482 (1981), by thehomology alignment algorithm of Needleman & Wunsch, J. Mol. Biol.48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (see generally Ausubel et al., infra).

[0151] Ranges recited herein are understood to be shorthand for all of the values within the range, inclusive of the recited endpoints. For example, 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.

[0152] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Anti-IL-13 Antibodies Antibody Structure

[0153] The present application provides antibodies and compositions comprising an antibody which binds IL-13.

[0154] 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 possessed by its heavy chain. There are five major classes of antibodies: 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 heavy chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0155] 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. The terms variable light chain (VL) and variable heavy chain (VH) refer to these light and heavy chain domains respectively. The IgG1 heavy chain comprises of the VH, CH1, CH2, and CH3 domains respectively from the N- to C-terminus. The light chain comprises of the VL and CLdomains from N- to C-terminus. The IgG1 heavy chain comprises a hinge between the CH1 and CH2 domains. In certain embodiments, the immunoglobulin constructs comprise at least one immunoglobulin domain from IgG, IgM, IgA, IgD, or IgE connected to a therapeutic polypeptide. In some embodiments, the immunoglobulin domain found in an antibody provided herein, is from or derived from an immunoglobulin based construct such as a diabody or a nanobody. In certain embodiments, the immunoglobulin constructs described herein comprise at least one immunoglobulin domain from a heavy chain antibody such as a camelid antibody. In certain embodiments, 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.

[0156] In some embodiments, the antibodies provided herein comprise a heavy chain. In one embodiment, the heavy chain is an IgA. In one embodiment, 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.

[0157] 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. In some embodiments, an antibody is an IgG4 antibody.

[0158] Generally, native four-chain antibodies comprise six hypervariable regions (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. HVRs are also referred to as CDRs, and these terms are used herein interchangeably in reference to portions of the variable region that form the antigen-binding 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., J Mol Biol 196:901-917 (1987), 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 usedherein. The exact 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.

[0159] 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., Dev. Comp. Immunol., 2003, 27:55-77 (“IMGT” numbering scheme); and Honegge and Plückthun, J. Mol. Biol., 2001, 309:657-70 (“AHo” numbering scheme); each of which is incorporated by reference in its entirety.

[0160] Table 1 provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR- H2, and CDR-H3 as identified by the Kabat and Chothia schemes. For CDR-H1, residue numbering is provided using both the Kabat and Chothia numbering schemes.

[0161] 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. Residues in CDRs according to Kabat and Chothia numbering schemes.* The C-terminus of CDR-H1, when numbered using the Kabat numbering convention, varies between H32 and H34, depending on the length of the CDR.

[0162] The “EU numbering scheme” is generally used when referring to a residue in an antibody heavy chain constant region (e.g., as reported in Kabat et al., supra). Unless stated otherwise, the EU numbering scheme is used to refer to residues in antibody heavy chain constant regions described herein

[0163] One example of 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.

[0164] Epitopes frequently consist of surface-accessible amino acid residues and / or sugar side chains and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter may be lost in the presence of denaturing solvents. An epitope may comprise amino acid residues that are directly involved in the binding and other amino acid residues, which are not directly involved in the binding. The epitope to which an antibody binds can be determined using known techniques for epitope determination such as, for example, testing for antibody binding to IL-13 variants with different point-mutations or to chimeric IL-13 variants.

[0165] To screen for antibodies which bind to an epitope on a target antigen bound by an antibody of interest (e.g., IL-13), a routine cross-blocking assay such as that described in Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1988), can be performed. Alternatively, or additionally, epitope mapping can be performed by methods known in the art.

[0166] Chimeric antibodies are antibodies in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0167] Human antibodies are antibodies 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.

[0168] A humanized antibody has a sequence that differs from the sequence of an antibody derived from a non-human species by one or more amino acid substitutions, deletions, and / or additions, such that the humanized antibody is less likely to induce an immune response, and / or induces a less severe immune response, as compared to the non- human species antibody, when it is administered to a human subject. In one embodiment, certain amino acids in the framework and constant domains of the heavy and / or light chainsof the non-human species antibody are mutated to produce the humanized antibody. In another embodiment, the constant domain(s) from a human antibody are fused to the variable domain(s) of a non-human species. In another embodiment, 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., Nature, 1986, 321:522-525; Riechmann et al., Nature, 1988, 332:323-329; and Presta, Curr. Op. Struct. Biol., 1992, 2:593-596, each of which is incorporated by reference in its entirety.

[0169] The two or more different epitopes may be epitopes on the same antigen (e.g., a single IL-13) or on different antigens (e.g., different IL-13 molecules, or a IL-13 molecule and a non- IL-13 molecule). In some embodiments, a multi-specific antibody binds two different epitopes (i.e., a “bispecific antibody”). In some embodiments, a multi-specific antibody binds three different epitopes (i.e., a “trispecific antibody”).

[0170] Anti-IL-13 antibodies can include those described herein such as the clones set forth in the drawings and / or tables. In some embodiments, 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.

[0171] In some embodiments the antibodies are monoclonal antibodies.

[0172] In some embodiments the antibodies are polyclonal antibodies.

[0173] 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.

[0174] 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.

[0175] In some embodiments the antibodies may be polyfunctional antibodies, recombinant antibodies, human antibodies, humanized antibodies, fragments or variants thereof. In particular embodiments, the antibody fragment or a derivative thereof is selected from a Fab fragment, a Fab′2 fragment, a CDR, and ScFv.

[0176] In some embodiments, the antibodies are capable of forming an immune complex. For example, an immune complex can be a tumor cell covered by antibodies.

[0177] For sequence comparison, typically one sequence acts as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, test and 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.

[0178] Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math.2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol.48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat’l. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (see generally Ausubel et al., infra).

[0179] One example of an algorithm that is suitable for determining percent sequence identity and sequence similarity is the BLAST algorithm, which is described in Altschul et al., J. Mol. Biol.215:403-410 (1990). Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov / ). Sequences of IL-13 Antibodies VH Domains

[0180] In some embodiments, an antibody provided herein comprises a VH sequence selected from SEQ ID NOs: 1-32.

[0181] In some embodiments, 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: 1-32. In some embodiments, an antibody provided herein comprises a VH sequence provided in SEQ IDNOs: 1-32, with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, 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. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies. VL Domains

[0182] In some embodiments, an antibody provided herein comprises a VL sequence selected from SEQ ID NOs: 33-57.

[0183] In some embodiments, 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: 33-57. In some embodiments, an antibody provided herein comprises a VL sequence provided in SEQ ID NOs: 33-57 with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, 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. In some embodiments, 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. VH-VL Combinations

[0184] In some embodiments, an antibody provided herein comprises a VH sequence selected from SEQ ID NOs: 1-32; and a VL sequence selected from SEQ ID NOs: 33-57, such as the VH-VL combinations set forth for Constructs 3-127 and 132-144 in Table 2, below.

[0185] In certain aspects, any of SEQ ID NOs: 1-32 can be combined with any of SEQ ID NOs: 33-57.

[0186] In certain embodiments, the antibody comprises a VH sequence selected from the sequences set forth in SEQ ID NOs: 1-32 and a VL sequence set forth in SEQ ID NO: 49.

[0187] In certain embodiments, the antibody comprises a VH sequence selected from the sequences set forth in SEQ ID NOs: 1-32 and a VL sequence set forth in SEQ ID NO: 51.

[0188] In some embodiments, an antibody provided herein comprises a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to an VH sequence provided in SEQ ID NOs: 1-32; and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to an VL sequence provided in SEQ ID NOs: 33-57. In some embodiments, an antibody provided herein comprises a VH sequence provided in SEQ ID NOs: 1-32, with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions; and a VL sequence provided in SEQ ID NOs: 33-57, with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, 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. In some embodiments, 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.

[0189] In some embodiments, an antibody provided herein comprises a VH sequence and a VL sequence selected from combinations set forth for Constructs 3-127 and 132-144 in Table 2, below, or a VH sequence or VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 1 and a VL sequence set forth in SEQ ID NO: 33. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 2 and a VL sequence set forth in SEQ ID NO: 33. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 3 and a VL sequence set forth in SEQ ID NO: 35. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 4 and a VL sequence set forth in SEQ ID NO: 35. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 5 and a VL sequence set forth inSEQ ID NO: 35. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 6 and a VL sequence set forth in SEQ ID NO: 35. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 35. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 3 and a VL sequence set forth in SEQ ID NO: 36. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 4 and a VL sequence set forth in SEQ ID NO: 36. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 5 and a VL sequence set forth in SEQ ID NO: 36. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 6 and a VL sequence set forth in SEQ ID NO: 36. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 36. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 3 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 4 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 5 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 6 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 3 and a VL sequence set forth in SEQ ID NO: 40. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 4 and a VL sequence set forth in SEQ ID NO: 40. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 5 and a VL sequence set forth in SEQ ID NO: 40. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 6 and a VL sequence set forth in SEQ ID NO: 40. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 40. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 8 and a VL sequence set forth in SEQ ID NO: 42. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 9 and a VL sequence set forth in SEQ ID NO: 43. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 44. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth inSEQ ID NO: 45. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 46. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 47. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 48. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 49. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 50. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 51. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 52. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 53. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 54. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 55. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 56. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 7 and a VL sequence set forth in SEQ ID NO: 57. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 10 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 11 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 12 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 13 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 14 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 15 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 16 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 17 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 18 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 19 anda VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 20 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 21 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 22 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 23 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 24 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 25 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 26 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 27 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 28 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 28 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 29 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 30 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 31 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 32 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 8 and a VL sequence set forth in SEQ ID NO: 39. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 8 and a VL sequence set forth in SEQ ID NO: 51. In certain embodiments, the antibody comprises a VH sequence set forth in SEQ ID NO: 3 and a VL sequence set forth in SEQ ID NO: 51.

[0190] In certain embodiments, the isolated antibody comprises a heavy chain variable domain comprising a framework region sequence selected from a sequence set forth in SEQ ID NOs: 198-229, 255-256, 258-259, 261-285, 311-315, 317-342, 368-369, 371-399, and 540-580. In certain embodiments, the isolated antibody comprises a heavy chain variable domain comprising 1, 2, 3, or 4 framework region sequences selected from a sequence set forth in SEQ ID NOs: 198-229, 255-256, 258-259, 261-285, 311-315, 317-342, 368-369, 371-399, and 540-580.

[0191] In certain embodiments, the isolated antibody comprises a light chain variable domain comprising a framework region sequence selected from a sequence set forth in SEQ ID NOs: 230-231, 233-235, 239, 241-254, 286, 288, 290-291, 293, 296-310, 343-345, 347, 400-424, and 581-609. In certain embodiments, the isolated antibody comprises a light chain variable domain comprising 1, 2, 3, or 4 framework region sequences selected from a sequence set forth in SEQ ID NOs: 230-231, 233-235, 239, 241-254, 286, 288, 290-291, 293, 296-310, 343-345, 347, 400-424, and 581-609.

[0192] In certain embodiments, the isolated antibody comprises a heavy chain variable domain comprising 1, 2, 3, or 4 framework region sequences selected from a sequence set forth in SEQ ID NOs: 198-229, 255-256, 258-259, 261-285, 311-315, 317-342, 368-369, 371-399, and 540-580, and comprises a light chain variable domain comprising 1, 2, 3, or 4 framework region sequences selected from a sequence set forth in SEQ ID NOs: 230-231, 233-235, 239, 241-254, 286, 288, 290-291, 293, 296-310, 343-345, 347, 400-424, and 581- 609. Table 2. Anti-interleukin (IL)-13 antibody VH-VL sequences*Names correspond with name in informal sequence listing

[0193] In some embodiments, a VH domain listed for any one of Constructs 3-127 and 132-144 in Table 2 can be combined with a heavy chain constant (HC) domain provided herein. In certain embodiments, an anti-IL-13 antibody comprises a VH domain selected from any one the VH domains of Constructs 3-127 and 132-144 in Table 2 or a VH domain having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and a heavy chain constant (HC) domain comprising a sequence selected from any one of SEQ ID NOs: 425-468, 484-539, and 610-709 or an HC domain having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto. Each and every combination of (1) VH / VL listed for Constructs 3-127 and 132-144 in Table 2 and (2) HC domain is contemplated herein. In some embodiments, a VH domain listed for any one of Constructs 3-127 and 132-144 in Table 2 can be combined with a heavy chain constant (HC) domain provided herein. In certain embodiments, an anti-IL-13 antibody comprises a VH domain selected from any one the VH domains of Constructs 3-127 and 132-144 in Table 2 or a VH domain having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, and a HC domain comprising a sequence selected from any one of SEQ ID NOs: 610, 615-641, and 654-709 or an HC domain having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto. In certain embodiments, the HC domain is an IgG1 HC domain. In certain embodiments, the VL domain of any one of Constructs 3-127 and 132-144 in Table 2 is combined with an IgG1 light chain constant (LC) domain. In certain embodiments, the VL domain of any one of Constructs 3-127 and 132-144 in Table 2 is combined with a LC domain comprising SEQ ID NO: 469 or an LC domain having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto.

[0194] In certain embodiments, the HC domain includes IgG4-SP, hIgG1-LALA-YTE, hIgG1-LAGA YTE, hIgG1-LALA-LS, IgG4-YTE HC, and IgG4-LS.

[0195] In some embodiments, such an IgG4-SP HC constant domain has the sequence: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS RLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 427).

[0196] In some embodiments, such a hIgG1-LALA-YTE HC constant domain has the sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP EAAGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 439).

[0197] In some embodiments, such a hIgG1-LAGA YTE HC constant domain has the sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP ELAGAPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 440).

[0198] In some embodiments, such a hIgG1-LALA-LS HC constant domain has the sequence:

[0199] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG (SEQ ID NO: 446).

[0200] In some embodiments, such an IgG4-YTE HC constant domain has the sequence: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLG GPSVFLFPPKPKDTLYITREPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS RLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 457).

[0201] In some embodiments, such an IgG4-LS HC constant domain has the sequence:ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS RLTVDKSRWQEGNVFSCSVLHEALHSYTQKSLSLSLGK (SEQ ID NO: 460).

[0202] In some embodiments, such a hIgG1-LALA-YTE HC C-terminal lysine variant constant domain has the sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP EAAGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 624).

[0203] In some embodiments, such a hIgG1-LAGA YTE HC C-terminal lysine variant constant domain has the sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP ELAGAPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 625).

[0204] In some embodiments, such a hIgG1-LALA-LS HC C-terminal lysine variant constant domain has the sequence:

[0205] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO: 631).

[0206] In some embodiments, a VL domain listed for Constructs 3-127 and 132-144 in Table 2 or a VL domain having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto can be combined with a light chain constant (LC) domain provided herein. In some embodiments, the LC domain is a human kappa LC constant domain. In some embodiments, such a human kappa LC constant domain has the sequence: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 469). CDRs

[0207] In some embodiments, an antibody provided herein comprises one to three CDRs of a VH domain selected from SEQ ID NOs: 1-32, such as any of the CDRs listed in Table 3, Table 4, or Table 5, below. In some embodiments, an antibody provided herein comprises two to three CDRs of a VH domain selected from SEQ ID NOs: 1-32 . In some embodiments, an antibody provided herein comprises three CDRs of a VH domain selected from SEQ ID NOs: 1-32. In some embodiments, the CDRs are Exemplary CDRs. In some embodiments, the CDRs are Kabat CDRs. In some embodiments, the CDRs are Chothia CDRs. In some embodiments, the CDRs are IMGT CDRs. In some embodiments, the CDRs are AbM CDRs. In some embodiments, the CDRs are Contact CDRs.

[0208] In some embodiments, the CDRs are CDRs having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with a CDR-H1, CDR-H2, or CDR-H3 of SEQ ID NOs: 58-140. In some embodiments, the CDR-H1 is a CDR-H1 of a VH domain selected from SEQ ID NOs: 1-32, with up to 1, 2, 3, 4, or 5 amino acid substitutions. In some embodiments, the CDR-H2 is a CDR-H2 of a VH domain of SEQ ID NO: 1-32, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the CDR-H3 is a CDR-H3 of a VH domain selected from SEQ ID NOs: 1-32, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, 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. In some embodiments, such variants are not derived from a sequence provided herein and may, forexample, be isolated de novo according to the methods provided herein for obtaining antibodies.

[0209] In some embodiments, an antibody provided herein comprises one to three CDRs of a VL domain of SEQ ID NOs: 33-57, such as any of the CDRs listed in Table 6, Table 7, or Table 8, below. In some embodiments, an antibody provided herein comprises two to three CDRs of a VL domain of SEQ ID NOs: 33-57. In some embodiments, an antibody provided herein comprises three CDRs of a VL domain of SEQ ID NOs: 33-57. In some embodiments, the CDRs are Exemplary CDRs. In some embodiments, the CDRs are Kabat CDRs. In some embodiments, the CDRs are Chothia CDRs. In some embodiments, the CDRs are IMGT CDRs. In some embodiments, the CDRs are AbM CDRs. In some embodiments, the CDRs are Contact CDRs.

[0210] In some embodiments, the CDRs are CDRs having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with a CDR-L1, CDR-L2, or CDR-L3 of SEQ ID NOs: 141-188. In some embodiments, the CDR-L1 is a CDR-L1 of a VL domain of SEQ ID NOs: 33-57, with up to 1, 2, 3, 4, or 5 amino acid substitutions. In some embodiments, the CDR-L2 is a CDR-L2 of a VL domain of SEQ ID NOs: 33-57, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the CDR-L3 is a CDR- L3 of a VL domain of SEQ ID NOs: 33-57, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, 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. In some embodiments, 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.

[0211] In some embodiments, an antibody provided herein comprises one to three CDRs of a VH domain selected from SEQ ID NOs: 1-32 and one to three CDRs of a VL domain of SEQ ID NOs: 33-57. In some embodiments, an antibody provided herein comprises two to three CDRs of a VH domain selected from SEQ ID NOs: 1-32 and two to three CDRs of a VL domain of SEQ ID NOs: 33-57. In some embodiments, an antibody provided herein comprises three CDRs of a VH domain selected from SEQ ID NOs: 1-32 and three CDRs of a VL domain of SEQ ID NOs: 33-57. In some embodiments, the CDRs are Exemplary CDRs.In some embodiments, the CDRs are Kabat CDRs. In some embodiments, the CDRs are Chothia CDRs. In some embodiments, the CDRs are IMGT CDRs. In some embodiments, the CDRs are AbM CDRs. In some embodiments, the CDRs are Contact CDRs.

[0212] In some embodiments, an antibody provided herein comprises a CDR-H3 selected of SEQ ID NOs: 112-120 and 130-40. In some embodiments, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H3 of SEQ ID NOs: 112-120 or 130-40. In some embodiments, the CDR-H3 is a CDR-H3 selected of SEQ ID NOs: 112-120 and 130-40, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, 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. In some embodiments, 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.

[0213] In some embodiments, an antibody provided herein comprises a CDR-H1 of SEQ ID NOs: 58-99 and 121. In some embodiments, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 of SEQ ID NOs: 58-99 or 121. In some embodiments, the CDR-H1 is a CDR-H1 of SEQ ID NOs: 58-99 or 121, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, 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. In some embodiments, 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.

[0214] In some embodiments, an antibody provided herein comprises a CDR-H2 of any one of SEQ ID NOs: 100-111. In some embodiments, the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of any one of SEQ ID NOs: 100-111. In some embodiments, the CDR-H2 is a CDR-H2 of any one of SEQ ID NOs: 100-111, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In someembodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, 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. In some embodiments, 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.

[0215] In some embodiments, an antibody provided herein comprises a CDR-L3 selected from SEQ ID NOs: 165-172. In some embodiments, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L3 of SEQ ID NOs: 165-172. In some embodiments, the CDR-L3 is a CDR-L3 of SEQ ID NOs: 165- 172, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, 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. In some embodiments, 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.

[0216] In some embodiments, an antibody provided herein comprises a CDR-L2 selected from SEQ ID NOs: 153-158 and the amino acid sequence LAS. In some embodiments, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L2 selected from SEQ ID NOs: 153-158 and the amino acid sequence LAS. In some embodiments, the CDR-L2 is a CDR-L2 selected from SEQ ID NOs: 153-158 and the amino acid sequence LAS, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, 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. In some embodiments, 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.

[0217] In some embodiments, an antibody provided herein comprises a CDR-L1 selected from SEQ ID NOs: 141-144 and 149-152. In some embodiments, the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR- L1 selected from SEQ ID NOs: 141-144 and 149-152. In some embodiments, the CDR-L1 is a CDR-L1 selected from SEQ ID NOs: 141-144 and 149-152, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, 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. In some embodiments, 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.

[0218] In some embodiments, an antibody provided herein comprises a CDR-H3 selected from SEQ ID NOs: 112-120 and 130-140, a CDR-H2 of SEQ ID NOs: 100-111, a CDR-H1 selected from SEQ ID NOs: 58-99 and 121, a CDR-L3 selected from SEQ ID NOs: 165-172, a CDR-L2 selected from SEQ ID NOs: 153-158 and the amino acid sequence LAS, and a CDR-L1 selected from SEQ ID NOs: 141-144 and 149-152. In some embodiments, the CDR- H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H3 selected from SEQ ID NOs: 112-120 and 130-140, the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of SEQ ID NOs: 100-111, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 selected from SEQ ID NOs: 58-99 and 121, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L3 selected from SEQ ID NOs: 165-172, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L2 selected from SEQ ID NOs: 153-158 and the amino acid sequence LAS, and the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L1 selected from SEQ ID NOs: 141-144 and 149-152. In some embodiments, the CDR-H3 is a CDR-H3 selected from SEQ ID NOs: 112-120 and 130-140, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H2 is a CDR- H2 of SEQ ID NOs: 100-111, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H1 is a CDR-H1 selected from SEQ ID NOs: 58-99 and 121, with up to 1, 2, 3, 4, or 5amino acid substitutions; the CDR-L3 is a CDR-L3 selected from SEQ ID NOs: 165-172, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L2 is a CDR-L2 selected from SEQ ID NOs: 153-158 and the amino acid sequence LAS, with up to 1, 2, 3, or 4 amino acid substitutions; and the CDR-L1 is a CDR-L1 selected from SEQ ID NOs: 141-144 and 149- 152, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[0219] In some embodiments, an antibody provided herein comprises a CDR-H3 of SEQ ID NOs: 112, 121, and 130, a CDR-H2 of SEQ ID NOs: 100, 104, and 108, a CDR-H1 of SEQ ID NOs: 58, 68, and 85, a CDR-L3 of SEQ ID NOs: 168, 173, and 181, a CDR-L2 of SEQ ID NOs: 153 and the amino acid sequence LAS, and a CDR-L1 of SEQ ID NOs: 141 and 149. In some embodiments, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H3 of SEQ ID NOs: 112 or 130, the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of SEQ ID NOs: 100, 104 or 108, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 of SEQ ID NOs: 58, 68 or 85, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L3 of SEQ ID NO: 168, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L2 of SEQ ID NOs: 153 or the amino acid sequence LAS, and the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR- L1 of SEQ ID NOs: 141 or 149. In some embodiments, the CDR-H3 is a CDR-H3 of SEQ ID NOs: 112 or 130, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H2 is a CDR-H2 of SEQ ID NOs: 100, 104 or 108, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H1 is a CDR-H1 of SEQ ID NOs: 58, 68 or 85, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L3 is a CDR-L3 of SEQ ID NO: 168 with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L2 is a CDR-L2 of SEQ ID NOs: 153 or the amino acid sequence LAS, with up to 1, 2, 3, or 4 amino acid substitutions; and the CDR-L1 is a CDR-L1 of SEQ ID NOs: 141 or 149, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[0220] In some embodiments, an antibody provided herein comprises a CDR-H3 of SEQ ID NOs: 112, 121 or 130, a CDR-H2 of SEQ ID NOs: 100, 104 or 108, a CDR-H1 of SEQ ID NOs: 58, 68, or 85, a CDR-L3 of SEQ ID NO: 165, a CDR-L2 of SEQ ID NOs: 153 or the amino acid sequence LAS, and a CDR-L1 of SEQ ID NOs: 141 or 149. In some embodiments, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98% or 99% identity with a CDR-H3 of SEQ ID NOs: 112 or 130, the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of SEQ ID NOs: 100, 104 or 108, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 of SEQ ID NOs: 58, 68 or 85, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L3 of SEQ ID NO: 165, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L2 of SEQ ID NOs: 153 or the amino acid sequence LAS, and the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L1 of SEQ ID NOs: 141 or 149. In some embodiments, the CDR-H3 is a CDR-H3 of SEQ ID NOs: 112 or 130, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H2 is a CDR-H2 of SEQ ID NOs: 100, 104 or 108, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H1 is a CDR-H1 of SEQ ID NOs: 58, 68 or 85, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L3 is a CDR-L3 of SEQ ID NO: 165, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L2 is a CDR-L2 of SEQ ID NO: 153 or the amino acid sequence LAS, with up to 1, 2, 3, or 4 amino acid substitutions; and the CDR-L1 is a CDR-L1 of SEQ ID NOs: 141 or 149, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[0221] In some embodiments, an antibody provided herein comprises a CDR-H3 of SEQ ID NOs: 112 or 130, a CDR-H2 of SEQ ID NOs: 100, 104, or 108, a CDR-H1 of SEQ ID NOs: 58, 68, or 85, a CDR-L3 of SEQ ID NO: 165, a CDR-L2 of SEQ ID NO: 158 or the amino acid sequence LAS, and a CDR-L1 of SEQ ID NOs: 141 or 149. In some embodiments, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H3 of SEQ ID NOs: 112 or 130, the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of SEQ ID NOs: 100, 104, or108, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 of SEQ ID NOs: 58, 68 or 85, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L3 of SEQ ID NO: 165, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L2 of SEQ ID NO: 158 or the amino acid sequence LAS, and the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L1 of SEQ ID NOs: 141 or 149. In some embodiments, the CDR-H3 is a CDR-H3 of SEQ ID NOs: 112 or 130, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H2 is a CDR-H2of SEQ ID NOs: 100, 104, or 108, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H1 is a CDR-H1 of SEQ ID NOs: 58, 68, or 85, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L3 is a CDR-L3 of SEQ ID NO: 165, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L2 is a CDR-L2 of SEQ ID NO: 158 or the amino acid sequence LAS, with up to 1, 2, 3, or 4 amino acid substitutions; and the CDR-L1 is a CDR- L1 of SEQ ID NOs: 141 or 149, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[0222] In some embodiments, an antibody provided herein comprises a CDR-H3 of SEQ ID NOs: 112, 121 or 130, a CDR-H2 of SEQ ID NOs: 100, 104 or 108, a CDR-H1 of SEQ ID NOs: 58, 67, or 84, a CDR-L3 of SEQ ID NO: 165, a CDR-L2 of SEQ ID NOs: 153 or the amino acid sequence LAS, and a CDR-L1 of SEQ ID NOs: 141 or 149. In some embodiments, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H3 of SEQ ID NOs: 112 or 130, the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of SEQ ID NOs: 100, 104 or 108, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 of SEQ ID NOs: 58, 67 or 84, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L3 of SEQ ID NO: 165, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L2 of SEQ ID NOs: 153 or the amino acid sequence LAS, and the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L1 of SEQ ID NOs: 141 or 149. In some embodiments, the CDR-H3 is a CDR-H3 of SEQ ID NOs: 112 or 130, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H2 is a CDR-H2 of SEQ ID NOs: 100, 104 or 108, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H1 is a CDR-H1 of SEQ ID NOs: 58, 67 or 84, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L3 is a CDR-L3 of SEQ ID NO: 165, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L2 is a CDR-L2 of SEQ ID NO: 153 or the amino acid sequence LAS, with up to 1, 2, 3, or 4 amino acid substitutions; and the CDR-L1 is a CDR-L1 of SEQ ID NOs: 141 or 149, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[0223] In some embodiments, an antibody provided herein comprises a CDR-H3 of SEQ ID NOs: 112 or 130, a CDR-H2 of SEQ ID NOs: 100, 104, or 108, a CDR-H1 of SEQ ID NOs: 58, 67, or 84, a CDR-L3 of SEQ ID NO: 165, a CDR-L2 of SEQ ID NO: 158 or the amino acid sequence LAS, and a CDR-L1 of SEQ ID NOs: 141 or 149. In some embodiments, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98% or 99% identity with a CDR-H3 of SEQ ID NOs: 112 or 130, the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of SEQ ID NOs: 100, 104, or108, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 of SEQ ID NOs: 58, 67 or 84, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L3 of SEQ ID NO: 165, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L2 of SEQ ID NO: 158 or the amino acid sequence LAS, and the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L1 of SEQ ID NOs: 141 or 149. In some embodiments, the CDR-H3 is a CDR-H3 of SEQ ID NOs: 112 or 130, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H2 is a CDR-H2 of SEQ ID NOs: 100, 104, or 108, with up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; the CDR-H1 is a CDR-H1 of SEQ ID NOs: 58, 67, or 84, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L3 is a CDR-L3 of SEQ ID NO: 165, with up to 1, 2, 3, 4, or 5 amino acid substitutions; the CDR-L2 is a CDR-L2 of SEQ ID NO: 158 or the amino acid sequence LAS, with up to 1, 2, 3, or 4 amino acid substitutions; and the CDR-L1 is a CDR- L1 of SEQ ID NOs: 141 or 149, with up to 1, 2, 3, 4, 5, or 6 amino acid substitutions.

[0224] In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this disclosure are referred to herein as “variants” or “clones”. In some embodiments, 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. In some embodiments, 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.

[0225] In certain aspects, the antibodies disclosed herein do not include antibodies disclosed in US Patent number 9,067,994.Constr ID 5, 10, 1 20, 133 136, an 141-14 6, 11, 1 and 21C ID 7 a 8 aCon ID 9, 1 24, 104 and 140 25Co ID 26 10Co ID 106 107Con ID 108 109C I 1 1C ID 11 11C ID 11 11Con ID 120 121Co ID 12 12Cons ID 124 125Con ID 126 127Co t I 1 (le m an 13 3Co t I 4 5, 20 13 14C t 6 a 7 aC t 8 a 9 2 1 a 1C t 2 2Con t ID 105 106Cons t ID 107 108Cons t ID 109 110Co t I 11 11C t 1 1C t I 11 11Co t I 11 11Con t ID 121 122Con t ID 123 124C t 1 1Const ID 1 (lebrik mab), and 12 131 3C I 6 a 7 aCo ID 8, an 9, 24 10 an 14Con ID 25 26Con ID 105 106Con ID 109 110C I 1 1Co ID 11 11Co ID 11 11C ID 1 1Con ID 119 120Co ID 12 12C ID 1 1Co ID 12 12C I - 5C ID 20 -C I 2 2C I 9 9C ID 9 9Co ID 99 100Co ID 10 10C ID 1 (l m a 1 3C I - 1 1 a 1Co ID 20- -Co ID 25 26C I 9 9C I 9 9C ID 9 9 1C I 9 1Co ID 10 10C I 1 1C I 9 9Fc Region

[0226] The structures of the Fc regions of various immunoglobulins, and the glycosylation sites contained therein, are known in the art. See Schroeder and Cavacini, J. Allergy Clin. Immunol., 2010, 125:S41-52, incorporated by reference in its entirety. The Fc region may be a naturally occurring Fc region, or an Fc region modified as described in the art or elsewhere in this disclosure.

[0227] Unless otherwise specified herein, 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. For example, 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.

[0228] The terms “Fc receptor” and “FcR” are used to describe a receptor that binds to the Fc region of an antibody. For example, an FcR can be a native sequence human FcR. Generally, an FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced forms of these receptors. FcγRII receptors include FcγRIIA (an “activating receptor”) and FcγRIIB (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 FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain (reviewed in Daëron, Annu. Rev. Immunol.15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med.126:330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term “FcR” herein. The term also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol.117:587 (1976); and Kim et al., J. Immunol.24:249 (1994)).

[0229] Modifications in the CH2 domain can affect the binding of FcRs to the Fc. A number of amino acid modifications in the Fc region are known in the art for selectively altering the affinity of the Fc for different Fcgamma receptors. In some aspects, the Fc comprises one or more modifications to promote selective binding of Fc-gamma receptors.

[0230] Exemplary mutations that alter the binding of FcRs to the Fc are listed below:

[0231] S298A / E333A / K334A, S298A / E333A / K334A / K326A (Lu Y, Vernes JM, Chiang N, et al. J Immunol Methods.2011 Feb 28;365(1-2):132-41);

[0232] F243L / R292P / Y300L / V305I / P396L, F243L / R292P / Y300L / L235V / P396L (Stavenhagen JB, Gorlatov S, Tuaillon N, et al. Cancer Res.2007 Sep 15;67(18):8882- 90; Nordstrom JL, Gorlatov S, Zhang W, et al. Breast Cancer Res.2011 Nov 30;13(6):R123);

[0233] F243L (Stewart R, Thom G, Levens M, et al. Protein Eng Des Sel.2011 Sep;24(9):671-8.), S298A / E333A / K334A (Shields RL, Namenuk AK, Hong K, et al. J Biol Chem.2001 Mar 2;276(9):6591-604);

[0234] S239D / I332E / A330L, S239D / I332E (Lazar GA, Dang W, Karki S, et al. Proc Natl Acad Sci U S A.2006 Mar 14;103(11):4005-10);

[0235] S239D / S267E, S267E / L328F (Chu SY, Vostiar I, Karki S, et al. Mol Immunol. 2008 Sep;45(15):3926-33);

[0236] S239D / D265S / S298A / I332E, S239E / S298A / K326A / A327H, G237F / S298A / A330 L / I332E, S239D / I332E / S298A, S239D / K326E / A330L / I332E / S298A, G236A / S239D / D270L / I332E, S239E / S267E / H268D, L234F / S267E / N325L, G237F / V266L / S267D and other mutations listed in WO2011 / 120134 and WO2011 / 120135, herein incorporated by reference. Therapeutic Antibody Engineering (by William R. Strohl and Lila M. Strohl, Woodhead Publishing series in Biomedicine No 11, ISBN 1907568379, Oct 2012) lists mutations on page 283.

[0237] In certain embodiments 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 9 summarizes various designs reported in the literature for effector function engineering.

[0238] Methods of producing antibodies with little or no fucose on the Fc glycosylation site (Asn 297 EU numbering) without altering the amino acid sequence are well known in the art. The GlymaX® technology (ProBioGen AG) is based on the introduction of a gene for an enzyme which deflects the cellular pathway of fucose biosynthesis into cells used forantibody production. This prevents the addition of the sugar “fucose” to the N-linked antibody carbohydrate part by antibody-producing cells. (von Horsten et al. (2010) Glycobiology.2010 Dec; 20 (12):1607-18.) Another approach to obtaining antibodies with lowered levels of fucosylation can be found in U.S. 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.

[0239] Thus, in one embodiment, an antibody described herein can include a dimeric Fc that comprises one or more amino acid modifications as noted in Table 9 that confer improved effector function. In another embodiment, the antibody can be afucosylated to improve effector function. Table 9. CH2 domains and effector function engineering Reference Modification(s) Effect C C C C C C C C C C C

[0240] Fc modifications reducing FcgR and / or complement binding and / or effector function are known in the art. Recent publications describe strategies that have been used toengineer 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). These strategies include reduction of effector function through modification of glycosylation, use of IgG2 / IgG4 scaffolds, or the introduction of mutations in the hinge or CH2 regions of the Fc. For example, U.S. Patent Publication No. 2011 / 0212087 (Strohl), International Patent Publication No. WO 2006 / 105338 (Xencor), U.S. Patent Publication No. 2012 / 0225058 (Xencor), U.S. Patent Publication No. 2012 / 0251531 (Genentech), and Strop et al. ((2012) J. Mol. Biol. 420: 204- 219) describe specific modifications to reduce FcgR or complement binding to the Fc.

[0241] Specific, non-limiting examples of known amino acid modifications to reduce FcgR or complement binding to the Fc include those identified in the following Table 10:Table 10. Modifications to reduce FcgR or complement binding to the Fc

[0242] Methods of producing antibodies with little or no fucose on the Fc glycosylation site (Asn 297 EU numbering) without altering the amino acid sequence are well known in the art. The GlymaxX® technology (ProBioGen AG) is based on the introduction of a gene for an enzyme which deflects the cellular pathway of fucose biosynthesis into cells used for antibody production. This prevents the addition of the sugar “fucose” to the N-linked antibody carbohydrate part by antibody-producing cells. (von Horsten et al. (2010) Glycobiology.2010; 20 (12):1607-18.) 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 von Horsten et al., 2010, supra) or Lec13 CHO cells, which are deficient in protein fucosylation (see Ripka et al., Arch. Biochem. Biophys., 1986, 249:533-545; U.S. Pat. Pub. No.2003 / 0157108; WO 2004 / 056312; each of which is incorporated by reference in its entirety), and knockout cell lines, such as alpha-1,6-fucosyltransferase gene or FUT8 knockout CHO cells (see Yamane- Ohnuki et al., Biotech. Bioeng., 2004, 87: 614-622; Kanda et al., Biotechnol. Bioeng., 2006, 94:680-688; and WO 2003 / 085107; each of which is incorporated by reference in its entirety). Another approach to obtaining antibodies with lowered levels of fucosylation can be found in U.S. Patent No.8,409,572, which teaches selecting cell lines for antibody production for their ability to yield lower levels of fucosylation on antibodies.

[0243] 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 von Horsten et al., 2010, supra) or Lec13 CHO cells, which are deficient in protein fucosylation (see Ripka et al., Arch. Biochem. Biophys., 1986, 249:533-545; U.S. Pat. Pub. No.2003 / 0157108; WO 2004 / 056312; each of which is incorporated by reference in its entirety), and knockout cell lines, such as alpha-1,6- fucosyltransferase gene or FUT8 knockout CHO cells (see Yamane-Ohnuki et al., Biotech. Bioeng., 2004, 87: 614-622; Kanda et al., Biotechnol. Bioeng., 2006, 94:680-688; and WO 2003 / 085107; each of which is incorporated by reference in its entirety).

[0244] 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.

[0245] In some aspects, an antibody provided herein comprises an IgG1 domain with reduced fucose content at position Asn 297 compared to a naturally occurring IgG1 domain.Such Fc domains are known to have improved ADCC. See Shields et al., J. Biol. Chem., 2002, 277:26733-26740, incorporated by reference in its entirety. In some aspects, such antibodies do not comprise any fucose at position Asn 297. The amount of fucose may be determined using any suitable method, for example as described in WO 2008 / 077546, incorporated by reference in its entirety.

[0246] In certain embodiments, 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. In certain embodiments, 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.

[0247] Other illustrative glycosylation variants which may be incorporated into the antibodies provided herein are described, for example, in U.S. Pat. Pub. Nos.2003 / 0157108, 2004 / 0093621, 2003 / 0157108, 2003 / 0115614, 2002 / 0164328, 2004 / 0093621, 2004 / 0132140, 2004 / 0110704, 2004 / 0110282, 2004 / 0109865; International Pat. Pub. Nos.2000 / 61739, 2001 / 29246, 2003 / 085119, 2003 / 084570, 2005 / 035586, 2005 / 035778; 2005 / 053742, 2002 / 031140; Okazaki et al., J. Mol. Biol., 2004, 336:1239-1249; and Yamane-Ohnuki et al., Biotech. Bioeng., 2004, 87: 614-622; each of which is incorporated by reference in its entirety.

[0248] In certain embodiments, 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. Examples of such antibody variants are described, for example, in WO 1997 / 30087; WO 1998 / 58964; and WO 1999 / 22764; each of which his incorporated by reference in its entirety.

[0249] In certain embodiments, 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.

[0250] In certain embodiments, an antibody provided herein comprises a heavy chain comprising a constant heavy chain (HC) region comprising an amino acid sequence set forth in SEQ ID NO: 439 or SEQ ID NO: 624.

[0251] In certain embodiments, an antibody provided herein comprises a constant light chain (LC) region comprising an amino acid sequence set forth in SEQ ID NO: 469.

[0252] In certain embodiments, an antibody provided herein comprises (1) a constant heavy chain (HC) region comprising an amino acid sequence set forth in SEQ ID NO: 439 or SEQ ID NO: 624 or a HC region comprising sequence comprising an amino acid sequence having at least 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 439 or SEQ ID NO: 624 (1) a constant light chain (LC) region comprising an amino acid sequence set forth in SEQ ID NO: 469, or a LC region comprising sequence comprising an amino acid sequence having at least 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 469 (3) a VH comprising an amino acid sequence set forth in SEQ ID NO: 3 or a VH having at least 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3 and (4) a VL comprising an amino acid sequence set forth in SEQ ID NO: 39 or a VL comprising an amino acid sequence at least 95% 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 39.

[0253] In certain embodiments, the isolated antibody comprises a heavy chain constant (HC) region comprising an amino acid sequence set forth in SEQ ID NO: 439 or 624 and a light chain constant (LC) region comprising an amino acid sequence set forth in SEQ ID NO: 469, wherein the antibody further comprises a VH comprising an amino acid sequence having at least 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3 and a VL comprising an amino acid sequence at least 95% 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 39, wherein the VH comprises a HCDR1 comprising SEQ ID NO: 58, SEQ ID NO: 68, or SEQ ID NO: 85; a HCDR2 comprising SEQ ID NO: 100, SEQ ID NO: 104, or SEQ ID NO: 108; and a HCDR3 comprising SEQ ID NO: 112 or SEQ ID NO: 130; and the VL comprises a LCDR1 comprising SEQ ID NO: 141 or SEQ ID NO: 149; a LCDR2 comprising SEQ ID NO: 153 or SEQ ID NO: 164, and a LCDR3 comprising SEQ ID NO: 165.

[0254] In certain embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions result in increased antibody half-life, increased ADCC activity, increased ADCP activity, or increased CDC activity compared with the Fc without the one or more substitutions. In certain embodiments, 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.

[0255] In certain embodiments, the one or more amino acid substitutions is selected from the group consisting of S228P (SP); M252Y, S254T, T256E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311V, A378V, E380A, M428L, N434A, N434S, N297A, D265A, L234A, L235A, and N434W. In certain embodiments, the one ormore amino acid substitutions comprises a plurality of amino acid substitutions selected from the group consisting of M428L / N434S (LS); M252Y / S254T / T256E (YTE); T250Q / M428L; T307A / E380A / N434A; T256D / T307Q (DQ); T256D / T307W (DW); M252Y / T256D (YD); T307Q / Q311V / A378V (QVV); T256D / H285D / T307R / Q311V / A378V (DDRVV); L309D / Q311H / N434S (DHS); S228P / L235E (SPLE); L234A / L235A (LA), M428L / N434A L234A / G237A (LALA), L234A / L235A / G237A, L234A / L235A / P329G, N297A, D265A / YTE, LALA / YTE, LAGA / YTE, LALAGA / YTE, LALAPG / YTE, N297A / LS; D265A / LS; LALA / LS; LALAGA / LS; LALAPG / LS; N297A / DHS; D265A / DHS; LALA / DHS; LAGA / DHS; LALAGA / DHS; LALAPG / DHS; SP / YTE; SPLE / YTE; SP / LS; SPLE / LS, SP / DHS; SPLE / DHS; N297A / LA; D265A / LA, LALA / LA, LAGA / LA, LALAGA / LA, LALAPG / LA, N297A / N434A; D265A / N434A; LALA / N434A, LAGA / N434A, LALAGA / N434A, LALAPG / N434A, N297A / N434W, D265A / N434W, LALA / N434W, LAGA / N434W, LALAGA / N434W, LALAPG / N434W, N297A / DQ, D265A / DQ, LALA / DQ, LAGA / DQ, LALAGA / DQ, LALAPG / DQ, N297A / DW, D265A / DW, LALA / DW, LAGA / DW, LALAGA / DW, LALAPG / DW N297A / YD, D265A / YD, LALA / YD, LAGA / YD, LALAGA / YD, LALAPG / YD, T307Q / Q311V / A378V (QVV), N297A / QVV, D265A / QVV, LALA / QVV, LAGA / QVV, LALAGA / QVV, LALAPG / QVV, DDRVV, N297A / DDRVV, D265A / DDRVV, LALA / DDRVV, LAGA / DDRVV, LALAGA / DDRVV, and LALAPG / DDRVV.

[0256] In certain embodiments, the Fc region binds an Fcγ Receptor selected from the group consisting of: FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, and FcγRIIIb. In certain embodiments, the Fc region binds an Fcγ Receptor with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region. Modifications YTE Substitutions

[0257] In certain embodiments, the fragment crystallizable region (Fc region) of the anti- IL-13 antibody described herein carries a triple substitution M252Y / S254T / T256E (YTE) designed to increase the half-life of the IgG. YTE substitutions (also referred to herein as YTE mutations) increase the binding of the modified IgG to the human neonatal Fc receptor (FcRn). FcRn-bound IgG is recycled via lysosomal salvage, resulting in the IgG returning to the circulation. Thus, the YTE mutations confer greater FcRn-IgG binding, prolonging the IgG serum half-life compared to an unmodified IgG.LALA Substitutions

[0258] In certain embodiments, the anti-IL-13 antibodies described herein additionally carries Fc region amino acid substitutions L234A / L235A in the IgG1 heavy chain, commonly called LALA substitutions or LALA mutations. These changes impair Fc receptor binding to IgG and prevent undesired effector cell activation. Binding

[0259] In certain embodiments, an anti-IL-13 antibody described herein is a high-affinity IgG1 humanized monoclonal antibody (mAb) that binds IL-13. In certain embodiments, the anti-IL-13 antibody described herein comprises a IgG1 constant region comprising YTE substitutions and LALA substitutions.

[0260] Without wishing to be bound by theory, the binding of the anti-IL-13 antibodies described herein to IL-13 is believed to prevent the formation of the IL-13Rα1 / IL-4Rα active receptor heterodimer and subsequent IL-13-mediated signaling. The direct consequences of IL-13 signaling in atopic dermatitis (AD) pathology include dermal thickening, increased CD4+T cell infiltration, and dermal barrier disruption. Consequently, preventing receptor heterodimer formation is believed to decrease the clinical severity of AD.

[0261] The affinity of a molecule X for its partner Y can be represented by the dissociation equilibrium constant (KD). 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®).

[0262] With regard to the binding of an antibody to a target molecule, the terms “bind,” “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction (e.g., with a non-target molecule). Specific binding can be measured, for example, by measuring binding to a target molecule (i.e., IL-13) and comparing it to binding to a non-target molecule. Specific binding can also be determined by competition with a control molecule that mimics the epitope recognized on the target molecule. In that case, specific binding is indicated if the binding of the antibody to the target molecule is competitively inhibited by the control molecule. In certain embodiments, the affinity of an anti-IL-13 antibody for anon-target molecule is less than about 50% of the affinity for IL-13. In certain embodiments, the affinity of an anti-IL-13 antibody for a non-target molecule is less than about 40% of the affinity for IL-13. In certain embodiments, the affinity of an anti-IL-13 antibody for a non- target molecule is less than about 30% of the affinity for IL-13. In certain embodiments, the affinity of an anti-IL-13 antibody for a non-target molecule is less than about 20% of the affinity for IL-13. In certain embodiments, the affinity of an anti-IL-13 antibody for a non- target molecule is less than about 10% of the affinity for IL-13. In certain embodiments, the affinity of an anti-IL-13 antibody for a non-target molecule is less than about 1% of the affinity for IL-13. In certain embodiments, the affinity of an anti-IL-13 antibody for a non- target molecule is less than about 0.1% of the affinity for IL-13.

[0263] When used herein in the context of two or more antibodies, the term “competes with” or “cross-competes with” indicates that the two or more antibodies compete for binding to an antigen (e.g., IL-13). In one exemplary assay, IL-13 is coated on a surface and contacted with a first anti-IL-13 antibody, after which a second anti-IL-13 antibody is added. In another exemplary assay, a first anti-IL-13 antibody is coated on a surface and contacted with IL-13, and then a second anti-IL-13 antibody is added. If the presence of the first anti- IL-13 antibody reduces binding of the second anti-IL-13 antibody, in either assay, then the antibodies compete with each other. The term “competes with” also includes combinations of antibodies where one antibody reduces binding of another antibody, but where no competition is observed when the antibodies are added in the reverse order. However, in certain embodiments, the first and second antibodies inhibit binding of each other, regardless of the order in which they are added. In certain embodiments, 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-13 and the valency of the antibodies. The assays described in this definition are illustrative, and a skilled artisan can utilize any suitable assay to determine if antibodies compete with each other. Suitable assays are described, for example, in Cox et al., “Immunoassay Methods,” in Assay Guidance Manual [Internet], Updated December 24, 2014 (ncbi.nlm.nih.gov / books / NBK92434 / ; accessed September 29, 2015); Silman et al., Cytometry, 2001, 44:30-37; and Finco et al., J. Pharm. Biomed. Anal., 2011, 54:351-358; each of which is incorporated by reference in its entirety.

[0264] 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 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 (competing antibody) 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. For example, a second, competing antibody can be identified that competes for binding to IL-13 with a first antibody described herein. In certain instances, 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. In certain instances, the second antibody can displace the first antibody by greater than 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.

[0265] In certain embodiments, the antibody binds an IL-13 sequence set forth in SEQ ID NOs: 472-475.

[0266] In certain embodiments, the antibody binds to an IL-13 sequence set forth in SEQ ID NOs: 472-475 with a KD of less than or equal to about 1, 2, 3, 4, 5, 6, 7, 8, 9 x 10-9M, as measured by surface plasmon resonance (SPR). In certain embodiments, the antibody binds to an IL-13 sequence set forth in SEQ ID NOs: 472-475 with a KD of less than or equal to about 1 x 10-10M, as measured by surface plasmon resonance (SPR). In certain embodiments, the antibody binds to human IL-13 with a KD of less than or equal to about 1 x 10-9M, as measured by surface plasmon resonance (SPR).

[0267] In certain embodiments, an antibody provided herein binds IL-13 with a KD of less than or equal to about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.95, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 x 10-8M, as measured by ELISA or any other suitable method known in the art. In certain embodiments, an antibody provided herein binds IL-13 with a KD of less than or equal to about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.95, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 x 10-9M, as measured by ELISA or any other suitable method known in the art.

[0268] In certain embodiments, the KD of an antibody provided herein for the binding of IL-13 is between about 0.001-0.01, 0.01-0.1, 0.01-0.05, 0.05-0.1, 0.1-0.5, 0.5-1, 0.25-0.75, 0.25-0.5, 0.5-0.75, 0.75-1, 0.75-2, 1.1-1.2, 1.2-1.3, 1.3-1.4, 1.4-1.5, 1.5-1.6, 1.6-1.7, 1.7-1.8, 1.8-1.9, 1.9-2, 1-2, 1-5, 2-7, 3-8, 3-5, 4-6, 5-7, 6-8, 7-9, 7-10, or 5-10 x 10-8M, as measuredby ELISA or any other suitable method known in the art. In certain embodiments, an antibody provided herein binds IL-13 with a KD of less than or equal to about 1 x 10-8M, or less than or equal to above 1 x 10-9M as measured by ELISA or any other suitable method known in the art.

[0269] In certain embodiments, an antibody provided herein binds IL-13 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 10-8M, or less, as measured by ELISA or any other suitable method known in the art . In certain embodiments, an antibody provided herein binds IL-13 with a KD between 5-3, 4-2, 3- 1, 1.9-1.8, 1.8-1.7, 1.7-1.6, 1.6-1.5, 1.9-1.5, 1.5-1, 1-0.8, 1-0.5, 0.9-0.6, 0.7-0.4, 0.6-0.2, 0.5- 0.3, 0.3-0.2, 0.2-0.1, 0.1-0.01, 0.01-0.001, or 0.001-0.0001 x 10-8M as measured by ELISA or any other suitable method known in the art.

[0270] In certain embodiments, an antibody provided herein results in inhibition of pSTAT6 with an IC50 of at least about 60 days, at least about 65 days, at least about 70 days, at least about 75 days, at least about 80 days, at least about 85 days, at least about 90 days, at least about 95 days, at least about 100 days, or at least about 105 days. In certain embodiments, an antibody provided herein results in inhibition of pSTAT6 with an IC50 of between about 85 and about 100 days, between about 90 and about 95 days, or between about 91 and about 93 days. In certain embodiments, inhibition of pSTAT6 is determined by administering an antibody provided herein to a mammal, collecting whole blood, staining with a fluorescent anti-pSTAT6 antibody, and using FACS to determine the concentration of antibody needed to inhibit 50% of the maximum MFI of pSTAT6. In certain embodiments, inhibition of pSTAT6 is determined by contacting cells with IL-13 or IL-4 and an antibody provided herein, staining the cell with a fluorescent anti-pSTAT6 antibody, and using FACS to determine the concentration of antibody needed to inhibit 50% of the maximum MFI of pSTAT6. Pharmaceutical compositions

[0271] The present application provides compositions comprising the antibodies including pharmaceutical compositions comprising any one or more of the antibodies described herein with one or more pharmaceutically acceptable excipients. In certain embodiments the composition is sterile. The pharmaceutical compositions generally comprise an effective amount of an antibody.

[0272] In certain aspects, a composition comprises 150 mg / mL, 180 mg / mL, or 200 mg / mL of an anti-IL-13 antibody described herein. In certain embodiments, the anti-IL-13 antibody comprises a VH comprising an amino acid sequence as set forth in SEQ ID NO: 3 and a VL comprising an amino acid sequence as set forth in SEQ ID NO: 39. In certain embodiments, the anti-IL-13 antibody comprises a light chain variable domain comprising a framework region sequence selected from a sequence set forth in SEQ ID NO: 439 or 624 and SEQ ID NO: 469, wherein the antibody further comprises a VH comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3 and a VL comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95% 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 39, wherein the VH comprises a HCDR1 comprising SEQ ID NO: 58, SEQ ID NO: 68, or SEQ ID NO: 85; a HCDR2 comprising SEQ ID NO: 100, SEQ ID NO: 104, or SEQ ID NO: 108; and a HCDR3 comprising SEQ ID NO: 112 or SEQ ID NO: 130; and the VL comprises a LCDR1 comprising SEQ ID NO: 141 or SEQ ID NO: 149; a LCDR2 comprising SEQ ID NO: 153 or SEQ ID NO: 164, and a LCDR3 comprising SEQ ID NO: 165.

[0273] These 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, intraperitoneal routes.

[0274] In certain embodiments, the composition comprises a histidine buffer, arginine and / or methionine and optionally a surfactant and / or sucrose. In certain embodiments, the surfactant is polysorbate (e.g., polysorbate 80) or a poloxamer (e.g., poloxamer 188).

[0275] 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. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol can be included.

[0276] For intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction, 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. Those ofrelevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer’s Injection, Lactated Ringer’s Injection. Preservatives, stabilizers, buffers, antioxidants and / or other additives can be included, as required.

[0277] The anti-IL-13 antibody that is to be given to an individual, 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 protein aggregation disease being treated. Prescription of treatment, e.g., decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington’s Pharmaceutical Sciences, 16thedition, Osol, A. (ed), 1980.

[0278] 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

[0279] Antibodies described herein can be produced using recombinant methods and compositions, e.g., as described in U.S. Pat. No.4,816,567. In one embodiment, isolated nucleic acid encoding an antibody described herein is provided. Such 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 VH of a single domain antibody. In a further embodiment, one or more vectors (e.g., expression vectors) comprising such nucleic acid are provided. In one embodiment, the nucleic acid is provided in a multicistronic vector. In a further embodiment, a host cell comprising such nucleic acid is provided. In one such embodiment, 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 theVL 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. In one embodiment, the host cell is eukaryotic, e.g., a Chinese Hamster Ovary (CHO) cell, or human embryonic kidney (HEK) cell, or lymphoid cell (e.g., Y0, NS0, Sp20 cell). In one embodiment, a method of making an antibody is provided, wherein the method 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).

[0280] For recombinant production of the antibody, 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. Such 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).

[0281] When a antibody or variant thereof is recombinantly produced by the host cells, 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 weight of the cells. When the antibody or variant thereof is recombinantly produced by the host 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. In certain embodiments, “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.

[0282] Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells described herein.

[0283] 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, aplasmid, 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.

[0284] For example, antibody may be produced in bacteria, in particular when glycosylation and Fc effector function are not needed. For 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. coli.) After expression, the antibody may be isolated from the bacterial cell paste in a soluble fraction and can be further purified.

[0285] In addition to prokaryotes, 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).

[0286] 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.

[0287] 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 PLANTIBODIES™ technology for producing antibodies in transgenic plants).

[0288] Vertebrate cells may also be used as hosts. For example, mammalian cell lines that are adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney line (293 or 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. Reprod.23:243-251 (1980)); 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. USA 77:4216 (1980)); and myeloma cell lines such as Y0, NS0 and Sp2 / 0. For a review of certain mammalian host cell lines suitable for antibody production, see, e.g., Yazaki and Wu, Methods in Molecular Biology, Vol.248 (B.K.C. Lo, ed., Humana Press, Totowa, N.J.), pp.255-268 (2003).

[0289] In one embodiment, the antibodies described herein are produced in stable mammalian cells, by a method comprising: transfecting at least one stable mammalian cell with: nucleic acid encoding the antibody, in a predetermined ratio; and expressing the nucleic acid in the at least one mammalian cell. In certain embodiments, 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.

[0290] In certain embodiments, is the method of producing an antibody in stable mammalian cells as described herein wherein the expression product of the at least one stable mammalian cell comprises a larger percentage of the desired glycosylated antibody as compared to the monomeric heavy or light chain polypeptides, or other antibodies.

[0291] In certain embodiments, is the method of producing a glycosylated antibody in stable mammalian cells described herein, said method comprising identifying and purifying the desired glycosylated antibody. In certain embodiments, the said identification is by one or both of liquid chromatography and mass spectrometry.

[0292] If required, 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. As is well known in the art, a variety of natural proteins bind Fc and antibodies, and these proteins can find use in the present invention for purification of antibodies. For example, the bacterial proteins A and G bind to the Fc region. Likewise, the bacterial protein L binds to the Fab region of some antibodies. Purification can often be enabled by a particular fusion partner. For example, antibodies may be purified using glutathione resin if a GST fusion is employed, Ni+2affinity chromatography if a His-tag is employed or immobilized anti-flag antibody if a flag-tag is used. For general guidance in suitable purification techniques, see, e.g., incorporated entirely by reference ProteinPurification: Principles and Practice, 3rdEd., 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.

[0293] In certain embodiments, 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.

[0294] In specific embodiments, 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.

[0295] In addition, 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. Freeman & Co., N.Y and Hunkapiller et al., Nature, 310:105-111 (1984)). For example, a polypeptide corresponding to a fragment of a polypeptide can be synthesized by use of a peptide synthesizer. Furthermore, if desired, 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. Furthermore, the amino acid can be D (dextrorotary) or L (levorotary). Methods of Use

[0296] The present application provides methods of treating an inflammatory disorder or disease, such as atopic dermatitis, in a patient in need thereof. In certain embodiments, the patient has been diagnosed with moderate-to-severe atopic dermatitis. In certain embodiments, the patient has had moderate-to-severe atopic dermatitis for at least one year. In certain embodiments, the patient is a pediatric patient.

[0297] In certain embodiments, the patient has one or more of: (a) an Eczema Area and Severity Index Score (EASI) of ≥10 (e.g., an EASI of ≥16 or an EASI ≥10 and <16), (b) anInvestigator Global Assessment (IGA) score of ≥3 and (c) a body surface area (BSA) of ≥10%. In certain embodiments, the patient has an Eczema Area and Severity Index Score (EASI) of ≥10. In certain embodiments, the patient has an Eczema Area and Severity Index Score (EASI) of ≥16. In certain embodiments, the patient has an Eczema Area and Severity Index Score (EASI) of ≥10 and less than 16. In certain embodiments, the patient has an Investigator Global Assessment (IGA) score of ≥3. In certain embodiments, the patient has a body surface area (BSA) of ≥10%.

[0298] The “Investigator Global Assessment” or “IGA” is an assessment measure used globally to rate the severity of the patient’s AD (Simpson E, et al. J Am Acad Dermatol. 2020;83(3):839-846). It is based on a 5-point scale ranging from 0 (clear) to 4 (severe) and a score is selected using descriptors that best describe the overall appearance of the lesions at a given time point. It is not necessary that all characteristics under Morphological Description be present. The IGA can be conducted prior to conducting the EASI and BSA assessments.

[0299] The “Eczema Area and Severity Index” or “EASI is a measure used in clinical settings to assess the severity and extent of AD (Hanifin et al., Exp Dermatol.2001; 10: 11- 18). EASI is a composite index with scores ranging from 0 to 72, with the higher values indicating more severe and or extensive disease. The severity of erythema, induration / papulation, excoriation, and lichenification can be assessed by a clinician or other medical professional on a scale of 0 (absent) to 3 (severe) for each of the 4 body areas: head and neck, trunk, upper limbs, and lower limbs, with half points allowed. In addition, the extent of AD involvement in each of the 4 body areas can be assessed as a percentage by body surface area of head, trunk, upper limbs, and lower limbs, and converted to a score of 0 to 6. A total score (0 – 72) is assigned based on the sum of total scores for each of the four body region scores. In a clinical trial setting, the terms “EASI-50”, “EASI-75”, and “EASI- 90” indicate the proportion of patients with an improvement over 50, 75, and 90% in EASI.

[0300] The “Scoring of Atopic Dermatitis” or “SCORAD” is a validated clinical tool for assessing the extent and intensity of AD developed by the European Task Force on Atopic Dermatitis (Consensus report of the European Task Force on Atopic Dermatitis. Dermatology.1993; 186(l):23-31). There are 3 components to the assessment: (i) the extent of AD is assessed as a percentage of each defined body area and reported as the sum of all areas, with a score ranging from 0 to 100 (assigned as “A” in the overall SCORAD calculation); (ii) the severity of 6 symptoms of AD: redness, swelling, oozing / crusting, excoriation, skin thickening / lichenification, dryness. Each item is graded as follows: none (0), mild (1), moderate (2), or severe (3) (for a maximum of 18 total points, assigned as “B”in the overall SCORAD calculation); (iii) subjective assessment of itch and of sleeplessness is recorded for each symptom using a visual analogue scale (VAS), where 0 is no itch (or sleeplessness) and 10 is the worst imaginable itch (or sleeplessness), with a maximum possible score of 20 (assigned as “C” in the overall SCORAD calculation). The SCORAD Index formula is: A / 5 + 7B / 2 + C. The maximal score of the SCORAD Index is 103.

[0301] Pruritus Numerical Rating Scale (NRS) is an 11 -point scale used by patients (and if applicable, with help of parents / caregiver if required) to rate their worst itch severity over the past 24 hours with 0 indicating “No itch” and 10 indicating “Worst itch imaginable” (Phan NQ, et al. Acta Derm Venereol 2012; 92: 502-507). Assessments are recorded by the patient daily using an electronic diary. The baseline pruritus NRS is determined based on the average of daily Pruritus NRS during the 7 days immediately preceding baseline. A minimum of 4 daily scores out of the 7 days immediately preceding baseline is required for this calculation.

[0302] Sleep loss scale rates patient’s sleep loss due to pruritus on a 5-point Likert scale (with scores ranging from 0 [not at all], 1 [a little], 2 [moderately], 3 [quite a bit], to 4 [unable to sleep at all]). Assessments will be recorded daily by the patient using an electronic diary. In certain embodiments, the sleep loss scale is the Atopic Dermatitis Sleep Scale (ADSS).

[0303] The Patient-Oriented Eczema Measure (POEM) is a 7-item, validated, questionnaire completed by the patient (and if applicable, with help of parents / caregiver if required) to assess disease symptoms over the last week (Centre of Evidence Based Dermatology. POEM – Patient Oriented Eczema Measure. Available at www.nottingham.ac.uk / research / groups / cebd / resources / poem.aspx). Patients are asked to respond to 7 questions on skin dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping. All 7 answers carry equal weight with a total possible score from 0 to 28 (answers scored as: No days=0; 1- 2 days = 1; 3-4 days = 2; 5-6 days = 3; everyday = 4). A high score is Indicative of a poor quality of life. POEM responses are captured weekly using an electronic diary.

[0304] The Dermatology Life Quality Index (DLQI) is a 10-item, validated questionnaire completed by the patient or caregiver, used to assess the impact of skin disease on the quality of life of the patient (Finlay, A. Y. and Khan, G. K.1994. Clinical and Experimental Dermatology 1993 Sep 23; 19:210-216). The 10 questions cover the following topics: symptoms, embarrassment, shopping and home care, clothes, social and leisure, sport, work or study, close relationships, sex, and treatment, over the previous week. Each question isscored from 0 to 3 (“not at all,” “a little,” “a lot,” and “very much”), giving a total score ranging from 0 to 30. A high score is indicative of a poor quality of life.

[0305] In certain embodiments, methods described herein comprise determining one or more of the following characteristics of the patient at baseline and during and after the induction period: Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Body Surface Area (BSA), Pruritus Numerical Rating Scale (NRS), Sleep loss scale, SCORing Atopic Dermatitis (SCORAD), Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Eczema Area and Severity Index (EASI). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Investigator Global Assessment (IGA). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Body Surface Area (BSA). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Pruritus Numerical Rating Scale (NRS). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Sleep loss scale, SCORing Atopic Dermatitis (SCORAD). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Patient Oriented Eczema Measure (POEM). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Dermatology Life Quality Index (DLQI).

[0306] In certain embodiments, a patient described herein is determined to have one or more of the following characteristics of the patient at baseline and during and after the induction period: Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Body Surface Area (BSA), Pruritus Numerical Rating Scale (NRS), Skin Pain Numerical Rating Scale (SP-NRS), Sleep loss scale, SCORing Atopic Dermatitis (SCORAD), Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), Asthma Control Questionnaire 5-item version (ACQ-5) score, Sino-nasal Outcome Test 22-item version (SNOT-22) score. In certain embodiments, a patient herein is determined to have a characteristic Eczema Area and Severity Index (EASI) at baseline and during and after the induction period. In certain embodiments, a patient herein is determinedto have a characteristic Investigator Global Assessment (IGA) at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Body Surface Area (BSA) at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Pruritus Numerical Rating Scale (NRS) at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Skin Pain Numerical Rating Scale (SP-NRS) at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Sleep loss scale, SCORing Atopic Dermatitis (SCORAD) at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Patient Oriented Eczema Measure (POEM) at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Dermatology Life Quality Index (DLQI) at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Asthma Control Questionnaire 5-item version (ACQ-5) score at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Sino- nasal Outcome Test 22-item version (SNOT-22) score at baseline and during and after the induction period.

[0307] In an aspect, the present application provides methods of contacting IL-13 with an anti-IL-13 antibody, such as a human or humanized antibody, which results in inhibition of IL-13 binding to an IL-13 receptor expressed on a cell.

[0308] In an aspect, the present application provides methods of using the isolated anti- IL-13 antibodies described herein for treatment of a disorder or disease in a subject. In certain aspects, described herein is a method for treating a subject in need thereof with an anti-IL-13 antibody, the method comprising administering to a mammalian subject a therapeutically effective amount of an anti-IL-13 antibody or pharmaceutical composition comprising an anti-IL-13 antibody described herein. In certain embodiments, the present application provides methods of treating a disorder or disease associated with elevated levels of IL-13 and / or IgE in a subject.

[0309] In certain aspects, described herein are methods for treating a pathology associated with IL-13 activity, the method comprising administering to a mammalian subject a therapeutically effective amount an isolated anti-IL-13 antibody or a pharmaceutical composition comprising an isolated anti-IL-13 antibody described herein.

[0310] In certain aspects, 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. In certain embodiments, the inflammatory disorder or disease is atopic dermatitis. In certain embodiments, the inflammatory disorder or disease is asthma. In certain embodiments, the inflammatory disorder or disease is idiopathic pulmonary fibrosis.

[0311] In certain aspects, described herein are methods for treating a pathology associated with elevated levels of IL-13 in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount an antibody or a pharmaceutical composition described herein.

[0312] In certain aspects, described herein are methods of reducing biological activity of IL-13 in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount an antibody or a pharmaceutical composition described herein.

[0313] In certain aspects, described herein are methods for inhibiting the TH2 type allergic response in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount an antibody or a pharmaceutical composition described herein.

[0314] In certain aspects, described herein are methods for reducing levels of Thymus and Activation Regulated Chemokine (TARC) / CCL17 in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount an antibody or a pharmaceutical composition described herein.

[0315] In certain aspects, described herein are methods of preventing an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount an antibody or a pharmaceutical composition described herein. Dosing Regimes

[0316] In an aspect, the present application provides a method of treating atopic dermatitis in a patient in need thereof, the method comprising subcutaneously administering to the patient: a) one to five (e.g., two to three) or more (e.g., six, seven, eight, nine, or ten) induction doses, each selected from 100 mg, 125 mg, 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 360mg, 400 mg, 450 mg, 600 mg, 720 mg, 800 mg, 900 mg, 1080 mg, or 1200 mg or adose listed in any one of Tables 11-13 of an anti-IL-13 antibody; and b) one or more maintenance doses administered about 4-16 (e.g., about 5-15, 6-14, 7-13, 8-12, 9-11, or 10) weeks or more (e.g., 17 weeks, 18 weeks, 19 weeks, or 20 weeks) after the first induction dose; wherein the maintenance dose is 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 360 mg, 400 mg, 450 mg, 600 mg, 720 mg, 800 mg, 1080 mg, or 1200 mg or a dose listed in Table 14 of the anti-IL-13 antibody. The anti-IL-13 antibody can be selected from an anti-IL-13 antibody disclosed herein. In certain embodiments, the anti-IL-13 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence as set forth in SEQ ID NO: 3 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto and a light chain variable region (VL) comprising an amino acid sequence as set forth in SEQ ID NO: 39 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto. In certain embodiments, the VH comprises a HCDR1 comprising SEQ ID NO: 58, SEQ ID NO: 68, or SEQ ID NO: 85; a HCDR2 comprising SEQ ID NO: 100, SEQ ID NO: 104, or SEQ ID NO: 108; and a HCDR3 comprising SEQ ID NO: 112 or SEQ ID NO: 130; and the VL comprises a LCDR1 comprising SEQ ID NO: 141 or SEQ ID NO: 149; a LCDR2 comprising SEQ ID NO: 153 or SEQ ID NO: 164, and a LCDR3 comprising SEQ ID NO: 165.

[0317] In certain embodiments, the one to five or more induction doses comprise two to three induction doses.

[0318] In certain embodiments, the one to five or more induction doses comprise one induction dose. In certain embodiments, the one to five or more induction doses comprise two induction doses. In certain embodiments, the one to five or more induction doses comprise three induction doses. In certain embodiments, the one to five or more induction doses comprise four induction doses. In certain embodiments, the one to five or more induction doses comprise five induction doses.

[0319] In certain embodiments, the one to five induction doses are each 100 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 125 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 150 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 180 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 200 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 250 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 300 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 350 mg of an anti-IL-13 antibody. In certainembodiments, the one to five induction doses are each 360 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 400 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 450 mg of an anti- IL-13 antibody. In certain embodiments, the one to five induction doses are each 500 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 550 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 600 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 650 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 700 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 720 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 750 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 800 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 850 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 900 mg of an anti- IL-13 antibody. In certain embodiments, the one to five induction doses are each 950 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 1000 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 1050 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 1100 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 1150 mg of an anti-IL-13 antibody. In certain embodiments, the one to five induction doses are each 1200 mg of an anti-IL-13 antibody.

[0320] In certain embodiments, the one to five induction doses are each any dose listed in any one of Tables 11-13 of an anti-IL-13 antibody.

[0321] In certain embodiments, one or more of the one to five induction doses is or are 100 mg of an anti-IL-13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 125 mg of an anti-IL-13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 150 mg of an anti-IL-13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 180 mg of an anti-IL- 13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 200 mg of an anti-IL-13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 250 mg of an anti-IL-13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 300 mg of an anti-IL-13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 350 mg of an anti-IL- 13 antibody. In certain embodiments, one or more of the one to five induction doses is or are360 mg of an anti-IL-13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 400 mg of an anti-IL-13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 450 mg of an anti-IL-13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 500 mg of an anti-IL- 13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 550 mg of an anti-IL-13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 600 mg of an anti-IL-13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 650 mg of an anti-IL-13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 700 mg of an anti-IL- 13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 720 mg of an anti-IL-13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 750 mg of an anti-IL-13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 800 mg of an anti-IL-13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 850 mg of an anti-IL- 13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 900 mg of an anti-IL-13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 950 mg of an anti-IL-13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 1000 mg of an anti-IL-13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 1050 mg of an anti-IL- 13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 1100 mg of an anti-IL-13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 1150 mg of an anti-IL-13 antibody. In certain embodiments, one or more of the one to five induction doses is or are 1200 mg of an anti-IL-13 antibody.

[0322] In certain embodiments, one or more of the one to five induction doses is or are a dose listed in any one of Tables 11-13 of an anti-IL-13 antibody.

[0323] In certain embodiments, the first induction dose is 150 mg, 300 mg, 360 mg, or 600 mg. In certain embodiments, the first induction dose is 150 mg. In certain embodiments, the first induction dose is 180 mg. In certain embodiments, the first induction dose is 200 mg. In certain embodiments, the first induction dose is 250 mg. In certain embodiments, the first induction dose is 300 mg. In certain embodiments, the first induction dose is 350 mg. In certain embodiments, the first induction dose is 360 mg. In certain embodiments, the first induction dose is 400 mg. In certain embodiments, the first induction dose is 450 mg. In certain embodiments, the first induction dose is 500 mg. In certain embodiments, the first induction dose is 550 mg. In certain embodiments, the first induction dose is 600 mg.

[0324] In certain embodiments, the method comprises administering a second, third, fourth, and / or fifth induction dose of 300 mg of the anti-IL-13 antibody. In certain embodiments, the method comprises administering a second induction dose of 300 mg of the anti-IL-13 antibody. In certain embodiments, the method comprises administering a third induction dose of 300 mg of the anti-IL-13 antibody. In certain embodiments, the method comprises administering a fourth induction dose of 300 mg of the anti-IL-13 antibody.

[0325] In certain embodiments, the method comprises administering a second, third, fourth, and / or fifth induction dose of 360 mg of the anti-IL-13 antibody. In certain embodiments, the method comprises administering a second induction dose of 360 mg of the anti-IL-13 antibody. In certain embodiments, the method comprises administering a third induction dose of 360 mg of the anti-IL-13 antibody. In certain embodiments, the method comprises administering a fourth induction dose of 360 mg of the anti-IL-13 antibody.

[0326] In certain embodiments, the method comprises administering a second, third, fourth, and / or fifth induction dose of 600 mg of the anti-IL-13 antibody. In certain embodiments, the method comprises administering a second induction dose of 600 mg of the anti-IL-13 antibody. In certain embodiments, the method comprises administering a third induction dose of 600 mg of the anti-IL-13 antibody. In certain embodiments, the method comprises administering a fourth induction dose of 600 mg of the anti-IL-13 antibody.

[0327] In certain embodiments, the second induction dose is administered about 2 to about 16 weeks after the first induction dose. In certain embodiments, the second induction dose is administered about 3 to about 15 weeks after the first induction dose. In certain embodiments, the second induction dose is administered about 4 to about 14 weeks after the first induction dose. In certain embodiments, the second induction dose is administered about 5 to about 13 weeks after the first induction dose. In certain embodiments, the second induction dose is administered about 6 to about 12 weeks after the first induction dose. In certain embodiments, the second induction dose is administered about 7 to about 11 weeks after the first induction dose. In certain embodiments, the second induction dose is administered about 8 to about 10 weeks after the first induction dose. In certain embodiments, the second induction dose is administered about 9 weeks after the first induction dose.

[0328] In certain embodiments, the second induction dose is administered about 1 week after the first induction dose. In certain embodiments, the second induction dose is administered about 2 weeks after the first induction dose. In certain embodiments, the second induction dose is administered about 3 weeks after the first induction dose. In certain embodiments, the second induction dose is administered about 4 weeks after the firstinduction dose. In certain embodiments, the second induction dose is administered about 5 weeks after the first induction dose. In certain embodiments, the second induction dose is administered about 6 weeks after the first induction dose. In certain embodiments, the second induction dose is administered about 7 weeks after the first induction dose. In certain embodiments, the second induction dose is administered about 8 weeks after the first induction dose. In certain embodiments, the second induction dose is administered about 9 weeks after the first induction dose. In certain embodiments, the second induction dose is administered about 10 weeks after the first induction dose. In certain embodiments, the second induction dose is administered about 11 weeks after the first induction dose. In certain embodiments, the second induction dose is administered about 12 weeks after the first induction dose. In certain embodiments, the second induction dose is administered about 13 weeks after the first induction dose. In certain embodiments, the second induction dose is administered about 14 weeks after the first induction dose. In certain embodiments, the second induction dose is administered about 15 weeks after the first induction dose. In certain embodiments, the second induction dose is administered about 16 weeks after the first induction dose.

[0329] In certain embodiments, the one or more maintenance doses are administered about 4-17 weeks or more after the first induction dose. In certain embodiments, the one or more maintenance doses comprise administration about 5-16 weeks or more after the first induction dose. In certain embodiments, the one or more maintenance doses comprise administration about 6-15 weeks or more after the first induction dose. In certain embodiments, the one or more maintenance doses comprise administration about 7-14 weeks or more after the first induction dose. In certain embodiments, the one or more maintenance doses comprise administration about 8-13 weeks or more after the first induction dose. In certain embodiments, the one or more maintenance doses comprise administration about 9-12 weeks or more after the first induction dose. In certain embodiments, the one or more maintenance doses comprise administration about 10-11 weeks or more after the first induction dose.

[0330] In certain embodiments, the one or more maintenance doses are administered about 4-17 weeks or 12-17 weeks after the first induction dose. In certain embodiments, the one or more maintenance doses are administered about 4-17 weeks after the first induction dose. In certain embodiments, the one or more maintenance doses are administered about 5- 16 weeks after the first induction dose. In certain embodiments, the one or more maintenance doses are administered about 6-15 weeks after the first induction dose. In certainembodiments, the one or more maintenance doses are administered about 7-14 weeks after the first induction dose. In certain embodiments, the one or more maintenance doses are administered about 8-13 weeks after the first induction dose. In certain embodiments, the one or more maintenance doses are administered about 9-12 weeks after the first induction dose. In certain embodiments, the one or more maintenance doses are administered about 10-11 weeks after the first induction dose.

[0331] In certain embodiments, the one or more maintenance doses are administered about 12-17 weeks after the first induction dose. In certain embodiments, the one or more maintenance doses are administered about 13-16 weeks after the first induction dose. In certain embodiments, the one or more maintenance doses are administered about 14-15 weeks after the first induction dose.

[0332] In certain embodiments, the one or more maintenance doses comprise administration about 4 weeks or more after the first induction dose. In certain embodiments, the one or more maintenance doses comprise administration about 5 weeks or more after the first induction dose. In certain embodiments, the one or more maintenance doses comprise administration about 6 weeks or more after the first induction dose. In certain embodiments, the one or more maintenance doses comprise administration about 7 weeks or more after the first induction dose. In certain embodiments, the one or more maintenance doses comprise administration about 8 weeks or more after the first induction dose. In certain embodiments, the one or more maintenance doses comprise administration about 9 weeks or more after the first induction dose. In certain embodiments, the one or more maintenance doses comprise administration about 10 weeks or more after the first induction dose. In certain embodiments, the one or more maintenance doses comprise administration about 11 weeks or more after the first induction dose. In certain embodiments, the one or more maintenance doses comprise administration about 12 weeks or more after the first induction dose. In certain embodiments, the one or more maintenance doses comprise administration about 13 weeks or more after the first induction dose. In certain embodiments, the one or more maintenance doses comprise administration about 14 weeks or more after the first induction dose. In certain embodiments, the one or more maintenance doses comprise administration about 15 weeks or more after the first induction dose. In certain embodiments, the one or more maintenance doses comprise administration about 16 weeks or more after the first induction dose. In certain embodiments, the one or more maintenance doses comprise administration about 17 weeks or more after the first induction dose.

[0333] In certain embodiments, the maintenance dose is 100 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 150 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 180 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 200 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 250 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 300 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 350 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 360 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 400 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 450 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 500 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 550 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 600 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 650 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 700 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 720 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 750 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 800 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 850 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 900 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 950 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 1000 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 1050 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 1100 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 1150 mg of the anti-IL-13 antibody. In certain embodiments, the maintenance dose is 1200 mg of the anti-IL-13 antibody.

[0334] In certain embodiments, the maintenance dose is any dose listed in Table 14 of the anti-IL-13 antibody.

[0335] In certain embodiments, the maintenance dose is 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 350 mg, 360 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 720 mg, 750 mg, or 800 mg and is administered every 3 months, every 12 weeks, or 4 times a year. In certain embodiments, the maintenance dose is 150 mg and is administered every 3 months, every 12 weeks, or 4 times a year. In certain embodiments, the maintenance dose is180 mg and is administered every 3 months, every 12 weeks, or 4 times a year. In certain embodiments, the maintenance dose is 200 mg and is administered every 3 months, every 12 weeks, or 4 times a year. In certain embodiments, the maintenance dose is 250 mg and is administered every 3 months, every 12 weeks, or 4 times a year. In certain embodiments, the maintenance dose is 300 mg and is administered every 3 months, every 12 weeks, or 4 times a year. In certain embodiments, the maintenance dose is 360 mg and is administered every 3 months, every 12 weeks, or 4 times a year. In certain embodiments, the maintenance dose is 350 mg and is administered every 3 months, every 12 weeks, or 4 times a year. In certain embodiments, the maintenance dose is 360 mg and is administered every 3 months, every 12 weeks, or 4 times a year. In certain embodiments, the maintenance dose is 400 mg and is administered every 3 months, every 12 weeks, or 4 times a year. In certain embodiments, the maintenance dose is 450 mg and is administered every 3 months, every 12 weeks, or 4 times a year. In certain embodiments, the maintenance dose is 500 mg and is administered every 3 months, every 12 weeks, or 4 times a year. In certain embodiments, the maintenance dose is 550 mg and is administered every 3 months, every 12 weeks, or 4 times a year. In certain embodiments, the maintenance dose is 600 mg and is administered every 3 months, every 12 weeks, or 4 times a year. In certain embodiments, the maintenance dose is 650 mg and is administered every 3 months, every 12 weeks, or 4 times a year. In certain embodiments, the maintenance dose is 700 mg and is administered every 3 months, every 12 weeks, or 4 times a year. In certain embodiments, the maintenance dose is 720 mg and is administered every 3 months, every 12 weeks, or 4 times a year. In certain embodiments, the maintenance dose is 750 mg and is administered every 3 months, every 12 weeks, or 4 times a year. In certain embodiments, the maintenance dose is 800 mg and is administered every 3 months, every 12 weeks, or 4 times a year.

[0336] In certain embodiments, the maintenance dose is administered every 3 months. In certain embodiments, the maintenance dose is administered every 12 weeks. In certain embodiments, the maintenance dose is administered 4 times a year.

[0337] In certain embodiments, the maintenance dose is 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 360 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg and is administered every 2 months or every 8 weeks. In certain embodiments, the maintenance dose is 150 mg and is administered every 2 months or every 8 weeks. In certain embodiments, the maintenance dose is 200 mg and is administered every 2 months or every 8 weeks. In certain embodiments, the maintenance dose is 250 mg and is administered every 2 months or every 8 weeks. In certain embodiments, the maintenance dose is 300 mg and isadministered every 2 months or every 8 weeks. In certain embodiments, the maintenance dose is 350 mg and is administered every 2 months or every 8 weeks. In certain embodiments, the maintenance dose is 360 mg and is administered every 2 months or every 8 weeks. In certain embodiments, the maintenance dose is 400 mg and is administered every 2 months or every 8 weeks. In certain embodiments, the maintenance dose is 450 mg and is administered every 2 months or every 8 weeks. In certain embodiments, the maintenance dose is 500 mg and is administered every 2 months or every 8 weeks. In certain embodiments, the maintenance dose is 550 mg and is administered every 2 months or every 8 weeks. In certain embodiments, the maintenance dose is 600 mg and is administered every 2 months or every 8 weeks. In certain embodiments, the maintenance dose is 650 mg and is administered every 2 months or every 8 weeks. In certain embodiments, the maintenance dose is 700 mg and is administered every 2 months or every 8 weeks. In certain embodiments, the maintenance dose is 720 mg and is administered every 2 months or every 8 weeks. In certain embodiments, the maintenance dose is 750 mg and is administered every 2 months or every 8 weeks. In certain embodiments, the maintenance dose is 800 mg and is administered every 2 months or every 8 weeks.

[0338] In certain embodiments, the maintenance dose is 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 350 mg, 360 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 720 mg, 750 mg, or 800 mg and is administered every 2 months. In certain embodiments, the maintenance dose is 150 mg and is administered every 2 months. In certain embodiments, the maintenance dose is 180 mg and is administered every 2 months. In certain embodiments, the maintenance dose is 200 mg and is administered every 2 months. In certain embodiments, the maintenance dose is 250 mg and is administered every 2 months. In certain embodiments, the maintenance dose is 300 mg and is administered every 2 months. In certain embodiments, the maintenance dose is 350 mg and is administered every 2 months. In certain embodiments, the maintenance dose is 360 mg and is administered every 2 months. In certain embodiments, the maintenance dose is 400 mg and is administered every 2 months. In certain embodiments, the maintenance dose is 450 mg and is administered every 2 months. In certain embodiments, the maintenance dose is 500 mg and is administered every 2 months. In certain embodiments, the maintenance dose is 550 mg and is administered every 2 months. In certain embodiments, the maintenance dose is 600 mg and is administered every 2 months. In certain embodiments, the maintenance dose is 650 mg and is administered every 2 months. In certain embodiments, the maintenance dose is 700 mg and is administered every 2 months. In certain embodiments, the maintenance dose is 720 mg and is administered every 2 months.In certain embodiments, the maintenance dose is 750 mg and is administered every 2 months. In certain embodiments, the maintenance dose is 800 mg and is administered every 2 months.

[0339] In certain embodiments, the maintenance dose is 150 mg, 180, 200 mg, 250 mg, 300 mg, 350 mg, 360 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 720 mg, 750 mg, or 800 mg and is administered every 8 weeks. In certain embodiments, the maintenance dose is 150 mg and is administered every 8 weeks. In certain embodiments, the maintenance dose is 180 mg and is administered every 8 weeks. In certain embodiments, the maintenance dose is 200 mg and is administered every 8 weeks. In certain embodiments, the maintenance dose is 250 mg and is administered every 8 weeks. In certain embodiments, the maintenance dose is 300 mg and is administered every 8 weeks. In certain embodiments, the maintenance dose is 350 mg and is administered every 8 weeks. In certain embodiments, the maintenance dose is 360 mg and is administered every 8 weeks. In certain embodiments, the maintenance dose is 400 mg and is administered every 8 weeks. In certain embodiments, the maintenance dose is 450 mg and is administered every 8 weeks. In certain embodiments, the maintenance dose is 500 mg and is administered every 8 weeks. In certain embodiments, the maintenance dose is 550 mg and is administered every 8 weeks. In certain embodiments, the maintenance dose is 600 mg and is administered every 8 weeks. In certain embodiments, the maintenance dose is 650 mg and is administered every 8 weeks. In certain embodiments, the maintenance dose is 700 mg and is administered every 8 weeks. In certain embodiments, the maintenance dose is 720 mg and is administered every 8 weeks. In certain embodiments, the maintenance dose is 750 mg and is administered every 8 weeks. In certain embodiments, the maintenance dose is 800 mg and is administered every 8 weeks.

[0340] In certain embodiments, the maintenance dose is 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 350 mg, 360 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 720 mg, 750 mg, or 800 mg and is administered every 16 weeks or three times a year. In certain embodiments, the maintenance dose is 150 mg and is administered every 16 weeks or three times a year. In certain embodiments, the maintenance dose is 180 mg and is administered every 16 weeks or three times a year. In certain embodiments, the maintenance dose is 200 mg and is administered every 16 weeks or three times a year. In certain embodiments, the maintenance dose is 250 mg and is administered every 16 weeks or three times a year. In certain embodiments, the maintenance dose is 300 mg and is administered every 16 weeks or three times a year. In certain embodiments, the maintenance dose is 350 mg and is administered every 16 weeks or three times a year. In certain embodiments, the maintenance dose is 360 mg and is administered every 16 weeks or three times a year. Incertain embodiments, the maintenance dose is 400 mg and is administered every 16 weeks or three times a year. In certain embodiments, the maintenance dose is 450 mg and is administered every 16 weeks or three times a year. In certain embodiments, the maintenance dose is 500 mg and is administered every 16 weeks or three times a year. In certain embodiments, the maintenance dose is 550 mg and is administered every 16 weeks or three times a year. In certain embodiments, the maintenance dose is 600 mg and is administered every 16 weeks or three times a year. In certain embodiments, the maintenance dose is 650 mg and is administered every 16 weeks or three times a year. In certain embodiments, the maintenance dose is 700 mg and is administered every 16 weeks or three times a year. In certain embodiments, the maintenance dose is 720 mg and is administered every 16 weeks or three times a year. In certain embodiments, the maintenance dose is 750 mg and is administered every 16 weeks or three times a year. In certain embodiments, the maintenance dose is 800 mg and is administered every 16 weeks or three times a year.

[0341] In certain embodiments, the maintenance dose is 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 350 mg, 360 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 720 mg, 750 mg, or 800 mg and is administered every 16 weeks. In certain embodiments, the maintenance dose is 150 mg and is administered every 16 weeks. In certain embodiments, the maintenance dose is 180 mg and is administered every 16 weeks. In certain embodiments, the maintenance dose is 200 mg and is administered every 16 weeks. In certain embodiments, the maintenance dose is 250 mg and is administered every 16 weeks. In certain embodiments, the maintenance dose is 300 mg and is administered every 16 weeks. In certain embodiments, the maintenance dose is 350 mg and is administered every 16 weeks. In certain embodiments, the maintenance dose is 360 mg and is administered every 16 weeks. In certain embodiments, the maintenance dose is 400 mg and is administered every 16 weeks. In certain embodiments, the maintenance dose is 450 mg and is administered every 16 weeks. In certain embodiments, the maintenance dose is 500 mg and is administered every 16 weeks. In certain embodiments, the maintenance dose is 550 mg and is administered every 16 weeks. In certain embodiments, the maintenance dose is 600 mg and is administered every 16 weeks. In certain embodiments, the maintenance dose is 650 mg and is administered every 16 weeks. In certain embodiments, the maintenance dose is 700 mg and is administered every 16 weeks. In certain embodiments, the maintenance dose is 720 mg and is administered every 16 weeks. In certain embodiments, the maintenance dose is 750 mg and is administered every 16 weeks. In certain embodiments, the maintenance dose is 800 mg and is administered every 16 weeks.

[0342] In certain embodiments, the maintenance dose is 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 350 mg, 360 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 720 mg, 750 mg, or 800 mg and is administered every three times a year. In certain embodiments, the maintenance dose is 150 mg and is administered every three times a year. In certain embodiments, the maintenance dose is 180 mg and is administered every three times a year. In certain embodiments, the maintenance dose is 200 mg and is administered every three times a year. In certain embodiments, the maintenance dose is 250 mg and is administered every three times a year. In certain embodiments, the maintenance dose is 300 mg and is administered every three times a year. In certain embodiments, the maintenance dose is 350 mg and is administered every three times a year. In certain embodiments, the maintenance dose is 360 mg and is administered every three times a year. In certain embodiments, the maintenance dose is 400 mg and is administered every three times a year. In certain embodiments, the maintenance dose is 450 mg and is administered every three times a year. In certain embodiments, the maintenance dose is 500 mg and is administered every three times a year. In certain embodiments, the maintenance dose is 550 mg and is administered every three times a year. In certain embodiments, the maintenance dose is 600 mg and is administered every three times a year. In certain embodiments, the maintenance dose is 650 mg and is administered every three times a year. In certain embodiments, the maintenance dose is 700 mg and is administered every three times a year. In certain embodiments, the maintenance dose is 720 mg and is administered every three times a year. In certain embodiments, the maintenance dose is 750 mg and is administered every three times a year. In certain embodiments, the maintenance dose is 800 mg and is administered every three times a year.

[0343] In certain embodiments, the maintenance dose is 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 350 mg, 360 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 720 mg, 750 mg, or 800 mg and is administered every 20 weeks. In certain embodiments, the maintenance dose is 150 mg and is administered every 20 weeks. In certain embodiments, the maintenance dose is 180 mg and is administered every 20 weeks. In certain embodiments, the maintenance dose is 200 mg and is administered every 20 weeks. In certain embodiments, the maintenance dose is 250 mg and is administered every 20 weeks. In certain embodiments, the maintenance dose is 300 mg and is administered every 20 weeks. In certain embodiments, the maintenance dose is 350 mg and is administered every 20 weeks. In certain embodiments, the maintenance dose is 360 mg and is administered every 20 weeks.In certain embodiments, the maintenance dose is 450 mg and is administered every 20 weeks. In certain embodiments, the maintenance dose is 500 mg and is administered every 20 weeks. In certain embodiments, the maintenance dose is 550 mg and is administered every 20 weeks. In certain embodiments, the maintenance dose is 600 mg and is administered every 20 weeks. In certain embodiments, the maintenance dose is 650 mg and is administered every 20 weeks. In certain embodiments, the maintenance dose is 700 mg and is administered every 20 weeks. In certain embodiments, the maintenance dose is 720 mg and is administered every 20 weeks. In certain embodiments, the maintenance dose is 750 mg and is administered every 20 weeks. In certain embodiments, the maintenance dose is 800 mg and is administered every 20 weeks.

[0344] In certain embodiments, the maintenance dose is 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 350 mg, 360 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 720 mg, 750 mg, or 800 mg and is administered every 6 months or twice a year. In certain embodiments, the maintenance dose is 150 mg and is administered every 6 months or twice a year. In certain embodiments, the maintenance dose is 180 mg and is administered every 6 months or twice a year. In certain embodiments, the maintenance dose is 200 mg and is administered every 6 months or twice a year. In certain embodiments, the maintenance dose is 250 mg and is administered every 6 months or twice a year. In certain embodiments, the maintenance dose is 300 mg and is administered every 6 months or twice a year. In certain embodiments, the maintenance dose is 350 mg and is administered every 6 months or twice a year. In certain embodiments, the maintenance dose is 360 mg and is administered every 6 months or twice a year. In certain embodiments, the maintenance dose is 400 mg and is administered every 6 months or twice a year. In certain embodiments, the maintenance dose is 450 mg and is administered every 6 months or twice a year. In certain embodiments, the maintenance dose is 500 mg and is administered every 6 months or twice a year. In certain embodiments, the maintenance dose is 550 mg and is administered every 6 months or twice a year. In certain embodiments, the maintenance dose is 600 mg and is administered every 6 months or twice a year. In certain embodiments, the maintenance dose is 650 mg and is administered every 6 months or twice a year. In certain embodiments, the maintenance dose is 700 mg and is administered every 6 months or twice a year. In certain embodiments, the maintenance dose is 720 mg and is administered every 6 months or twice a year. In certain embodiments, the maintenance dose is 750 mg and is administered every 6 months or twice a year. In certain embodiments, the maintenance dose is 800 mg and is administered every 6 months or twice a year.

[0345] In certain embodiments, the maintenance dose is 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 350 mg, 360 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 720 mg, 750 mg, or 800 mg and is administered every 6 months. In certain embodiments, the maintenance dose is 150 mg and is administered every 6 months. In certain embodiments, the maintenance dose is 180 mg and is administered every 6 months. In certain embodiments, the maintenance dose is 200 mg and is administered every 6 months. In certain embodiments, the maintenance dose is 250 mg and is administered every 6 months. In certain embodiments, the maintenance dose is 300 mg and is administered every 6 months. In certain embodiments, the maintenance dose is 350 mg and is administered every 6 months. In certain embodiments, the maintenance dose is 360 mg and is administered every 6 months. In certain embodiments, the maintenance dose is 400 mg and is administered every 6 months. In certain embodiments, the maintenance dose is 450 mg and is administered every 6 months. In certain embodiments, the maintenance dose is 500 mg and is administered every 6 months. In certain embodiments, the maintenance dose is 550 mg and is administered every 6 months. In certain embodiments, the maintenance dose is 600 mg and is administered every 6 months. In certain embodiments, the maintenance dose is 650 mg and is administered every 6 months. In certain embodiments, the maintenance dose is 700 mg and is administered every 6 months. In certain embodiments, the maintenance dose is 720 mg and is administered every 6 months. In certain embodiments, the maintenance dose is 750 mg and is administered every 6 months. In certain embodiments, the maintenance dose is 800 mg and is administered every 6 months.

[0346] In certain embodiments, the maintenance dose is 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 350 mg, 360 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 720 mg, 750 mg, or 800 mg and is administered twice a year. In certain embodiments, the maintenance dose is 150 mg and is administered twice a year. In certain embodiments, the maintenance dose is 180 mg and is administered twice a year. In certain embodiments, the maintenance dose is 200 mg and is administered twice a year. In certain embodiments, the maintenance dose is 250 mg and is administered twice a year. In certain embodiments, the maintenance dose is 300 mg and is administered twice a year. In certain embodiments, the maintenance dose is 350 mg and is administered twice a year. In certain embodiments, the maintenance dose is 360 mg and is administered twice a year. In certain embodiments, the maintenance dose is 400 mg and is administered twice a year. In certain embodiments, the maintenance dose is 450 mg and is administered twice a year. In certain embodiments, the maintenance dose is 500 mg and is administered twice a year. In certain embodiments, the maintenance dose is 550 mg and is administered twice a year. In certain embodiments, themaintenance dose is 600 mg and is administered twice a year. In certain embodiments, the maintenance dose is 650 mg and is administered twice a year. In certain embodiments, the maintenance dose is 700 mg and is administered twice a year. In certain embodiments, the maintenance dose is 720 mg and is administered twice a year. In certain embodiments, the maintenance dose is 750 mg and is administered twice a year. In certain embodiments, the maintenance dose is 800 mg and is administered twice a year.

[0347] In certain embodiments, the maintenance dose is 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 350 mg, 360 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 720 mg, 750 mg, or 800 mg and is administered once a year. In certain embodiments, the maintenance dose is 150 mg and is administered once a year. In certain embodiments, the maintenance dose is 180 mg and is administered once a year. In certain embodiments, the maintenance dose is 200 mg and is administered once a year. In certain embodiments, the maintenance dose is 250 mg and is administered once a year. In certain embodiments, the maintenance dose is 300 mg and is administered once a year. In certain embodiments, the maintenance dose is 350 mg and is administered once a year. In certain embodiments, the maintenance dose is 360 mg and is administered once a year. In certain embodiments, the maintenance dose is 400 mg and is administered once a year. In certain embodiments, the maintenance dose is 450 mg and is administered once a year. In certain embodiments, the maintenance dose is 500 mg and is administered once a year. In certain embodiments, the maintenance dose is 550 mg and is administered once a year. In certain embodiments, the maintenance dose is 600 mg and is administered once a year. In certain embodiments, the maintenance dose is 650 mg and is administered once a year. In certain embodiments, the maintenance dose is 700 mg and is administered once a year. In certain embodiments, the maintenance dose is 720 mg and is administered once a year. In certain embodiments, the maintenance dose is 750 mg and is administered once a year. In certain embodiments, the maintenance dose is 800 mg and is administered once a year.

[0348] In certain embodiments, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered every 3 months, every 12 weeks, or 4 times a year. In certain embodiments, the maintenance dose is 300 mg and is administered every 3 months, every 12 weeks, or 4 times a year. In certain embodiments, the maintenance dose is 300 mg and is administered every 3 months. In certain embodiments, the maintenance dose is 300 mg and is administered every 12 weeks. In certain embodiments, the maintenance dose is 300 mg and is administered 4 times a year.

[0349] In certain embodiments, the maintenance dose is 360 mg and is administered every 3 months, every 12 weeks, or 4 times a year. In certain embodiments, the maintenance dose is 360 mg and is administered every 3 months. In certain embodiments, the maintenance dose is 360 mg and is administered every 12 weeks. In certain embodiments, the maintenance dose is 360 mg and is administered 4 times a year.

[0350] In certain embodiments, the maintenance dose is 600 mg and is administered every 3 months, every 12 weeks, or 4 times a year. In certain embodiments, the maintenance dose is 600 mg and is administered every 3 months. In certain embodiments, the maintenance dose is 600 mg and is administered every 12 weeks. In certain embodiments, the maintenance dose is 600 mg and is administered 4 times a year.

[0351] In certain embodiments, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered every 2 months or every 8 weeks. In certain embodiments, the maintenance dose is 300 mg and is administered every 2 months or every 8 weeks. In certain embodiments, the maintenance dose is 300 mg and is administered every 2 months. In certain embodiments, the maintenance dose is 300 mg and is administered every 8 weeks.

[0352] In certain embodiments, the maintenance dose is 360 mg and is administered every 2 months or every 8 weeks. In certain embodiments, the maintenance dose is 360 mg and is administered every 2 months or every 8 weeks. In certain embodiments, the maintenance dose is 360 mg and is administered every 2 months. In certain embodiments, the maintenance dose is 360 mg and is administered every 8 weeks.

[0353] In certain embodiments, the maintenance dose is 600 mg and is administered every 2 months or every 8 weeks. In certain embodiments, the maintenance dose is 600 mg and is administered every 2 months. In certain embodiments, the maintenance dose is 600 mg and is administered every 8 weeks.

[0354] In certain embodiments, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered every 16 weeks or three times a year. In certain embodiments, the maintenance dose is 300 mg and is administered every 16 weeks or three times a year. In certain embodiments, the maintenance dose is 300 mg and is administered every 16 weeks In certain embodiments, the maintenance dose is 300 mg and is administered three times a year.

[0355] In certain embodiments, the maintenance dose is 360 mg and is administered every 16 weeks or three times a year. In certain embodiments, the maintenance dose is 360 mg and is administered every 16 weeks In certain embodiments, the maintenance dose is 360 mg and is administered three times a year.

[0356] In certain embodiments, the maintenance dose is 600 mg and is administered every 16 weeks or three times a year. In certain embodiments, the maintenance dose is 600 mg and is administered every 16 weeks In certain embodiments, the maintenance dose is 600 mg and is administered three times a year.

[0357] In certain embodiments, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered every 20 weeks. In certain embodiments, the maintenance dose is 300 mg and is administered every 20 weeks. In certain embodiments, the maintenance dose is 360 mg and is administered every 20 weeks. In certain embodiments, the maintenance dose is 600 mg and is administered every 20 weeks.

[0358] In certain embodiments, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered every 6 months or twice a year. In certain embodiments, the maintenance dose is 300 and is administered every 6 months or twice a year. In certain embodiments, the maintenance dose is 300 and is administered every 6 months. In certain embodiments, the maintenance dose is 300 and is administered every twice a year.

[0359] In certain embodiments, the maintenance dose is 360 and is administered every 6 months or twice a year. In certain embodiments, the maintenance dose is 360 and is administered every 6 months. In certain embodiments, the maintenance dose is 360 and is administered every twice a year.

[0360] In certain embodiments, the maintenance dose is 600 and is administered every 6 months or twice a year. In certain embodiments, the maintenance dose is 600 and is administered every 6 months. In certain embodiments, the maintenance dose is 600 and is administered every twice a year.

[0361] In certain embodiments, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered once a year. In certain embodiments, the maintenance dose is 300 mg and is administered once a year. In certain embodiments, the maintenance dose is 360 mg and is administered once a year. In certain embodiments, the maintenance dose is 600 mg and is administered once a year.

[0362] In certain aspects, the method comprises administering a loading dose prior to the one to four or more induction doses, wherein the loading dose is 2 times the induction dose.

[0363] In certain embodiments, the loading dose, which is 2 times the induction dose, is 200 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 300 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 360 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 400 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 500mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 600 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 700 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 720 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 800 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 900 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 1000 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 1100 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 1200 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 1300 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 1400 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 1500 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 1600 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 1700 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 1800 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 1900 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 2000 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 2100 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 2200 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 2300 mg. In certain embodiments, the loading dose, which is 2 times the induction dose, is 2400 mg.

[0364] In certain embodiments, a unit dose is administered as a composition comprising about 100 mg / mL to about 200 mg / mL of the anti-IL-13 antibody. In certain embodiments, a unit dose is administered as a composition comprising 100 mg / mL, 125 mg / mL, 150 mg / mL, 175 mg / mL, 180 mg / mL, or 200 mg / mL of the anti-IL-13 antibody. In certain embodiments, a unit dose is administered as a composition comprising 100 mg / mL of the anti-IL-13 antibody. In certain embodiments, a unit dose is administered as a composition comprising 125 mg / mL of the anti-IL-13 antibody. In certain embodiments, a unit dose is administered as a composition comprising 150 mg / mL of the anti-IL-13 antibody. In certain embodiments, a unit dose is administered as a composition comprising 175 mg / mL of the anti-IL-13 antibody. In certain embodiments, a unit dose is administered as a composition comprising 180 mg / mL of the anti-IL-13 antibody. In certain embodiments, a unit dose is administered as a composition comprising 200 mg / mL of the anti-IL-13 antibody.

[0365] In certain embodiments, the unit dose has an extractable volume of about 1 mL to about 3 mL. In certain embodiments, the unit dose has an extractable volume of about 1 mL, 1.25 mL, 1.5 mL, 1.75 mL, 2 mL, 2.25 mL, 2.5 mL, 2.7 mL, 2.75 mL, or 3 mL. In certain embodiments, the unit dose has an extractable volume of about 1 mL. In certain embodiments, the unit dose has an extractable volume of about 1.25 mL. In certain embodiments, the unit dose has an extractable volume of about 1.5 mL. In certain embodiments, the unit dose has an extractable volume of about 1.75 mL. In certain embodiments, the unit dose has an extractable volume of about 2 mL. In certain embodiments, the unit dose has an extractable volume of about 2.25 mL. In certain embodiments, the unit dose has an extractable volume of about 2.5 mL. In certain embodiments, the unit dose has an extractable volume of about 2.7 mL. In certain embodiments, the unit dose has an extractable volume of about 2.75 mL. In certain embodiments, the unit dose has an extractable volume of about 3 mL. As used herein, the “extractable volume” of the vial is the amount that can be withdrawn from the receptacle. The fill volume is greater than the extractable volume to ensure that the extractable volume can be obtained.

[0366] In an aspect, the present application provides a method of treating atopic dermatitis in a patient in need thereof, the method comprising: subcutaneously administering to the patient an anti-IL-13 antibody for an induction period of 4 to 16 weeks (e.g., 5 to 15, 6 to 14, 7 to 13, 8 to 12, 9 to 11, or 10), wherein, during the induction period, the anti-IL-13 antibody is administered once or twice at a loading dose of from about 150 mg to about 1200 mg (e.g., about 100 mg to about 1200 mg, 150 mg to about 1150 mg, 200 mg to about 1100 mg, 250 mg to about 1050 mg, 300 mg to about 1000 mg, 350 mg to about 950 mg, 400 mg to about 900 mg, 450 mg to about 850 mg, 500 mg to about 800 mg, 550 mg to about 750 mg, 600 mg to about 700 mg, or about 650 mg) and, optionally, at least once (e.g., once, twice, or thrice) at a dose that is at one-half (e.g., 50 mg, 62.5 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, or 600 mg) or one-quarter (e.g., 25 mg, 31.25 mg, 37.5 mg, 50 mg, 62.5 mg, 75 mg, 87.5 mg, 90 mg, 100 mg, 112.5 mg, 125 mg, 137.5 mg, 150 mg, 162.5 mg, 175 mg, 180 mg, 187.5 mg, 200 mg, 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg) of the loading dose; and subcutaneously administering to the patient the anti-IL-13 antibody at a dose of from about 100 mg to about 1200 mg (e.g., about 100 mg to about 1200 mg, 150 mg to about 1150 mg, 200 mg to about 1100 mg, 250 mg to about 1050 mg, 300 mg to about1000 mg, 350 mg to about 950 mg, 400 mg to about 900 mg, 450 mg to about 850 mg, 500 mg to about 800 mg, 550 mg to about 750 mg, 600 mg to about 700 mg, or about 650 mg) for a maintenance period; wherein the anti-IL-13 antibody comprises a VH comprising an amino acid sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to SEQ ID NO: 3 and a VL comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to SEQ ID NO: 39, wherein the VH comprises a HCDR1 comprising SEQ ID NO: 58, SEQ ID NO: 68, or SEQ ID NO: 85; a HCDR2 comprising SEQ ID NO: 100, SEQ ID NO: 104, or SEQ ID NO: 108; and a HCDR3 comprising SEQ ID NO: 112 or SEQ ID NO: 130; and the VL comprises a LCDR1 comprising SEQ ID NO: 141 or SEQ ID NO: 149; a LCDR2 comprising SEQ ID NO: 153 or SEQ ID NO: 164, and a LCDR3 comprising SEQ ID NO: 165.

[0367] In certain embodiments, the method comprises subcutaneously administering to the patient an anti-IL-13 antibody for an induction period of 4 to 16 weeks (e.g., 5 to 15, 6 to 14, 7 to 13, 8 to 12, 9 to 11, or 10). In certain embodiments, the method comprises subcutaneously administering to the patient an anti-IL-13 antibody for an induction period of 4 to 16 weeks. In certain embodiments, the method comprises subcutaneously administering to the patient an anti-IL-13 antibody for an induction period of 5 to 15 weeks. In certain embodiments, the method comprises subcutaneously administering to the patient an anti-IL- 13 antibody for an induction period of 6 to 14 weeks. In certain embodiments, the method comprises subcutaneously administering to the patient an anti-IL-13 antibody for an induction period of 7 to 13 weeks. In certain embodiments, the method comprises subcutaneously administering to the patient an anti-IL-13 antibody for an induction period of 8 to 12 weeks. In certain embodiments, the method comprises subcutaneously administering to the patient an anti-IL-13 antibody for an induction period of 9 to 11 weeks. In certain embodiments, the method comprises subcutaneously administering to the patient an anti-IL- 13 antibody for an induction period of 10 weeks.

[0368] In certain embodiments, the method comprises subcutaneously administering to the patient an anti-IL-13 antibody for an induction period of 4 weeks. In certain embodiments, the method comprises subcutaneously administering to the patient an anti-IL- 13 antibody for an induction period of 5 weeks. In certain embodiments, the method comprises subcutaneously administering to the patient an anti-IL-13 antibody for an induction period of 6 weeks. In certain embodiments, the method comprises subcutaneously administering to the patient an anti-IL-13 antibody for an induction period of 7 weeks. Incertain embodiments, the method comprises subcutaneously administering to the patient an anti-IL-13 antibody for an induction period of 8 weeks. In certain embodiments, the method comprises subcutaneously administering to the patient an anti-IL-13 antibody for an induction period of 9 weeks. In certain embodiments, the method comprises subcutaneously administering to the patient an anti-IL-13 antibody for an induction period of 10 weeks. In certain embodiments, the method comprises subcutaneously administering to the patient an anti-IL-13 antibody for an induction period of 11 weeks. In certain embodiments, the method comprises subcutaneously administering to the patient an anti-IL-13 antibody for an induction period of 12 weeks. In certain embodiments, the method comprises subcutaneously administering to the patient an anti-IL-13 antibody for an induction period of 13 weeks. In certain embodiments, the method comprises subcutaneously administering to the patient an anti-IL-13 antibody for an induction period of 14 weeks. In certain embodiments, the method comprises subcutaneously administering to the patient an anti-IL-13 antibody for an induction period of 15 weeks. In certain embodiments, the method comprises subcutaneously administering to the patient an anti-IL-13 antibody for an induction period of 16 weeks.

[0369] In certain embodiments, the method comprises an induction period, wherein the anti-IL-13 antibody is administered once or twice at a loading dose of from about 150 mg to about 1200 mg (e.g., about 100 mg to about 1200 mg, 150 mg to about 1150 mg, 200 mg to about 1100 mg, 250 mg to about 1050 mg, 300 mg to about 1000 mg, 350 mg to about 950 mg, 400 mg to about 900 mg, 450 mg to about 850 mg, 500 mg to about 800 mg, 550 mg to about 750 mg, 600 mg to about 700 mg, or about 650 mg). In certain embodiments, the anti- IL-13 antibody is administered once or twice at a loading dose of from about 100 mg to about 1200 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of from about 150 mg to about 1150 mg. In certain embodiments, the anti-IL- 13 antibody is administered once or twice at a loading dose of from about 200 mg to about 1100 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of from about 250 mg to about 1050 mg. In certain embodiments, the anti-IL- 13 antibody is administered once or twice at a loading dose of from about 300 mg to about 1000 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of from about 350 mg to about 950 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of from about 400 mg to about 900 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of from about 450 mg to about 850 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of from about 500 mg to about 800mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of from about 550 mg to about 750 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of from about 600 mg to about 700 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 650 mg.

[0370] In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 100 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 125 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 150 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 180 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 200 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 250 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 300 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 350 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 360 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 400 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 450 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 500 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 550 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 600 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 650 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 700 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 720 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 750 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 800 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 850 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 900 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 950 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 1000 mg. Incertain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 1050 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 1100 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 1150 mg. In certain embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 1200 mg.

[0371] In certain embodiments, the method comprises administering at least once (e.g., once, twice, or thrice) at a dose that is at one-half (e.g., 50 mg, 62.5 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, or 600 mg) of the loading dose. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 50 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 62.5 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 75 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 100 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 125 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 150 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 175 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 180 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 200 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 225 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 250 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 275 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 300 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 325 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 350 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 360 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 375 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 400 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 425 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 450 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 475 mg. In certain embodiments, adose that is at one-half of the loading dose comprises a dose of about 500 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 525 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 550 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 575 mg. In certain embodiments, a dose that is at one-half of the loading dose comprises a dose of about 600 mg.

[0372] In certain embodiments, the method comprises administering at least once (e.g., once, twice, or thrice) at a dose that is at one-quarter (e.g., 25 mg, 31.25 mg, 37.5 mg, 50 mg, 62.5 mg, 75 mg, 87.5 mg, 90 mg, 100 mg, 112.5 mg, 125 mg, 137.5 mg, 150 mg, 162.5 mg, 175 mg, 180 mg, 187.5 mg, 200 mg, 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg) of the loading dose. In certain embodiments, a dose that is at one- quarter of the loading dose comprises a dose of about 25 mg. In certain embodiments, a dose that is at one-quarter of the loading dose comprises a dose of about 31.25 mg. In certain embodiments, a dose that is at one-quarter of the loading dose comprises a dose of about 37.5 mg. In certain embodiments, a dose that is at one-quarter of the loading dose comprises a dose of about 50 mg. In certain embodiments, a dose that is at one-quarter of the loading dose comprises a dose of about 62.5 mg. In certain embodiments, a dose that is at one- quarter of the loading dose comprises a dose of about 75 mg. In certain embodiments, a dose that is at one-quarter of the loading dose comprises a dose of about 87.5 mg. In certain embodiments, a dose that is at one-quarter of the loading dose comprises a dose of about 90 mg. In certain embodiments, a dose that is at one-quarter of the loading dose comprises a dose of about 100 mg. In certain embodiments, a dose that is at one-quarter of the loading dose comprises a dose of about 112.5 mg. In certain embodiments, a dose that is at one- quarter of the loading dose comprises a dose of about 125 mg. In certain embodiments, a dose that is at one-quarter of the loading dose comprises a dose of about 137.5 mg. In certain embodiments, a dose that is at one-quarter of the loading dose comprises a dose of about 150 mg. In certain embodiments, a dose that is at one-quarter of the loading dose comprises a dose of about 162.5 mg. In certain embodiments, a dose that is at one-quarter of the loading dose comprises a dose of about 175 mg. In certain embodiments, a dose that is at one-quarter of the loading dose comprises a dose of about 180 mg. In certain embodiments, a dose that is at one-quarter of the loading dose comprises a dose of about 187.5 mg. In certain embodiments, a dose that is at one-quarter of the loading dose comprises a dose of about 200 mg. In certain embodiments, a dose that is at one-quarter of the loading dose comprises a dose of about 212.5 mg. In certain embodiments, a dose that is at one-quarter of the loadingdose comprises a dose of about 225 mg. In certain embodiments, a dose that is at one-quarter of the loading dose comprises a dose of about 237.5 mg. In certain embodiments, a dose that is at one-quarter of the loading dose comprises a dose of about 250 mg. In certain embodiments, a dose that is at one-quarter of the loading dose comprises a dose of about 262.5 mg. In certain embodiments, a dose that is at one-quarter of the loading dose comprises a dose of about 275 mg. In certain embodiments, a dose that is at one-quarter of the loading dose comprises a dose of about 287.5 mg. In certain embodiments, a dose that is at one-quarter of the loading dose comprises a dose of about or 300 mg.

[0373] In certain embodiments, the method comprises subcutaneously administering to the patient the anti-IL-13 antibody at a dose of from about 100 mg to about 1200 mg (e.g., about 100 mg to about 1200 mg, 150 mg to about 1150 mg, 200 mg to about 1100 mg, 250 mg to about 1050 mg, 300 mg to about 1000 mg, 350 mg to about 950 mg, 400 mg to about 900 mg, 450 mg to about 850 mg, 500 mg to about 800 mg, 550 mg to about 750 mg, 600 mg to about 700 mg, or about 650 mg) for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of from about 150 mg to about 1150 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of from about 200 mg to about 1100 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of from about 250 mg to about 1050 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of from about 300 mg to about 1000 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of from about 350 mg to about 950 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of from about 400 mg to about 900 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of from about 450 mg to about 850 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of from about 500 mg to about 800 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of from about 550 mg to about 750 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of from about 600 mg to about 700 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 650 mg for a maintenance period.

[0374] In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 100 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 150 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 180 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 200 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 250 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 300 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 350 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 360 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 400 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 450 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 500 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 550 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 600 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 650 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 700 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 720 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 750 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 800 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 850 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 900 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 950 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 1000 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 1050mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 1100 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 1150 mg for a maintenance period. In certain embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 1200 mg for a maintenance period.

[0375] In certain embodiments, the loading dose is about 100 mg. In certain embodiments, the loading dose is about 125 mg. In certain embodiments, the loading dose is about 150 mg. In certain embodiments, the loading dose is about 180 mg. In certain embodiments, the loading dose is about 200 mg. In certain embodiments, the loading dose is about 250 mg. In certain embodiments, the loading dose is about 300 mg. In certain embodiments, the loading dose is about 350 mg. In certain embodiments, the loading dose is about 360 mg. In certain embodiments, the loading dose is about 400 mg. In certain embodiments, the loading dose is about 450 mg. In certain embodiments, the loading dose is about 500 mg. In certain embodiments, the loading dose is about 550 mg. In certain embodiments, the loading dose is about 600 mg. In certain embodiments, the loading dose is about 650 mg. In certain embodiments, the loading dose is about 700 mg. In certain embodiments, the loading dose is about 720 mg. In certain embodiments, the loading dose is about 750 mg. In certain embodiments, the loading dose is about 800 mg. In certain embodiments, the loading dose is about 850 mg. In certain embodiments, the loading dose is about 900 mg. In certain embodiments, the loading dose is about 950 mg. In certain embodiments, the loading dose is about 1000 mg. In certain embodiments, the loading dose is about 1050 mg. In certain embodiments, the loading dose is about 1100 mg. In certain embodiments, the loading dose is about 1150 mg. In certain embodiments, the loading dose is about 1200 mg.

[0376] In certain embodiments, during the induction period, the loading dose (e.g., about 100 mg to about 1200 mg, 150 mg to about 1150 mg, 200 mg to about 1100 mg, 250 mg to about 1050 mg, 300 mg to about 1000 mg, 350 mg to about 950 mg, 400 mg to about 900 mg, 450 mg to about 850 mg, 500 mg to about 800 mg, 550 mg to about 750 mg, 600 mg to about 700 mg, or about 650 mg) is administered at week 0 and week 2.

[0377] In certain embodiments, during the induction period, the loading dose (e.g., about 100 mg to about 1200 mg, 150 mg to about 1150 mg, 200 mg to about 1100 mg, 250 mg to about 1050 mg, 300 mg to about 1000 mg, 350 mg to about 950 mg, 400 mg to about 900 mg, 450 mg to about 850 mg, 500 mg to about 800 mg, 550 mg to about 750 mg, 600 mg to about 700 mg, or about 650 mg) is administered at week 0 and week 4.

[0378] In certain embodiments, during the induction period, the loading dose (e.g., about 100 mg to about 1200 mg, 150 mg to about 1150 mg, 200 mg to about 1100 mg, 250 mg to about 1050 mg, 300 mg to about 1000 mg, 350 mg to about 950 mg, 400 mg to about 900 mg, 450 mg to about 850 mg, 500 mg to about 800 mg, 550 mg to about 750 mg, 600 mg to about 700 mg, or about 650 mg) is administered at week 0 and week 8.

[0379] In certain embodiments, during the induction period, the loading dose (e.g., about 100 mg to about 1200 mg, 150 mg to about 1150 mg, 200 mg to about 1100 mg, 250 mg to about 1050 mg, 300 mg to about 1000 mg, 350 mg to about 950 mg, 400 mg to about 900 mg, 450 mg to about 850 mg, 500 mg to about 800 mg, 550 mg to about 750 mg, 600 mg to about 700 mg, or about 650 mg) is administered at week 0 and week 12.

[0380] In certain embodiments, during the induction period, the one-half (e.g., 50 mg, 62.5 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, or 600 mg) or one-quarter (e.g., 25 mg, 31.25 mg, 37.5 mg, 50 mg, 62.5 mg, 75 mg, 87.5 mg, 90 mg, 100 mg, 112.5 mg, 125 mg, 137.5 mg, 150 mg, 162.5 mg, 175 mg, 180 mg, 187.5 mg, 200 mg, 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg) dose is administered at weeks 8, 12, and 16. In certain embodiments, during the induction period, the one-half dose is administered at weeks 8, 12, and 16. In certain embodiments, during the induction period, the one-quarter dose is administered at weeks 8, 12, and 16.

[0381] In certain embodiments, during the induction period, the one-half (e.g., 50 mg, 62.5 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, or 600 mg) or one-quarter (e.g., 25 mg, 31.25 mg, 37.5 mg, 50 mg, 62.5 mg, 75 mg, 87.5 mg, 90 mg, 100 mg, 112.5 mg, 125 mg, 137.5 mg, 150 mg, 162.5 mg, 175 mg, 180 mg, 187.5 mg, 200 mg, 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg) dose is administered at weeks 4, 8, 12, and 16. In certain embodiments, during the induction period, the one-half dose is administered at weeks 4, 8, 12, and 16. In certain embodiments, during the induction period, the one-quarter dose is administered at weeks 4, 8, 12, and 16.

[0382] In certain embodiments, during the induction period, the one-half (e.g., 50 mg, 62.5 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, or 600 mg) or one-quarter (e.g., 25 mg, 31.25 mg, 37.5 mg, 50 mg,62.5 mg, 75 mg, 87.5 mg, 90 mg, 100 mg, 112.5 mg, 125 mg, 137.5 mg, 150 mg, 162.5 mg, 175 mg, 180 mg, 187.5 mg, 200 mg, 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg) dose is administered at weeks 4 and 12. In certain embodiments, during the induction period, the one-half dose is administered at weeks 4 and 12. In certain embodiments, during the induction period, the one-quarter dose is administered at weeks 4 and 12.

[0383] In certain embodiments, during the induction period, the one-half (e.g., 50 mg, 62.5 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, or 600 mg) or one-quarter (e.g., 25 mg, 31.25 mg, 37.5 mg, 50 mg, 62.5 mg, 75 mg, 87.5 mg, 90 mg, 100 mg, 112.5 mg, 125 mg, 137.5 mg, 150 mg, 162.5 mg, 175 mg, 180 mg, 187.5 mg, 200 mg, 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg) dose is administered at weeks 2, 4, and 12. In certain embodiments, during the induction period, the one-half dose is administered at weeks 2, 4, and 12. In certain embodiments, during the induction period, the one-quarter dose is administered at weeks 2, 4, and 12.

[0384] In certain embodiments, during the induction period, the one-half (e.g., 50 mg, 62.5 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, or 600 mg) or one-quarter (e.g., 25 mg, 31.25 mg, 37.5 mg, 50 mg, 62.5 mg, 75 mg, 87.5 mg, 90 mg, 100 mg, 112.5 mg, 125 mg, 137.5 mg, 150 mg, 162.5 mg, 175 mg, 180 mg, 187.5 mg, 200 mg, 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg) dose is administered at weeks 2 and 12. In certain embodiments, during the induction period, the one-half dose is administered at weeks 2 and 12. In certain embodiments, during the induction period, the one-quarter dose is administered at weeks 2 and 12.

[0385] In certain embodiments, during the induction period, the one-half (e.g., 50 mg, 62.5 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, or 600 mg) or one-quarter (e.g., 25 mg, 31.25 mg, 37.5 mg, 50 mg, 62.5 mg, 75 mg, 87.5 mg, 90 mg, 100 mg, 112.5 mg, 125 mg, 137.5 mg, 150 mg, 162.5 mg, 175 mg, 180 mg, 187.5 mg, 200 mg, 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg) dose is administered at week 12. In certain embodiments, duringthe induction period, the one-half dose is administered at week 12. In certain embodiments, during the induction period, the one-quarter dose is administered at week 12.

[0386] In certain embodiments, during the induction period, the one-half (e.g., 50 mg, 62.5 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, or 600 mg) or one-quarter (e.g., 25 mg, 31.25 mg, 37.5 mg, 50 mg, 62.5 mg, 75 mg, 87.5 mg, 90 mg, 100 mg, 112.5 mg, 125 mg, 137.5 mg, 150 mg, 162.5 mg, 175 mg, 180 mg, 187.5 mg, 200 mg, 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg) dose is administered at weeks 8 and 16. In certain embodiments, during the induction period, the one-half dose is administered at weeks 8 and 16. In certain embodiments, during the induction period, the one-quarter dose is administered at weeks 8 and 16.

[0387] In certain embodiments, during the induction period, the one-half (e.g., 50 mg, 62.5 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, or 600 mg) or one-quarter (e.g., 25 mg, 31.25 mg, 37.5 mg, 50 mg, 62.5 mg, 75 mg, 87.5 mg, 90 mg, 100 mg, 112.5 mg, 125 mg, 137.5 mg, 150 mg, 162.5 mg, 175 mg, 180 mg, 187.5 mg, 200 mg, 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg) dose is administered at week 16. In certain embodiments, during the induction period, the one-half dose is administered at week 16. In certain embodiments, during the induction period, the one-quarter dose is administered at week 16.

[0388] In certain embodiments, during the induction period, the one-half (e.g., 50 mg, 62.5 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, or 600 mg) or one-quarter (e.g., 25 mg, 31.25 mg, 37.5 mg, 50 mg, 62.5 mg, 75 mg, 87.5 mg, 90 mg, 100 mg, 112.5 mg, 125 mg, 137.5 mg, 150 mg, 162.5 mg, 175 mg, 180 mg, 187.5 mg, 200 mg, 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg) dose is administered at weeks 4 and 14. In certain embodiments, during the induction period, the one-half dose is administered at weeks 4 and 14. In certain embodiments, during the induction period, the one-quarter dose is administered at weeks 4 and 14.

[0389] In certain embodiments, during the induction period, the one-half (e.g., 50 mg, 62.5 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg,525 mg, 550 mg, 575 mg, or 600 mg) or one-quarter (e.g., 25 mg, 31.25 mg, 37.5 mg, 50 mg, 62.5 mg, 75 mg, 87.5 mg, 90 mg, 100 mg, 112.5 mg, 125 mg, 137.5 mg, 150 mg, 162.5 mg, 175 mg, 180 mg, 187.5 mg, 200 mg, 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg) dose is administered at week 14. In certain embodiments, during the induction period, the one-half dose is administered at week 14. In certain embodiments, during the induction period, the one-quarter dose is administered at week 14.

[0390] In certain embodiments, during the induction period, the one-half (e.g., 50 mg, 62.5 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, or 600 mg) or one-quarter (e.g., 25 mg, 31.25 mg, 37.5 mg, 50 mg, 62.5 mg, 75 mg, 87.5 mg, 90 mg, 100 mg, 112.5 mg, 125 mg, 137.5 mg, 150 mg, 162.5 mg, 175 mg, 180 mg, 187.5 mg, 200 mg, 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg) dose is administered at weeks 2, 4, and 14. In certain embodiments, during the induction period, the one-half dose is administered at weeks 2, 4, and 14. In certain embodiments, during the induction period, the one-quarter dose is administered at weeks 2, 4, and 14.

[0391] In certain embodiments, the maintenance dose is 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 360 mg, 400 mg, 450 mg, 600 mg, 800 mg, or 900 mg. In certain embodiments, the maintenance dose is 100 mg. In certain embodiments, the maintenance dose is 150 mg. In certain embodiments, the maintenance dose is 180 mg. In certain embodiments, the maintenance dose is 200 mg. In certain embodiments, the maintenance dose is 250 mg. In certain embodiments, the maintenance dose is 300 mg. In certain embodiments, the maintenance dose is 360 mg. In certain embodiments, the maintenance dose is 400 mg. In certain embodiments, the maintenance dose is 450 mg. In certain embodiments, the maintenance dose is 600 mg. In certain embodiments, the maintenance dose is 720 mg. In certain embodiments, the maintenance dose is 800 mg. In certain embodiments, the maintenance dose is 900 mg.

[0392] In certain embodiments, during the maintenance period (e.g., the maintenance dose is 100 mg, 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 360 mg, 400 mg, 450 mg, 600 mg, 720 mg, 800 mg, 900 mg, 1080 mg, or 1200 mg), the anti-IL-13 antibody is administered every 12 weeks or 4 times a year. In certain embodiments, during the maintenance period, the anti-IL-13 antibody is administered every 12 weeks. In certain embodiments, during the maintenance period, the anti-IL-13 antibody is administered 4 times a year.

[0393] In certain embodiments, during the maintenance period (e.g., the maintenance dose is 100 mg, 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 360 mg, 400 mg, 450 mg, 600 mg, 720 mg, 800 mg, 900 mg, 1080 mg, or 1200 mg), the anti-IL-13 antibody is administered every 2 months or 8 weeks. In certain embodiments, during the maintenance period, the anti- IL-13 antibody is administered every 2 months. In certain embodiments, during the maintenance period, the anti-IL-13 antibody is administered every 8 weeks.

[0394] In certain embodiments, during the maintenance period (e.g., the maintenance dose is 100 mg, 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 360 mg, 400 mg, 450 mg, 600 mg, 720 mg, 800 mg, 900 mg, 1080 mg, or 1200 mg), the anti-IL-13 antibody is administered every 16 weeks or three times a year. In certain embodiments, during the maintenance period, the anti-IL-13 antibody is administered every 16 weeks. In certain embodiments, during the maintenance period, the anti-IL-13 antibody is administered three times a year.

[0395] In certain embodiments, during the maintenance period (e.g., the maintenance dose is 100 mg, 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 360 mg, 400 mg, 450 mg, 600 mg, 720 mg, 800 mg, 900 mg, 1080 mg, or 1200 mg), the anti-IL-13 antibody is administered every 20 weeks.

[0396] In certain embodiments, during the maintenance period (e.g., the maintenance dose is 100 mg, 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 360 mg, 400 mg, 450 mg, 600 mg, 720 mg, 800 mg, 900 mg, 1080 mg, or 1200 mg), the anti-IL-13 antibody is administered every 6 months or twice a year. In certain embodiments, during the maintenance period, the anti-IL-13 antibody is administered every 6 months. In certain embodiments, during the maintenance period, the anti-IL-13 antibody is administered twice a year.

[0397] In certain embodiments, during the maintenance period (e.g., the maintenance dose is 100 mg, 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 360 mg, 400 mg, 450 mg, 600 mg, 720 mg, 800 mg, 900 mg, 1080 mg, or 1200 mg), the anti-IL-13 antibody is administered once a year.

[0398] Exemplary dosing regimes (e.g., induction and maintenance) described herein include any and all regimes provided in Tables 11-14, below. Table 11. Exemplary Induction Dosing Regimes # Regimen Wk 0 Wk 2 Wk 4 Wk 6 Wk 8 Wk Wk Wk WkTable 12. Exemplary Induction Dosing RegimesD W N Re Re Re Re Re Re Re Re Re Re Re Re Re Re Re Re Re Re ReR R R R R R R R R R R R R *Att D kt N AOE002WO I m c N R M R M R M R R R R R R R R R A *Attorney Docket No. AOE-002WO ** To be used in combination with any one of Regimen IA-IH in Table 13. 228

[0399] In an aspect, the present application provides a method of treating atopic dermatitis in a patient in need thereof, the method comprising subcutaneously administering to the patient: a) two loading doses of 720 mg of an anti-IL-13 antibody prior to two induction doses; b) two induction doses of 360 mg of the anti-IL-13 antibody; and c) one or more maintenance doses of 360 mg of the anti-IL-13 antibody administered starting at about 12 weeks or more after the first induction dose; and wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid set forth in SEQ ID NO: 3 and a light chain variable region (VL) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid set forth in SEQ ID NO: 39.

[0400] In certain embodiments, the second loading dose is administered about 2 weeks after the first loading dose.

[0401] In certain embodiments, the first induction dose is administered about 2 weeks after the second loading dose.

[0402] In certain embodiments, the second induction dose is administered about 8 weeks after the first induction dose.

[0403] In certain embodiments, the maintenance dose is administered every 3 months.

[0404] In certain embodiments, the maintenance dose is administered every 6 months.

[0405] In certain embodiments, the composition is a unit dose with an extractable volume of 2 mL, 2.25 mL, or 2.7 mL. In certain embodiments, the composition is a unit dose with an extractable volume of 2 mL. In certain embodiments, the composition is a unit dose with an extractable volume of 2.25 mL. In certain embodiments, the composition is a unit dose with an extractable volume of 2.7 mL.

[0406] In certain embodiments, the composition is a unit dose with an extractable volume of 2 mL.

[0407] In certain embodiments, a dose described herein is adjusted by weight, age, and / or body surface area.

[0408] In an aspect, the present application provides a method of treating atopic dermatitis in a patient in need thereof, the method comprising subcutaneously administering to the patient: a) one loading dose of 720 mg of an anti-IL-13 antibody prior to two induction doses; b) two induction doses of 360 mg of the anti-IL-13 antibody; and c) one or more maintenance doses of 360 mg of the anti-IL-13 antibody administered starting at about 12 weeks or more after the first induction dose; andwherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid set forth in SEQ ID NO: 3 and a light chain variable region (VL) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid set forth in SEQ ID NO: 39.

[0409] In certain embodiments, the first induction dose is administered about 4 weeks after the loading dose.

[0410] In certain embodiments, the second induction dose is administered about 8 weeks after the first induction dose.

[0411] In certain embodiments, the maintenance dose is administered every 3 months.

[0412] In certain embodiments, the maintenance dose is administered every 6 months.

[0413] In certain embodiments, the composition is a unit dose with an extractable volume of 2 mL, 2.25 mL, or 2.7 mL. In certain embodiments, the composition is a unit dose with an extractable volume of 2 mL. In certain embodiments, the composition is a unit dose with an extractable volume of 2.25 mL. In certain embodiments, the composition is a unit dose with an extractable volume of 2.7 mL.

[0414] In certain embodiments, the composition is a unit dose with an extractable volume of 2 mL.

[0415] In certain embodiments, a dose described herein is adjusted by weight, age, and / or body surface area.

[0416] In an aspect, the present application provides a method of treating atopic dermatitis in a patient in need thereof, the method comprising subcutaneously administering to the patient: a) one loading dose of 360 mg of an anti-IL-13 antibody prior to two induction doses; b) two induction doses of 180 mg of the anti-IL-13 antibody; and c) one or more maintenance doses of 180 mg of the anti-IL-13 antibody administered starting at about 12 weeks or more after the first induction dose; and wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid set forth in SEQ ID NO: 3 and a light chain variable region (VL) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid set forth in SEQ ID NO: 39.

[0417] In certain embodiments, the first induction dose is administered about 4 weeks after the loading dose.

[0418] In certain embodiments, the second induction dose is administered about 8 weeks after the first induction dose.

[0419] In certain embodiments, the maintenance dose is administered every 3 months.

[0420] In certain embodiments, the maintenance dose is administered every 6 months.

[0421] In certain embodiments, the composition is a unit dose with an extractable volume of 2 mL, 2.25 mL, or 2.7 mL. In certain embodiments, the composition is a unit dose with an extractable volume of 2 mL. In certain embodiments, the composition is a unit dose with an extractable volume of 2.25 mL. In certain embodiments, the composition is a unit dose with an extractable volume of 2.7 mL.

[0422] In certain embodiments, the composition is a unit dose with an extractable volume of 2 mL.

[0423] In certain embodiments, a dose described herein is adjusted by weight, age, and / or body surface area. Methods of Administration

[0424] In certain embodiments, the methods provided herein are useful for the treatment of a disease or disorder in an individual. In an embodiment, the individual is a human and the antibody is an anti-IL-13 antibody described herein.

[0425] In certain embodiments, the anti-IL-13 antibody is administered by autoinjector or a prefilled syringe.

[0426] In certain embodiments, provided herein is an autoinjector configured to deliver a composition comprising 100 mg / mL, 125 mg / mL, 150 mg / mL, 175 mg / mL, 180 mg / mL, 200 mg / mL, 225 mg / mL, 250 mg / mL or 300 mg / mL of an anti-IL-13 antibody, wherein the anti-IL- 13 antibody comprises a VH comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid set forth in SEQ ID NO: 3 and a VL comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid set forth in SEQ ID NO: 39.

[0427] In certain embodiments, 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-13 antibody may be administered for the treatment of a disease or disorder. The appropriate dosage of the anti-IL-13 antibody may be determined based on the type of disease or disorder to be treated, the type of the anti-IL-13 antibody, the severity andcourse 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.

[0428] In certain 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-13 and / or IgE.

[0429] The additional therapeutic agent can be administered by any suitable means. In certain embodiments, an antibody provided herein and the additional therapeutic agent are included in the same pharmaceutical composition. In certain embodiments, an antibody provided herein and the additional therapeutic agent are included in different pharmaceutical compositions.

[0430] In embodiments where 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. In certain embodiments, administration of an antibody provided herein and the additional therapeutic agent occur within about one month of each other. In certain embodiments, administration of an antibody provided herein and the additional therapeutic agent occur within about one week of each other. In certain embodiments, administration of an antibody provided herein and the additional therapeutic agent occur within about one day of each other. In certain embodiments, administration of an antibody provided herein and the additional therapeutic agent occur within about twelve hours of each other. In certain 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

[0431] The present application provides kits comprising any one or more of the antibody compositions described herein and instructions for use. In certain embodiments, the kits further contain a component selected from any of secondary antibodies, reagents for immunohistochemistry analysis, pharmaceutically acceptable excipient and instruction manual and any combination thereof. In one specific embodiment, the kit comprises a pharmaceutical composition comprising any one or more of the antibody compositions described herein, with one or more pharmaceutically acceptable excipients.

[0432] 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). Examples

[0433] Below are examples of specific embodiments for carrying out the present invention. The examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should, of course, be allowed for.

[0434] The practice of the present invention will employ, unless otherwise indicated, conventional methods of protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. See, e.g., T.E. Creighton, Proteins: Structures and Molecular Properties (W.H. Freeman and Company, 1993); A.L. Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Sambrook, et al., Molecular Cloning: A Laboratory Manual (2nd Edition, 1989); Methods In Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.); Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry 3rdEd. (Plenum Press) Vols A and B (1992). Example 1: Engineered anti-IL-13 Antibodies Exhibit Enhanced Binding to Human FcRn and Ablated Binding to Fc-receptors and C1q Materials and Methods Determination of Antibody Affinity to Fc Receptors and C1q

[0435] Binding affinity (KD) of antibodies to Fc receptors and C1q were determined through surface plasmon resonance (SPR) using a Biacore 8K and ELISA, respectively. Briefly, an SPR chip functionalized with an anti-kappa light-chain antibody was used to capture purified antibodies normalized to 5 mg / mL, at a flow rate of 10 uL / min for 90 seconds or 120 seconds. A paired channel with only buffer was used as reference. Subsequently, varying concentrations of recombinant human FcRn, FcγRI, FcγRIIa (H131), FcγRIIa (R131), FcγRIIb, FcγRIIIa (F158), FcγRIIIa (V158), and C1q were injected over the surface with captured purified antibody as well as the reference channel. Regeneration of the chip between different concentrations of different antigens were performed with 10 mM Glycine HCl, pH 1.5 andantibody was again captured. Association and dissociation rate constants were subsequently determined through fitting to a 1:1 Langmuir binding model or steady-state analysis model, whichever applicable, using the Biacore Insight Evaluation Software from which a KD value was derived. Results Antibody Affinity to Fc Receptors and C1q

[0436] Construct 133 was also compared to an IgG1 positive control, and demonstrated YTE-dependent increase in FcRn binding and a LALA-dependent ablation of Fc-dependent binding (Table 15). The enhanced binding to human FcRn and ablated binding to Fc-receptors and C1q confirmed the function of the YTE and LALA amino acid substitutions, respectively. Table 15. Antibody Affinity to Fc Receptors and C1q Ligand Construct 133 KD(M) IgG1 positive control KD(M) F R 44 1-812 1-6)Example 2: An Engineered Anti-IL13 Antibody Variant Demonstrated Significantly Extended Half-life and pSTAT6 Inhibition in NHPs

[0437] To demonstrate the potential of engineered anti-IL13 antibody variants to improve dosing over current and anticipated standard of care mAbs in AD, among other diseases, Construct 133 (see Construct 133 sequences in Tables 2-8), comprising SEQ ID NOs: 3, 39, 439 and 469, was studied in female non-human primates (NHPs) following a single bolus dose of 3 mg / kg, given either IV or SQ. Additionally, a variant clone of Construct 133 with a different FcRN-related half-life extending Fc modification, LS, (“Construct 133-LS”) was assessed. Blood samples were collected serially starting with a sample pre-dose and subsequently at 0.167, 1, 4, 8, 24, 48, 96, 168, 336, 504, 674, 840, 1334, 1680 and 2160 hours post-dose. PK parameters of maximum observed serum concentration (Cmax), time to maximum observed serum concentration (Tmax), area under the serum concentration versus time curvefrom time 0 extrapolated to infinity (AUC0-inf), clearance (CL), volume of distribution at steady- state (Vss), half-life (T1 / 2) and absolute subcutaneous bioavailability (F) were calculated (Table 16). Data was analyzed to show mean serum concentration with standard deviation over time and a regression fit was performed.

[0438] Inhibition of pSTAT6 in whole blood isolated from NHPs dosed SC with Construct 133-LS was assessed ex vivo. Table 16. Pharmacokinetics of Construct 133 and Lebrikizumab Following a Single Bolus IV or SQ Dose in Cynomolgus Monkeys** Both CL and VSS of SQ administration were dose-normalized using the subcutaneous bioavailability (F) indicated in Table 20. *** F (%) was calculated by dividing the mean dose-normalized AUC0-inf following subcutaneous administration by the mean dose-normalized AUC0-inf following IV administration.

[0439] In our head-to-head studies of Construct 133 and lebrikizumab in NHPs, both IV and SQ formulations of Construct 133 showed a significantly longer half-life than lebrikizumab. In these studies, the average half-life of Construct 133 was 27.6 days, as compared to 17 to 18 days for lebrikizumab, as shown in Figure 2. Further, Construct 133 exhibited an average clearance rate of 1.45 (mL day-1kg-1) in NHPs. The steady-state volume of distribution was observed to be 55.65 (mL kg-1). Construct 133 was well-absorbed, with subcutaneousbioavailability determined to be 81.22%. Lebrikizumab exhibited an average clearance rate of 2.93 (mL day-1kg-1) in NHPs. The steady-state volume of distribution was observed to be 52.10 (mL kg-1). Lebrikizumab was well-absorbed, with subcutaneous bioavailability determined to be 75.70%. Specifically, the t1 / 2of lebrikizumab was 18.0 days, CL was 2.93 mL day-1kg-1, Vss was 52.10 mL kg-1, and F was 75.70%.

[0440] Serum concentration >5 µg / mL of Construct 133-LS or lebrikizumab maintained complete inhibition of pSTAT6 in NHP whole blood. pSTAT6 inhibition was sustained for a longer duration by Construct 133-LS (IC90=56.8 days post-dose, IC50=92.6 days) compared to lebrikizumab (IC90=27.9 days, IC50=48.9 days).

[0441] Consistent with the YTE-dependent increase in t1 / 2and exposure and reduced clearance exhibited by Construct 133, Construct 133-LS (which has another FcRN-related amino acid substitution) inhibited pSTAT6 for a longer duration compared to lebrikizumab. It is expected that Construct 133 will exhibit a similar increase in duration of pSTAT6 inhibition.

[0442] Without being bound by theory, because Construct 133 was engineered to have a YTE amino-acid substitutions in the Fc region, the half-life of the IgG may have been prolonged by increasing binding to neonatal Fc receptor (FcRn) under acidic pH conditions. FcRn-bound IgG is recycled via lysosomal salvage, resulting in the IgG returning to the circulation. Construct 133’s prolonged half-life may enable less frequent dosing compared to currently available treatments, which could reduce injection burden and increase compliance for patients living with atopic dermatitis and other IL-13-driven diseases.

[0443] In a non-head-to-head comparison against third-party NHP data, Construct 133 demonstrated the highest normalized AUC0-∞(Cnorm*day), or area under the curve (AUC) from dosing to infinity, among antibodies with the YTE substitution, as shown in Figure 3. Thus, the PK profile of Construct 133 appears to provide the greatest sustained concentrations, or levels of drug in the blood stream, relative to other antibodies with the YTE substitution.

[0444] The half-life extension for mAbs with YTE amino acid substitutions is dependent on the type of target (receptor vs. soluble). Therefore, the translation of NHP half-life data to human half-life data for mAbs with soluble targets was studied, and it was found that human half-life is approximately three to four times longer than NHP half-life (mean: 3.5x, median 3.1x; data not shown).

[0445] It is expected, based on this NHP half-life data, that Construct 133 will have a human half-life of approximately 80 to 110 days based on comparable mAbs with YTE amino acid substitution.

[0446] Further, based on PK modeling, with a 33 day human half-life (which, to Applicant’s knowledge, would be lower than the lowest half-life for a mAb with the YTE amino acidsubstitutions reported to date), it is believed that Construct 133 can be dosed effectively with an every two month maintenance dosing schedule. With a 50-day half-life, it is believed that Construct 133 can be dosed effectively with an every three month maintenance dosing schedule.

[0447] To understand the maintenance dosing schedule that Construct 133 may be able to achieve, known PK parameters for lebrikizumab were used. These PK parameters provided an understanding of how lebrikizumab is distributed throughout the body and cleared. Based on these known parameters, a two-compartment PK model with first-order absorption was built, which is standard for mAbs, to predict concentration, or drug levels, over time of both lebrikizumab and Construct 133. Key parameters included 0.156 L / day for clearance (CL), 4.10 L for central volume (Vc), 0.239 day-1 for absorption rate (ka) and 85.6% for bioavailability.

[0448] It is believed that efficacy in inflammatory conditions, such as AD, is driven by Ctrough, or the minimal concentration of the mAb. Therefore, based on the model described above, the target Ctrough of Construct 133 was set to be equal to lebrikizumab’s Ctrough in maintenance with every one month dosing, which was 31.3 mg / L. Given the overlapping epitopes of lebrikizumab and certain antibodies disclosed herein, and similarity in potency across multiple in vitro assays, the necessary exposures for potential clinical activity of Construct 133 can be predicted. By modeling Kelimination, the elimination rate constant or the fraction of drug eliminated in a given time, and half-life to maintain concentrations of the disclosed antibodies above 31.3 mg / L, at least a 33-day half-life is would be required to dose Construct 133 every two months in maintenance and at least a 50-day half-life would be required to dose Construct 133 every three months in maintenance assuming a dose of 300 mg.

[0449] Thus, with a 33-day human half-life, it is believed that Construct 133 can be dosed effectively with an every two month maintenance dosing schedule. With a 50-day half-life, it is believed that Construct 133 can be dosed effectively with an every three month maintenance dosing schedule. Example 3: A Multi-Dose, 29-Day GLP Study in NHPs was Completed with No Adverse Findings in All Cohorts, Including the Highest Cohort Tested, Which Was Considered the No Observed Adverse Effect Level (NOAEL)

[0450] A 29-day repeat-dose, GLP-compliant toxicology study was conducted in NHPs. NHPs (3 to 5 animals per sex per group) were administered Construct 133 weekly (5 doses in total) at 0, 30, 75, or 150 mg / kg / dose via SC administration. No adverse findings were observed up to the highest dose tested (150 mg / kg), which was the maximum feasible dose and was considered the no observed adverse effect level (NOAEL) in this study. IPTS / 1285530013Example 4. Monomer Purity after Affinity Capture from Stable Pools

[0451] The monomer purity from one-step affinity capture is a determinant for the final yield and unit cost of an antibody under cGMP production. To characterize this, briefly, CHO stable pools were generated separately for each antibody in a workstream that led to master cell bank selection for cGMP production. The affinity capture step was performed using a Mabselect SuRe column. Novel IgG1 variants (e.g., Constructs 132, 133, 136, 137, 140, 141, and 144) remained a clear solution with < 15% aggregate after the one-step purification. Novel IgG4 variants (Constructs 134, 135, 138, 139, 142, and 143) had an opalescent appearance with some precipitation and an aggregation sensitivity (> 68% aggregate) when using an elution buffer of 50 mM sodium citrate, 150 mM sodium chloride at pH 3.0. The novel IgG4 variants had lower aggregate levels when eluted with either 50 mM acetic acid, pH 2.8 or with 100 mM sodium acetate, 800 mM arginine at pH 3.5. At the higher pH of 3.5, the arginine was needed to retain a suitable recovery.

[0452] Results are summarized in Table 17. Novel IgG1 and IgG4 variants demonstrate greater monomer purity directly out of affinity capture with optimized elution conditions when compared to lebrikizumab variants (Constructs 128-131). Table 17. Anti-IL-13 Antibody Monomer PurityIPTS / 1285530013*See construct sequences in Tables 2-8. Example 5. Accelerated Stability

[0453] As demonstrated by this example, novel variants in an IgG1 construct had a lower propensity to aggregate and were more resistant to changes in the basic species under various stress conditions, as shown in Table 18. The proportion of basic species was determined through capillary isoelectric focusing (ciEF), performed as known in the art. The variants related to lebrikizumab (Constructs 128-131) and IgG4 variants (Constructs 134, 135, 142, and 143); as described in Examples 1-7) were more susceptible to aggregation and changes in the basic species compared to the novel IgG1 variants (e.g., Constructs 132, 133, 136, 137, 140, 141, and 144). Table 18. Anti-IL-13 Antibody Stability ChangeIPTS / 1285530013*See construct sequences in Tables 2-8. Assessment of clones for changes in monomer purity and basic species were evaluated at day 0 and day 14 for 40 ℃ stability and at day 0 and day 2 for pH 3.5 stability. N.T. – Not Tested. Example 6: A Phase 1, Randomized, Double-Blind, Placebo-Controlled Single and Multiple Ascending Dose First-in-Human Study of the Safety, Tolerability, and Pharmacokinetics of an Anti-IL-13 Antibody in Healthy Subjects Study Design and Methodology

[0454] This is a Phase 1, randomized, double-blind, placebo-controlled, parallel group, first- in-human (FIH) study of the anti-IL-13 antibody herein in healthy subjects. The anti-IL-13 antibody is administered subcutaneously (SC) in single- and multiple-ascending doses (SAD and MAD, respectively). Up to 5 SAD cohorts and 2 MAD cohorts are investigated in this study. Each cohort consists of 8 healthy subjects, randomized 6:2 to anti-IL-13 antibody or placebo.

[0455] Subjects are screened within 42 days prior to dosing to assess eligibility for study entry. For each anti-IL-13 antibody dose administered, subjects reside in a clinical research unit (CRU) for 5 consecutive days (1 day prior to dosing, the dosing day, and 3 days following dosing). Sentinel dosing in 2 subjects (1 active, 1 placebo) is employed for all SAD cohorts. Outpatient monitoring continues through the End of Study (EOS) visit (on Day 337). SAD Cohorts

[0456] Up to a maximum of 5 SAD cohorts are enrolled, with 4 ascending dose levels (150, 300, 600, and 1200 mg; Figure 1). Alternatively, starting dose in the first SAD cohort is 300 mg (Figure 4). Each SAD cohort enrolls 8 subjects. Subjects are randomized in a blinded fashion 6:2 to anti-IL-13 antibody or placebo. The first 2^participants in each cohort (sentinel participants) are randomized 1:1 (active:placebo) in blinded fashion and followed for at least 24 hours post-dose before the remainder of the cohort is treated. The remaining 6 participants are randomized 5:1 (active:placebo). A schematic is provided in Figure 1.

[0457] Subjects are admitted to the CRU 1 day prior to dosing (Day −1). On Day 1 (day of dosing), subjects receive an SC dose of anti-IL-13 antibody or placebo. On Day 4 (72 hours IPTS / 1285530013post-dose) subjects are discharged from the CRU after completion of all in-clinic assessments on that day. The duration of CRU stay is adjusted for Cohorts 2 and beyond based on emerging data from previous cohorts.

[0458] The starting dose in the first SAD cohort is 150 mg; this dose reflects a >10-fold safety margin from the human equivalent dose of the no-observed-adverse-event level in a good laboratory practices 28-day non-human primate toxicology study for a subject of at least 60 kg. Alternatively, the starting dose in the first SAD cohort is 300 mg.

[0459] After SAD Cohort 1, doses for evaluation include 300, 600, and 1200 mg (or alternatively 600 and 1200 mg (Figure 4)); however, dose escalation and actual dose increments / decrements are determined by a Safety Review Committee (SRC). The SRC makes the determination based on at least 14 days of post-dose safety data from the previous dose level. Specifically, the SRC determines whether any protocol-defined dose-limiting toxicities (DLTs) occur through Day 15 in subjects who receive the anti-IL-13 antibody in the current cohort and whether any stopping rules are met. At least 6 of the 8 subjects in the cohort have Day 15 safety data for the SRC to convene. In addition, available trailing pharmacokinetic (PK) results are reviewed to assess the appropriateness of the next planned dose and to guide revisions of the next dose that is evaluated, if necessary. Dose escalation in subsequent cohorts does not exceed a 2-fold increase. The highest single dose tested does not exceed 1200 mg.

[0460] Subjects receive an SC dose of the anti-IL-13 antibody or placebo in the CRU on Day 1. Vital signs, electrocardiograms (ECG), evaluation of adverse events (AEs) and blood draws for PK and safety laboratory tests are obtained serially. After completion of CRU confinement (through Day 4), subjects return for outpatient visits on Days 8, 15, 22, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, and 309 followed by an EOS visit on Day 337, which covers approximately 5 half-lives. The follow-up visit schedule, PK sampling times, and duration of study are adjusted depending on the safety and PK results of prior cohorts. MAD Cohorts

[0461] Up to a maximum of 3 cohorts are enrolled, with 2 ascending dose levels (150 mg every 4 weeks [Q4W] × 2 doses, the starting dose; and 300 mg Q4W × 2 doses) and others at the discretion of the SRC and Sponsor, based on emerging data. Alternatively, 2 multiple-dose (MD) cohorts are investigated in this study with subjects receiving 720 mg of Construct 133 at week 0 and 2 and 360 mg of Construct 133 at weeks 4 and 12 (induction phase). In the maintenance phase, subjects receive 360 mg of Construct 133 every 3 months (Q12W) or 6 months (Q24W); see Figure 4. The actual starting dose and dosing frequency are ultimately determined by the SRC based on available data from SAD cohorts, including available PK data. IPTS / 1285530013The first cohort is enrolled after the SRC has reviewed a minimum of 14 days of safety data and PK data from the SAD cohort with a total dose at least equal to the total dose given to subjects in the MAD (i.e., SAD safety review completion for single dose of 300 mg allows opening a MAD cohort with dosing at 150 mg Q4W × 2 doses, which equates to a total dose of 300 mg).

[0462] After MAD Cohort 1, ascension and actual dose increments / decrements are determined by the SRC. Specifically, the SRC determines whether any protocol-defined dose- limiting toxicities (DLTs) occur through 14 days after the last dose of study drug was given in subjects who receive the anti-IL-13 antibody in the current cohort and whether any stopping rules are met. At least 5 of the 8 subjects in the cohort must have Day 43 (i.e., 14 days after the second dose was given on Day 29) safety data for the SRC to convene. In addition, available trailing PK results are reviewed to assess the appropriateness of the next planned dose and to guide revisions of the next dose evaluated, if necessary. Dose escalation in subsequent cohorts does not exceed a 2-fold increase. The highest MAD dose tested does not exceed a total of 1200 mg during the dosing period.

[0463] Subjects receive 2 SC doses of the anti-IL-13 antibody in the CRU: one on Day 1 and one on Day 29. Subjects remain in the CRU for 72 hour following each dose, which is adjusted for subsequent cohorts based on emerging data. Vital signs, electrocardiograms (ECGs), evaluation of AEs, and blood draws for PK and safety laboratory tests are obtained serially.

[0464] After completion of CRU confinement, subjects return for outpatient visits on Days 8, 15, 22 following the first dose of study drug and on Days 50, 57, 85, 113, 141, 169, 197, 225, 253, 281, and 309 following the second dose of study drug. An EOS visit occurs on Day 337, which is expected to cover approximately 5 half-lives. The follow-up visit schedule, PK sampling times, and duration of study are adjusted depending on the safety and PK results of prior cohorts. Duration of Study

[0465] The duration of any individual subject is up to 378 days. Number of Subjects

[0466] Up to 64 (8 subjects in each of up to 8 cohorts). Key Eligibility Criteria Inclusion Criteria IPTS / 1285530013

[0467] Inclusion criteria include: healthy males and nonpregnant females, as determined by physical examination and laboratory screening tests; 18 to 65 years of age (inclusive) with a body mass index of 18 to 34 kg / m2(inclusive); willingness to use an adequate method of contraception from admission through 6 months or 5 half-lives, whichever is longer, after the last administration of study drug; willingness to use an adequate method of contraception from admission through 6 months or 5 half-lives, whichever is longer, after the last administration of study drug; and non-tattooed injection site suitable for SC injection Exclusion Criteria

[0468] Exclusion criteria include: evidence of clinically significant abnormalities or disease, including, but not limited to, the following: hemoglobin A1c ≥ 6.5% and / or diagnosis of diabetes; positive test for human immunodeficiency virus (HIV) antibody; acute or chronic hepatitis B or C as evidenced by hepatitis B surface antigen (HBsAg) and / or hepatitis C antibody (HCV Ab); evidence of resolved infection or status post vaccination with the presence of antibodies or documented absence of viral deoxyribonucleic acid (DNA) on polymerase chain reaction is allowed; positive tuberculosis blood test at screening; diagnosis or suspected diagnosis of immunodeficiency or autoimmune diseases, or undergoing immunosuppressive therapy such as anticancer chemotherapy or radiotherapy before the trial, or have received systemic corticosteroid treatment within the past 120 days; any other laboratory, vital sign, ECG abnormality, clinically significant medical condition, or finding that, in the Investigator’s opinion, is likely to unfavorably alter the risk-benefit of study participation, confound study results, or interfere with the study conduct or compliance. Additional exclusion criteria include a fever within 7 days before study drug administration; known history of drug abuse and / or alcoholism within 2 years prior to Screening; positive screen for drugs of abuse at Screening or admission to the CRU; or regular use of > 5 cigarettes per day (or equivalent amount of nicotine containing product); history of severe allergic reactions, or a history of allergy to any of the ingredients in the anti-IL-13 antibody or placebo; if female, nursing, lactating, pregnant, or plans to become pregnant within 6 months of the EOS visit; donation or loss of ≥ 1 unit (450 mL) of blood within 1 month prior to dosing; use of any prescription or non-prescription medication within 7 days prior to dosing (exception: contraceptives or acetaminophen up to 2 g per day prior to dosing is permitted); and use of any investigational drug therapy within 30 days or 5 half-lives (whichever is longer) prior to study drug dosing through 30 days or 5 half-lives (whichever is longer) after the last dose of study drug. Investigational Product, Dosage, and Mode of Administration IPTS / 1285530013

[0469] The anti-IL-13 antibody described of the Example is a high-affinity IgG1 humanized monoclonal antibody that binds IL-13. The anti-IL-13 antibody solution will be administered via subcutaneous (SC) injection.

[0470] In the SAD part of the study, the starting dose is 150 mg; anticipated ascending doses are 300, 600, and 1200 mg. In the MAD part of the study, doses are 150 and 300 mg, every 4 weeks (Q4W) for a total of 2 doses. Beyond the starting dose (150 mg in the SAD study), dose levels and regimens are determined based on emerging safety data review by the SRC. No subject in the SAD part of the study receives a single dose > 1200 mg; and no subject in the MAD part of the study receives a total dose of > 1200 mg. In the alternative MAD part of the study, the dose is 300 mg, at Day 1 and 29 or Day 1 and 15. Criteria for Evaluation Pharmacokinetics

[0471] The following PK parameters are determined for both the SAD and MAD parts of the study: maximum observed concentration (Cmax), time to Cmax (Tmax), the terminal elimination rate constant (λz) and terminal half-life (T1 / 2).

[0472] In the SAD study, the following additional PK parameters are determined: area under the concentration-time curve from time zero to the last quantifiable time point (AUC0-last), the apparent clearance (CL / F), and the apparent volume of distribution (Vz / F).

[0473] In the MAD study, the following additional PK parameters are determined: AUC for the dosing interval (AUC0-τ) after the first and last dose, the accumulation ratio (RAUC), CL / F, and Vz / F.

[0474] Pharmacokinetic properties as used herein are described in Table 19, below. Table 19. PK ParametersIPTS / 1285530013Anti-drug Antibodies

[0475] Presence of ADAs and impact of ADAs on the PK of the anti-IL-13 antibody. Pharmacodynamics

[0476] Changes over time in pSTAT6 and other blood biomarkers (including, for example, TARC and IgE). Safety IPTS / 1285530013

[0477] Safety include assessment of treatment-emergent adverse events (TEAEs), clinical laboratory tests (e.g., hematology, serum chemistry, and urinalysis), vital signs, ECGs, and physical examinations. Statistical Methods Analysis Populations

[0478] The following 3 analysis populations are defined for this study. (1) The Safety Population, defined as all subjects who receive at least 1 dose of study drug and have at least 1 post-baseline safety assessment. (2) The PK Population, defined as all enrolled subjects for whom at least 1 PK parameter of interest are calculated. In general, on a parameter-by- parameter basis, an individual subject’s data is excluded from an analysis if insufficient data are available for that subject to calculate the specific parameter in question. (3) The Full Analysis Population, defined as all randomized subjects who complete the study without experiencing major protocol deviations or violations. Sample Size

[0479] The sample size is typical for FIH studies and allows preliminary determination of tolerability, safety, and efficacy as well as a comprehensive determination of single- and multiple-dose PK in healthy subjects. Pharmacokinetic Analysis

[0480] Anti-IL-13 antibody plasma concentrations are summarized by dose and time point using descriptive statistics for the PK population. Mean and individual plasma anti-IL-13 antibody concentrations over time are presented in figures using linear and semilog scales. PK parameters are calculated using a noncompartmental analysis and summarized by dose. AUC and Cmax are tested across dose levels for dose proportionality; accumulation of AUC and Cmax at steady-state are calculated. Safety Analysis

[0481] Safety data will be summarized using descriptive statistics. All subjects receiving treatment regardless of duration will be included in the summaries of safety data. TEAEs will be coded using the Medical Dictionary for Regulatory Activities and the subject incidence of TEAEs will be summarized by treatment, dose, system organ class, and preferred term. The subject incidence of TEAEs will also be summarized by severity and relationship to study drug. IPTS / 1285530013Objectives and Endpoints

[0482] The objectives and endpoints are provided in Table 20, below: Table 20. Multiple Ascending Dose Study Objectives and EndpointsAbbreviations: ADA = anti-drug antibody; AE = adverse event; AUC0–∞ = area under the plasma concentration-time curve from time zero extrapolated to infinity; AUC0–last = area under the plasma concentration-time curve from time zero to the last quantifiable time point; AUC0–τ = area under the plasma concentration-time curve for the dosing interval; CL / F = apparent clearance; Cmax = maximum observed plasma concentration; PK = pharmacokinetic(s); RAUC = accumulation ratio; Tmax = time to maximum plasma concentration; T1 / 2 = terminal elimination half-life; Vz / F = apparent volume of distribution; λz = terminal elimination rate constant Example 7: A Phase 1, Randomized, Double-Blind, Placebo-Controlled Single and Multiple Ascending Dose First-in-Human Study of the Safety, Tolerability, and Pharmacokinetics of an Anti-IL-13 Antibody in Healthy Subjects IPTS / 1285530013Study Design and Methodology

[0483] This was a Phase 1, randomized, double-blind, placebo-controlled, parallel group, first-in-human (FIH) study of Construct 133 in healthy subjects. The anti-IL-13 antibody was administered subcutaneously (SC) in single- and multiple-doses (SAD and MAD, respectively). 3 SAD cohorts and 1 MAD cohort were investigated in this study. Criteria for Evaluation Key Eligibility Criteria Inclusion Criteria

[0484] See description in Example 6. Exclusion Criteria

[0485] See description in Example 6. Pharmacokinetics

[0486] See description in Example 6. Anti-drug Antibodies

[0487] See description in Example 6. Pharmacodynamics

[0488] See description in Example 6. Safety

[0489] See description in Example 6. Statistical Methods Analysis Populations

[0490] See description in Example 6. Sample Size

[0491] See description in Example 6. Pharmacokinetic Analysis

[0492] See description in Example 6. Safety Analysis

[0493] See description in Example 6. Objectives and Endpoints

[0494] See description in Example 6. SAD Cohorts IPTS / 1285530013

[0495] 24 participants enrolled in SAD Cohorts 1 to 3. The 3 SAD cohorts enrolled included 3 ascending dose levels (300, 600, and 1200 mg). Each SAD cohort enrolled 8 subjects. Subjects were randomized in a blinded fashion 6:2 to anti-IL-13 antibody or placebo. The first 2^participants in each cohort (sentinel participants) were randomized 1:1 (active:placebo) in blinded fashion and followed for at least 24 hours post-dose before the remainder of the cohort was treated. The remaining 6 participants were ...

Claims

Claims 1. A method of treating atopic dermatitis in a patient in need thereof, the method comprising subcutaneously administering to the patient: a) one to five or more induction doses, each selected from 100 mg, 125 mg, 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 360 mg, 400 mg, 450 mg, 600 mg, 720 mg, 800 mg, 900 mg, 1080 mg, or 1200 mg of an anti-IL-13 antibody; and b) one or more maintenance doses administered starting at about 4-17 weeks or more after the first induction dose; wherein the maintenance dose is 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 360 mg, 400 mg, 450 mg, 600 mg, 800 mg, 1080 mg, or 1200 mg of the anti-IL-13 antibody; and wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to the sequence set forth in SEQ ID NO: 3 and a light chain variable region (VL) comprising an amino acid sequence having at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to the sequence set forth in SEQ ID NO:

39.

2. The method of claim 1, further comprising administering a loading dose prior to the one to five or more induction doses, wherein the loading dose is 2 times the induction dose.

3. The method of claim 1, wherein the one or more maintenance doses are administered about 4-16 weeks or 12-16 weeks after the first induction dose.

4. The method of any one of claims 1-3, where the first induction dose is 150 mg, 300 mg, 360 mg, or 600 mg.

5. The method of any one of claims 1-4, comprising administering a second, third, fourth, and / or fifth induction dose of 300 mg or 360 mg of the anti-IL-13 antibody.

6. The method of claim 5 wherein the second induction dose is administered about 2 to about 16 weeks after the first induction dose.

7. The method of claim 5, wherein the second induction dose is administered about two or about eight weeks after the first induction dose.

8. The method of any one of claims 1-4, comprising administering a second, third, fourth, and / or fifth induction dose of 600 mg of the anti-IL-13 antibody.

9. The method of claim 8, wherein the second induction dose is administered about 2 to about 16 weeks after the first induction dose.

10. The method of claim 8, wherein the second induction dose is administered about 2 weeks after the first induction dose.

11. The method of any one of claims 1-10, wherein the maintenance dose is 150 mg, 200 mg, 300 mg, 360 mg, 400 mg, 600 mg, or 800 mg and is administered every 3 months, every 12 weeks, or 4 times a year.

12. The method of any one of claims 1-10, wherein the maintenance dose is 150 mg, 200 mg, 300 mg, 360 mg, 400 mg, 600 mg, or 800 mg and is administered every 2 months or every 8 weeks.

13. The method of any one of claims 1-10, wherein the maintenance dose is 150 mg, 200 mg, 300 mg, 360 mg, 400 mg, 600 mg, or 800 mg and is administered every 16 weeks or three times a year.

14. The method of any one of claims 1-10, wherein the maintenance dose is 150 mg, 200 mg, 300 mg, 360 mg, 400 mg, 600 mg, or 800 mg and is administered every 20 weeks.

15. The method of any one of claims 1-10, wherein the maintenance dose is 150 mg, 200 mg, 300 mg, 360 mg, 400 mg, 600 mg, or 800 mg and is administered every 6 months or twice a year.

16. The method of any one of claims 1-10, wherein the maintenance dose is 150 mg, 200 mg, 300 mg, 360 mg, 400 mg, 600 mg, or 800 mg and is administered once a year.

17. The method of any one of claims 1-10, wherein the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered every 3 months, 12 weeks, or 4 times a year.

18. The method of any one of claims 1-10, wherein the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered every 2 months or 8 weeks.

19. The method of any one of claims 1- 10, wherein the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered every 16 weeks or three times a year.

20. The method of any one of claims 1-10, wherein the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered every 20 weeks.

21. The method of any one of claims 1-10, wherein the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered every 6 months or twice a year.

22. The method of any one of claims 1-10, wherein the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered once a year.

23. The method of any one of claims 1-22, wherein each unit dose is administered as composition comprising 150 mg / mL, 180 mg / mL, or 200 mg / mL of the anti-IL-13 antibody.

24. The method of claim 23, wherein the unit dose has an extractable volume of about 2 mL, about 2.25 mL, or about 2.7 mL.

25. The method of any one of claims 1-24, wherein the anti-IL-13 antibody is administered by an autoinjector.

26. The method of any one of claims 1-24, wherein the anti-IL-13 antibody is administered by a pre-filled syringe.

27. The method of any one of claims 1-26, wherein the patient has been diagnosed with moderate-to-severe atopic dermatitis.

28. The method of any one of claims 1-27, wherein the patient has had moderate-to-severe atopic dermatitis for at least one year.

29. The method of any one of claims 1-28, wherein the patient has one or more of: (a) an Eczema Area and Severity Index Score (EASI) of ≥10, (b) an Investigator Global Assessment (IGA) score of ≥3 and (c) a body surface area (BSA) of ≥10%.

30. The method of any one of claims 1-29, further comprising determining one or more of the following characteristics of the patient at baseline and during and after the induction period: Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Body Surface Area (BSA), Pruritus Numerical Rating Scale (NRS), Sleep loss scale, SCORing Atopic Dermatitis (SCORAD), Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI).

31. A method of treating atopic dermatitis in a patient in need thereof, the method comprising: subcutaneously administering to the patient an anti-IL-13 antibody for an induction period of 4 to 17 weeks, wherein, during the induction period, the anti-IL-13 antibody is administered once or twice at a loading dose of from about 100 mg to about 1200 mg or a dose listed in any one of Tables 11-13, and, optionally, at least once at a dose that is at one-half or one-quarter of the loading dose; and subcutaneously administering to the patient the anti-IL-13 antibody at a dose of from about 100 mg to about 1200 mg or a dose listed in Table 14 for a maintenance period; wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to SEQ ID NO: 3 and a light chain variable region (VL) comprising an amino acid sequence at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to SEQ ID NO: 39, wherein the VH comprises a HCDR1 comprising SEQ ID NO: 58, SEQ ID NO: 68, or SEQ ID NO: 85; a HCDR2 comprising SEQ ID NO: 100, SEQ ID NO: 104, or SEQ ID NO: 108; and a HCDR3 comprising SEQ ID NO: 112 or SEQ ID NO: 130; and the VL comprises a LCDR1comprising SEQ ID NO: 141 or SEQ ID NO: 149; a LCDR2 comprising SEQ ID NO: 153 or SEQ ID NO: 164, and a LCDR3 comprising SEQ ID NO:

165.

32. The method of claim 31, wherein the loading dose is about 100 mg, 150 mg, 180 mg, 200 mg, 300 mg, 360 mg, 400 mg, 450 mg, 600 mg, 720 mg, 800 mg, 900 mg, 1080 mg, or 1200 mg.

33. The method of claim 31 or 32, wherein, during the induction period, the loading dose is administered at week 0 and week 2.

34. The method of claim 31 or 32, wherein, during the induction period, the loading dose is administered at week 0 and week 4.

35. The method of claim 31 or 32, wherein, during the induction period, the loading dose is administered at week 0 and week 8.

36. The method of claim 31 or 32, wherein, during the induction period, the loading dose is administered at week 0 and week 12.

37. The method of any one of claims 31-36, wherein, during the induction period, the one- half or one-quarter dose is administered at weeks 8, 12, and 16.

38. The method of any one of claims 31-36, wherein, during the induction period, the one- half or one-quarter dose is administered at weeks 4, 8, 12, and 16.

39. The method of any one of claims 31-36, wherein, during the induction period, the one- half or one-quarter dose is administered at weeks 4 and 12.

40. The method of any one of claims 31-36, wherein, during the induction period, the one- half or one-quarter dose is administered at weeks 2, 4, and 12.

41. The method of any one of claims 31-36, wherein, during the induction period, the one- half or one-quarter dose is administered at weeks 2 and 12.

42. The method of any one of claims 31-36, wherein, during the induction period, the one- half or one-quarter dose is administered at week 12.

43. The method of any one of claims 31-36, wherein, during the induction period, the one- half or one-quarter dose is administered at weeks 8 and 16.

44. The method of any one of claims 31-36, wherein, during the induction period, the one- half or one-quarter dose is administered at week 16.

45. The method of any one of claims 31-36, wherein, during the induction period, the one- half or one-quarter dose is administered at weeks 4 and 14.

46. The method of any one of claims 31-36, wherein, during the induction period, the one- half or one-quarter dose is administered at week 14.

47. The method of any one of claims 31-36, wherein, during the induction period, the one- half or one-quarter dose is administered at weeks 2, 4, and 14.

48. The method of any one of claims 31-47, wherein the maintenance dose is 100 mg, 150 mg, 180 mg, 200 mg, 300 mg, 360 mg, 400 mg, 450 mg, 600 mg, 720 mg, 800 mg, or 900 mg.

49. The method of any one of claims 31-48, wherein, during the maintenance period, the anti-IL-13 antibody is administered 3 months, every 12 weeks, or 4 times a year.

50. The method of any one of claims 31-48, wherein, during the maintenance period, the anti-IL-13 antibody is administered every 2 months or 8 weeks.

51. The method of any one of claims 31-48, wherein, during the maintenance period, the anti-IL-13 antibody is administered every 16 weeks or three times a year.

52. The method of any one of claims 31-48, wherein, during the maintenance period, the anti-IL-13 antibody is administered every 20 weeks.

53. The method of any one of claims 31-48, wherein, during the maintenance period, the anti-IL-13 antibody is administered every 6 months or twice a year.

54. The method of any one of claims 31-48, wherein, during the maintenance period, the anti-IL-13 antibody is administered once a year.

55. The method of any one of claims 31-54, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence as set forth in SEQ ID NO: 3 and a light chain variable region (VL) comprising an amino acid sequence as set forth in SEQ ID NO:

39.

55. A method of treating atopic dermatitis in a patient in need thereof, the method comprising subcutaneously administering to the patient: a) two loading doses of 720 mg of an anti-IL-13 antibody prior to two induction doses; b) two induction doses of 360 mg of the anti-IL-13 antibody; and c) one or more maintenance doses of 360 mg of the anti-IL-13 antibody administered starting at about 12 weeks or more after the first induction dose; and wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence as set forth in SEQ ID NO: 3 and a light chain variable region (VL) comprising an amino acid sequence as set forth in SEQ ID NO:

39.

56. The method of claim 55, wherein the second loading dose is administered about 2 weeks after the first loading dose.

57. The method of claim 55 or 56, wherein the first induction dose is administered about 2 weeks after the second loading dose.

58. The method of any one of claims 55-57, wherein the second induction dose is administered about 8 weeks after the first induction dose.

59. The method of any one of claims 55-58, wherein the maintenance dose is administered every 3 months.

60. The method of any one of claims 55-58, wherein the maintenance dose is administered every 6 months.

61. A method of treating atopic dermatitis in a patient in need thereof, the method comprising subcutaneously administering to the patient: a) a loading dose of 720 mg of an anti-IL-13 antibody prior to two induction doses; b) two induction doses of 360 mg of the anti-IL-13 antibody; and c) one or more maintenance doses of 360 mg of the anti-IL-13 antibody administered starting at about 12 weeks or more after the first induction dose; and wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence as set forth in SEQ ID NO: 3 and a light chain variable region (VL) comprising an amino acid sequence as set forth in SEQ ID NO:

39.

62. The method of claim 61, wherein the first induction dose is administered about 4 weeks after the loading dose.

63. The method of any one of claims 61-62, wherein the second induction dose is administered about 8 weeks after the first induction dose.

64. The method of any one of claims 61-63, wherein the maintenance dose is administered every 3 months.

65. The method of any one of claims 61-64, wherein the maintenance dose is administered every 6 months.

66. A method of treating atopic dermatitis in a patient in need thereof, the method comprising subcutaneously administering to the patient: a) a loading dose of 360 mg of an anti-IL-13 antibody prior to two induction doses; b) two induction doses of 180 mg of the anti-IL-13 antibody; and c) one or more maintenance doses of 180 mg of the anti-IL-13 antibody administered starting at about 12 weeks or more after the first induction dose; and wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence as set forth in SEQ ID NO: 3 and a light chain variable region (VL) comprising an amino acid sequence as set forth in SEQ ID NO: 39.

67. The method of claim 66, wherein the first induction dose is administered about 4 weeks after the loading dose.

68. The method of any one of claims 66-67, wherein the second induction dose is administered about 8 weeks after the first induction dose.

69. The method of any one of claims 66-68, wherein the maintenance dose is administered every 3 months.

70. The method of any one of claims 66-69, wherein the maintenance dose is administered every 6 months.

71. The method of any one of claims 66-70, wherein each dose is administered as a composition comprising 150 mg / mL, 180 mg / mL, or 200 mg / mL of the anti-IL-13 antibody.

72. The method of claim 71, wherein the composition is a unit dose with an extractable volume of 2 mL, 2.25, or 2.7 mL.

73. The method of claim 72, wherein the composition is a unit dose with an extractable volume of 2 mL.

74. The method of any one of claims 31-73, wherein the patient has been diagnosed with moderate-to-severe atopic dermatitis.

75. The method of any one of claims 31-74, wherein the patient has had moderate-to-severe atopic dermatitis for at least one year.

76. The method of any one of claims 31-75, wherein the patient has one or more of: (a) an Eczema Area and Severity Index Score (EASI) of ≥10, (b) an Investigator Global Assessment (IGA) score of ≥3 and (c) a body surface area (BSA) of ≥10%.

77. The method of any one of claims 31-76, further comprising determining one or more of the following characteristics of the patient at baseline and during and after the induction period: Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Body Surface Area (BSA), Pruritus Numerical Rating Scale (NRS), Skin Pain Numerical Rating Scale (SP-NRS), Sleep loss scale, SCORing Atopic Dermatitis (SCORAD), Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), Asthma Control Questionnaire 5-item version (ACQ-5), Sino-nasal Outcome Test 22-item version (SNOT-22).

78. A composition comprising 150 mg / mL, 180 mg / mL, or 200 mg / mL of an anti-IL-13 antibody, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence as set forth in SEQ ID NO: 3 and a light chain variable region (VL) comprising an amino acid sequence as set forth in SEQ ID NO: 39.

79. The composition of claim 78, wherein the composition is a unit dose with an extractable volume of 2 mL, 2.25 mL, or 2.7 mL.

80. The composition of claim 79, wherein the composition is a unit dose with an extractable volume of 2 mL.

81. An autoinjector configured to deliver a composition comprising 150 mg / mL, 180 mg / mL, or 200 mg / mL of an anti-IL-13 antibody, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence as set forth in SEQ ID NO: 3 and a light chain variable region (VL) comprising an amino acid sequence as set forth in SEQ ID NO:

39.

82. The autoinjector of claim 81, wherein the composition is a unit dose with an extractable volume of 2 mL 2.25 mL, or 2.7 mL.

83. The method, composition, or autoinjector of any of the preceding claims, further comprising a heavy chain constant region of SEQ ID NO: 439 or SEQ ID NO: 624 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto.

84. The method, composition, or autoinjector of any of the preceding claims, further comprising a light chain constant region of SEQ ID NO: 469 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto.

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