Methods of administering antibodies that bind to interleukin 13

Abstract

Described herein are methods of administering and methods of using antibodies that bind to interleukin 13 (IL-13). In certain aspects, methods of inhibiting the biological activity of IL-13 are described herein. In certain aspects, the antibodies and methods described herein are useful for the treatment of inflammatory disorders or diseases.

Description

Cross-reference to related applications

[0001] This application claims the benefits and priorities of the following: U.S. Provisional Application No. 63 / 462,832, filed April 28, 2023; U.S. Provisional Application No. 63 / 469,180, filed May 26, 2023; U.S. Provisional Application No. 63 / 471,088, filed June 5, 2023; U.S. Provisional Application No. 63 / 521,614, filed June 16, 2023; U.S. Provisional Application No. 63 / 541,581, filed September 29, 2023; U.S. Provisional Application No. 63 / 612,871, filed December 20, 2023; U.S. Provisional Application No. 63 / 621,479, filed January 16, 2024; and U.S. Provisional Application No. 63 / 621,479, filed March 4, 2024. 63 / 561,097, the entire contents of each of which are publicly available are incorporated herein by reference in their entirety for all purposes. Background Technology

[0002] Interleukin (IL)-13 is a T helper cell class 2 (Th2) cytokine and belongs to the type I cytokine family. However, IL-13 is involved in the differentiation of naive T cells into Th2 cells. IL-13 promotes B cell proliferation and induces class conversion to IgG4 and IgE, as well as CD40 / CD40L co-stimulation (IL-13 upregulates FcεRI, thus facilitating IgE pre-stimulation of mast cells). In monocytes / macrophages, IL-13 upregulates the expression of CD23 and MHC class I and II antigens; downregulates CD14 expression; inhibits antibody-dependent cytotoxicity; and promotes eosinophil survival, activation, and recruitment. IL-13 also exhibits important functions in non-hematopoietic cells such as smooth muscle cells, epithelial cells, endothelial cells, and fibroblasts. IL-13 enhances smooth muscle proliferation and cholinergic-induced smooth muscle contraction. In epithelial cells, IL-13 strongly induces the production of chemokines, alters mucociliary differentiation, reduces the ciliary beating frequency of ciliated epithelial cells, and induces goblet cell metaplasia. In endothelial cells, IL-13 is a potent inducer of vascular cell adhesion molecule 1 (VCAM-1), which is crucial for eosinophil recruitment. In human dermal fibroblasts, IL-13 induces type I collagen synthesis.

[0003] Inhibition of IL-13 can be used to treat or prevent inflammatory diseases and disorders, such as those associated with elevated IgE levels, including but not limited to: asthma, allergic rhinitis, rubella, and allergic or atopic dermatitis. Therefore, there is a need to develop potent and specific inhibitors of IL-13, such as inhibitors that maintain activity for a longer period when administered to subjects, to prevent and / or treat IL-13 and IgE-mediated diseases or disorders. Attached Figure Description

[0004] These and other features, aspects, and advantages of the invention will be better understood with reference to the following description and accompanying drawings, wherein: Figure 1 This diagram illustrates single-dose escalation and multiple-dose escalation studies (SAD and MAD, respectively) designed using the anti-IL-13 antibody described herein. Bold arrows indicate equivalent doses between the SAD and MAD dosing regimens. Abbreviations: Q4wk, every 4 weeks; SRC, Safety Review Committee; SC, SQ, Subcutaneous.

[0005] Figure 2 This graph depicts the serum concentrations (ng / mL) of construct 133 and lebrikizumab over time (days post-injection) in non-human primates (NHP). The half-life of construct 133 is 27.6 days, compared to 17-18 days for lebrikizumab.

[0006] Figure 3 To depict the normalized AUC from administration to infinity in antibodies with YTE substitution. 0-∞ (C 归一化*天 A graph of the area under the curve (AUC).

[0007] Figure 4 This diagram illustrates the design of single-dose escalation and multiple-dose escalation studies (SAD and MAD, respectively) using the construct 133 described herein. Abbreviations: PK, pharmacokinetics; ADA, anti-drug antibody; pSTAT6, phosphorylated signal transducer and activator or transcription 6; TARC, thymus and activation-regulated chemokine; SQ, subcutaneous.

[0008] Figure 5 To depict in Figure 4 A set of graphs showing the serum concentration (µg / mL) of human construct 133 recruited in the SAD (left) and MAD (right) studies described in the article. Abbreviations: D1, day 1; 29, day 29.

[0009] Figure 6To depict in Figure 4 A graph showing the median percentage change in inhibition of IL-13-induced STAT6 phosphorylation (pSTAT6) in people enrolled in the SAD study described in the figure. At approximately three months (week 12, up arrow) of the most recent follow-up, pSTAT6 inhibition remained after a single dose of construct 133.

[0010] Figure 7 To depict in Figure 4 A set of graphs showing the median percentage change from baseline in the inhibition of IL-13-induced thymus and activation-regulated chemokine (TARC) release among individuals enrolled in the SAD study described in the paper.

[0011] Figure 8 This is a schematic diagram illustrating the design of a phase 2 clinical trial using construct 133 described herein. Summary of the Invention

[0012] In some respects, this article describes a method for treating atopic dermatitis in patients in need, the method comprising subcutaneously administering the following to the patient: a) One to five or more induction doses, each induction dose selected from the doses of anti-IL-13 antibody of 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 any of the doses listed in Tables 11-13; and b) One or more maintenance doses, which are administered approximately 4–17 weeks or longer after the first induction dose; 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 anti-IL-13 antibody, or the doses listed in Table 14; and The anti-IL-13 antibody comprises: a heavy chain variable region (VH) containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acids shown in SEQ ID NO: 3, and a light chain variable region (VL) containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acids shown in SEQ ID NO: 39.

[0013] In some embodiments, the method further includes administering a loading dose before one to five or more induction doses, wherein the loading dose is twice the induction dose.

[0014] In some implementations, one or more maintenance doses are administered approximately 4–16 weeks or 12–16 weeks after the first induction dose.

[0015] In some embodiments, the first induction dose is 150 mg, 300 mg, 360 mg, or 600 mg. In some embodiments, the first induction dose is 360 mg.

[0016] In some embodiments, the method further includes administering 300 mg or 360 mg of anti-IL-13 antibody at a second, third, fourth, and / or fifth induction dose.

[0017] In some implementations, the second induction dose is administered approximately 2 weeks to approximately 16 weeks after the first induction dose.

[0018] In some embodiments, the second induction dose is administered approximately two weeks or approximately eight weeks after the first induction dose.

[0019] In some embodiments, the method further includes administering 600 mg of anti-IL-13 antibody at a second, third, fourth, and / or fifth induction dose.

[0020] In some implementations, the second induction dose is administered approximately 2 weeks to approximately 16 weeks after the first induction dose.

[0021] In some implementations, the second induction dose is administered approximately 2 weeks to approximately 16 weeks after the first induction dose.

[0022] In some implementations, the maintenance dose is 150 mg, 200 mg, 300 mg, 360 mg, 400 mg, 600 mg, or 800 mg and is administered once every 3 months, once every 12 weeks, or 4 times a year.

[0023] In some implementations, the maintenance dose is 150 mg, 200 mg, 300 mg, 360 mg, 400 mg, 600 mg, or 800 mg and is administered once every 2 months or every 8 weeks. 13.

[0024] In some implementations, the maintenance dose is 150 mg, 200 mg, 300 mg, 360 mg, 400 mg, 600 mg, or 800 mg and is administered once every 16 weeks or three times a year.

[0025] In some implementations, the maintenance dose is 150 mg, 200 mg, 300 mg, 360 mg, 400 mg, 600 mg, or 800 mg and is administered once every 20 weeks.

[0026] In some implementations, the maintenance dose is 150 mg, 200 mg, 300 mg, 360 mg, 400 mg, 600 mg, or 800 mg and is administered once every 24 weeks, once every 26 weeks, once every 6 months, or twice a year.

[0027] In some implementations, 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.

[0028] In some implementations, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered once every 3 months, once every 12 weeks, or 4 times a year.

[0029] In some implementations, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered once every 2 months or every 8 weeks.

[0030] In some implementations, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered once every 16 weeks or three times a year.

[0031] In some implementations, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered once every 20 weeks.

[0032] In some implementations, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered once every 6 months or twice a year.

[0033] In some implementations, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered once a year.

[0034] In some embodiments, each unit dose is administered as a composition containing 150 mg / mL, 180 mg / mL, or 200 mg / mL of anti-IL-13 antibody.

[0035] In some implementations, the unit dose has an extractable volume of about 2 mL, about 2.25 mL, or about 2.7 mL.

[0036] In some implementations, the anti-IL-13 antibody is administered via an auto-injector or a pre-filled syringe.

[0037] In some implementations, the patient has been diagnosed with moderate to severe atopic dermatitis.

[0038] In some implementation schemes, the patient has had moderate to severe atopic dermatitis for at least one year.

[0039] In some implementations, the patient has one or more of the following: (a) Eczema Area and Severity Index Score (EASI) ≥ 10, (b) Investigator Global Assessment (IGA) score ≥3 and (c) Body surface area (BSA) ≥ 10%.

[0040] In some implementations, the method further includes measuring one or more of the following characteristics of the patient at baseline, 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 Deprivation Scale, Atopic Dermatitis Score (SCORing Atopic Dermatitis (SCORAD), Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), Asthma Control Questionnaire 5-item version (ACQ-5), and Sino-nasal Outcome Test 22-item version (SNOT-22).

[0041] In some respects, this article describes a method for treating atopic dermatitis in patients in need, the method comprising: The patient was given an induction period of 4 to 17 weeks via subcutaneous administration of anti-IL-13 antibodies. During this induction period, the anti-IL-13 antibodies were administered as follows: Administer once or twice with a loading dose of about 100 mg to about 1200 mg or the dose listed in any of Tables 11-13, and optionally at least once with a dose equal to half or a quarter of the loading dose; and Administer anti-IL-13 antibodies subcutaneously to the patient at a dose of approximately 100 mg to approximately 1200 mg or at the doses listed in Table 14 for a maintenance period; The anti-IL-13 antibody comprises: a heavy chain variable region (VH) containing 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 with SEQ ID NO: 3; and a light chain variable region (VL) containing 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 with SEQ ID NO: 39, wherein the VH contains HCDR1 containing SEQ ID NO: 58, SEQ ID NO: 68, or SEQ ID NO: 85; HCDR2 containing SEQ ID NO: 100, SEQ ID NO: 104, or SEQ ID NO: 108; and HCDR2 containing SEQ ID NO: 112 or SEQ ID NO: 112. HCDR3 of 130; and VL contains LCDR1 containing SEQ ID NO: 141 or SEQ ID NO: 149; LCDR2 containing SEQ ID NO: 5 and LCDR3 containing SEQ ID NO: 6. 32.

[0042] In some embodiments, the loading dose during the induction period 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.

[0043] In some implementations, during the induction period, the loading dose is administered in weeks 0 and 2.

[0044] In some implementations, during the induction period, the loading dose is administered at weeks 0 and 4.

[0045] In some implementations, during the induction period, the loading dose is administered at weeks 0 and 8.

[0046] In some implementations, during the induction period, the loading dose is administered at weeks 0 and 12.

[0047] In some implementations, half or a quarter of the dose is administered during the induction period at weeks 8, 12, and 16.

[0048] In some implementations, half or a quarter of the dose is administered during the induction period at weeks 4, 8, 12, and 16.

[0049] In some implementations, half or a quarter of the dose is administered during the induction period at weeks 4 and 12.

[0050] In some implementations, half or a quarter of the dose is administered during the induction period at weeks 2, 4, and 12.

[0051] In some implementations, half or a quarter of the dose is administered during the induction period at weeks 2 and 12.

[0052] In some implementations, half or a quarter of the dose is administered during the induction period at week 12.

[0053] In some implementations, half or a quarter of the dose is administered during the induction period at weeks 8 and 16.

[0054] In some implementations, half or a quarter of the dose is administered at week 16 during the induction period.

[0055] In some implementations, half or a quarter of the dose is administered during the induction period at weeks 4 and 14.

[0056] In some implementations, half or a quarter of the dose is administered at week 14 during the induction period.

[0057] In some implementations, half or a quarter of the dose is administered during the induction period at weeks 2, 4, and 14.

[0058] In some implementations, 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.

[0059] In some implementations, during the maintenance period, the anti-IL-13 antibody is administered once every 3 months, once every 12 weeks, or 4 times a year.

[0060] In some implementations, the anti-IL-13 antibody is administered every 2 months or every 8 weeks during the maintenance period.

[0061] In some implementations, during the maintenance period, the anti-IL-13 antibody is administered once every 16 weeks or three times a year.

[0062] In some implementations, the anti-IL-13 antibody is administered once every 20 weeks during the maintenance period.

[0063] In some implementations, during the maintenance period, the anti-IL-13 antibody is administered once every 6 months or twice a year.

[0064] In some implementations, the anti-IL-13 antibody is administered once a year during the maintenance period.

[0065] In some embodiments, the anti-IL-13 antibody comprises: a heavy chain variable region (VH) containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acids shown in SEQ ID NO: 3, and a light chain variable region (VL) containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acids shown in SEQ ID NO: 39.

[0066] In some respects, this article describes a method for treating atopic dermatitis in patients in need, the method comprising subcutaneously administering an anti-IL-13 antibody to the patient as follows: a) Two loading doses of 720 mg of anti-IL-13 antibody prior to two induction doses; b) Two induction doses of 360 mg of anti-IL-13 antibody; and c) One or more maintenance doses of 360 mg anti-IL-13 antibody, initiated approximately 12 weeks or longer after the first induction dose; and The anti-IL-13 antibody comprises: a heavy chain variable region (VH) containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acids shown in SEQ ID NO: 3, and a light chain variable region (VL) containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acids shown in SEQ ID NO: 39.

[0067] In some implementations, the second loading dose is administered approximately two weeks after the first loading dose.

[0068] In some implementations, the first induction dose is administered approximately two weeks after the second loading dose.

[0069] In some implementations, the second induction dose is administered approximately 8 weeks after the first induction dose.

[0070] In some implementations, the maintenance dose is administered every 3 months.

[0071] In some implementations, the maintenance dose is administered every 6 months.

[0072] In some respects, this article describes a method for treating atopic dermatitis in patients in need, the method comprising subcutaneously administering an anti-IL-13 antibody to the patient as follows: a) A loading dose of 720 mg of anti-IL-13 antibody prior to two induction doses; b) Two induction doses of 360 mg of anti-IL-13 antibody; and c) One or more maintenance doses of 360 mg of anti-IL-13 antibody, administered starting approximately 12 weeks or longer after the first induction dose; and said anti-IL-13 antibody comprising: 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 with the amino acids shown 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 with the amino acids shown in SEQ ID NO: 39.

[0073] In some implementations, the first induction dose is administered approximately 4 weeks after the loading dose.

[0074] In some implementations, the second induction dose is administered approximately 8 weeks after the first induction dose.

[0075] In some implementations, the maintenance dose is administered every 3 months.

[0076] In some implementations, the maintenance dose is administered every 6 months.

[0077] In some respects, this article describes a method for treating atopic dermatitis in patients in need, the method comprising subcutaneously administering an anti-IL-13 antibody to the patient as follows: a) A loading dose of 360 mg of anti-IL-13 antibody prior to two induction doses; b) Two induction doses of 180 mg of anti-IL-13 antibody; and c) One or more maintenance doses of 180 mg of anti-IL-13 antibody, administered starting approximately 12 weeks or longer after the first induction dose; and said anti-IL-13 antibody comprising: 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 with the amino acids shown 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 with the amino acids shown in SEQ ID NO: 39.

[0078] In some implementations, the first induction dose is administered approximately 4 weeks after the loading dose.

[0079] In some implementations, the second induction dose is administered approximately 8 weeks after the first induction dose.

[0080] In some implementations, the maintenance dose is administered every 3 months.

[0081] In some implementations, the maintenance dose is administered every 6 months.

[0082] In some embodiments, each dose is administered as a composition comprising 150 mg / mL, 180 mg / mL, or 200 mg / mL of anti-IL-13 antibody.

[0083] In some embodiments, the composition is a unit dose having a drawable volume of 2 mL.

[0084] In some implementations, the patient has been diagnosed with moderate to severe atopic dermatitis.

[0085] In some implementation schemes, the patient has had moderate to severe atopic dermatitis for at least one year.

[0086] In some implementations, the patient has one or more of the following: (a) Eczema Area and Severity Index (EASI) score ≥10, (b) Investigator Global Assessment (IGA) score ≥3 and (c) Body surface area (BSA) ≥ 10%.

[0087] In some implementations, the method further includes measuring one or more of the following characteristics of the patient at baseline, during and after the induction period: Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Body Surface Area (BSA), Numerical Rating Scale for Pruritus (NRS), Numerical Rating Scale for Skin Pain (SP-NRS), Sleep Deprivation Scale, Scoliosis Atopic Dermatitis Rating (SCORAD), Patient-Oriented Eczema Measurement (POEM), Dermatology Quality of Life Index (DLQI), 5-Item Asthma Control Questionnaire (ACQ-5), and 22-Item Nasal and Sinus Outcome Test (SNOT-22).

[0088] In some aspects, this document describes 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 with the amino acids shown 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 with the amino acids shown in SEQ ID NO: 39.

[0089] In some embodiments, the composition is a unit dose having a drawable volume of 2 mL, 2.25 mL, or 2.7 mL.

[0090] In some aspects, this document describes 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 with the amino acids shown 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 with the amino acids shown in SEQ ID NO: 39.

[0091] In some embodiments, the composition is a unit dose having a drawable volume of 2 mL, 2.25 mL, or 2.7 mL.

[0092] In some embodiments, the methods, compositions, or autoinjectors described herein further comprise 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 with it.

[0093] In some embodiments, the methods, compositions, or autoinjectors described herein further comprise 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 with it. Detailed Implementation

[0094] definition Unless otherwise defined, all technical terms, symbols, and other scientific terms used herein are intended to have the meaning commonly understood by one of ordinary skill in the art. In some cases, for clarity and / or ease of reference, terms with their commonly understood meanings are defined herein, and the inclusion of such definitions should not necessarily be construed as indicating a difference from the general understanding in the art. One of ordinary skill in the art generally has a full understanding of the techniques and procedures described or referenced herein and typically employs them using conventional methods, such as the widely used molecular cloning methods described in Sambrook et al., Molecular Cloning: A Laboratory Manual 4th Edition (2012), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. Where necessary, unless otherwise indicated, procedures involving the use of commercially available kits and reagents are generally performed according to the protocols and conditions defined by the manufacturer.

[0095] Unless otherwise indicated, the singular forms “a”, “an” and “the” as used herein include multiple indicators.

[0096] It should be understood that the aspects and embodiments of the invention described herein include aspects and embodiments that "comprise", aspects and embodiments that "are composed of", and aspects and embodiments that "are substantially composed of".

[0097] For all compositions described herein and all methods using the compositions described herein, the composition may comprise or may “consist substantially of” the listed components or steps. When a composition is described as “consistent substantially of” the listed components, the composition contains the listed components and may contain other components that substantially do not affect the disease being treated, but does not contain any other components besides those explicitly listed that significantly affect the disease being treated; or if the composition contains additional components besides those listed that significantly affect the disease being treated, the composition does not contain the concentration or amount of said additional components sufficient to significantly affect the disease being treated. When a method is described as “consistent substantially of” the listed steps, the method contains the listed steps and may contain other steps that substantially do not affect the disease being treated, but the method does not contain any other steps besides those explicitly listed that significantly affect the disease being treated. As a non-limiting specific example, when a composition is described as 'consistently composed of 'components', the composition may additionally contain any amount of pharmaceutically acceptable carriers, mediators or diluents and other such components that do not substantially affect the disease being treated.

[0098] As used herein, the term "vector" refers to a nucleic acid molecule capable of delivering another nucleic acid it is linked to. This term includes vectors that present as self-replicating nucleic acid structures as well as vectors incorporated into the genome of a host cell into which they have been introduced. Some vectors are capable of guiding the expression of the nucleic acid to which they are operatively linked. These vectors are referred to herein as "expression vectors."

[0099] The terms “host cell,” “host cell line,” and “host cell culture” are used interchangeably and refer to cells in which exogenous nucleic acids have been introduced and their progeny. Host cells include “transformers” (or “transformed cells”) and “transfectants” (or “transfected cells”), each comprising primary transformed or transfected cells and their derived progeny. The nucleic acid content of these progeny cells may not be identical to that of the parent cells and may contain mutations. “Recombinant host cell” or “host cell” refers to a cell containing exogenous polynucleotides, regardless of the method used for insertion (e.g., direct uptake, transduction, f-factor conjugation (f-mating), or other methods known in the art for generating recombinant host cells).

[0100] As used in this article, the term "eukaryote" refers to organisms belonging to the eukaryote domain of phylogenetics, 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, microsporidiids, protozoa, etc.

[0101] As used herein, the term "prokaryote" refers to prokaryotes. For example, non-eukaryotic organisms can be eubacteria (including but not limited to *Escherichia coli*). Escherichia coli Thermostats ( ) Thermus thermophilus ), thermophilic steatobacterium ( Bacillus stearothermophilus ), Fluorescent Pseudomonas ( Pseudomonas fluorescens ), Pseudomonas aeruginosa ( Pseudomonas aeruginosa ), Pseudomonas putida ( Pseudomonas putida Phylogenetic domains or archaea (including but not limited to Methanococcus jandii) Methanococcus jannaschii Thermotrophic methanobacterium ( Methanobacterium thermoautotrophicum ), Halobacterium (e.g., Halophilic bacilli) Haloferax volcanii ) and halophilic bacteria species NRC-1 Archaeocystis scintillans ( ) Archaeoglobus fulgidus ), Vibrio parahaemolyticus ( Pyrococcus furiosus ), Fireball bacteria ( Pyrococcus horikoshii ), Agile thermophilic bacteria ( Aeuropyrum pernix Phylogenetic domains, etc.

[0102] As used herein, "effective amount" or "therapeutic effective amount" refers to the amount of a therapeutic compound (e.g., an anti-IL-13 antibody) administered to an individual as a single dose or as part of a series of doses (alone or in combination with another treatment) that effectively produces or enhances the desired therapeutic effect. Examples of desired therapeutic effects include enhancing the immune response; slowing or delaying tumor development; stabilizing the disease; and improving one or more symptoms. An effective amount can be given in one or more doses.

[0103] The term "treating" (and its variations, such as "treat" or "treatment") refers to a clinical intervention that attempts to alter the natural course of a disease or ailment in a subject in need. Treatment can be administered during the course of the clinical lesion. The desired effects of treatment include preventing disease recurrence, relieving symptoms, mitigating any direct or indirect pathological consequences of the disease, preventing cancer metastasis, slowing the rate of disease progression, improving or alleviating the disease condition, and mitigating or improving prognosis.

[0104] The term "sufficient amount" means an amount sufficient to produce the desired effect, such as an amount sufficient to modulate the immune response of a subject.

[0105] As used herein, the terms “subject,” “patient,” and “individual” are used interchangeably. The terms “subject,” “patient,” or “individual” refer to a mammalian subject. Exemplary subjects include humans, monkeys, dogs, cats, mice, rats, cattle, horses, camels, goats, rabbits, and sheep. In some embodiments, the subject is a human. In some embodiments, the subject suffers from a disease or ailment that can be treated with the antibodies provided herein. In some aspects, the disease or ailment is cancer. In some aspects, the disease or ailment is a viral infection.

[0106] The term "in vitro" refers to processes that occur in living cells that grow separately from living organisms, such as those growing in tissue cultures.

[0107] The term "in vivo" refers to processes that occur within a living organism.

[0108] The term "instructions for use" refers to the package insert that is typically included in the commercial packaging of a therapeutic or diagnostic product (such as a test kit), and contains information about indications, usage, dosage, administration, combination therapy, contraindications, and / or warnings related to the use of such therapeutic or diagnostic products.

[0109] The term "pharmaceutical composition" refers to a formulation that is in a form that permits the biological activity of the active ingredient contained therein to be effective in treating a subject and does not contain any other components that would be unacceptably toxic to the subject in the amount provided in the pharmaceutical composition.

[0110] The terms "co-administration," "co-administer," and "in combination with" include the simultaneous, parallel, or sequential administration of two or more therapeutic agents without a specific time limit. In one embodiment, the agents are simultaneously present in cells or in the subject's body, or exert their biological or therapeutic effects simultaneously. 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 some embodiments, the first agent may be administered prior to the administration of the second therapeutic agent.

[0111] The terms “modulate” and “modulation” refer to reducing or inhibiting, or alternatively activating or increasing, the described variable.

[0112] The terms “increase” and “activation” refer to an increase of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 2 times, 3 times, 4 times, 5 times, 10 times, 20 times, 50 times, 100 times or more in the described variable.

[0113] The terms “reduction” and “suppression” refer to a reduction of the described variable by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 2 times, 3 times, 4 times, 5 times, 10 times, 20 times, 50 times, 100 times or more.

[0114] The term "about" indicates and covers a specified value as well as a range above and below that value. In some embodiments, the term "about" indicates a specified value ± 10%, ± 5%, or ± 1%. In some embodiments, where applicable, the term "about" indicates a specified value ± one standard deviation of the value.

[0115] The term "activator" refers to the activation of receptor signaling to induce a biological response associated with receptor activation. An "agonist" is an entity that binds to a receptor and has an activating effect on it.

[0116] The term "antagonist" refers to the inhibition of receptor signaling to suppress biological responses associated with receptor activation. An "antagonist" is an entity that binds to and antagonizes the receptor.

[0117] For any of the structural and functional features described herein, the methods for determining these features are known in the art.

[0118] The term “optionally” when used sequentially means to include one to all of the listed combinations and to cover all sub-combinations.

[0119] The term "amino acid" refers to twenty common, naturally occurring amino acids. These 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).

[0120] The term "affinity" refers to the strength of the overall non-covalent interaction between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen or epitope). Unless otherwise indicated, as used herein, "affinity" refers to the inherent binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen or epitope).

[0121] As used in this article, the term "kd" (sec⁻¹) refers to the dissociation rate constant of a specific antibody-antigen interaction. This value is also known as the koff value.

[0122] As used in this article, the term "ka" (M⁻¹×sec⁻¹) refers to the association rate constant of a specific antibody-antigen interaction. This value is also known as the kon value.

[0123] As used herein, the term "KD" (M) refers to the dissociation equilibrium constant of a particular antibody-antigen interaction. KD = kd / ka. In some embodiments, the affinity of an antibody is described by the KD of the interaction between such an antibody and its antigen. For clarity, as is known in the art, a smaller KD value indicates a higher affinity interaction, while a larger KD value indicates a lower affinity interaction.

[0124] As used herein, the term "KA" (M-1) refers to the association equilibrium constant of a specific antibody-antigen interaction. KA = ka / kd.

[0125] The term "antibody" is used in its broadest sense here and includes certain types of immunoglobulin molecules that contain one or more antigen-binding domains that specifically bind to an antigen or epitope. Antibodies include, in particular, intact antibodies (e.g., intact immunoglobulins), antibody fragments, and multispecific antibodies.

[0126] "Anti-IL-13 antibody", "IL-13 antibody" or "IL-13 specific antibody" refers to an antibody that specifically binds to the antigen IL-13, as described herein.

[0127] The term "epitope" refers to a portion of an antigen that specifically binds to an antibody.

[0128] As used herein, the term “hypervariant region” or “HVR” refers to each region in the antibody variable domain that exhibits high sequence variability and / or forms a structurally defined loop (“hypervariant loop”).

[0129] The term "antigen-binding domain" refers to the portion of an antibody that can specifically bind to an antigen or epitope.

[0130] The term "chimeric antibody" refers to an antibody in which a portion of the heavy chain and / or light chain originates from a specific source or species, while the remainder of the heavy chain and / or light chain originates from a different source or species.

[0131] The term "human antibody" refers to an antibody having an amino acid sequence corresponding to an antibody produced by a human or human cell, or an amino acid sequence derived from a non-human source using a human antibody profile or a human antibody coding sequence (e.g., obtained from or redesigned from a human source). Human antibodies specifically exclude humanized antibodies.

[0132] The term "humanized antibody" refers to a protein whose sequence differs from that of an antibody derived from a non-human species by one or more amino acid substitutions, deletions, and / or additions, such that when administered to human subjects, the humanized antibody is less likely to induce an immune response and / or induces a less severe immune response compared to the non-human species antibody.

[0133] The term "multispecific antibody" refers to an antibody that contains two or more antigen-binding domains that share a common specificity in binding to two or more different epitopes.

[0134] A "monospecific antibody" is an antibody containing one or more binding sites that specifically bind to a single epitope. An example of a monospecific antibody is the naturally occurring IgG molecule, which, although bivalent (i.e., having two antigen-binding domains), recognizes the same epitope at each of the two antigen-binding domains. Binding specificity can exist at any suitable valence.

[0135] The term "monoclonal antibody" refers to an antibody derived from a population of largely homogeneous antibodies. A population of largely homogeneous antibodies contains antibodies that are largely similar and bind to the same epitopes, excluding variants that may typically occur during monoclonal antibody production. These variants are generally present in small quantities. Monoclonal antibodies are typically obtained through a process involving the selection of a single antibody from a plurality of clones. For example, the selection process may involve choosing a unique clone from a plurality of clones, such as a group of fusionoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody may be further modified, for example, to increase its affinity for the target ("affinity maturation"), humanize the antibody, increase its yield in cell cultures, and / or decrease its immunogenicity in subjects.

[0136] The term "single-chain" refers to a molecule comprising amino acid monomers linearly linked by peptide bonds. In a particular embodiment of this type, in a single-chain Fab molecule, the C-terminus of the Fab light chain is linked to the N-terminus of the Fab heavy chain. As described in more detail herein, the variable domain of the light chain (VL) of the scFv is linked from its C-terminus to the N-terminus of the variable domain of the heavy chain (VH) via a polypeptide chain. Alternatively, the scFv comprises a polypeptide chain in which the C-terminus of the VH is linked to the N-terminus of the VL via a polypeptide chain.

[0137] The “Fab fragment” (also known as the antigen-binding fragment) contains a constant domain (CL) of the light chain and a first constant domain (CH1) of the heavy chain, as well as variable domains VL and VH on the light and heavy chains, respectively. The variable domains contain a complementarity-determining loop (CDR, also known as a hypervariable region) involved in antigen binding. The Fab' fragment differs from the Fab fragment in that it has several residues added at the carboxyl terminus of the CH1 domain of the heavy chain, including one or more cysteine ​​residues from the antibody hinge region.

[0138] The “F(ab’)2” fragment contains two Fab’ fragments connected by disulfide bonds near the hinge region. The F(ab’)2 fragment can be produced, for example, by recombinant methods or by pepsin digestion of an intact antibody. The F(ab’) fragment can be dissociated, for example, by treatment with β-mercaptoethanol.

[0139] The “Fv” fragment contains a non-covalently linked dimer of a heavy chain variable domain and a light chain variable domain.

[0140] A “single-chain Fv” or “sFv” or “scFv” comprises the VH and VL domains of an antibody, wherein these domains are contained within a single polypeptide chain. In one embodiment, the Fv polypeptide also includes a polypeptide linker between the VH and VL domains, which allows the scFv to form the structure required for antigen binding. For a review of scFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, Vol. 113, edited by Rosenburg and Moore, Springer-Verlag, New York, pp. 269–315 (1994). HER2 antibody scFv fragments are described in WO93 / 16185; U.S. Patent No. 5,571,894; and U.S. Patent No. 5,587,458.

[0141] The “scFv-Fc” fragment contains an scFv attached to an Fc domain. For example, the Fc domain may be attached to the C-terminus of the scFv. The Fc domain may follow either 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 contains an IgG4 Fc domain.

[0142] The term "single-domain antibody" or "sdAb" refers to a molecule in which one of the antibody's variable domains specifically binds to the antigen in the absence of other variable domains. Single-domain antibodies and their fragments are described by Arabi Ghahroudi et al. FEBS Letters , 1998, 414:521-526 and Muyldermans et al., Trends in Biochem. Sci. In 2001, 26:230-245, each reference is incorporated in full. Single-domain antibodies are also known as sdAbs or nanobodies. Sdabs are extremely stable and readily express fusion couples with the Fc chain of antibodies (Harmsen MM, De Haard HJ (2007). "Properties, production, and applications of camelids single-domain antibody fragments"). Appl. Microbiol Biotechnol . 77(1): 13-22).

[0143] The terms "full-length antibody," "intact antibody," and "complete antibody" are used interchangeably in this document and refer to an antibody that has a structure substantially similar to that of naturally occurring antibodies and has a heavy chain containing an Fc region. For example, when referring to IgG molecules, a "full-length antibody" is an antibody that contains two heavy chains and two light chains.

[0144] The term "antibody fragment" refers to an antibody that contains a portion of a complete antibody, such as the antigen-binding region or variable region of a complete antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab')2 fragments, Fab' fragments, scFv (sFv) fragments, and scFv-Fc fragments.

[0145] The term "Fc domain" or "Fc region" in this article is used to define the C-terminal region of an immunoglobulin heavy chain containing at least a portion of a constant region. This term includes native Fc regions and variant Fc regions.

[0146] The term “largely purified” means that the construct or variant thereof described herein is substantially or substantially free of components typically associated with or interacting with the protein found in its natural environment (i.e., native cells; or, in the case of antibodies produced in a recombinant manner, host cells), and in some embodiments, is substantially free of cellular material, including protein formulations 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% (on a dry weight) of contaminating protein.

[0147] In the case of two or more nucleic acid or polypeptide sequences, the term "identity" percentage refers to the percentage of identical nucleotide or amino acid residues in two or more sequences or subsequences when comparing and aligning for maximum correspondence, 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 those skilled in the art) or by visual inspection. Software used for performing BLAST analysis is publicly available through the National Center for Biotechnology Information (ncbi.nlm.nih.gov). Those skilled in the art can determine the parameters suitable for aligning sequences, including any algorithm required to achieve maximum alignment across the full length of the sequences being compared. Depending on the application, the "identity" percentage may be present in the compared sequence regions, such as functional domains, or alternatively across the full length of the two sequences to be compared.

[0148] For sequence comparisons, a reference sequence is typically used as the test sequence for comparison. When using a sequence comparison algorithm, the test and reference sequences are input into the computer, with subsequence coordinates specified if necessary, and the sequence comparison algorithm program parameters are also specified. Subsequently, the sequence comparison algorithm calculates the percentage of sequence identity between the test sequence and the reference sequence based on the specified program parameters.

[0149] The best alignment of sequences for comparison can be achieved, for example, by Smith and Waterman. Adv. Appl. Math. The local homology algorithm of 2:482 (1981), through Needleman and Wunsch, J. Mol. Biol. The homology comparison algorithm of 48:443 (1970), through Pearson and Lipman, Proc. Nat'l. Acad. Sci. The similarity search method described in USA 85:2444 (1988) is performed either by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 ScienceDr., Madison, Wis.) or by visual inspection (generally see Ausubel et al., see below).

[0150] The ranges listed in this document should be understood as abbreviations of all values ​​within the range, including the stated endpoints. For example, the range 1 to 50 should be understood as including any number, combination of numbers, or subrange from the following groups: 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.

[0151] It must be noted that, unless the context clearly specifies otherwise, the singular forms “a”, “an” and “the” as used in this specification and the appended claims include a plurality of indicators.

[0152] Anti-IL-13 antibody Antibody structure This application provides compositions comprising an antibody that binds to IL-13 and an antibody that binds to IL-13.

[0153] The identified immunoglobulin genes include κ, λ, α, γ, δ, ε, and μ constant region genes, as well as various immunoglobulin variable region genes. Light chains are classified as κ or λ. 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 main antibody classes: IgA, IgD, IgE, IgG, and IgM, and several of these can be further subdivided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The constant domains of the heavy chain corresponding to different classes of immunoglobulins are respectively named α, δ, ε, γ, and μ.

[0154] An exemplary immunoglobulin (antibody) structural unit consists of two pairs of polypeptide chains, each pair having a "light" chain (approximately 25 kD) and a "heavy" chain (approximately 50-70 kD). The N-terminal domain of each chain defines a variable region of approximately 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 contains VH, CH1, CH2, and CH3 domains from the N-terminus to the C-terminus. The light chain contains VL and CL domains from the N-terminus to the C-terminus. The IgG1 heavy chain includes a hinge between the CH1 and CH2 domains. In some embodiments, the immunoglobulin construct includes at least one immunoglobulin domain from IgG, IgM, IgA, IgD, or IgE, said immunoglobulin domain being linked to a therapeutic polypeptide. In some embodiments, the immunoglobulin domains found in the antibodies provided herein are derived from or derived from immunoglobulin-based constructs, such as double-chain antibodies or nanobodies. In some embodiments, the immunoglobulin constructs described herein comprise at least one immunoglobulin domain derived from a heavy-chain antibody, such as a camelid antibody. In some embodiments, the immunoglobulin constructs provided herein comprise at least one immunoglobulin domain derived from a mammalian antibody, such as a bovine antibody, a human antibody, a camelid antibody, a mouse antibody, or any chimeric antibody.

[0155] In some embodiments, the antibodies provided herein comprise a heavy chain. In one embodiment, the heavy chain is IgA. In one embodiment, the heavy chain is IgD. In one embodiment, the heavy chain is IgE. In one embodiment, the heavy chain is IgG. In one embodiment, the heavy chain is IgM. In one embodiment, the heavy chain is IgG1. In one embodiment, the heavy chain is IgG2. In one embodiment, the heavy chain is IgG3. In one embodiment, the heavy chain is IgG4. In one embodiment, the heavy chain is IgA1. In one embodiment, the heavy chain is IgA2.

[0156] In some embodiments, the antibody is an IgG1 antibody. In some embodiments, the antibody is an IgG3 antibody. In some embodiments, the antibody is an IgG2 antibody. In some embodiments, the antibody is an IgG4 antibody.

[0157] Generally, native four-chain antibodies contain six hypervariable regions (HVRs); three in the VH (H1, H2, and H3) and three in the VL (L1, L2, and L3). The HVRs typically contain amino acid residues from the hypervariable loop and / or from the complementarity-determining region (CDR), which has the highest sequence variability and / or is involved in antigen recognition. Except for CDR1 in the VH, the CDRs generally contain amino acid residues that form the hypervariable loop. HVRs are also referred to as CDRs, and these terms are used interchangeably in this document when referring to the variable region that forms the antigen-binding region. This specific region has been identified by Kabat et al., US Dept. of Health and Human Services, Sequences of Proteins of Immunological Interest (1983) and Chothia et al., J Mol Biol The definitions described in 196:901-917 (1987) include overlaps or subsets of amino acid residues when compared with each other. However, the application of any definition relating to a CDR of an antibody or a variant thereof is intended to be within the scope of the terminology as defined and used herein. The exact number of residues covering a particular CDR will vary depending on the sequence and size of the CDR. In the case of specifying the amino acid sequence of the variable region of an antibody, those skilled in the art can determine in a conventional manner which residues contain a particular CDR.

[0158] The amino acid sequence boundaries of the CDR can be determined by those skilled in the art using any of a variety of known numbering schemes, including those described below: Kabat et al., above (“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 reference is included in full text.

[0159] Table 1 provides the locations 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.

[0160] CDRs can be specified, for example, using antibody numbering software, such as the Abnum available at www.bioinf.org.uk / abs / abnum / , and as described by Abhinandan and Martin. Immunology In , 2008, 45:3832-3839, it is incorporated by full citation.

[0161] Table 1. Residues in the CDR according to the Kabat and Chothia numbering scheme.

[0162] *When using the Kabat numbering convention, the C terminal of CDR-H1 varies between H32 and H34, depending on the length of the CDR.

[0163] When referring to residues in the constant region of the antibody heavy chain, the “EU numbering scheme” is generally used (e.g., as reported by Kabat et al. above). Unless otherwise stated, the EU numbering scheme is used to refer to residues in the constant region of the antibody heavy chain as described herein.

[0164] An example of an antigen-binding domain is one formed by the VH-VL dimer of an antibody. Another example of an antigen-binding domain is one formed by the diversification of certain loops from the type III fibronectin domain of adnectin. An antigen-binding domain may include CDR 1, CDR 2, and CDR 3 from the heavy chain, in the order CDR 1, CDR 2, and CDR 3; and CDR 1, CDR 2, and CDR 3 from the light chain, in the order CDR 1, CDR 2, and CDR 3.

[0165] Epitopes are often composed of surface-accessible amino acid residues and / or sugar side chains and may possess specific three-dimensional structural features and specific charge characteristics. The difference between conformational and non-conformational epitopes is that binding to conformational epitopes may be lost in the presence of denaturing solvents, while binding to non-conformational epitopes will not. Epitopes may contain amino acid residues directly involved in binding and other amino acid residues not directly involved in binding. Antibody-bound epitopes can be determined using known techniques for epitope assays, such as testing the binding of antibodies to IL-13 variants with different point mutations or to chimeric IL-13 variants.

[0166] To screen for antibodies that bind to epitopes on target antigens (e.g., IL-13) that bind to antibodies of interest, conventional cross-blocking assays can be performed, such as those described in *Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory*, edited by Harlow and David Lane (1988). Alternatively or additionally, epitope localization can be performed using methods known in the art.

[0167] Chimeric antibodies are antibodies from a specific source or species in which a portion of the heavy chain and / or light chain is derived, while the remainder of the heavy chain and / or light chain is derived from antibodies from different sources or species.

[0168] Human antibodies are antibodies having an amino acid sequence corresponding to an antibody produced by a human or human cell, or an amino acid sequence derived from a non-human source using a human antibody profile or a human antibody coding sequence (e.g., obtained from or redesigned from a human source). Human antibodies, in particular, exclude humanized antibodies.

[0169] Humanized antibodies have sequences differing from those of antibodies derived from non-human species by one or more amino acid substitutions, deletions, and / or additions, such that when administered to human subjects, humanized antibodies are less likely to induce an immune response and / or induce a less severe immune response compared to antibodies from non-human species. In one embodiment, humanized antibodies are generated by mutating certain amino acids in the framework and constant domains of the heavy and / or light chains of a non-human species antibody. In another embodiment, a constant domain from a human antibody is fused with a variable domain from a non-human species. In yet another embodiment, one or more amino acid residues in one or more CDR sequences of a non-human antibody are altered to reduce the potential immunogenicity of the non-human antibody when administered to a human subject, wherein the altered amino acid residues are not important for the immune-specific binding of the antibody to its antigen, or the alteration to the amino acid sequence is a conserved change 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 prepare humanized antibodies can be found in U.S. Patent 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, where each reference is included in full text.

[0170] Two or more distinct epitopes can be epitopes on the same antigen (e.g., a single IL-13) or on different antigens (e.g., different IL-13 molecules, or IL-13 molecules and non-IL-13 molecules). In some embodiments, the multispecific antibody binds to two distinct epitopes (i.e., a "bispecific antibody"). In some embodiments, the multispecific antibody binds to three distinct epitopes (i.e., a "trispecific antibody").

[0171] Anti-IL-13 antibodies may include those antibodies described herein, such as the clones illustrated in the diagrams 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 antibody fragments. In some embodiments, the antibody consists essentially of antibody fragments.

[0172] In some implementations, the antibody is a monoclonal antibody.

[0173] In some implementations, the antibody is a polyclonal antibody.

[0174] In some embodiments, antibodies are generated via fusion tumors. In other embodiments, antibodies are generated via recombinant cells engineered to express desired variable and constant domains.

[0175] In some implementations, the antibody may be a single-chain antibody or other antibody derivative that retains antigen specificity and the lower hinge region or a variant thereof.

[0176] In some embodiments, the antibody may be a multifunctional antibody, a recombinant antibody, a human antibody, a humanized antibody, a fragment, or a variant thereof. In a particular embodiment, the antibody fragment or its derivative is selected from Fab fragments, Fab′2 fragments, CDRs, and scFvs.

[0177] In some implementations, antibodies can form immune complexes. For example, immune complexes can be tumor cells coated with antibodies.

[0178] For sequence comparisons, a reference sequence is typically used as the test sequence for comparison. When using a sequence comparison algorithm, the test and reference sequences are input into the computer, with subsequence coordinates specified if necessary, and the sequence comparison algorithm program parameters are also specified. Subsequently, the sequence comparison algorithm calculates the percentage of sequence identity between the test sequence and the reference sequence based on the specified program parameters.

[0179] The best alignment of sequences for comparison can be achieved, for example, by Smith and Waterman. Adv. Appl. Math.The local homology algorithm of 2:482 (1981), through Needleman and Wunsch, J. Mol. Biol. The homology comparison algorithm of 48:443 (1970), through Pearson and Lipman, Proc. Nat'l. Acad. Sci.USA Similarity search methods, as described in 85:2444 (1988), are performed either 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 (generally see Ausubel et al., see below).

[0180] An example of an algorithm suitable for determining sequence identity and the percentage of sequence similarity is the BLAST algorithm, described by Altschul et al. J. Mol. Biol. 215:403-410 (1990). The software used for BLAST analysis is available from the National Center for Biotechnology Information (NCBI). www.ncbi.nlm.nih.gov / (Originally obtained)

[0181] IL-13 antibody sequence VH domain In some embodiments, the antibodies provided herein comprise a VH sequence selected from SEQ ID NO: 1-32.

[0182] In some embodiments, the antibodies provided herein comprise a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the exemplary VH sequences provided in SEQ ID NO: 1-32. In some embodiments, the antibodies provided herein comprise a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the exemplary VH sequences provided in SEQ ID NO: 1-32. H The sequence has at most 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 conserved. In some embodiments, the antibody described in this paragraph is referred to herein as a "variant". In some embodiments, such variants are derived from the 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 the sequence provided herein and can be re-isolated, for example, according to the methods provided herein for obtaining antibodies.

[0183] VL domain In some embodiments, the antibodies provided herein comprise a VL sequence selected from SEQ ID NO: 33-57.

[0184] In some embodiments, the antibodies provided herein comprise a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the exemplary VL sequence provided in SEQ ID NO: 33-57. In some embodiments, the antibodies provided herein comprise the VL sequence provided in SEQ ID NO: 33-57 having at most 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 conserved 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 the sequences 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 implementations, such variants are not derived from the sequences provided herein and can be re-isolated, for example, according to the methods provided herein for obtaining antibodies.

[0185] VH-VL combination In some embodiments, the antibodies provided herein comprise a VH sequence selected from SEQ ID NO: 1-32; and a VL sequence selected from SEQ ID NO: 33-57, such as the VH-VL combinations shown in constructs 3-127 and 132-144 in Table 2 below.

[0186] In some respects, any of SEQ ID NO: 1-32 may be combined with any of SEQ ID NO: 33-57.

[0187] In some embodiments, the antibody comprises a VH sequence selected from the sequences shown in SEQ ID NO: 1-32 and a VL sequence shown in SEQ ID NO: 49.

[0188] In some embodiments, the antibody comprises a VH sequence selected from the sequences shown in SEQ ID NO: 1-32 and a VL sequence shown in SEQ ID NO: 51.

[0189] In some embodiments, the antibodies provided herein comprise a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the VH sequence provided in SEQ ID NO: 1-32; and a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the VL sequence provided in SEQ ID NO: 33-57. In some embodiments, the antibodies provided herein comprise the VH sequence provided in SEQ ID NO: 1-32, having 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 the VL sequence provided in SEQ ID NO: 33-57, having 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 conserved. In some embodiments, the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from the sequences 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 the sequences provided herein and can be re-isolated, for example, according to the methods provided herein for obtaining antibodies.

[0190] In some embodiments, the antibodies provided herein comprise a VH sequence and a VL sequence selected from the combinations shown in 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 therewith. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 1 and the VL sequence shown in SEQ ID NO: 33. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 2 and the VL sequence shown in SEQ ID NO: 33. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 3 and the VL sequence shown in SEQ ID NO: 35. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 4 and the VL sequence shown in SEQ ID NO: 35. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 5 and the VL sequence shown in SEQ ID NO: 35. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 6 and the VL sequence shown in SEQ ID NO: 35. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 7 and the VL sequence shown in SEQ ID NO: 35. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 3 and the VL sequence shown in SEQ ID NO: 36. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 4 and the VL sequence shown in SEQ ID NO: 36. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 5 and the VL sequence shown in SEQ ID NO: 36. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 6 and the VL sequence shown in SEQ ID NO: 36. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 7 and the VL sequence shown in SEQ ID NO: 36. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 3 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 4 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 5 and the VL sequence shown in SEQ ID NO: 39.In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 6 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 7 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 3 and the VL sequence shown in SEQ ID NO: 40. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 4 and the VL sequence shown in SEQ ID NO: 40. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 5 and the VL sequence shown in SEQ ID NO: 40. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 6 and the VL sequence shown in SEQ ID NO: 40. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 7 and the VL sequence shown in SEQ ID NO: 40. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 8 and the VL sequence shown in SEQ ID NO: 42. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 9 and the VL sequence shown in SEQ ID NO: 43. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 7 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 7 and the VL sequence shown in SEQ ID NO: 44. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 7 and the VL sequence shown in SEQ ID NO: 45. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 7 and the VL sequence shown in SEQ ID NO: 46. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 7 and the VL sequence shown in SEQ ID NO: 47. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 7 and the VL sequence shown in SEQ ID NO: 48. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 7 and the VL sequence shown in SEQ ID NO: 49. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 7 and the VL sequence shown in SEQ ID NO: 50.In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 7 and the VL sequence shown in SEQ ID NO: 51. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 7 and the VL sequence shown in SEQ ID NO: 52. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 7 and the VL sequence shown in SEQ ID NO: 53. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 7 and the VL sequence shown in SEQ ID NO: 54. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 7 and the VL sequence shown in SEQ ID NO: 55. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 7 and the VL sequence shown in SEQ ID NO: 56. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 7 and the VL sequence shown in SEQ ID NO: 57. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 10 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 11 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 12 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 13 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 14 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 15 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 16 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 17 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 18 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 19 and the VL sequence shown in SEQ ID NO: 39.In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 20 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 21 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 22 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 23 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 24 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 25 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 26 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 27 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 28 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 28 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 29 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 30 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 31 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 32 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 8 and the VL sequence shown in SEQ ID NO: 39. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 8 and the VL sequence shown in SEQ ID NO: 51. In some embodiments, the antibody comprises the VH sequence shown in SEQ ID NO: 3 and the VL sequence shown in SEQ ID NO: 51.

[0191] In some embodiments, the isolated antibody comprises a heavy chain variable domain comprising a frame region sequence selected from the sequences shown below: SEQ ID NO: 198-229, 255-256, 258-259, 261-285, 311-315, 317-342, 368-369, 371-399, and 540-580. In some embodiments, the isolated antibody comprises a heavy chain variable domain comprising one, two, three, or four frame region sequences selected from the sequences shown below: SEQ ID NO: 198-229, 255-256, 258-259, 261-285, 311-315, 317-342, 368-369, 371-399, and 540-580.

[0192] In some embodiments, the isolated antibody comprises a light chain variable domain comprising a frame region sequence selected from the sequences shown below: SEQ ID NO: 230-231, 233-235, 239, 241-254, 286, 288, 290-291, 293, 296-310, 343-345, 347, 400-424, and 581-609. In some embodiments, the isolated antibody comprises one, two, three, or four light chain variable domains comprising a frame region sequence selected from the sequences shown below: SEQ ID NO: 230-231, 233-235, 239, 241-254, 286, 288, 290-291, 293, 296-310, 343-345, 347, 400-424, and 581-609.

[0193] In some embodiments, the isolated antibody comprises a heavy chain variable domain comprising one, two, three, or four frame region sequences selected from the sequences shown below: SEQ ID NO: 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 one, two, three, or four frame region sequences selected from the sequences shown below: SEQ ID NO: 230-231, 233-235, 239, 241-254, 286, 288, 290-291, 293, 296-310, 343-345, 347, 400-424, and 581-609.

[0194] Table 2. VH-VL sequence of anti-interleukin (IL)-13 antibody

[0195] *The names correspond to the names in the informal sequence list. In some embodiments, the VH domain listed in any of constructs 3-127 and 132-144 in Table 2 may be combined with the heavy chain constant (HC) domain provided herein. In some embodiments, the anti-IL-13 antibody comprises a VH domain selected from any of 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 with it, and a heavy chain constant (HC) domain comprising a sequence selected from any of SEQ ID NO: 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 with it. This document anticipates each combination of (1) the VH / VL domains listed in constructs 3-127 and 132-144 of Table 2 with (2) the HC domain. In some embodiments, the VH domain listed in any of constructs 3-127 and 132-144 of Table 2 may be combined with the heavy chain constant (HC) domain provided herein. In some embodiments, the anti-IL-13 antibody comprises a VH domain selected from any of 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 with the VH domain, and an HC domain comprising a sequence selected from any of SEQ ID NO: 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 with the HC domain. In some embodiments, the HC domain is an IgG1 HC domain. In some embodiments, the VL domain of any of the constructs 3-127 and 132-144 in Table 2 is combined with an IgG1 light chain constant (LC) domain. In some implementations, the VL domain of any of the constructs 3-127 and 132-144 in Table 2 is combined with an LC domain containing SEQ ID NO: 469 or with an LC domain having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it.

[0196] In some implementations, the HC domain includes IgG4-SP, hIgG1-LALA-YTE, hIgG1-LAGA YTE, hIgG1-LALA-LS, IgG4-YTE HC, and IgG4-LS.

[0197] In some implementations, this type of IgG4-SP HC constant domain has the following sequence: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 427).

[0198] In some implementations, this type of hIgG1-LALA-YTE HC constant domain has the following sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 439).

[0199] In some implementations, this type of hIgG1-LAGA YTE HC constant domain has the following sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELAGAPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 440).

[0200] In some implementations, this type of hIgG1-LALA-LS HC constant domain has the following sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG (SEQ ID NO: 446).

[0201] In some implementations, this type of IgG4-YTE HC constant domain has the following sequence: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 457).

[0202] In some implementations, this type of IgG4-LS HC constant domain has the following sequence: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHSYTQKSLSLSLGK (SEQ ID NO: 460).

[0203] In some implementations, the constant domain of this type of hIgG1-LALA-YTE HC C-terminal lysine variant has the following sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 624).

[0204] In some implementations, the constant domain of this type of hIgG1-LAGA YTE HC C-terminal lysine variant has the following sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELAGAPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 625).

[0205] In some implementations, the constant domain of this type of hIgG1-LALA-LS HC C-terminal lysine variant has the following sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (SEQ ID NO: 631).

[0206] In some embodiments, the VL domains listed in constructs 3-127 and 132-144 in Table 2, or VL domains having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with them, may be combined with the light chain constant (LC) domains provided herein. In some embodiments, the LC domain is a human κ LC constant domain. In some embodiments, such human κ LC constant domains have the following sequence: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 469).

[0207] CDR In some embodiments, the antibodies provided herein comprise one to three CDRs selected from the VH domain of SEQ ID NO: 1-32, such as any of the CDRs listed in Tables 3, 4, or 5 below. In some embodiments, the antibodies provided herein comprise two to three CDRs selected from the VH domain of SEQ ID NO: 1-32. In some embodiments, the antibodies provided herein comprise three CDRs selected from the VH domain of SEQ ID NO: 1-32. In some embodiments, the CDRs are exemplary CDRs. In some embodiments, the CDR is the Kabat CDR. In some embodiments, the CDR is the Chothia CDR. In some embodiments, the CDR is the IMGT CDR. In some embodiments, the CDR is the AbM CDR. In some embodiments, the CDR is the Contact CDR.

[0208] In some embodiments, the CDR is a CDR having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with CDR-H1, CDR-H2, or CDR-H3 of SEQ ID NO: 58-140. In some embodiments, CDR-H1 is a CDR-H1 selected from the VH domain of SEQ ID NO: 1-32, having at most 1, 2, 3, 4, or 5 amino acid substitutions. In some embodiments, CDR-H2 is a CDR-H2 of the VH domain of SEQ ID NO: 1-32, having at most 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, CDR-H3 is a CDR-H3 selected from the VH domain of SEQ ID NO: 1-32, having at most 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conserved amino acid substitutions. In some embodiments, the antibody described in this paragraph is referred to herein as a "variant". In some embodiments, such variants are derived from the 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 the sequence provided herein and can be re-isolated, for example, according to the methods provided herein for obtaining antibodies.

[0209] In some embodiments, the antibodies provided herein comprise one to three CDRs of the VL domain of SEQ ID NO: 33-57, such as any of the CDRs listed in Tables 6, 7, or 8 below. In some embodiments, the antibodies provided herein comprise two to three CDRs of the VL domain of SEQ ID NO: 33-57. In some embodiments, the antibodies provided herein comprise three CDRs of the VL domain of SEQ ID NO: 33-57. In some embodiments, the CDRs are exemplary CDRs. In some embodiments, the CDR is the Kabat CDR. In some embodiments, the CDR is the Chothia CDR. In some embodiments, the CDR is the IMGT CDR. In some embodiments, the CDR is the AbM CDR. In some embodiments, the CDR is the Contact CDR.

[0210] In some embodiments, the CDR is a CDR having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with CDR-L1, CDR-L2, or CDR-L3 of SEQ ID NO: 141-188. In some embodiments, CDR-L1 is the CDR-L1 of the VL domain of SEQ ID NO: 33-57, having at most 1, 2, 3, 4, or 5 amino acid substitutions. In some embodiments, CDR-L2 is the CDR-L2 of the VL domain of SEQ ID NO: 33-57, having at most 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, CDR-L3 is the CDR-L3 of the VL domain of SEQ ID NO: 33-57, having at most 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conserved 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 the sequences 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 the sequences provided herein and can be re-isolated, for example, according to the methods provided herein for obtaining antibodies.

[0211] In some embodiments, the antibodies provided herein comprise one to three CDRs of the VH domain selected from SEQ ID NO: 1-32 and one to three CDRs of the VL domain selected from SEQ ID NO: 33-57. In some embodiments, the antibodies provided herein comprise two to three CDRs of the VH domain selected from SEQ ID NO: 1-32 and two to three CDRs of the VL domain selected from SEQ ID NO: 33-57. In some embodiments, the antibodies provided herein comprise three CDRs of the VH domain selected from SEQ ID NO: 1-32 and three CDRs of the VL domain selected from SEQ ID NO: 33-57. In some embodiments, the CDRs are exemplary CDRs. In some embodiments, the CDR is a Kabat CDR. In some embodiments, the CDR is a Chothia CDR. In some embodiments, the CDR is an IMGT CDR. In some embodiments, the CDR is an AbM CDR. In some embodiments, the CDR is a Contact CDR.

[0212] In some embodiments, the antibodies provided herein comprise CDR-H3 selected from SEQ ID NO: 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 the CDR-H3 of SEQ ID NO: 112-120 or 130-40. In some embodiments, the CDR-H3 is selected from CDR-H3 of SEQ ID NO: 112-120 and 130-40, having at most 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conserved 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 the sequences 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 implementations, such variants are not derived from the sequences provided herein and can be re-isolated, for example, according to the methods provided herein for obtaining antibodies.

[0213] In some embodiments, the antibodies provided herein comprise CDR-H1 of SEQ ID NO: 58-99 and 121. In some embodiments, CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with CDR-H1 of SEQ ID NO: 58-99 or 121. In some embodiments, CDR-H1 is CDR-H1 of SEQ ID NO: 58-99 or 121, having at most 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conserved 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 the sequences 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 implementations, such variants are not derived from the sequences provided herein and can be re-isolated, for example, according to the methods provided herein for obtaining antibodies.

[0214] In some embodiments, the antibody provided herein comprises CDR-H2 of any of SEQ ID NO: 100-111. In some embodiments, CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with CDR-H2 of any of SEQ ID NO: 100-111. In some embodiments, CDR-H2 is CDR-H2 of any of SEQ ID NO: 100-111, having at most 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conserved amino acid substitutions. In some embodiments, the antibody described in this paragraph is referred to herein as a “variant.” In some embodiments, such variants are derived from the sequences 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 implementations, such variants are not derived from the sequences provided herein and can be re-isolated, for example, according to the methods provided herein for obtaining antibodies.

[0215] In some embodiments, the antibodies provided herein comprise CDR-L3 selected from SEQ ID NO: 165-172. In some embodiments, CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with CDR-L3 of SEQ ID NO: 165-172. In some embodiments, CDR-L3 is CDR-L3 of SEQ ID NO: 165-172, having at most 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conserved 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 the sequences 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 the sequences provided herein and can be re-isolated, for example, according to the methods provided herein for obtaining antibodies.

[0216] In some embodiments, the antibodies provided herein comprise CDR-L2 selected from SEQ ID NO: 153-158 and the amino acid sequence LAS. In some embodiments, CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with CDR-L2 selected from SEQ ID NO: 153-158 and the amino acid sequence LAS. In some embodiments, CDR-L2 is CDR-L2 selected from SEQ ID NO: 153-158 and the amino acid sequence LAS, having at most 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conserved 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 the sequences 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 implementations, such variants are not derived from the sequences provided herein and can be re-isolated, for example, according to the methods provided herein for obtaining antibodies.

[0217] In some embodiments, the antibodies provided herein comprise CDR-L1 selected from SEQ ID NO: 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 the CDR-L1 selected from SEQ ID NO: 141-144 and 149-152. In some embodiments, the CDR-L1 is the CDR-L1 selected from SEQ ID NO: 141-144 and 149-152, having at most 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conserved 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 the sequences 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 implementations, such variants are not derived from the sequences provided herein and can be re-isolated, for example, according to the methods provided herein for obtaining antibodies.

[0218] In some embodiments, the antibodies provided herein comprise CDR-H3 selected from SEQ ID NO: 112-120 and 130-140, CDR-H2 selected from SEQ ID NO: 100-111, CDR-H1 selected from SEQ ID NO: 58-99 and 121, CDR-L3 selected from SEQ ID NO: 165-172, CDR-L2 selected from SEQ ID NO: 153-158 and amino acid sequence LAS, and CDR-L1 selected from SEQ ID NO: 141-144 and 149-152. In some embodiments, CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with CDR-H3 selected from SEQ ID NO: 112-120 and 130-140; CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with CDR-H2 selected from SEQ ID NO: 100-111; CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with CDR-H1 selected from SEQ ID NO: 58-99 and 121; and CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with CDR-H3 selected from SEQ ID NO: 112-120 and 130-140. CDR-L3 of NO:165-172 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with CDR-L2 selected from SEQ ID NO: 153-158 and amino acid sequence LAS, and CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with CDR-L2 selected from SEQ ID NO: 141-144 and 149-152.In some embodiments, CDR-H3 is selected from SEQ ID NO: 112-120 and 130-140, having at most 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; CDR-H2 is selected from SEQ ID NO: 100-111, having at most 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; CDR-H1 is selected from SEQ ID NO: 58-99 and 121, having at most 1, 2, 3, 4, or 5 amino acid substitutions; CDR-L3 is selected from SEQ ID NO: 165-172, having at most 1, 2, 3, 4, or 5 amino acid substitutions; CDR-L2 is selected from SEQ ID NO: 112-120 and 130-140, having at most 1, 2, 3, 4, or 5 amino acid substitutions; CDR-L2 is selected from SEQ ID NO: 112-120 and 130-140, having at most 1, 2, 3, 4, or 5 amino acid substitutions; CDR-L2 of SEQ ID NO:153-158 and amino acid sequence LAS, having at most 1, 2, 3 or 4 amino acid substitutions; and CDR-L1 is selected from SEQ ID NO: 141-144 and 149-152, having at most 1, 2, 3, 4, 5 or 6 amino acid substitutions.

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

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

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

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

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

[0224] In some embodiments, the amino acid substitutions are conserved amino acid substitutions. In some embodiments, the antibodies described herein are referred to as “variants” or “clones.” In some embodiments, such variants or clones are derived from the sequences 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 the sequences provided herein and can be re-isolated, for example, according to the methods provided herein for obtaining antibodies.

[0225] In some respects, the antibodies disclosed herein do not include those disclosed in U.S. Patent No. 9,067,994.

[0226] Fc region The structure of the Fc region of different immunoglobulins and the glycosylation sites therein are known in the art. See Schroeder and Cavacini, J. Allergy Clin. Immunol., 2010, 125:S41-52, which are incorporated herein by reference in their entirety. The Fc region can be a naturally occurring Fc region or a modified Fc region as described elsewhere in the art or in this disclosure.

[0227] Unless otherwise stated herein, the amino acid residues in the Fc region or constant region are numbered according to the EU numbering system, also known as 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. As used herein, an “Fc polypeptide” of a dimer Fc refers to one of the two polypeptides forming the dimer Fc domain, i.e., a polypeptide containing the C-terminal constant region of the immunoglobulin heavy chain, which is capable of stable self-association. For example, the Fc polypeptide of a dimer IgG Fc contains the IgG CH2 and IgG CH3 constant domain sequences. Fc can belong to the classes IgA, IgD, IgE, IgG, and IgM, and some of these can be further subdivided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0228] The terms “Fc receptor” and “FcR” are used to describe receptors that bind to the Fc region of an antibody. For example, an FcR can be a native human FcR sequence. Generally, an FcR is an FcR (γ receptor) that binds to IgG antibodies and includes receptors of the FcγRI, FcγRII, and FcγRIII subclasses (including allelic variants and alternative splicing forms of these receptors). FcγRII receptors include FcγRIIA (“activating receptor”) and FcγRIIB (“inhibiting receptor”), both having similar amino acid sequences, differing primarily in their cytoplasmic domains. Other isoimmunoglobulins can also be bound by certain FcRs (see, for example, Janeway et al., Immuno Biology: the immune system in health and disease (Elsevier Science Ltd., NY) (4th ed., 1999)). The activating receptor FcγRIIA contains an immunoreceptor tyrosine activation motif (ITIM) in its cytoplasmic domain. The inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine inhibitory motif (ITIM) in its cytoplasmic domain. (Commentary by Daëron) Annu. Rev. Immunol. 15:203-234 (1997). FcR commented on 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. Med126:330-41 (1995). Other FcRs, including those to be identified in the future, are covered by the term "FcR" herein. The term also includes neonatal receptor FcRn, which is responsible for delivering maternal IgG 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 Fc receptors to Fc. Various amino acid modifications in the Fc region are known in the art for selectively altering the affinity of Fc for different Fcγ receptors. In some respects, Fc contains one or more modifications that promote the selective binding of Fc-γ receptors.

[0230] The following are exemplary mutations that alter the binding of FcR to Fc: S298A / E333A / K334A, S298A / E333A / K334A / K326A (Lu Y, Vernes JM, Chiang N et al., J Immunol Methods February 28, 2011; 365(1-2):132-41); F243L / R292P / Y300L / V305I / P396L, F243L / R292P / Y300L / L235V / P396L (Stavenhagen JB, Gorlatov S, Tuaillon N et al.) Cancer Res September 15, 2007; 67(18):8882-90; Nordstrom JL, Gorlatov S, Zhang W et al. Breast Cancer Res . November 30, 2011; 13(6):R123); F243L (Stewart R, Thom G, Levens M, et al.) Protein Eng Des Sel September 2011; 24(9):671-8.), S298A / E333A / K334A (Shields RL, Namenuk AK, Hong K et al., J Biol Chem March 2, 2001; 276(9):6591-604); S239D / I332E / A330L, S239D / I332E (Lazar GA, Dang W, Karki S et al., Proc Natl Acad Sci U S AMarch 14, 2006; 103(11):4005-10); S239D / S267E, S267E / L328F (Chu SY, Vostiar I, Karki S et al., Mol Immunol September 2008; 45(15):3926-33); The following mutations are listed in S239D / D265S / S298A / I332E, S239E / S298A / K326A / A327H, G237F / S298A / A330L / 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, which are incorporated herein by reference. Therapeutic Antibody Engineering (William R. Strohl and Lila M. Strohl, Woodhead Publishingseries in Biomedicine, Vol. 11, ISBN 1 907568 37 9, October 2012) The mutations are listed on page 283.

[0231] In some embodiments, the antibodies described herein include modifications that enhance their ability to mediate effector function. Such modifications are known in the art and include defucosylation, or Fc affinity engineering for activating receptors, primarily FCGR3a for ADCC and C1q for CDC. Table 9 below summarizes the different designs reported in the literature for effector function engineering.

[0232] Methods for generating antibodies with little or no fucose at the Fc glycosylation site (Asn 297 EU number) without altering the amino acid sequence are well known in the art. GlymaX® technology (ProBioGen AG) is based on the introduction of genes into cells that derail the cellular pathway of fucose biosynthesis. This prevents the sugar “fucose” from being added to the N-linked carbohydrate moiety of the antibody by the antibody-producing cell. (von Horsten et al. (2010)) Glycobiology(December 2010; 20(12):1607-18.) Another method for obtaining antibodies with reduced levels of fucosylation can be found in U.S. Patent No. 8,409,572, which teaches the selection of cell lines capable of producing antibodies with lower levels of fucosylation for antibody production, which may be completely defucosylated (meaning they contain no detectable fucosylation) or partially defucosylated, 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 fucosylation typically detected by similar antibodies produced by mammalian expression systems.

[0233] Therefore, in one embodiment, the antibody described herein may comprise a dimer Fc containing one or more amino acid modifications as indicated in Table 9, said amino acid modifications conferring improved effector function. In another embodiment, the antibody may be defucosylated to improve effector function.

[0234] Table 9. Engineering of CH2 domains and functionalities

[0235] Fc modifications that reduce FcgR and / or complement binding and / or effector function are known in the art. Recent publications describe strategies that have been used to engineer antibodies with reduced or silenced effector activity (see Strohl, WR (2009)). Curr Opin Biotech 20:685-691 and Strohl, WR and Strohl LM, “Antibody Fc engineering for optimal antibody performance”, Therapeutic Antibody Engineering, Cambridge: Woodhead Publishing (2012), pp. 225-249). These strategies include reducing effector function through glycosylation modification, using an IgG2 / IgG4 scaffold, or introducing mutations in the hinge or CH2 region 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 Strohl et al. (2012). J. Mol. Biol. 420: 204-219) describes specific modifications for reducing FcgR or complement binding to Fc.

[0236] Specific non-limiting examples of known amino acid modifications that reduce FcgR or complement binding to Fc include those identified in Table 10 below: Table 10. Modifications used to reduce FcgR or complement binding to Fc

[0237] Methods for generating antibodies with little or no fucose at the Fc glycosylation site (Asn 297 EU number) without altering the amino acid sequence are well known in the art. GlymaxX® technology (ProBioGen AG) is based on the introduction of genes into cells that derail the cellular pathway of fucose biosynthesis. This prevents the addition of the sugar "fucose" to the N-linked carbohydrate moiety of the antibody by the antibody-producing cell. (von Horsten et al. (2010)) Glycobiology 2010; 20 (12):1607-18. Examples of cell lines capable of producing defucosylated antibodies include CHO-DG44 cells stably overexpressing the bacterial oxidoreductase GDP-6-deoxy-D-lythose-4-hexose reductase (RMD) (see von Horsten et al., 2010, ibid.) or Lec13 CHO cells lacking protein fucosylation (see Ripka et al., 2010; 20 (12):1607-18.). Arch. Biochem. Biophys. , 1986, 249:533-545; US Patent Publication No. 2003 / 0157108; WO 2004 / 056312; each of which is incorporated herein by reference in its entirety) and gene knockout cell lines, such as α-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. (See , 2006, 94:680-688; and WO 2003 / 085107; each of which is incorporated herein by reference in its entirety). Another method for obtaining antibodies with reduced levels of fucosylation can be found in U.S. Patent No. 8,409,572, which teaches the selection of cell lines capable of producing antibodies with lower levels of fucosylation for antibody production.

[0238] Examples of cell lines capable of producing defucosylated antibodies include CHO-DG44 cells with stable overexpression of the bacterial oxidoreductase GDP-6-deoxy-D-lythose-4-hexose reductase (RMD) (see von Horsten et al., 2010, ibid.) or Lec13 CHO cells lacking protein fucosylation (see Ripka et al., ...). Arch. Biochem. Biophys. , 1986, 249:533-545; US Patent Publication No. 2003 / 0157108; WO 2004 / 056312; each of which is incorporated herein by reference in its entirety) and gene knockout cell lines, such as α-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 herein by reference in its entirety.

[0239] The antibody may be completely defucosylated (meaning it contains no detectable fucose) or partially defucosylated, meaning 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 typically detected by similar antibodies produced by mammalian expression systems.

[0240] In some respects, the antibody presented herein contains an IgG1 domain with reduced fucose content at position Asn297, compared to the naturally occurring IgG1 domain. Such Fc domains are known to have improved ADCC. See Shields et al. J. Biol. Chem. , 2002, 277:26733-26740, which is incorporated herein by reference in its entirety. In some respects, this type of antibody does not contain any fucose at position Asn 297. The amount of fucose can be determined using any suitable method, such as that described in WO 2008 / 077546, which is incorporated herein by reference in its entirety.

[0241] In some embodiments, the antibodies provided herein comprise an Fc region having one or more amino acid substitutions having a modified ADCC, such as substituted Fc regions at positions 298, 333, and 334. In some embodiments, the antibodies provided herein comprise Fc regions having one or more amino acid substitutions at positions 239, 332, and 330, as in Lazar et al. Proc. Natl. Acad. Sci. USA,As described in 2006, 103:4005-4010 (incorporated in full).

[0242] Other exemplary glycosylation variants of the antibodies described herein may be incorporated into, for example, U.S. Patent Publication No. 2003 / 0157108, 2004 / 0093621, 2003 / 0157108, 2003 / 0115614, 2002 / 0164328, 2004 / 0093621, 2004 / 0132140, 2004 / 0110704, 2004 / 0110282, 2004 / 0109865; International Patent Publication 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 in full by reference.

[0243] In some embodiments, the antibodies provided herein comprise at least one galactose residue of an oligosaccharide attached to the Fc region. Such antibody variants may have modified CDC function. Examples of such antibody variants are described, for example, in WO1997 / 30087, WO 1998 / 58964 and WO 1999 / 22764; each of which is incorporated herein by reference in its entirety.

[0244] In some embodiments, the antibodies provided herein comprise one or more alterations that modify or reduce C1q binding and / or CDC. See U.S. Patent No. 6,194,551; WO 99 / 51642; and Idusogie et al. J. Immunol ., 2000, 164:4178-4184; each of which is incorporated in full by reference.

[0245] In some embodiments, the antibodies provided herein comprise a heavy chain having a constant heavy chain (HC) region comprising the amino acid sequence shown in SEQ ID NO: 439 or SEQ ID NO: 624.

[0246] In some embodiments, the antibody provided herein comprises a constant light chain (LC) region containing the amino acid sequence shown in SEQ ID NO: 469.

[0247] In some embodiments, the antibody provided herein comprises: (1) a constant heavy chain (HC) region comprising the amino acid sequence shown in SEQ ID NO: 439 or SEQ ID NO: 624, or an HC region comprising an amino acid sequence having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO: 439 or SEQ ID NO: 624; (2) a constant light chain (LC) region comprising the amino acid sequence shown in SEQ ID NO: 469, or an LC region comprising an amino acid sequence having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO: 469; (3) a VH region comprising the amino acid sequence shown in SEQ ID NO: 3, or a VH region having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO: 3; and (4) a region comprising SEQ ID NO: VL of the amino acid sequence shown in SEQ ID NO: 39 or VL containing an amino acid sequence having at least 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 39.

[0248] In some embodiments, the isolated antibody comprises a heavy chain constant (HC) region comprising the amino acid sequence shown in SEQ ID NO: 439 or 624 and a light chain constant (LC) region comprising the amino acid sequence shown in SEQ ID NO: 469, wherein the antibody further comprises a VH region comprising an amino acid sequence having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO: 3 and a VL region comprising an amino acid sequence having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO: 39, wherein VH comprises HCDR1 comprising SEQ ID NO: 58, SEQ ID NO: 68, or SEQ ID NO: 85; HCDR2 comprising SEQ ID NO: 100, SEQ ID NO: 104, or SEQ ID NO: 108; and HCDR3 comprising SEQ ID NO: 112 or SEQ ID NO: 130; and VL comprises a region comprising SEQ ID NO: 624, SEQ ID NO: 439, SEQ ID NO: 624, SEQ ID NO: 424, SEQ ID NO: 424, SEQ ID NO: 424, SEQ ID NO: 6 ... LCDR1 containing SEQ ID NO: 141 or SEQ ID NO: 149; LCDR2 containing SEQ ID NO: 153 or SEQ ID NO: 164 and LCDR3 containing SEQ ID NO: 165.

[0249] In some embodiments, the Fc region contains one or more amino acid substitutions, wherein, compared to an Fc region without said one or more substitutions, said one or more substitutions cause an increase in antibody half-life, ADCC activity, ADCP activity, or CDC activity. In some embodiments, said one or more amino acid substitutions cause an increase in antibody half-life at pH 6.0 compared to an antibody containing a wild-type Fc region.

[0250] In some embodiments, one or more amino acid substitutions are 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 some embodiments, one or more amino acid substitutions comprise 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, LALAG A / 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. ;

[0251] In some embodiments, the Fc region binds to an Fcγ receptor selected from the group consisting of: FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, and FcγRIIIb. In some embodiments, the Fc region binds to the Fcγ receptor with higher affinity at pH 6.0 compared to antibodies containing a wild-type Fc region.

[0252] Modification YTE replaces In some embodiments, the crystallizable region (Fc region) of the anti-IL-13 antibody fragment described herein carries a trisubstituted M252Y / S254T / T256E (YTE), which is designed to prolong the half-life of IgG. The YTE substitution (also referred to herein as the YTE mutation) increases the binding of modified IgG to the human neonatal Fc receptor (FcRn). FcRn-bound IgG is recycled via lysosomal rescue, causing IgG to return to circulation. Therefore, compared to unmodified IgG, the YTE mutation confers greater FcRn-IgG binding, prolonging the serum half-life of IgG.

[0253] LALA replaces In some embodiments, the anti-IL-13 antibodies described herein additionally carry Fc region amino acid substitutions L234A / L235A in the IgG1 heavy chain, commonly referred to as LALA substitutions or LALA mutations. These changes weaken the binding of the Fc receptor to IgG and prevent unwanted effector cell activation.

[0254] Combination In some embodiments, the anti-IL-13 antibody described herein is a high-affinity humanized IgG1 monoclonal antibody (mAb) that binds to IL-13. In some embodiments, the anti-IL-13 antibody described herein contains an IgG1 constant region comprising YTE and LALA substitutions.

[0255] Not wanting to be bound by theory, I believe that the anti-IL-13 antibody described in this article binds to IL-13 and prevents the formation of the IL-13Rα1 / IL-4Rα active receptor heterodimer and subsequent IL-13-mediated signal transduction. Direct consequences of IL-13 signaling in the pathology of atopic dermatitis (AD) include skin thickening and CD4+. + Increased T-cell infiltration and skin barrier disruption. Therefore, it is believed that preventing the formation of receptor heterodimers reduces the clinical severity of AD.

[0256] The affinity of molecule X for its partner Y can be expressed by the dissociation equilibrium constant (K). D The following describes in more detail the dynamic components that contribute to the dissociation equilibrium constant. Affinity can be measured by common methods known in the art, including those described herein, such as surface plasma resonance (SPR) techniques (e.g., BIACORE®) or biolayer interferometry (e.g., FORTEBIO®).

[0257] Regarding antibody binding to target molecules, the terms "binding," "specific binding" to a specific antigen (e.g., a peptide target) or an epitope on a specific antigen, "specifically binding" to it, "specifically binding" to it, "selectively binding" to it, and "selectively binding" to it all refer to binding that is measurably different from nonspecific or nonselective interactions (e.g., with non-target molecules). Specific binding can be measured, for example, by measuring binding to a target molecule (i.e., IL-13) and comparing it to binding to non-target molecules. Specific binding can also be determined by competing with a control molecule that mimics an epitope recognized on a target molecule. In that case, if the binding of the antibody to the target molecule is competitively inhibited by the control molecule, specific binding is indicated. In some embodiments, the affinity of the anti-IL-13 antibody for non-target molecules is less than about 50% of its affinity for IL-13. In some embodiments, the affinity of the anti-IL-13 antibody for non-target molecules is less than about 40% of its affinity for IL-13. In some embodiments, the anti-IL-13 antibody has an affinity for non-target molecules less than about 30% of its affinity for IL-13. In some embodiments, the anti-IL-13 antibody has an affinity for non-target molecules less than about 20% of its affinity for IL-13. In some embodiments, the anti-IL-13 antibody has an affinity for non-target molecules less than about 10% of its affinity for IL-13. In some embodiments, the anti-IL-13 antibody has an affinity for non-target molecules less than about 1% of its affinity for IL-13. In some embodiments, the anti-IL-13 antibody has an affinity for non-target molecules less than about 0.1% of its affinity for IL-13.

[0258] When used herein in the context of two or more antibodies, the terms “competing with” or “cross-competing with” indicate that two or more antibodies compete to bind to an antigen (e.g., IL-13). In one exemplary assay, IL-13 is coated onto a surface and contacted with a first anti-IL-13 antibody, followed by the addition of a second anti-IL-13 antibody. In another exemplary assay, a first anti-IL-13 antibody is coated onto a surface and contacted with IL-13, followed by the addition of a second anti-IL-13 antibody. If the presence of the first anti-IL-13 antibody reduces the binding of the second anti-IL-13 antibody in either assay, the antibodies compete with each other. The term “competing with” also includes combinations of antibodies in which one antibody reduces the binding of another antibody, but where no competition is observed when the antibodies are added in reverse order. However, in some embodiments, the first and second antibodies inhibit each other’s binding regardless of the order in which they are added. In some embodiments, the competitive binding assay measures that an antibody reduces the 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%. Those skilled in the art can select the concentration of the antibody used in the competitive assay based on the antibody's affinity for IL-13 and the antibody valence. The assays described in this definition are illustrative, and those skilled in the art can use any suitable assay to determine whether antibodies compete with each other. Suitable assays are described, for example, in Cox et al., “Immunoassay Methods”, 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 in full by reference.

[0259] If, in a competitive binding assay, an excess of the test antibody (e.g., at least 2×, 5×, 10×, 20×, or 100×) inhibits or blocks the binding of the reference antibody by, for example, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%, then the test antibody competes with the reference antibody. Antibodies identified by a competitive assay (competitive antibody) include antibodies that bind to the same epitope as the reference antibody and antibodies that bind to adjacent epitopes sufficiently close to the epitope bound by the reference antibody, thus causing steric hindrance. For example, a second competitive antibody can be identified as competing with the first antibody described herein for binding to IL-13. In some cases, in a competitive binding assay, the second antibody can block or inhibit the binding of the first antibody by, for example, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. In some cases, the second antibody can displace the first antibody by more than 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.

[0260] In some implementations, the antibody binds to the IL-13 sequence shown in SEQ ID NO: 472-475.

[0261] In some implementations, the antibody is measured by surface plasma resonance (SPR) at a value less than or equal to about 1 × 10⁻⁶. - 9 M, 2×10 -9 M, 3×10 -9 M, 4×10 -9 M, 5×10 -9 M, 6×10 -9 M, 7×10 -9 M, 8×10 -9 M, 9×10 -9 M of K D It binds to the IL-13 sequence shown in SEQ ID NO: 472-475. In some embodiments, the antibody binds to a concentration less than or equal to about 1 × 10⁻⁶ by surface plasma resonance (SPR) measurement. -10 M of K D It binds to the IL-13 sequence shown in SEQ ID NO: 472-475. In some embodiments, the antibody binds to a concentration less than or equal to about 1 × 10⁻⁶ by surface plasma resonance (SPR) measurement. -9 M of K D It binds to human IL-13.

[0262] In some embodiments, the antibody presented herein is measured by ELISA or any other suitable method known in the art to be less than or equal to about 0.01 × 10⁻⁶. -8 M, 0.02×10-8 M, 0.03×10 -8 M, 0.04×10 -8 M, 0.05×10 -8 M, 0.06×10 -8 M, 0.07×10 -8 M, 0.08×10 -8 M, 0.09×10 -8 M, 0.1×10 -8 M, 0.2×10 -8 M, 0.3×10 -8 M, 0.4×10 -8 M, 0.5×10 -8 M, 0.6×10 -8 M, 0.7×10 -8 M, 0.8×10 -8 M, 0.9×10 -8 M, 1×10 -8 M, 1.1×10 -8 M, 1.2×10 -8 M, 1.3×10 -8 M, 1.4×10 -8 M, 1.5×10 -8 M, 1.6×10 -8 M, 1.7×10 -8 M, 1.8×10 -8 M, 1.9×10 -8 M, 1.95×10 -8 M, 2×10 -8 M, 2.5×10 -8 M, 3×10 -8 M, 3.5×10 -8 M, 4×10 -8 M, 4.5×10 -8 M, 5×10 -8 M, 6×10 -8 M, 7×10 -8 M, 8×10 -8 M, 9×10 -8 M or 10×10 -8 M of K D Binding to IL-13. In some embodiments, the antibody provided herein, when measured by ELISA or any other suitable method known in the art, yields a value less than or equal to about 0.01 × 10⁻⁶. -9 M, 0.02×10 -9 M, 0.03×10 -9 M, 0.04×10 -9 M, 0.05×10 -9M, 0.06×10 -9 M, 0.07×10 -9 M, 0.08×10 -9 M, 0.09×10 -9 M, 0.1×10 -9 M, 0.2×10 -9 M, 0.3×10 -9 M, 0.4×10 -9 M, 0.5×10 -9 M, 0.6×10 -9 M, 0.7×10 -9 M, 0.8×10 -9 M, 0.9×10 -9 M, 1×10 -9 M, 1.1×10 -9 M, 1.2×10 -9 M, 1.3×10 -9 M, 1.4×10 -9 M, 1.5×10 -9 M, 1.6×10 -9 M, 1.7×10 -9 M, 1.8×10 -9 M, 1.9×10 -9 M, 1.95×10 -9 M, 2×10 -9 M, 2.5×10 -9 M, 3×10 -9 M, 3.5×10 -9 M, 4×10 -9 M, 4.5×10 -9 M, 5×10 -9 M, 6×10 -9 M, 7×10 -9 M, 8×10 -9 M, 9×10 -9 M or 10×10 -9 M of K D Combined with IL-13.

[0263] In some embodiments, the K+ binding of the antibody provided herein to IL-13 is measured by ELISA or any other suitable method known in the art. DBetween approximately 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 5-10×10 -8 Between M. In some embodiments, the antibody provided herein, when measured by ELISA or any other suitable method known in the art, is less than or equal to about 1 × 10⁻⁶. -8 M is less than or equal to 1×10 -9 M of K D Combined with IL-13.

[0264] In some embodiments, the antibodies provided herein are measured by ELISA or any other suitable method known in the art to be less than or equal to about 10 × 10⁻⁶. -8 M, 9×10 -8 M, 8×10 -8 M, 7×10 -8 M, 6×10 -8 M, 5×10 -8 M, 4.5×10 -8 M, 4×10 -8 M, 3.5×10 -8 M, 3×10 -8 M, 2.5×10 -8 M, 2×10 -8 M, 1.98×10 -8 M, 1.95×10 - 8 M, 1.9×10 -8 M, 1.85×10 -8 M, 1.8×10 -8 M, 1.75×10 -8 M, 1.7×10 -8 M, 1.65×10 -8 M, 1.6×10 - 8 M, 1.55×10 -8 M, 1.50×10 -8 M, 1.45×10 -8 M, 1.4×10 -8 M, 1.3×10 -8 M, 1.2×10-8 M, 1.1×10 - 8 M, 1×10 -8 M, 0.9×10 -8 M, 0.85×10 -8 M, 0.8×10 -8 M, 0.75×10 -8 M, 0.7×10 -8 M, 0.65×10 -8 M, 0.6×10 -8 M, 0.55×10 -8 M, 0.5×10 -8 M, 0.45×10 -8 M, 0.4×10 -8 M, 0.35×10 -8 M, 0.3×10 -8 M, 0.25×10 -8 M, 0.2×10 -8 M, 0.15×10 -8 M, 0.1×10 -8 M, 0.05×10 -8 M, 0.01×10 -8 M, 0.005×10 - 8 M, 0.001×10 -8 M, 0.0005×10 -8 M or 0.0001×10 -8 M of K D Combined with IL-13. In some embodiments, the antibodies provided herein are measured by ELISA or any other suitable method known in the art in 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 × 10⁻¹⁰. -8 K between M D Combined with IL-13.

[0265] In some embodiments, the antibodies provided herein have an IC50 duration 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. 50Inhibits pSTAT6. In some embodiments, the antibody provided herein has an IC50 concentration between approximately 85 and approximately 100 days, between approximately 90 and approximately 95 days, or between approximately 91 and approximately 93 days. 50 Inhibition of pSTAT6. In some embodiments, pSTAT6 inhibition is determined by administering the antibody provided herein to a mammal, collecting whole blood, staining with a fluorescent anti-pSTAT6 antibody, and measuring the antibody concentration required to inhibit 50% of the maximum MFI of pSTAT6 using FACS. In some embodiments, pSTAT6 inhibition is determined by contacting cells with IL-13 or IL-4 and the antibody provided herein, staining the cells with a fluorescent anti-pSTAT6 antibody, and measuring the antibody concentration required to inhibit 50% of the maximum MFI of pSTAT6 using FACS.

[0266] Pharmaceutical Composition This application provides compositions comprising antibodies, said compositions comprising one or more of the antibodies described herein and one or more pharmaceutically acceptable excipients. In some embodiments, the composition is sterile. The pharmaceutical composition generally contains an effective amount of antibody.

[0267] In some aspects, the composition comprises 150 mg / mL, 180 mg / mL, or 200 mg / mL of the anti-IL-13 antibody described herein. In some embodiments, the anti-IL-13 antibody comprises a VH comprising the amino acid sequence shown in SEQ ID NO: 3 and a VL comprising the amino acid sequence shown in SEQ ID NO: 39. In some embodiments, the anti-IL-13 antibody comprises a light chain variable domain comprising a frame region sequence selected from the sequences shown 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 with 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 with SEQ ID NO: 39, wherein the VH comprises HCDR1 comprising SEQ ID NO: 58, SEQ ID NO: 68, or SEQ ID NO: 85; HCDR2 comprising SEQ ID NO: 100, SEQ ID NO: 104, or SEQ ID NO: 108; and HCDR2 comprising SEQ ID NO: 112 or SEQ ID NO: 108. HCDR3 of 130; and VL contains LCDR1 containing SEQ ID NO: 141 or SEQ ID NO: 149; LCDR2 containing SEQ ID NO: 153 or SEQ ID NO: 164 and LCDR3 containing SEQ ID NO: 165.

[0268] In addition to one or more of the antibodies disclosed herein, these compositions may contain pharmaceutically acceptable excipients, carriers, buffers, stabilizers, 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 may depend on the route of administration, such as oral, intravenous, skin or subcutaneous, nasal, intramuscular, or intraperitoneal routes.

[0269] In some embodiments, the composition comprises a histidine buffer, arginine and / or methionine, and optionally a surfactant and / or sucrose. In some embodiments, the surfactant is a polysorbate (e.g., polysorbate 80) or poloxamer (e.g., poloxamer 188).

[0270] Pharmaceutical compositions intended for oral administration may be in tablet, capsule, powder, or liquid form. Tablets may 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 oil, mineral oil, or synthetic oil. They may include physiological saline solutions, dextran or other sugar solutions, or glycols (e.g., ethylene glycol, propylene glycol, or polyethylene glycol).

[0271] For intravenous, subcutaneous, or subcutaneous injection, or injection at the site of pain, the active ingredient will be in a parenteral acceptable aqueous solution that is pyrogen-free and has suitable pH, isotonicity, and stability. Those skilled in the art are fully capable of preparing suitable solutions using, for example, isotonic media (e.g., sodium chloride injection, Ringer's injection, lactated Ringer's injection). Preservatives, stabilizers, buffers, antioxidants, and / or other additives may be included as needed.

[0272] Anti-IL-13 antibodies to be administered to an individual are preferably given at a “therapeutic effective dose” or a “prophylactic effective dose” (whichever is appropriate, but prophylaxis can be considered a therapy), which is sufficient to demonstrate benefit to the individual. The actual dose administered, as well as the rate and timing of administration, will depend on the nature and severity of the protein aggregation disorder being treated. Treatment prescriptions, such as dosage determination, are within the purview of general practitioners and other physicians, and generally take into account the condition being treated, the individual patient’s condition, the site of delivery, the method of administration, and other factors known to the physician. Examples of the techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed.), 1980.

[0273] The composition may be administered alone or in combination with other treatments simultaneously or sequentially, depending on the disease being treated.

[0274] method Preparation method The antibodies described herein can be generated using recombinant methods and compositions, such as those described in U.S. Patent No. 4,816,567. In one embodiment, an isolated nucleic acid encoding the antibody described herein is provided. Such nucleic acid may encode an amino acid sequence comprising a VL of the antibody and / or an amino acid sequence comprising a VH of the antibody (e.g., the light chain and / or heavy chain of the antibody) or an amino acid sequence comprising a VH of a single-domain antibody. In another embodiment, one or more vectors (e.g., expression vectors) comprising such nucleic acids are provided. In one embodiment, the nucleic acid is provided in a polycistronic vector. In another embodiment, a host cell comprising such nucleic acids is provided. In one such embodiment, the host cell comprises (e.g., having been transformed with): (1) a vector comprising nucleic acids encoding an amino acid sequence comprising a VL of the antibody and an amino acid sequence comprising a VH of an antigen-binding polypeptide construct; or (2) a first vector comprising nucleic acids encoding an amino acid sequence comprising a VL of the antigen-binding polypeptide construct, and a second vector comprising nucleic acids encoding an amino acid sequence comprising a VH of the antigen-binding polypeptide construct. In one embodiment, the host cell is a eukaryotic cell, such as Chinese hamster ovary (CHO) cells or human embryonic kidney (HEK) cells or lymphocytes (e.g., Y0, NSO, Sp20 cells). In one embodiment, a method for manufacturing an antibody is provided, wherein the method includes culturing a host cell containing nucleic acid encoding an antibody as described above under conditions suitable for antibody expression and optionally recovering the antibody from the host cell (or host cell culture medium).

[0275] To recombinantly generate antibodies, nucleic acids encoding antibodies, such as those described above, are isolated and inserted into one or more vectors for further cloning and / or expression in host cells. These nucleic acids can be readily isolated and sequenced using standard procedures, such as by using oligonucleotide probes capable of specifically binding to genes encoding the heavy and light chains of antibodies.

[0276] When antibodies or their variants are recombinantly produced by host cells, in some embodiments, the protein 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 cell dry weight. When antibodies or their variants are recombinantly produced by host cells, in some embodiments, the protein 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 cell dry weight. In some embodiments, the "corporately purified" antibody produced by the methods described herein is determined by appropriate methods such as SDS / PAGE analysis, RP-HPLC, SEC, and capillary electrophoresis to have 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, at least about 75%, 80%, 85%, and more specifically, at least about 90%, at least about 95%, at least about 99%, or greater.

[0277] Suitable host cells for cloning or expressing vectors encoding antibodies include prokaryotic or eukaryotic cells as described herein.

[0278] Recombinant host cells, or host cells in general, are cells comprising exogenous polynucleotides, regardless of the method used for insertion, such as direct uptake, transduction, f-factor conjugation, or other methods known in the art for generating recombinant host cells. The exogenous polynucleotides may be maintained as non-integrating vectors, such as plasmids, or alternatively, may be integrated into the host genome. Host cells may include CHO, CHO derivatives, NSO, Sp2O, CV-1, VERO-76, HeLa, HepG2, Per.C6, or BHK.

[0279] For example, antibodies can be produced in bacteria, especially where glycosylation and Fc effector function are not required. For information on the expression of antibody fragments and peptides in bacteria, see, for example, U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523 (see also Charlton, Methods in Molecular Biology, Vol. 248 (edited by BKC Lo, HumanaPress, Totowa, NJ, 2003), pp. 245–254, which describes the expression of antibody fragments in *E. coli*). After expression, the antibody can be separated from the bacterial cell paste as a soluble fraction and can be further purified.

[0280] Besides prokaryotes, eukaryotic microorganisms such as filamentous fungi or yeasts are suitable hosts for cloning or expressing antibody-encoding vectors, including fungal and yeast strains whose glycosylation pathways have been "humanized," resulting in antibodies with partial or complete human glycosylation patterns. See Gerngross. Nat. Biotech 22:1409-1414 (2004) and Li et al., Nat. Biotech 24:210-215 (2006).

[0281] Suitable host cells for expressing glycosylated antibodies also originate from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant cells and insect cells. Several baculovirus strains have been identified that can be used in combination with insect cells, particularly for transfecting the fall armyworm (Pterocarya stenoptera). Spodoptera frugiperda )cell.

[0282] Plant cell cultures can also be used as hosts. See, for example, U.S. Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (which describe PLATNIBODIES™ technology for generating antibodies in transgenic plants).

[0283] Vertebrate cells can also be used as hosts. For example, mammalian cell lines suitable for growth in suspension are applicable. Other examples of suitable mammalian host cell lines include the monkey kidney CV1 line transformed with SV40 (COS-7); human embryonic kidney cell lines (such as those described by Graham et al., ...). J. Gen Virol. 293 or 293 cells as described in 36:59 (1977); young hamster kidney cells (BHK); mouse sertoli cells (e.g., in Mather, Biol. Reprod. TM4 cells described in 23:243-251 (1980); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical cancer cells (HELA); canine kidney cells (MDCK); Buffalo rat liver cells (BRL 3A); human lung cells (W138); human hepatocytes (Hep G2); mouse mammary tumors (MMT 060562); as in, for example, Mather et al. Annals, NY Acad. Sci. TRI cells as described in 383:44-68 (1982); MRC 5 cells; and FS4 cells. Other suitable 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, NSO, and Sp2 / 0. For reviews of certain mammalian host cell lines suitable for antibody production, see, for example, Yazaki and Wu, Methods in Molecular Biology Volume 248 (edited by BKC Lo, HumanaPress, Totowa, NJ), pp. 255-268 (2003).

[0284] In one embodiment, the antibody described herein is generated in stable mammalian cells by a method comprising: transfecting at least one stable mammalian cell with a nucleic acid encoding the antibody at a predetermined ratio; and expressing the nucleic acid in at least one mammalian cell. In some embodiments, the predetermined nucleic acid ratio is determined in a transient transfection assay to determine the relative ratio of the input nucleic acid that produces the highest percentage of antibody in the expressed product.

[0285] In some embodiments, it is a method of generating antibodies in stable mammalian cells as described herein, wherein the expression product of at least one stable mammalian cell contains a larger percentage of the desired glycosylated antibody compared to a single heavy chain or light chain polypeptide or other antibody.

[0286] In some embodiments, the method involves generating glycosylated antibodies in stable mammalian cells as described herein, the method comprising identifying and purifying the desired glycosylated antibody. In some embodiments, the identification is performed by one or both of liquid chromatography and mass spectrometry.

[0287] If necessary, antibodies can be purified or isolated after expression. Proteins can be isolated or purified using a variety of methods known to those skilled in the art. Standard purification methods include chromatographic techniques, including ion exchange, hydrophobic interactions, affinity, size determination, or gel filtration and reversed-phase chromatography, performed at atmospheric pressure or under high pressure using systems such as FPLC and HPLC. Purification methods also include electrophoresis, immunoassay, precipitation, dialysis, and chromatographic focusing techniques. Ultrafiltration and diafiltration techniques combined with protein concentration are also applicable. As is well known in the art, many natural proteins bind to Fc and antibodies, and these proteins can be used in this invention to purify antibodies. For example, bacterial proteins A and G bind to the Fc region. Similarly, bacterial protein L binds to the Fab region of some antibodies. Purification can often be achieved using specific fusion couplers. For example, glutathione resin (if using GST fusions), Ni +2Purify the antibody using affinity chromatography (if His-tagged) or immobilized anti-flag antibody (if flag-tagged). For general guidance on suitable purification techniques, see, for example, Protein Purification: Principles and Practice, 3rd Edition, Scopes, Springer-Verlag, NY, 1994, which is incorporated in full. The required level of purification will vary depending on the intended use of the antibody. In some cases, purification is unnecessary.

[0288] In some implementations, anion exchange chromatography is used to purify antibodies, including (but not limited to) chromatography on Q-agarose gel, DEAE agarose gel, poros HQ, poros DEAF, Toyopearl Q, Toyopearl QAE, Toyopearl DEAE, Resource / Source Q and DEAE, and Fractogel Q and DEAE columns.

[0289] In certain embodiments, the proteins described herein are purified using cation exchange chromatography, including (but not limited to) SP-agarose gel, CM agarose gel, poros HS, poros CM, Toyopearl SP, Toyopearl CM, Resource / Source S and CM, Fractogel S and CM columns, and their equivalents and analogues.

[0290] Furthermore, the antibodies described herein can be chemically synthesized using techniques known in the art (see, for example, Creighton, 1983, Proteins: Structures and Molecular Principles, WHFreeman & Co., NY, and Hunkapiller et al.). Nature, 310:105-111 (1984)). For example, peptides corresponding to polypeptide fragments can be synthesized using a peptide synthesizer. Furthermore, non-classical amino acids or chemical amino acid analogs can be introduced as substitutions or additions to the polypeptide sequence, as needed. Generally, non-classical amino acids include (but are not limited to) D-isomers of common amino acids, 2,4-diaminobutyric acid, α-aminoisobutyric acid, 4-aminobutyric acid, Abu, 2-aminobutyric acid, g-Abu, e-Ahx, 6-aminohexanoic acid, Aib, 2-aminoisobutyric acid, 3-aminopropionic acid, ornithine, leucine, valine, hydroxyproline, sarcosine, citrulline, homocitrulline, sulfoalanine, tert-butylglycine, tert-butylalanine, phenylglycine, cyclohexylalanine, alanine, fluoroamino acids, designer amino acids (e.g., methyl amino acids, C-methyl amino acids, N-methyl amino acids), and amino acid analogs. In addition, amino acids can be D (dextral) or L (levorotatory).

[0291] How to use This application provides methods for treating inflammatory conditions or diseases, such as atopic dermatitis, in patients in need. In some embodiments, the patient has been diagnosed with moderate to severe atopic dermatitis. In some embodiments, the patient has had moderate to severe atopic dermatitis for at least one year. In some embodiments, the patient is a pediatric patient.

[0292] In some implementations, the patient has one or more of the following: (a) an Eczema Area and Severity Index (EASI) score ≥10 (e.g., EASI ≥16 or EASI ≥10 and <16), (b) an Investigator Global Assessment (IGA) score ≥3, and (c) a Body Surface Area (BSA) ≥10%. In some implementations, the patient's Eczema Area and Severity Index (EASI) score is ≥10. In some implementations, the patient's Eczema Area and Severity Index (EASI) score is ≥16. In some implementations, the patient's Eczema Area and Severity Index (EASI) score is ≥10 and <16. In some implementations, the patient's Investigator Global Assessment (IGA) score is ≥3. In some implementations, the patient's Body Surface Area (BSA) is ≥10%.

[0293] The Investigator Global Assessment (IGA) is an assessment measure used to comprehensively rate the severity of AD in patients (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 uses descriptive words that best describe the overall appearance of the lesion at a given time point to select the score. Not all features under morphological description are required. IGA can be performed before EASI and BSA assessment.

[0294] The Eczema Area and Severity Index (EASI) is a measure used in clinical settings to assess the severity and extent of Alzheimer's disease (AD) (Hanifin et al.). Exp Dermatol. EASI (2001; 10:11-18) is a composite index with scores ranging from 0 to 72, where higher values ​​indicate more severe and / or extensive disease. The severity of erythema, induration / papules, epidermal shedding, 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 following four body regions: head and neck, trunk, upper extremities, and lower extremities, with half-scores allowed. Furthermore, the extent of AD involvement in each of the four body regions can be assessed as a percentage of the body surface area of ​​the head, trunk, upper extremities, and lower extremities, and converted to a score of 0 to 6. The total score (0-72) is specified based on the sum of the total scores for each of the four body regions. In clinical trial settings, the terms “EASI-50,” “EASI-75,” and “EASI-90” indicate EASI improvement in more than 50%, 75%, and 90% of patients, respectively.

[0295] The "SCORAD" score is an effective clinical tool developed by the European Task Force on Atopic Dermatitis for assessing the extent and severity of atopic dermatitis (AD) (Consensus report of the European Task Force on Atopic Dermatitis. Dermatology. 1993;186(l):23-31). It assesses three components: (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 (designated as "A" in the overall SCORAD calculation); and (ii) the severity of six AD symptoms: redness, swelling, oozing / scabbing, epidermal shedding, thickening / lichenification of the skin, and dryness. Each symptom is rated as follows: none (0), mild (1), moderate (2), or severe (3) (totaling a maximum of 18 points, designated as “B” in the overall SCORAD calculation); (iii) subjective assessments of itching and insomnia for each symptom are recorded using the Visual Analogue Scale (VAS), where 0 represents no itching (or insomnia) and 10 represents the most severe itching (or insomnia) imaginable, with a maximum possible score of 20 (designated as “C” in the overall SCORAD calculation). The SCORAD index formula is: A / 5 + 7B / 2 + C. The maximum possible score for the SCORAD index is 103.

[0296] The Numerical Rating Scale for Pruritus (NRS) is an 11-point scale that patients (and, if applicable, with the assistance of a parent / caregiver) use to rate the severity of their most severe pruritus over the past 24 hours, where 0 represents "no pruritus" and 10 represents "the most severe pruritus imaginable" (Phan NQ et al.). Acta Derm Venereol 2012; 92:502-507). Patients used an electronic diary to record assessment results daily. The baseline pruritus NRS was determined based on the mean of the daily pruritus NRS over the most recent 7 days prior to baseline. This calculation required at least 4 daily scores over the most recent 7 days prior to baseline.

[0297] The Sleep Deprivation Scale assesses insomnia caused by pruritus using a 5-point Likert scale (scoring from 0 [completely absent], 1 [slightly], 2 [moderate], 3 [significant] to 4 [completely unable to sleep]). Patients will record their assessment results daily using an electronic diary. In some implementations, the Sleep Deprivation Scale is the Atopic Dermatitis Sleep Scale (ADSS).

[0298] The Patient Oriented Eczema Measure (POEM) is a valid 7-item questionnaire completed by the patient (and, if applicable, with the assistance of a parent / caregiver) to assess disease symptoms over the past 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 answer 7 questions about dry skin, itching, peeling, cracking, sleep deprivation, bleeding, and oozing. All 7 answers are weighted equally, with a total possible score from 0 to 28 (answer scores are: none = 0; 1-2 days = 1; 3-4 days = 2; 5-6 days = 3; daily = 4). High scores indicate poor quality of life. POEM responses are obtained weekly using an electronic diary.

[0299] The Dermatology Quality of Life Index (DLQI) is a 10-item questionnaire completed by patients or caregivers to assess the impact of dermatology on patients' quality of life (Finlay, AY and Khan, GK 1994). Clinical and Experimental Dermatology September 23, 1993; 19:210-216). Ten questions covered the following topics: symptoms over the past week, distress, shopping and home care, clothing, social and leisure activities, exercise, work or study, intimate relationships, sex, and therapy. Each question was rated on a scale of 0 to 3 ("not present at all," "slightly," "many," and "very many"), resulting in a total score ranging from 0 to 30. High scores indicated poor quality of life.

[0300] In some embodiments, the methods described herein include measuring one or more of the following patient characteristics at baseline, during the induction period, and after the induction period: Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Body Surface Area (BSA), Numerical Rating Scale for Pruritus (NRS), Sleep Deprivation Scale, Atopic Dermatitis Rating Scale (SCORAD), Patient-Oriented Eczema Measurement (POEM), and Dermatology Quality of Life Index (DLQI). In some embodiments, the methods described herein include measuring the following patient characteristic at baseline, during the induction period, and after the induction period: Eczema Area and Severity Index (EASI). In some embodiments, the methods described herein include measuring the following patient characteristic at baseline, during the induction period, and after the induction period: Investigator Global Assessment (IGA). In some embodiments, the methods described herein include measuring the following patient characteristic at baseline, during the induction period, and after the induction period: Body Surface Area (BSA). In some embodiments, the methods described herein include measuring the following patient characteristic at baseline, during the induction period, and after the induction period: Numerical Rating Scale for Pruritus (NRS). In some embodiments, the methods described herein include measuring the following patient characteristics at baseline, during the induction period, and after the induction period: Sleep Deprivation Scale, Atopic Dermatitis Rating Scale (SCORAD). In some embodiments, the methods described herein include measuring the following patient characteristics at baseline, during the induction period, and after the induction period: Patient-Directed Eczema Measurement (POEM). In some embodiments, the methods described herein include measuring the following patient characteristics at baseline, during the induction period, and after the induction period: Dermatology Quality of Life Index (DLQI).

[0301] In some implementations, the patients described herein were measured to have one or more of the following characteristics at baseline, during the induction period, and after the induction period: Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Body Surface Area (BSA), Numerical Rating Scale for Pruritus (NRS), Numerical Rating Scale for Skin Pain (SP-NRS), Sleep Deprivation Scale, Scoliosis Atopic Dermatitis Rating (SCORAD), Patient-Oriented Eczema Measurement (POEM), Dermatology Quality of Life Index (DLQI), Asthma Control Questionnaire-5 (ACQ-5) score, and Sinus Outcome Test-22 (SNOT-22) score. In some implementations, the patients described herein were measured to have a characteristic Eczema Area and Severity Index (EASI) at baseline, during the induction period, and after the induction period. In some implementations, the patients described herein were measured to have a characteristic Investigator Global Assessment (IGA) at baseline, during the induction period, and after the induction period. In some implementations, the patients described herein were measured to have a characteristic Body Surface Area (BSA) at baseline, during the induction period, and after the induction period. In some implementations, patients in this study were assessed with the Characteristic Pruritus Numerical Rating Scale (NRS) at baseline, during the induction period, and after the induction period. In some implementations, patients in this study were assessed with the Characteristic Skin Pain Numerical Rating Scale (SP-NRS) at baseline, during the induction period, and after the induction period. In some implementations, patients in this study were assessed with the Characteristic Sleep Deprivation Scale and the Atopic Dermatitis Rating (SCORAD) at baseline, during the induction period, and after the induction period. In some implementations, patients in this study were assessed with the Characteristic Patient-Oriented Eczema Measurement (POEM) at baseline, during the induction period, and after the induction period. In some implementations, patients in this study were assessed with the Characteristic Dermatology Quality of Life Index (DLQI) at baseline, during the induction period, and after the induction period. In some implementations, patients in this study were assessed with the Characteristic Asthma Control Questionnaire 5-Item Version (ACQ-5) score at baseline, during the induction period, and after the induction period. In some implementations, patients in this study were assessed with the Characteristic Nasal and Sinus Outcome Test 22-Item Version (SNOT-22) score at baseline, during the induction period, and after the induction period.

[0302] In one aspect, this application provides a method for contacting IL-13 with an anti-IL-13 antibody (e.g., a human antibody or a humanized antibody) to inhibit the binding of IL-13 to the IL-13 receptor expressed on cells.

[0303] In one aspect, this application provides a method for treating a subject's condition or disease using the isolated anti-IL-13 antibody described herein. In another aspect, this application describes a method for treating a subject in need using an anti-IL-13 antibody, the method comprising administering to a mammalian subject a therapeutically effective amount of the anti-IL-13 antibody or a pharmaceutical composition comprising the anti-IL-13 antibody described herein. In some embodiments, this application provides a method for treating a subject with a condition or disease associated with elevated IL-13 and / or IgE levels.

[0304] In some respects, this article describes a method for treating lesions associated with IL-13 activity, the method comprising administering to a mammalian subject a therapeutically effective amount of an isolated anti-IL-13 antibody or a pharmaceutical composition comprising an isolated anti-IL-13 antibody as described herein.

[0305] In some aspects, this document describes a method for treating an inflammatory condition or disease in a mammalian subject of need, the method comprising administering to the mammalian subject a therapeutically effective amount of the antibody or pharmaceutical composition described herein. In some embodiments, the inflammatory condition or disease is atopic dermatitis. In some embodiments, the inflammatory condition or disease is asthma. In some embodiments, the inflammatory condition or disease is idiopathic pulmonary fibrosis.

[0306] In some respects, this article describes a method for treating lesions associated with elevated IL-13 levels in mammalian subjects in need, the method comprising administering to the mammalian subject a therapeutically effective amount of the antibody or pharmaceutical composition described herein.

[0307] In some respects, this article describes methods for reducing the biological activity of IL-13 in mammalian subjects in need, the methods comprising administering to the mammalian subject a therapeutically effective amount of the antibody or pharmaceutical composition described herein.

[0308] In some respects, this article describes a method for suppressing TH2-type allergic reactions in mammalian subjects in need, the method comprising administering to the mammalian subject a therapeutically effective amount of the antibody or pharmaceutical composition described herein.

[0309] In some respects, this article describes a method for reducing thymus and activation-regulated chemokine (TARC) / CCL17 levels in mammalian subjects in need, the method comprising administering a therapeutically effective amount of the antibody or pharmaceutical composition described herein to the mammalian subject.

[0310] In some respects, this article describes methods for preventing inflammatory conditions or diseases in mammalian subjects in need, methods comprising administering to the mammalian subject a therapeutically effective amount of the antibody or pharmaceutical composition described herein.

[0311] Dosing regimen In one aspect, this application provides a method for treating atopic dermatitis in a patient in need, 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 induction dose 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. (a) an anti-IL-13 antibody at a dose of 150 mg or any of the doses listed in Tables 11-13; and (b) one or more maintenance doses, said maintenance doses being administered approximately 4-16 weeks (e.g., approximately 5-15 weeks, 6-14 weeks, 7-13 weeks, 8-12 weeks, 9-11 weeks, or 10 weeks) or longer (e.g., 17 weeks, 18 weeks, 19 weeks, or 20 weeks) after the first induction dose; wherein said maintenance dose is an anti-IL-13 antibody at a dose of 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 the doses listed in Table 14. The anti-IL-13 antibody may be selected from the anti-IL-13 antibodies disclosed herein. In some embodiments, the anti-IL-13 antibody comprises: a heavy chain variable region (VH) comprising an amino acid sequence as shown in SEQ ID NO: 3 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it; and a light chain variable region (VL) comprising an amino acid sequence as shown in SEQ ID NO: 39 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it. In some embodiments, VH includes HCDR1 containing SEQ ID NO: 58, SEQ ID NO: 68, or SEQ ID NO: 85; HCDR2 containing SEQ ID NO: 100, SEQ ID NO: 104, or SEQ ID NO: 108; and HCDR3 containing SEQ ID NO: 112 or SEQ ID NO: 130; and VL includes LCDR1 containing SEQ ID NO: 141 or SEQ ID NO: 149; LCDR2 containing SEQ ID NO: 153 or SEQ ID NO: 164; and LCDR3 containing SEQ ID NO: 165.

[0312] In some implementations, one to five or more induction doses comprise two to three induction doses.

[0313] In some embodiments, one to five or more induction doses comprise one induction dose. In some embodiments, one to five or more induction doses comprise two induction doses. In some embodiments, one to five or more induction doses comprise three induction doses. In some embodiments, one to five or more induction doses comprise four induction doses. In some embodiments, one to five or more induction doses comprise five induction doses.

[0314] In some embodiments, one to five induction doses are each 100 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 125 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 150 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 180 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 200 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 250 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 300 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 350 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 360 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 400 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 450 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 500 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 550 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 600 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 650 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 700 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 720 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 750 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 800 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 850 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 900 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 950 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 1000 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 1050 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 1100 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 1150 mg of anti-IL-13 antibody. In some embodiments, one to five induction doses are each 1200 mg of anti-IL-13 antibody.

[0315] In some implementations, one to five induction doses are each any dose of anti-IL-13 antibody listed in any of Tables 11-13.

[0316] In some embodiments, one or more of the one to five induction doses is 100 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses is 125 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses is 150 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses is 180 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses is 200 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses is 250 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses is 300 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses is 350 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses is 360 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses is 400 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses is 450 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses is 500 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses is 550 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses is 600 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses is 650 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses is 700 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses is 720 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses is 750 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses is 800 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses is 850 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses are 900 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses are 950 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses are 1000 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses are 1050 mg of anti-IL-13 antibody.In some embodiments, one or more of the one to five induction doses is 1100 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses is 1150 mg of anti-IL-13 antibody. In some embodiments, one or more of the one to five induction doses is 1200 mg of anti-IL-13 antibody.

[0317] In some embodiments, one or more of the one to five induction doses are doses of anti-IL-13 antibody listed in any of Tables 11-13.

[0318] In some embodiments, the first induction dose is 150 mg, 300 mg, 360 mg, or 600 mg. In some embodiments, the first induction dose is 150 mg. In some embodiments, the first induction dose is 180 mg. In some embodiments, the first induction dose is 200 mg. In some embodiments, the first induction dose is 250 mg. In some embodiments, the first induction dose is 300 mg. In some embodiments, the first induction dose is 350 mg. In some embodiments, the first induction dose is 360 mg. In some embodiments, the first induction dose is 400 mg. In some embodiments, the first induction dose is 450 mg. In some embodiments, the first induction dose is 500 mg. In some embodiments, the first induction dose is 550 mg. In some embodiments, the first induction dose is 600 mg.

[0319] In some embodiments, the method includes administering 300 mg of anti-IL-13 antibody at a second, third, fourth, and / or fifth induction dose. In some embodiments, the method includes administering 300 mg of anti-IL-13 antibody at a second induction dose. In some embodiments, the method includes administering 300 mg of anti-IL-13 antibody at a third induction dose. In some embodiments, the method includes administering 300 mg of anti-IL-13 antibody at a fourth induction dose.

[0320] In some embodiments, the method includes administering 360 mg of anti-IL-13 antibody at a second, third, fourth, and / or fifth induction dose. In some embodiments, the method includes administering 360 mg of anti-IL-13 antibody at a second induction dose. In some embodiments, the method includes administering 360 mg of anti-IL-13 antibody at a third induction dose. In some embodiments, the method includes administering 360 mg of anti-IL-13 antibody at a fourth induction dose.

[0321] In some embodiments, the method includes administering 600 mg of anti-IL-13 antibody at a second, third, fourth, and / or fifth induction dose. In some embodiments, the method includes administering 600 mg of anti-IL-13 antibody at a second induction dose. In some embodiments, the method includes administering 600 mg of anti-IL-13 antibody at a third induction dose. In some embodiments, the method includes administering 600 mg of anti-IL-13 antibody at a fourth induction dose.

[0322] In some embodiments, the second induction dose is administered approximately 2 weeks to approximately 16 weeks after the first induction dose. In some embodiments, the second induction dose is administered approximately 3 weeks to approximately 15 weeks after the first induction dose. In some embodiments, the second induction dose is administered approximately 4 weeks to approximately 14 weeks after the first induction dose. In some embodiments, the second induction dose is administered approximately 5 weeks to approximately 13 weeks after the first induction dose. In some embodiments, the second induction dose is administered approximately 6 weeks to approximately 12 weeks after the first induction dose. In some embodiments, the second induction dose is administered approximately 7 weeks to approximately 11 weeks after the first induction dose. In some embodiments, the second induction dose is administered approximately 8 weeks to approximately 10 weeks after the first induction dose. In some embodiments, the second induction dose is administered approximately 9 weeks after the first induction dose.

[0323] In some embodiments, the second induction dose is administered approximately 1 week after the first induction dose. In some embodiments, the second induction dose is administered approximately 2 weeks after the first induction dose. In some embodiments, the second induction dose is administered approximately 3 weeks after the first induction dose. In some embodiments, the second induction dose is administered approximately 4 weeks after the first induction dose. In some embodiments, the second induction dose is administered approximately 5 weeks after the first induction dose. In some embodiments, the second induction dose is administered approximately 6 weeks after the first induction dose. In some embodiments, the second induction dose is administered approximately 7 weeks after the first induction dose. In some embodiments, the second induction dose is administered approximately 8 weeks after the first induction dose. In some embodiments, the second induction dose is administered approximately 9 weeks after the first induction dose. In some embodiments, the second induction dose is administered approximately 10 weeks after the first induction dose. In some embodiments, the second induction dose is administered approximately 11 weeks after the first induction dose. In some embodiments, the second induction dose is administered approximately 12 weeks after the first induction dose. In some embodiments, the second induction dose is administered approximately 13 weeks after the first induction dose. In some embodiments, the second induction dose is administered approximately 14 weeks after the first induction dose. In some embodiments, the second induction dose is administered approximately 15 weeks after the first induction dose. In some implementations, the second induction dose is administered approximately 16 weeks after the first induction dose.

[0324] In some embodiments, one or more maintenance doses are administered approximately 4-17 weeks or longer after the first induction dose. In some embodiments, one or more maintenance doses are administered approximately 5-16 weeks or longer after the first induction dose. In some embodiments, one or more maintenance doses are administered approximately 6-15 weeks or longer after the first induction dose. In some embodiments, one or more maintenance doses are administered approximately 7-14 weeks or longer after the first induction dose. In some embodiments, one or more maintenance doses are administered approximately 8-13 weeks or longer after the first induction dose. In some embodiments, one or more maintenance doses are administered approximately 9-12 weeks or longer after the first induction dose. In some embodiments, one or more maintenance doses are administered approximately 10-11 weeks or longer after the first induction dose.

[0325] In some embodiments, one or more maintenance doses are administered approximately 4-17 weeks or 12-17 weeks after the first induction dose. In some embodiments, one or more maintenance doses are administered approximately 4-17 weeks after the first induction dose. In some embodiments, one or more maintenance doses are administered approximately 5-16 weeks after the first induction dose. In some embodiments, one or more maintenance doses are administered approximately 6-15 weeks after the first induction dose. In some embodiments, one or more maintenance doses are administered approximately 7-14 weeks after the first induction dose. In some embodiments, one or more maintenance doses are administered approximately 8-13 weeks after the first induction dose. In some embodiments, one or more maintenance doses are administered approximately 9-12 weeks after the first induction dose. In some embodiments, one or more maintenance doses are administered approximately 10-11 weeks after the first induction dose.

[0326] In some embodiments, one or more maintenance doses are administered approximately 12-17 weeks after the first induction dose. In some embodiments, one or more maintenance doses are administered approximately 13-16 weeks after the first induction dose. In some embodiments, one or more maintenance doses are administered approximately 14-15 weeks after the first induction dose.

[0327] In some embodiments, one or more maintenance doses are administered about 4 weeks or longer after the first induction dose. In some embodiments, one or more maintenance doses are administered about 5 weeks or longer after the first induction dose. In some embodiments, one or more maintenance doses are administered about 6 weeks or longer after the first induction dose. In some embodiments, one or more maintenance doses are administered about 7 weeks or longer after the first induction dose. In some embodiments, one or more maintenance doses are administered about 8 weeks or longer after the first induction dose. In some embodiments, one or more maintenance doses are administered about 9 weeks or longer after the first induction dose. In some embodiments, one or more maintenance doses are administered about 10 weeks or longer after the first induction dose. In some embodiments, one or more maintenance doses are administered about 11 weeks or longer after the first induction dose. In some embodiments, one or more maintenance doses are administered about 12 weeks or longer after the first induction dose. In some embodiments, one or more maintenance doses are administered about 13 weeks or longer after the first induction dose. In some embodiments, one or more maintenance doses are administered about 14 weeks or longer after the first induction dose. In some embodiments, one or more maintenance doses are administered about 15 weeks or longer after the first induction dose. In some embodiments, one or more maintenance doses are administered approximately 16 weeks or longer after the first induction dose. In some embodiments, one or more maintenance doses are administered approximately 17 weeks or longer after the first induction dose.

[0328] In some embodiments, the maintenance dose is 100 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 150 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 180 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 200 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 250 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 300 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 350 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 360 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 400 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 450 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 500 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 550 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 600 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 650 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 700 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 720 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 750 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 800 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 850 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 900 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 950 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 1000 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 1050 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose is 1100 mg of anti-IL-13 antibody. In some embodiments, the maintenance dose of anti-IL-13 antibody is 1150 mg. In some embodiments, the maintenance dose of anti-IL-13 antibody is 1200 mg.

[0329] In some implementations, the maintenance dose is any of the doses of anti-IL-13 antibody listed in Table 14.

[0330] In some 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, administered once every 3 months, once every 12 weeks, or four times a year. In some embodiments, the maintenance dose is 150 mg, administered once every 3 months, once every 12 weeks, or four times a year. In some embodiments, the maintenance dose is 180 mg, administered once every 3 months, once every 12 weeks, or four times a year. In some embodiments, the maintenance dose is 200 mg, administered once every 3 months, once every 12 weeks, or four times a year. In some embodiments, the maintenance dose is 250 mg, administered once every 3 months, once every 12 weeks, or four times a year. In some embodiments, the maintenance dose is 300 mg, administered once every 3 months, once every 12 weeks, or four times a year. In some embodiments, the maintenance dose is 360 mg, administered once every 3 months, once every 12 weeks, or four times a year. In some embodiments, the maintenance dose is 350 mg, administered once every 3 months, once every 12 weeks, or four times a year. In some embodiments, the maintenance dose is 360 mg, administered once every 3 months, once every 12 weeks, or four times a year. In some embodiments, the maintenance dose is 400 mg, administered once every 3 months, once every 12 weeks, or four times a year. In some embodiments, the maintenance dose is 450 mg, administered once every 3 months, once every 12 weeks, or four times a year. In some embodiments, the maintenance dose is 500 mg, administered once every 3 months, once every 12 weeks, or four times a year. In some embodiments, the maintenance dose is 550 mg, administered once every 3 months, once every 12 weeks, or four times a year. In some embodiments, the maintenance dose is 600 mg, administered once every 3 months, once every 12 weeks, or four times a year. In some embodiments, the maintenance dose is 650 mg, administered once every 3 months, once every 12 weeks, or four times a year. In some embodiments, the maintenance dose is 700 mg, administered once every 3 months, once every 12 weeks, or four times a year. In some embodiments, the maintenance dose is 720 mg, administered once every 3 months, once every 12 weeks, or four times a year. In some embodiments, the maintenance dose is 750 mg, administered once every 3 months, once every 12 weeks, or four times a year.In some implementations, the maintenance dose is 800 mg and is administered once every 3 months, once every 12 weeks, or 4 times a year.

[0331] In some implementations, the maintenance dose is administered every 3 months. In some implementations, the maintenance dose is administered every 12 weeks. In some implementations, the maintenance dose is administered 4 times a year.

[0332] In some 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 some embodiments, the maintenance dose is 150 mg and is administered every 2 months or every 8 weeks. In some embodiments, the maintenance dose is 200 mg and is administered every 2 months or every 8 weeks. In some embodiments, the maintenance dose is 250 mg and is administered every 2 months or every 8 weeks. In some embodiments, the maintenance dose is 300 mg and is administered every 2 months or every 8 weeks. In some embodiments, the maintenance dose is 350 mg and is administered every 2 months or every 8 weeks. In some embodiments, the maintenance dose is 360 mg and is administered every 2 months or every 8 weeks. In some embodiments, the maintenance dose is 400 mg and is administered every 2 months or every 8 weeks. In some embodiments, the maintenance dose is 450 mg and administered every 2 months or every 8 weeks. In some embodiments, the maintenance dose is 500 mg and administered every 2 months or every 8 weeks. In some embodiments, the maintenance dose is 550 mg and administered every 2 months or every 8 weeks. In some embodiments, the maintenance dose is 600 mg and administered every 2 months or every 8 weeks. In some embodiments, the maintenance dose is 650 mg and administered every 2 months or every 8 weeks. In some embodiments, the maintenance dose is 700 mg and administered every 2 months or every 8 weeks. In some embodiments, the maintenance dose is 720 mg and administered every 2 months or every 8 weeks. In some embodiments, the maintenance dose is 750 mg and administered every 2 months or every 8 weeks. In some embodiments, the maintenance dose is 800 mg and administered every 2 months or every 8 weeks.

[0333] In some 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 some embodiments, the maintenance dose is 150 mg and is administered every 2 months. In some embodiments, the maintenance dose is 180 mg and is administered every 2 months. In some embodiments, the maintenance dose is 200 mg and is administered every 2 months. In some embodiments, the maintenance dose is 250 mg and is administered every 2 months. In some embodiments, the maintenance dose is 300 mg and is administered every 2 months. In some embodiments, the maintenance dose is 350 mg and is administered every 2 months. In some embodiments, the maintenance dose is 360 mg and is administered every 2 months. In some embodiments, the maintenance dose is 400 mg and is administered every 2 months. In some embodiments, the maintenance dose is 450 mg every 2 months. In some embodiments, the maintenance dose is 500 mg every 2 months. In some embodiments, the maintenance dose is 550 mg every 2 months. In some embodiments, the maintenance dose is 600 mg every 2 months. In some embodiments, the maintenance dose is 650 mg every 2 months. In some embodiments, the maintenance dose is 700 mg every 2 months. In some embodiments, the maintenance dose is 720 mg every 2 months. In some embodiments, the maintenance dose is 750 mg every 2 months. In some embodiments, the maintenance dose is 800 mg every 2 months.

[0334] In some 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 administered every 8 weeks. In some embodiments, the maintenance dose is 150 mg and administered every 8 weeks. In some embodiments, the maintenance dose is 180 mg and administered every 8 weeks. In some embodiments, the maintenance dose is 200 mg and administered every 8 weeks. In some embodiments, the maintenance dose is 250 mg and administered every 8 weeks. In some embodiments, the maintenance dose is 300 mg and administered every 8 weeks. In some embodiments, the maintenance dose is 350 mg and administered every 8 weeks. In some embodiments, the maintenance dose is 360 mg and administered every 8 weeks. In some embodiments, the maintenance dose is 400 mg and administered every 8 weeks. In some embodiments, the maintenance dose is 450 mg administered every 8 weeks. In some embodiments, the maintenance dose is 500 mg administered every 8 weeks. In some embodiments, the maintenance dose is 550 mg administered every 8 weeks. In some embodiments, the maintenance dose is 600 mg administered every 8 weeks. In some embodiments, the maintenance dose is 650 mg administered every 8 weeks. In some embodiments, the maintenance dose is 700 mg administered every 8 weeks. In some embodiments, the maintenance dose is 720 mg administered every 8 weeks. In some embodiments, the maintenance dose is 750 mg administered every 8 weeks. In some embodiments, the maintenance dose is 800 mg administered every 8 weeks.

[0335] In some 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 every 16 weeks or three times a year. In some embodiments, the maintenance dose is 150 mg and is administered once every 16 weeks or three times a year. In some embodiments, the maintenance dose is 180 mg and is administered once every 16 weeks or three times a year. In some embodiments, the maintenance dose is 200 mg and is administered once every 16 weeks or three times a year. In some embodiments, the maintenance dose is 250 mg and is administered once every 16 weeks or three times a year. In some embodiments, the maintenance dose is 300 mg and is administered once every 16 weeks or three times a year. In some embodiments, the maintenance dose is 350 mg and is administered once every 16 weeks or three times a year. In some embodiments, the maintenance dose is 360 mg, administered once every 16 weeks or three times a year. In some embodiments, the maintenance dose is 400 mg, administered once every 16 weeks or three times a year. In some embodiments, the maintenance dose is 450 mg, administered once every 16 weeks or three times a year. In some embodiments, the maintenance dose is 500 mg, administered once every 16 weeks or three times a year. In some embodiments, the maintenance dose is 550 mg, administered once every 16 weeks or three times a year. In some embodiments, the maintenance dose is 600 mg, administered once every 16 weeks or three times a year. In some embodiments, the maintenance dose is 650 mg, administered once every 16 weeks or three times a year. In some embodiments, the maintenance dose is 700 mg, administered once every 16 weeks or three times a year. In some embodiments, the maintenance dose is 720 mg, administered once every 16 weeks or three times a year. In some embodiments, the maintenance dose is 750 mg, administered once every 16 weeks or three times a year. In some implementations, the maintenance dose is 800 mg and is administered once every 16 weeks or three times a year.

[0336] In some 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 administered every 16 weeks. In some embodiments, the maintenance dose is 150 mg and administered every 16 weeks. In some embodiments, the maintenance dose is 180 mg and administered every 16 weeks. In some embodiments, the maintenance dose is 200 mg and administered every 16 weeks. In some embodiments, the maintenance dose is 250 mg and administered every 16 weeks. In some embodiments, the maintenance dose is 300 mg and administered every 16 weeks. In some embodiments, the maintenance dose is 350 mg and administered every 16 weeks. In some embodiments, the maintenance dose is 360 mg and administered every 16 weeks. In some embodiments, the maintenance dose is 400 mg administered every 16 weeks. In some embodiments, the maintenance dose is 450 mg administered every 16 weeks. In some embodiments, the maintenance dose is 500 mg administered every 16 weeks. In some embodiments, the maintenance dose is 550 mg administered every 16 weeks. In some embodiments, the maintenance dose is 600 mg administered every 16 weeks. In some embodiments, the maintenance dose is 650 mg administered every 16 weeks. In some embodiments, the maintenance dose is 700 mg administered every 16 weeks. In some embodiments, the maintenance dose is 720 mg administered every 16 weeks. In some embodiments, the maintenance dose is 750 mg administered every 16 weeks. In some embodiments, the maintenance dose is 800 mg administered every 16 weeks.

[0337] In some 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 three times a year. In some embodiments, the maintenance dose is 150 mg and is administered three times a year. In some embodiments, the maintenance dose is 180 mg and is administered three times a year. In some embodiments, the maintenance dose is 200 mg and is administered three times a year. In some embodiments, the maintenance dose is 250 mg and is administered three times a year. In some embodiments, the maintenance dose is 300 mg and is administered three times a year. In some embodiments, the maintenance dose is 350 mg and is administered three times a year. In some embodiments, the maintenance dose is 360 mg and is administered three times a year. In some embodiments, the maintenance dose is 400 mg and is administered three times a year. In some embodiments, the maintenance dose is 450 mg and is administered three times a year. In some embodiments, the maintenance dose is 500 mg and administered three times a year. In some embodiments, the maintenance dose is 550 mg and administered three times a year. In some embodiments, the maintenance dose is 600 mg and administered three times a year. In some embodiments, the maintenance dose is 650 mg and administered three times a year. In some embodiments, the maintenance dose is 700 mg and administered three times a year. In some embodiments, the maintenance dose is 720 mg and administered three times a year. In some embodiments, the maintenance dose is 750 mg and administered three times a year. In some embodiments, the maintenance dose is 800 mg and administered three times a year.

[0338] In some 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 some embodiments, the maintenance dose is 150 mg and is administered every 20 weeks. In some embodiments, the maintenance dose is 180 mg and is administered every 20 weeks. In some embodiments, the maintenance dose is 200 mg and is administered every 20 weeks. In some embodiments, the maintenance dose is 250 mg and is administered every 20 weeks. In some embodiments, the maintenance dose is 300 mg and is administered every 20 weeks. In some embodiments, the maintenance dose is 350 mg and is administered every 20 weeks. In some embodiments, the maintenance dose is 360 mg and is administered every 20 weeks. In some embodiments, the maintenance dose is 400 mg administered every 20 weeks. In some embodiments, the maintenance dose is 450 mg administered every 20 weeks. In some embodiments, the maintenance dose is 500 mg administered every 20 weeks. In some embodiments, the maintenance dose is 550 mg administered every 20 weeks. In some embodiments, the maintenance dose is 600 mg administered every 20 weeks. In some embodiments, the maintenance dose is 650 mg administered every 20 weeks. In some embodiments, the maintenance dose is 700 mg administered every 20 weeks. In some embodiments, the maintenance dose is 720 mg administered every 20 weeks. In some embodiments, the maintenance dose is 750 mg administered every 20 weeks. In some embodiments, the maintenance dose is 800 mg administered every 20 weeks.

[0339] In some 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 every 6 months or twice a year. In some embodiments, the maintenance dose is 150 mg and is administered once every 6 months or twice a year. In some embodiments, the maintenance dose is 180 mg and is administered once every 6 months or twice a year. In some embodiments, the maintenance dose is 200 mg and is administered once every 6 months or twice a year. In some embodiments, the maintenance dose is 250 mg and is administered once every 6 months or twice a year. In some embodiments, the maintenance dose is 300 mg and is administered once every 6 months or twice a year. In some embodiments, the maintenance dose is 350 mg and is administered once every 6 months or twice a year. In some embodiments, the maintenance dose is 360 mg, administered once every 6 months or twice a year. In some embodiments, the maintenance dose is 400 mg, administered once every 6 months or twice a year. In some embodiments, the maintenance dose is 450 mg, administered once every 6 months or twice a year. In some embodiments, the maintenance dose is 500 mg, administered once every 6 months or twice a year. In some embodiments, the maintenance dose is 550 mg, administered once every 6 months or twice a year. In some embodiments, the maintenance dose is 600 mg, administered once every 6 months or twice a year. In some embodiments, the maintenance dose is 650 mg, administered once every 6 months or twice a year. In some embodiments, the maintenance dose is 700 mg, administered once every 6 months or twice a year. In some embodiments, the maintenance dose is 720 mg, administered once every 6 months or twice a year. In some embodiments, the maintenance dose is 750 mg, administered once every 6 months or twice a year. In some embodiments, the maintenance dose is 800 mg, administered once every 6 months or twice a year.

[0340] In some 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 some embodiments, the maintenance dose is 150 mg and is administered every 6 months. In some embodiments, the maintenance dose is 180 mg and is administered every 6 months. In some embodiments, the maintenance dose is 200 mg and is administered every 6 months. In some embodiments, the maintenance dose is 250 mg and is administered every 6 months. In some embodiments, the maintenance dose is 300 mg and is administered every 6 months. In some embodiments, the maintenance dose is 350 mg and is administered every 6 months. In some embodiments, the maintenance dose is 360 mg and is administered every 6 months. In some embodiments, the maintenance dose is 400 mg and is administered every 6 months. In some embodiments, the maintenance dose is 450 mg every 6 months. In some embodiments, the maintenance dose is 500 mg every 6 months. In some embodiments, the maintenance dose is 550 mg every 6 months. In some embodiments, the maintenance dose is 600 mg every 6 months. In some embodiments, the maintenance dose is 650 mg every 6 months. In some embodiments, the maintenance dose is 700 mg every 6 months. In some embodiments, the maintenance dose is 720 mg every 6 months. In some embodiments, the maintenance dose is 750 mg every 6 months. In some embodiments, the maintenance dose is 800 mg every 6 months.

[0341] In some 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 administered twice a year. In some embodiments, the maintenance dose is 150 mg and administered twice a year. In some embodiments, the maintenance dose is 180 mg and administered twice a year. In some embodiments, the maintenance dose is 200 mg and administered twice a year. In some embodiments, the maintenance dose is 250 mg and administered twice a year. In some embodiments, the maintenance dose is 300 mg and administered twice a year. In some embodiments, the maintenance dose is 350 mg and administered twice a year. In some embodiments, the maintenance dose is 360 mg and administered twice a year. In some embodiments, the maintenance dose is 400 mg and administered twice a year. In some embodiments, the maintenance dose is 450 mg and administered twice a year. In some embodiments, the maintenance dose is 500 mg and administered twice a year. In some embodiments, the maintenance dose is 550 mg and administered twice a year. In some embodiments, the maintenance dose is 600 mg and administered twice a year. In some embodiments, the maintenance dose is 650 mg and administered twice a year. In some embodiments, the maintenance dose is 700 mg and administered twice a year. In some embodiments, the maintenance dose is 720 mg and administered twice a year. In some embodiments, the maintenance dose is 750 mg and administered twice a year. In some embodiments, the maintenance dose is 800 mg and administered twice a year.

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

[0343] In some embodiments, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered once every 3 months, once every 12 weeks, or four times a year. In some embodiments, the maintenance dose is 300 mg and is administered once every 3 months, once every 12 weeks, or four times a year. In some embodiments, the maintenance dose is 300 mg and is administered once every 3 months. In some embodiments, the maintenance dose is 300 mg and is administered once every 12 weeks. In some embodiments, the maintenance dose is 300 mg and is administered four times a year.

[0344] In some embodiments, the maintenance dose is 360 mg and administered once every 3 months, once every 12 weeks, or four times a year.

[0345] In some embodiments, the maintenance dose is 600 mg and administered once every 3 months, once every 12 weeks, or four times a year.

[0346] In some embodiments, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered every 2 months or every 8 weeks. In some embodiments, the maintenance dose is 300 mg and is administered every 2 months or every 8 weeks. In some embodiments, the maintenance dose is 300 mg and is administered every 2 months. In some embodiments, the maintenance dose is 300 mg and is administered every 8 weeks.

[0347] In some embodiments, the maintenance dose is 360 mg and administered every 2 months or every 8 weeks.

[0348] In some embodiments, the maintenance dose is 600 mg and administered every 2 months or every 8 weeks.

[0349] In some embodiments, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered once every 16 weeks or three times a year. In some embodiments, the maintenance dose is 300 mg and is administered once every 16 weeks or three times a year. In some embodiments, the maintenance dose is 300 mg and is administered once every 16 weeks. In some embodiments, the maintenance dose is 300 mg and is administered three times a year.

[0350] In some embodiments, the maintenance dose is 360 mg and administered once every 16 weeks or three times a year.

[0351] In some embodiments, the maintenance dose is 600 mg and administered once every 16 weeks or three times a year.

[0352] In some embodiments, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered every 20 weeks. In some embodiments, the maintenance dose is 300 mg and is administered every 20 weeks. In some embodiments, the maintenance dose is 360 mg and is administered every 20 weeks. In some embodiments, the maintenance dose is 600 mg and is administered every 20 weeks.

[0353] In some embodiments, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered once every 6 months or twice a year. In some embodiments, the maintenance dose is 300 mg and is administered once every 6 months or twice a year. In some embodiments, the maintenance dose is 300 mg and is administered once every 6 months. In some embodiments, the maintenance dose is 300 mg and is administered twice a year.

[0354] In some embodiments, the maintenance dose is 360 and is administered once every 6 months or twice a year. In some embodiments, the maintenance dose is 360 and is administered once every 6 months. In some embodiments, the maintenance dose is 360 and is administered twice a year.

[0355] In some embodiments, the maintenance dose is 600 and administered once every 6 months or twice a year. In some embodiments, the maintenance dose is 600 and administered once every 6 months. In some embodiments, the maintenance dose is 600 and administered twice a year.

[0356] In some embodiments, the maintenance dose is 300 mg, 360 mg, or 600 mg and is administered once a year. In some embodiments, the maintenance dose is 300 mg and is administered once a year. In some embodiments, the maintenance dose is 360 mg and is administered once a year. In some embodiments, the maintenance dose is 600 mg and is administered once a year.

[0357] In some respects, the method includes administering a loading dose prior to one to four or more induction doses, wherein the loading dose is twice the induction dose.

[0358] In some embodiments, the loading dose is twice the induction dose, which is 200 mg. In some embodiments, the loading dose is twice the induction dose, which is 300 mg. In some embodiments, the loading dose is twice the induction dose, which is 360 mg. In some embodiments, the loading dose is twice the induction dose, which is 400 mg. In some embodiments, the loading dose is twice the induction dose, which is 500 mg. In some embodiments, the loading dose is twice the induction dose, which is 600 mg. In some embodiments, the loading dose is twice the induction dose, which is 700 mg. In some embodiments, the loading dose is twice the induction dose, which is 720 mg. In some embodiments, the loading dose is twice the induction dose, which is 800 mg. In some embodiments, the loading dose is twice the induction dose, which is 900 mg. In some embodiments, the loading dose is twice the induction dose, which is 1000 mg. In some embodiments, the loading dose is twice the induction dose, which is 1100 mg. In some embodiments, the loading dose is twice the induction dose, which is 1200 mg. In some embodiments, the loading dose is twice the induction dose, which is 1300 mg. In some embodiments, the loading dose is twice the induction dose, which is 1400 mg. In some embodiments, the loading dose is twice the induction dose, which is 1500 mg. In some embodiments, the loading dose is twice the induction dose, which is 1600 mg. In some embodiments, the loading dose is twice the induction dose, which is 1700 mg. In some embodiments, the loading dose is twice the induction dose, which is 1800 mg. In some embodiments, the loading dose is twice the induction dose, which is 1900 mg. In some embodiments, the loading dose is twice the induction dose, which is 2000 mg. In some embodiments, the loading dose is twice the induction dose, which is 2100 mg. In some embodiments, the loading dose is twice the induction dose, which is 2200 mg. In some embodiments, the loading dose is twice the induction dose, which is 2300 mg. In some implementations, the loading dose is twice the induction dose, which is 2400 mg.

[0359] In some embodiments, a unit dose is administered as a composition comprising about 100 mg / mL to about 200 mg / mL of anti-IL-13 antibody. In some 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 anti-IL-13 antibody. In some embodiments, a unit dose is administered as a composition comprising 100 mg / mL of anti-IL-13 antibody. In some embodiments, a unit dose is administered as a composition comprising 125 mg / mL of anti-IL-13 antibody. In some embodiments, a unit dose is administered as a composition comprising 150 mg / mL of anti-IL-13 antibody. In some embodiments, a unit dose is administered as a composition comprising 175 mg / mL of anti-IL-13 antibody. In some embodiments, a unit dose is administered as a composition comprising 180 mg / mL of anti-IL-13 antibody. In some embodiments, a unit dose is administered as a composition comprising 200 mg / mL of anti-IL-13 antibody.

[0360] In some embodiments, the unit dose has a removable volume of about 1 mL to about 3 mL. In some embodiments, the unit dose has a removable 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 some embodiments, the unit dose has a removable volume of about 1 mL. In some embodiments, the unit dose has a removable volume of about 1.25 mL. In some embodiments, the unit dose has a removable volume of about 1.5 mL. In some embodiments, the unit dose has a removable volume of about 1.75 mL. In some embodiments, the unit dose has a removable volume of about 2 mL. In some embodiments, the unit dose has a removable volume of about 2.25 mL. In some embodiments, the unit dose has a removable volume of about 2.5 mL. In some embodiments, the unit dose has a removable volume of about 2.7 mL. In some embodiments, the unit dose has a removable volume of about 2.75 mL. In some implementations, each dose has a retrievable volume of approximately 3 mL. As used herein, the “retrievable volume” of a vial is the amount that can be drawn from the container. The fill volume is larger than the retrievable volume to ensure that a retrievable volume can be obtained.

[0361] In one aspect, this application provides a method for treating atopic dermatitis in a patient in need, the method comprising: subcutaneously administering an anti-IL-13 antibody to the patient for an induction period of 4 to 16 weeks (e.g., 5 to 15 weeks, 6 to 14 weeks, 7 to 13 weeks, 8 to 12 weeks, 9 to 11 weeks, or 10 weeks), wherein during the induction period, the anti-IL-13 antibody is administered at a dose of 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). Administer once or twice with a loading dose of 50 mg (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 1 / 4 of the loading dose (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). mg, 200 mg, 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.Administer at least once (e.g., once, twice, or three times) at a dose of 5 mg or 300 mg; and subcutaneously administer anti-IL-13 antibody to the patient at a dose of 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; wherein the anti-IL-13 antibody comprises: containing at least 90% of SEQ ID NO: 3 VH comprising an amino acid sequence having at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO: 39, and VL 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 with SEQ ID NO: 39, wherein VH comprises HCDR1 comprising SEQ ID NO: 58, SEQ ID NO: 68, or SEQ ID NO: 85; HCDR2 comprising SEQ ID NO: 100, SEQ ID NO: 104, or SEQ ID NO: 108; and HCDR3 comprising SEQ ID NO: 112 or SEQ ID NO: 130; and VL comprises LCDR1 comprising SEQ ID NO: 141 or SEQ ID NO: 149; LCDR2 comprising SEQ ID NO: 153 or SEQ ID NO: 164; and SEQ ID NO: 149. NO: LCDR3 (165).

[0362] In some embodiments, the method includes an induction period of subcutaneous administration of anti-IL-13 antibody to a patient for 4 to 16 weeks (e.g., 5 to 15 weeks, 6 to 14 weeks, 7 to 13 weeks, 8 to 12 weeks, 9 to 11 weeks, or 10 weeks). In some embodiments, the method includes an induction period of subcutaneous administration of anti-IL-13 antibody to a patient for 4 to 16 weeks. In some embodiments, the method includes an induction period of subcutaneous administration of anti-IL-13 antibody to a patient for 5 to 15 weeks. In some embodiments, the method includes an induction period of subcutaneous administration of anti-IL-13 antibody to a patient for 6 to 14 weeks. In some embodiments, the method includes an induction period of subcutaneous administration of anti-IL-13 antibody to a patient for 7 to 13 weeks. In some embodiments, the method includes an induction period of subcutaneous administration of anti-IL-13 antibody to a patient for 8 to 12 weeks. In some embodiments, the method includes an induction period of subcutaneous administration of anti-IL-13 antibody to the patient for 9 to 11 weeks. In some embodiments, the method includes an induction period of subcutaneous administration of anti-IL-13 antibody to the patient for 10 weeks.

[0363] In some embodiments, the method includes an induction period of subcutaneous administration of anti-IL-13 antibody to the patient for up to 4 weeks. In some embodiments, the method includes an induction period of subcutaneous administration of anti-IL-13 antibody to the patient for up to 5 weeks. In some embodiments, the method includes an induction period of subcutaneous administration of anti-IL-13 antibody to the patient for up to 6 weeks. In some embodiments, the method includes an induction period of subcutaneous administration of anti-IL-13 antibody to the patient for up to 7 weeks. In some embodiments, the method includes an induction period of subcutaneous administration of anti-IL-13 antibody to the patient for up to 8 weeks. In some embodiments, the method includes an induction period of subcutaneous administration of anti-IL-13 antibody to the patient for up to 9 weeks. In some embodiments, the method includes an induction period of subcutaneous administration of anti-IL-13 antibody to the patient for up to 10 weeks. In some embodiments, the method includes an induction period of subcutaneous administration of anti-IL-13 antibody to the patient for up to 11 weeks. In some embodiments, the method includes an induction period of subcutaneous administration of anti-IL-13 antibody to the patient for up to 12 weeks. In some embodiments, the method includes an induction period of subcutaneous administration of anti-IL-13 antibody to the patient for up to 13 weeks. In some embodiments, the method includes an induction period of subcutaneous administration of anti-IL-13 antibody to the patient for up to 14 weeks. In some embodiments, the method includes an induction period of subcutaneous administration of anti-IL-13 antibody to the patient for up to 15 weeks. In some embodiments, the method includes an induction period of subcutaneous administration of anti-IL-13 antibody to the patient for up to 16 weeks.

[0364] In some embodiments, the method includes an induction period, wherein the anti-IL-13 antibody is administered once or twice at a loading dose of 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 some embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 100 mg to about 1200 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 150 mg to about 1150 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 200 mg to about 1100 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 250 mg to about 1050 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 300 mg to about 1000 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 350 mg to about 950 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 400 mg to about 900 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 450 mg to about 850 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 500 mg to about 800 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 550 mg to about 750 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 600 mg to about 700 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice at a loading dose of about 650 mg.

[0365] In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 100 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 125 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 150 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 180 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 200 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 250 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 300 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 350 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 360 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 400 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 450 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 500 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 550 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 600 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 650 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 700 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 720 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 750 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 800 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 850 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 900 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 950 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 1000 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 1050 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 1100 mg. In some embodiments, the anti-IL-13 antibody is administered once or twice as a loading dose of about 1150 mg.In some implementations, the anti-IL-13 antibody is administered once or twice as a loading dose of approximately 1200 mg.

[0366] In some embodiments, the method includes administering at least once (e.g., once, twice, or three times) a dose half the loading dose (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). In some embodiments, the loading dose half contains about 50 mg. In some embodiments, the loading dose half contains about 62.5 mg. In some embodiments, the loading dose half contains about 75 mg. In some embodiments, the loading dose half contains about 100 mg. In some embodiments, the loading dose half contains about 125 mg. In some embodiments, half the loading dose contains approximately 150 mg of the dose. In some embodiments, half the loading dose contains approximately 175 mg of the dose. In some embodiments, half the loading dose contains approximately 180 mg of the dose. In some embodiments, half the loading dose contains approximately 200 mg of the dose. In some embodiments, half the loading dose contains approximately 225 mg of the dose. In some embodiments, half the loading dose contains approximately 250 mg of the dose. In some embodiments, half the loading dose contains approximately 275 mg of the dose. In some embodiments, half the loading dose contains approximately 300 mg of the dose. In some embodiments, half the loading dose contains approximately 325 mg of the dose. In some embodiments, half the loading dose contains approximately 350 mg of the dose. In some embodiments, half the loading dose contains approximately 360 mg of the dose. In some embodiments, half the loading dose contains approximately 375 mg of the dose. In some embodiments, half the loading dose contains approximately 400 mg of the dose. In some embodiments, half the loading dose contains approximately 425 mg of the dose. In some embodiments, half the loading dose contains approximately 450 mg of the dose. In some embodiments, half the loading dose contains approximately 475 mg of the dose. In some embodiments, half the loading dose contains approximately 500 mg of the dose. In some embodiments, half the loading dose contains approximately 525 mg of the dose. In some embodiments, half the loading dose contains approximately 550 mg of the dose.In some embodiments, half the loading dose contains approximately 575 mg of the dose. In some embodiments, half the loading dose contains approximately 600 mg of the dose.

[0367] In some embodiments, the method includes administering at least one (e.g., once, twice, or three) a quarter-load dose (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). In some embodiments, a quarter-load dose comprises about 25 mg. In some embodiments, a quarter-load dose comprises about 31.25 mg. In some embodiments, a quarter-load dose comprises about 37.5 mg. In some embodiments, a quarter-load dose comprises about 50 mg. In some embodiments, a quarter of the loading dose contains approximately 62.5 mg of the dose. In some embodiments, a quarter of the loading dose contains approximately 75 mg of the dose. In some embodiments, a quarter of the loading dose contains approximately 87.5 mg of the dose. In some embodiments, a quarter of the loading dose contains approximately 90 mg of the dose. In some embodiments, a quarter of the loading dose contains approximately 100 mg of the dose. In some embodiments, a quarter of the loading dose contains approximately 112.5 mg of the dose. In some embodiments, a quarter of the loading dose contains approximately 125 mg of the dose. In some embodiments, a quarter of the loading dose contains approximately 137.5 mg of the dose. In some embodiments, a quarter of the loading dose contains approximately 150 mg of the dose. In some embodiments, a quarter of the loading dose contains approximately 162.5 mg of the dose. In some embodiments, a quarter of the loading dose contains approximately 175 mg of the dose. In some embodiments, a quarter of the loading dose contains approximately 180 mg of the dose. In some embodiments, a quarter of the loading dose contains approximately 187.5 mg of the dose. In some embodiments, a quarter of the loading dose contains approximately 200 mg of the dose. In some embodiments, a quarter of the loading dose contains approximately 212.5 mg of the dose. In some embodiments, a quarter of the loading dose contains approximately 225 mg of the dose. In some embodiments, a quarter of the loading dose contains approximately 237.5 mg of the dose. In some embodiments, a quarter of the loading dose contains approximately 250 mg of the dose.In some embodiments, a quarter of the loading dose contains approximately 262.5 mg of the dose. In some embodiments, a quarter of the loading dose contains approximately 275 mg of the dose. In some embodiments, a quarter of the loading dose contains approximately 287.5 mg of the dose. In some embodiments, a quarter of the loading dose contains approximately 300 mg of the dose.

[0368] In some embodiments, the method includes subcutaneously administering an anti-IL-13 antibody to a patient at a dose of 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 some embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 150 mg to about 1150 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is subcutaneously administered at a dose of about 200 mg to about 1100 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 250 mg to about 1050 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 300 mg to about 1000 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 350 mg to about 950 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 400 mg to about 900 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 450 mg to about 850 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 500 mg to about 800 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 550 mg to about 750 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 600 mg to about 700 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 650 mg for a maintenance period.

[0369] In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 100 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 150 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 180 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 200 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 250 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 300 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 350 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 360 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 400 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 450 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 500 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 550 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 600 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 650 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 700 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 720 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 750 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of about 800 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of approximately 850 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of approximately 900 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of approximately 950 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of approximately 1000 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of approximately 1050 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of approximately 1100 mg for a maintenance period. In some embodiments, the anti-IL-13 antibody is administered subcutaneously at a dose of approximately 1150 mg for a maintenance period.In some implementations, the anti-IL-13 antibody is administered subcutaneously at a dose of approximately 1200 mg for a maintenance period.

[0370] In some embodiments, the loading dose is about 100 mg. In some embodiments, the loading dose is about 125 mg. In some embodiments, the loading dose is about 150 mg. In some embodiments, the loading dose is about 180 mg. In some embodiments, the loading dose is about 200 mg. In some embodiments, the loading dose is about 250 mg. In some embodiments, the loading dose is about 300 mg. In some embodiments, the loading dose is about 350 mg. In some embodiments, the loading dose is about 360 mg. In some embodiments, the loading dose is about 400 mg. In some embodiments, the loading dose is about 450 mg. In some embodiments, the loading dose is about 500 mg. In some embodiments, the loading dose is about 550 mg. In some embodiments, the loading dose is about 600 mg. In some embodiments, the loading dose is about 650 mg. In some embodiments, the loading dose is about 700 mg. In some embodiments, the loading dose is about 720 mg. In some embodiments, the loading dose is about 750 mg. In some embodiments, the loading dose is about 800 mg. In some embodiments, the loading dose is about 850 mg. In some embodiments, the loading dose is about 900 mg. In some embodiments, the loading dose is about 950 mg. In some embodiments, the loading dose is about 1000 mg. In some embodiments, the loading dose is about 1050 mg. In some embodiments, the loading dose is about 1100 mg. In some embodiments, the loading dose is about 1150 mg. In some embodiments, the loading dose is about 1200 mg.

[0371] In some embodiments, during the induction period, a 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 in weeks 0 and 2.

[0372] In some embodiments, during the induction period, a 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 weeks 0 and 4.

[0373] In some embodiments, during the induction period, a 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.

[0374] In some embodiments, during the induction period, a 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.

[0375] In some embodiments, during the induction period, 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 a 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, 200 mg, 3 ... Doses of 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg were administered at weeks 8, 12, and 16. In some embodiments, half the dose was administered at weeks 8, 12, and 16 during the induction period. In some embodiments, a quarter dose was administered at weeks 8, 12, and 16 during the induction period.

[0376] In some embodiments, during the induction period, 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 a 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, 200 mg, 3 ... Doses of 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg were administered at weeks 4, 8, 12, and 16. In some embodiments, half the dose was administered at weeks 4, 8, 12, and 16 during the induction period. In some embodiments, a quarter dose was administered at weeks 4, 8, 12, and 16 during the induction period.

[0377] In some embodiments, during the induction period, 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 a 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, 200 mg, 3 ... Doses of 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg were administered at weeks 4 and 12. In some embodiments, half the dose was administered at weeks 4 and 12 during the induction period. In some embodiments, a quarter dose was administered at weeks 4 and 12 during the induction period.

[0378] In some embodiments, during the induction period, 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 a 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, 200 mg, 3 ... Doses of 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg are administered at weeks 2, 4, and 12. In some embodiments, half the dose is administered at weeks 2, 4, and 12 during the induction period. In some embodiments, a quarter dose is administered at weeks 2, 4, and 12 during the induction period.

[0379] In some embodiments, during the induction period, 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 a 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, 200 mg, 3 ... Doses of 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg are administered at weeks 2 and 12. In some embodiments, half the dose is administered at weeks 2 and 12 during the induction period. In some embodiments, a quarter dose is administered at weeks 2 and 12 during the induction period.

[0380] In some embodiments, during the induction period, 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 a 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, 200 mg, 3 ... The dose (212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg) is administered at week 12. In some embodiments, half the dose is administered at week 12 during the induction period. In some embodiments, a quarter of the dose is administered at week 12 during the induction period.

[0381] In some embodiments, during the induction period, 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 a 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, 200 mg, 3 ... Doses of 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg were administered at weeks 8 and 16. In some embodiments, half the dose was administered at weeks 8 and 16 during the induction period. In some embodiments, a quarter dose was administered at weeks 8 and 16 during the induction period.

[0382] In some embodiments, during the induction period, 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 a 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, 200 mg, 3 ... The dose (212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg) is administered at week 16. In some embodiments, half the dose is administered at week 16 during the induction period. In some embodiments, one-quarter of the dose is administered at week 16 during the induction period.

[0383] In some embodiments, during the induction period, 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 a 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, 200 mg, 3 ... Doses of 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg were administered at weeks 4 and 14. In some embodiments, half the dose was administered at weeks 4 and 14 during the induction period. In some embodiments, a quarter dose was administered at weeks 4 and 14 during the induction period.

[0384] In some embodiments, during the induction period, 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 a 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, 200 mg, 3 ... Doses of 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg are administered at week 14. In some embodiments, half the dose is administered at week 14 during the induction period. In some embodiments, a quarter dose is administered at week 14 during the induction period.

[0385] In some embodiments, during the induction period, 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 a 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, 200 mg, 3 ... Doses of 212.5 mg, 225 mg, 237.5 mg, 250 mg, 262.5 mg, 275 mg, 287.5 mg, or 300 mg are administered at weeks 2, 4, and 14. In some embodiments, half the dose is administered at weeks 2, 4, and 14 during the induction period. In some embodiments, a quarter dose is administered at weeks 2, 4, and 14 during the induction period.

[0386] In some 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 some embodiments, the maintenance dose is 100 mg. In some embodiments, the maintenance dose is 150 mg. In some embodiments, the maintenance dose is 180 mg. In some embodiments, the maintenance dose is 200 mg. In some embodiments, the maintenance dose is 250 mg. In some embodiments, the maintenance dose is 300 mg. In some embodiments, the maintenance dose is 360 mg. In some embodiments, the maintenance dose is 400 mg. In some embodiments, the maintenance dose is 450 mg. In some embodiments, the maintenance dose is 600 mg. In some embodiments, the maintenance dose is 720 mg. In some embodiments, the maintenance dose is 800 mg. In some embodiments, the maintenance dose is 900 mg.

[0387] In some embodiments, during the maintenance period (e.g., maintenance doses of 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 every 12 weeks or four times a year. In some embodiments, during the maintenance period, the anti-IL-13 antibody is administered once every 12 weeks. In some embodiments, during the maintenance period, the anti-IL-13 antibody is administered four times a year.

[0388] In some embodiments, during the maintenance period (e.g., maintenance doses of 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 every 8 weeks. In some embodiments, during the maintenance period, the anti-IL-13 antibody is administered every 2 months. In some embodiments, during the maintenance period, the anti-IL-13 antibody is administered every 8 weeks.

[0389] In some embodiments, during the maintenance period (e.g., maintenance doses of 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 every 16 weeks or three times a year. In some embodiments, during the maintenance period, the anti-IL-13 antibody is administered once every 16 weeks. In some embodiments, during the maintenance period, the anti-IL-13 antibody is administered three times a year.

[0390] In some embodiments, the anti-IL-13 antibody is administered once every 20 weeks during the maintenance period (e.g., maintenance doses of 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).

[0391] In some embodiments, during the maintenance period (e.g., maintenance doses of 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 every 6 months or twice a year. In some embodiments, during the maintenance period, the anti-IL-13 antibody is administered once every 6 months. In some embodiments, during the maintenance period, the anti-IL-13 antibody is administered twice a year.

[0392] In some implementations, the anti-IL-13 antibody is administered once a year during the maintenance period (e.g., maintenance doses of 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).

[0393] The exemplary dosing regimens (e.g., induction and maintenance) described herein include any and all of the regimens provided in Tables 11-14 below.

[0394] Table 11. Exemplary induction drug administration regimens

[0395] Table 12. Exemplary induction drug administration regimens

[0396] In one aspect, this application provides a method for treating atopic dermatitis in patients in need, the method comprising subcutaneously administering an anti-IL-13 antibody to the patient: a) Two loading doses of 720 mg of anti-IL-13 antibody prior to two induction doses; b) Two induction doses of 360 mg of anti-IL-13 antibody; and c) One or more maintenance doses of 360 mg anti-IL-13 antibody, initiated approximately 12 weeks or longer after the first induction dose; and The anti-IL-13 antibody comprises: a heavy chain variable region (VH) containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acids shown in SEQ ID NO: 3, and a light chain variable region (VL) containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acids shown in SEQ ID NO: 39.

[0397] In some implementations, the second loading dose is administered approximately two weeks after the first loading dose.

[0398] In some implementations, the first induction dose is administered approximately two weeks after the second loading dose.

[0399] In some implementations, the second induction dose is administered approximately 8 weeks after the first induction dose.

[0400] In some implementations, the maintenance dose is administered every 3 months.

[0401] In some implementations, the maintenance dose is administered every 6 months.

[0402] In some embodiments, the composition is a unit dose having a drawable volume of 2 mL, 2.25 mL, or 2.7 mL. In some embodiments, the composition is a unit dose having a drawable volume of 2 mL. In some embodiments, the composition is a unit dose having a drawable volume of 2.25 mL. In some embodiments, the composition is a unit dose having a drawable volume of 2.7 mL.

[0403] In some embodiments, the composition is a unit dose having a drawable volume of 2 mL.

[0404] In some implementations, the dosage described herein is adjusted based on weight, age, and / or body surface area.

[0405] In one aspect, this application provides a method for treating atopic dermatitis in patients in need, the method comprising subcutaneously administering an anti-IL-13 antibody to the patient: a) A loading dose of 720 mg of anti-IL-13 antibody prior to two induction doses; b) Two induction doses of 360 mg of anti-IL-13 antibody; and c) One or more maintenance doses of 360 mg anti-IL-13 antibody, initiated approximately 12 weeks or longer after the first induction dose; and The anti-IL-13 antibody comprises: a heavy chain variable region (VH) containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acids shown in SEQ ID NO: 3, and a light chain variable region (VL) containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acids shown in SEQ ID NO: 39.

[0406] In some implementations, the first induction dose is administered approximately 4 weeks after the loading dose.

[0407] In some implementations, the second induction dose is administered approximately 8 weeks after the first induction dose.

[0408] In some implementations, the maintenance dose is administered every 3 months.

[0409] In some implementations, the maintenance dose is administered every 6 months.

[0410] In some embodiments, the composition is a unit dose having a drawable volume of 2 mL, 2.25 mL, or 2.7 mL. In some embodiments, the composition is a unit dose having a drawable volume of 2 mL. In some embodiments, the composition is a unit dose having a drawable volume of 2.25 mL. In some embodiments, the composition is a unit dose having a drawable volume of 2.7 mL.

[0411] In some embodiments, the composition is a unit dose having a drawable volume of 2 mL.

[0412] In some implementations, the dosage described herein is adjusted based on weight, age, and / or body surface area.

[0413] In one aspect, this application provides a method for treating atopic dermatitis in patients in need, the method comprising subcutaneously administering the following to the patient: a) A loading dose of 360 mg of anti-IL-13 antibody prior to two induction doses; b) Two induction doses of 180 mg of anti-IL-13 antibody; and c) One or more maintenance doses of 180 mg of anti-IL-13 antibody, initiated approximately 12 weeks or longer after the first induction dose; and The anti-IL-13 antibody comprises: a heavy chain variable region (VH) containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acids shown in SEQ ID NO: 3, and a light chain variable region (VL) containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acids shown in SEQ ID NO: 39.

[0414] In some implementations, the first induction dose is administered approximately 4 weeks after the loading dose.

[0415] In some implementations, the second induction dose is administered approximately 8 weeks after the first induction dose.

[0416] In some implementations, the maintenance dose is administered every 3 months.

[0417] In some implementations, the maintenance dose is administered every 6 months.

[0418] In some embodiments, the composition is a unit dose having a drawable volume of 2 mL, 2.25 mL, or 2.7 mL. In some embodiments, the composition is a unit dose having a drawable volume of 2 mL. In some embodiments, the composition is a unit dose having a drawable volume of 2.25 mL. In some embodiments, the composition is a unit dose having a drawable volume of 2.7 mL.

[0419] In some embodiments, the composition is a unit dose having a drawable volume of 2 mL.

[0420] In some implementations, the dosage described herein is adjusted based on weight, age, and / or body surface area.

[0421] Application method In some embodiments, the methods provided herein can be used to treat an individual's disease or condition. In one embodiment, the individual is a person, and the antibody is the anti-IL-13 antibody described herein.

[0422] In some implementations, the anti-IL-13 antibody is administered via an auto-injector or a pre-filled syringe.

[0423] In some embodiments, this document provides 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 with the amino acids shown 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 with the amino acids shown in SEQ ID NO: 39.

[0424] In some implementations, the antibody is administered intravenously, intramuscularly, subcutaneously, superficially, orally, percutaneously, intraperitoneally, intraorally, intraorally, by implantation, by inhalation, intrathecal, intraventricular, or intranasal administration. An effective amount of anti-IL-13 antibody can be administered to treat the disease or condition. The appropriate dose of anti-IL-13 antibody may be determined based on: the type of disease or condition to be treated, the type of anti-IL-13 antibody, the severity and duration of the disease or condition, the individual's clinical condition, the individual's clinical history and response to treatment, and the judgment of the attending physician.

[0425] In some embodiments, the antibodies provided herein are administered in combination with at least one additional therapeutic agent. Any suitable additional therapeutic agent or immunotherapeutic agent may be administered in combination with the antibodies provided herein. Additional therapeutic agents include those for the treatment or prevention of diseases or conditions associated with elevated IL-13 and / or IgE levels, such as, but not limited to, inflammatory diseases or conditions.

[0426] Additional therapeutic agents may be administered by any suitable means. In some embodiments, the antibodies and additional therapeutic agents provided herein are included in the same pharmaceutical composition. In some embodiments, the antibodies and additional therapeutic agents provided herein are included in different pharmaceutical compositions.

[0427] In embodiments where the antibodies and additional therapeutic agents provided herein are included in different pharmaceutical compositions, the antibody may be administered before, simultaneously with, and / or after administration of the additional therapeutic agent. In some embodiments, the administration of the antibodies and additional therapeutic agents provided herein is performed within approximately one month of each other. In some embodiments, the administration of the antibodies and additional therapeutic agents provided herein is performed within approximately one week of each other. In some embodiments, the administration of the antibodies and additional therapeutic agents provided herein is performed within approximately one day of each other. In some embodiments, the administration of the antibodies and additional therapeutic agents provided herein is performed within approximately twelve hours of each other. In some embodiments, the administration of the antibodies and additional therapeutic agents provided herein is performed within approximately one hour of each other.

[0428] reagent kits and products This application provides a kit comprising one or more of the antibody compositions described herein and instructions for use. In some embodiments, the kit further comprises a component selected from any of the following: secondary antibody, immunohistochemical reagents, pharmaceutically acceptable excipients, and instructions for use, and any combination thereof. In one particular embodiment, the kit comprises a pharmaceutical composition comprising one or more of the antibody compositions described herein and one or more pharmaceutically acceptable excipients.

[0429] This application also provides articles comprising any of the antibody compositions or kits described herein. Examples of articles include vials (including sealed vials).

[0430] Example The following are embodiments of specific implementations of the invention. These embodiments are provided merely for illustrative purposes and are not, and are not intended to, limit the scope of the invention in any way. Every effort has been made to ensure the accuracy of the figures used (e.g., quantities, temperatures, etc.), but some experimental error and deviation should, of course, be allowed.

[0431] Unless otherwise indicated, the practice of this invention will be carried out using conventional methods of protein chemistry, biochemistry, DNA recombination techniques, and pharmacology within the art. Such techniques are well explained in the literature. See, for example, TECreighton, Proteins: Structures and Molecular Properties (WH Freeman and Company, 1993); AL Lehninger, Biochemistry (Worth Publishers, current edition); Sambrook et al., Molecular Cloning: A Laboratory Manual (2nd edition, 1989); Methods in Enzymology (edited by S. Colowick and N. Kaplan, Academic Press); Remington's Pharmaceutical Sciences, 18th edition (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry 3rd Edition (Plenum Press) Volume A and Volume B (1992).

[0432] Example 1: Engineered anti-IL-13 antibodies exhibited enhanced binding to human FcRn and eliminated binding to Fc receptors and C1q. Materials and methods Determine the affinity of the antibody for Fc receptor and C1q. The binding affinity (Kb) of the antibody to the Fc receptor and C1q was determined by surface plasma resonance (SPR) using Biacore 8K and ELISA, respectively. DIn short, an SPR chip functionalized with anti-κ light chain antibody was used to capture purified antibody normalized to 5 mg / mL at a flow rate of 10 μL / min for 90 or 120 seconds. Only the paired channel with buffer was used as a reference. Subsequently, different concentrations of recombinant human FcRn, FcγRI, FcγRIIa (H131), FcγRIIa (R131), FcγRIIb, FcγRIIIa (F158), FcγRIIIa (V158), and C1q were injected onto the surface with the captured purified antibody and the reference channel. The chip was regenerated between different antigens at different concentrations using 10 mM glycine-HCl pH 1.5, and the antibody was captured again. The K-chain binding model was then derived by fitting to a 1:1 Langmuir binding model or a steady-state analysis model (whichever is applicable). D The Biacore Insight evaluation software was used to determine the association rate constant and dissociation rate constant.

[0433] result antibody affinity for Fc receptor and C1q Construct 133 was also compared with the IgG1 positive control, demonstrating YTE-dependent increase in FcRn binding and LALA-dependent elimination of Fc-dependent binding (Table 15). Enhanced binding to human FcRn and elimination of binding to Fc receptor and C1q, respectively, confirmed the function of YTE and LALA amino acid substitution.

[0434] Table 15. Affinity of antibodies to Fc receptor and C1q

[0435] Example 2: Engineered anti-IL-13 antibody variants in NHP exhibit significantly prolonged half-life and pSTAT6 inhibition. To demonstrate the potential for engineered anti-IL-13 antibody variants to improve dosing compared to current and anticipated standard-of-care mAbs in Alzheimer's disease (AD) and other diseases, construct 133 (see construct 133 sequences in Tables 2-8) comprising SEQ ID NOs: 3, 39, 439, and 469 were studied in female nonhuman primates (NHPs) following a single bolus dose of 3 mg / kg (IV or SQ administration). Additionally, variant clones of construct 133 with Fc-modified LS exhibiting extended half-lives with different FcRN-associated characteristics (“construct 133-LS”) were evaluated. Blood samples were collected sequentially starting before sample administration and subsequently at 0.167 h, 1 h, 4 h, 8 h, 24 h, 48 h, 96 h, 168 h, 336 h, 504 h, 674 h, 840 h, 1334 h, 1680 h, and 2160 h post-administration. The following PK parameters were calculated: the observed maximum serum concentration (C0). max ), the time to reach the observed maximum serum concentration (T) max The area under the curve (AUC) of serum concentrations extrapolated from time 0 to infinity to time 2. 0-inf ), clearance rate (CL), steady-state distribution volume (V) ss ), half-life (T) 1 / 2 The mean serum concentration and absolute subcutaneous bioavailability (F) were calculated (Table 16). Data were analyzed to show the mean serum concentration versus standard deviation over time, and regression fitting was performed.

[0436] In vitro assessment of the inhibition of pSTAT6 in whole blood isolated from NHP of construct 133-LS administered from SC.

[0437] Table 16. Pharmacokinetics of construct 133 and lerizomonab after a single bolus IV or SQ dose in cynomolgus monkeys

[0438] *The monoclonal antibody is based on the publicly available sequence representation of levozo monoclonal antibody.

[0439] ** SQ applied CL and V SS Both were dose normalized using the subcutaneous bioavailability (F) indicated in Table 20.

[0440] ***AUC normalized by the average dose after subcutaneous administration 0-inf Divide by the AUC normalized to the mean dose after IV administration 0-inf To calculate F (%).

[0441] In head-to-head studies of construct 133 and lerezolizumab in NHP, both the IV and SQ formulations of construct 133 showed significantly longer half-lives than lerezolizumab. In these studies, the mean half-life of construct 133 was 27.6 days, compared to 17 to 18 days for lerezolizumab. Figure 2 As shown in the figure. Furthermore, construct 133 exhibited an average clearance rate of 1.45 (mL·day) in NHP. -1 ·kg -1 The steady-state volume distribution was observed to be 55.65 (mL·kg). -1 The construct 133 was adequately absorbed, with a subcutaneous bioavailability of 81.22%. Lereizumab exhibited a mean clearance rate of 2.93 (mL·day) in NHP. -1 ·kg -1 The steady-state volume distribution was observed to be 52.10 (mL·kg). -1 The lereizumab was fully absorbed, with a subcutaneous bioavailability of 75.70%. Specifically, the lereizumab's t... 1 / 2 For 18.0 days, C L 2.93 mL / day -1 ·kg -1 Vss is 52.10 mL·kg -1 And F is 75.70%.

[0442] Construct 133-LS or lereizumab at serum concentrations >5 µg / mL maintained complete inhibition of pSTAT6 in whole blood of NHP. Compared with lereizumab (IC50), [the following text appears to be incomplete and requires further context: "IC50"] 90 =27.9 days, IC 50 Compared to 48.9 days, construct 133-LS exhibited longer-lasting inhibition of pSTAT6 (IC50 = 48.9 days after administration). 90 =56.8 days, IC 50 =92.6 days).

[0443] The t exhibited by construct 133 1 / 2 Consistent with the increased and decreased clearance rates dependent on YTE exposure, construct 133-LS (which has another FcRN-related amino acid substitution) exhibited a longer duration of pSTAT6 inhibition than lerezo monoclonal antibody. Construct 133 is expected to show a similar increase in the duration of pSTAT6 inhibition.

[0444] Unbound by conventional theories, because construct 133 is engineered to have YTE amino acid substitutions in the Fc region, the half-life of IgG can be prolonged by increasing binding to the neonatal Fc receptor (FcRn) under acidic pH conditions. FcRn-bound IgG is recycled via lysosomal rescue, causing IgG to return to circulation. The prolonged half-life of construct 133 allows for a lower dosing frequency than currently available treatments, reducing the injection burden and increasing compliance in patients with atopic dermatitis and other IL-13-driven diseases.

[0445] In a non-head-to-head comparison with third-party NHP data, construct 133 exhibited the highest normalized AUC among antibodies with YTE substitution. 0-∞ (C 归一化*天 Or the area under the curve (AUC) from dosing to infinity, such as Figure 3 As shown in the diagram. Therefore, compared to other antibodies with YTE substitution, the PK distribution of construct 133 appears to provide the maximum sustained concentration or level of the drug in the bloodstream.

[0446] The extended half-life of mAbs with YTE amino acid substitutions depends on the type of target (e.g., receptor versus solubility). Therefore, the study converted NHP half-life data to human half-life data for mAbs with soluble targets and found that the human half-life was approximately three to four times longer than the NHP half-life (mean: 3.5 times, median: 3.1 times; data not shown).

[0447] Based on this NHP half-life data, construct 133 is expected to have a human half-life of approximately 80 to 110 days, based on comparable mAbs with YTE amino acid substitutions.

[0448] Furthermore, based on PK modeling, with a 33-day human half-life (which, to the applicant's knowledge, is lower than the lowest half-life reported to date for mAbs with YTE amino acid substitutions), construct 133 is believed to be effectively administered at a maintenance dosing schedule of every two months. With a 50-day half-life, construct 133 is believed to be effectively administered at a maintenance dosing schedule of every three months.

[0449] To understand the maintenance dosing duration achievable with construct 133, known PK parameters of lerizomba were used. These PK parameters provide insight into how lerizomba is distributed and cleared throughout the body. Based on these known parameters, a two-compartment PK model with first-order absorption, a standard mAb, was constructed to predict the concentrations, or drug levels, of both lerizomba and construct 133 over time. Key parameters included a clearance rate (CL) of 0.156 L / day, a central volume (Vc) of 4.10 L, an absorption rate (ka) of 0.239 days⁻¹, and a bioavailability of 85.6%.

[0450] It is believed that the efficacy in inflammatory diseases (such as AD) is due to C. 谷 Or driven by the lowest concentration of mAb. Therefore, based on the model described above, the target C of construct 133 is... 谷 Set to equal C of lerizotinib maintained by monthly dosing 谷 The concentration was 31.3 mg / L. Given the overlapping epitopes of levozo monoclonal antibody and some of the antibodies disclosed herein, as well as the similarity of efficacy across multiple in vitro assays, the exposure required for the potential clinical activity of construct 133 can be predicted. This is achieved by using the elimination rate constant K... 消除 Alternatively, a model could be developed for the fraction of drug eliminated within a given time period and for maintaining the concentration of the disclosed antibody above 31.3 mg / L for half-life. Assuming a dose of 300 mg, maintenance administration of construct 133 every two months should require a half-life of at least 33 days, and maintenance administration of construct 133 every three months should require a half-life of at least 50 days.

[0451] Therefore, with a human half-life of 33 days, construct 133 is believed to be effectively administered at a maintenance dosing schedule of every two months. With a half-life of 50 days, construct 133 is believed to be effectively administered at a maintenance dosing schedule of every three months.

[0452] Example 3: A multi-dose 29-day GLP study in NHP was completed. No adverse results were observed in any cohort, including the highest-test cohort, and this was considered a No Observed Adverse Effect Level (NOAEL). A 29-day repeated-dose, GLP-compliant toxicology study was conducted in NHP. Construct 133 was administered weekly via SC to NHP (3 to 5 animals per sex per group) at doses of 0, 30, 75, or 150 mg / kg / dose (5 doses in total). No adverse effects were observed up to the highest tested dose (150 mg / kg), which was the maximum feasible dose and was considered the No Observed Adverse Effect Level (NOAEL) in this study.

[0453] Example 4. Monomer purity after affinity trapping from the stabilization cell The purity of monomers obtained from one-step affinity capture is a determinant of the final antibody yield and unit cost under cGMP production. Simply put, to characterize this, CHO stabilization pools for each antibody are generated separately in a workflow that selects a master cell library for cGMP production. The affinity capture step is performed using a Mabselect SuRe column. After one-step purification, novel IgG1 variants (e.g., constructs 132, 133, 136, 137, 140, 141, and 144) remain clear solutions with <15% aggregates. Novel IgG4 variants (constructs 134, 135, 138, 139, 142, and 143) have a milky white appearance with some precipitation and readily aggregate (>68% aggregates) when eluted with a 50 mM sodium citrate, 150 mM sodium chloride elution buffer at pH 3.0. The novel IgG4 variant exhibited lower aggregate levels when eluted with 50 mM acetic acid at pH 2.8 or with 100 mM sodium acetate and 800 mM arginine at pH 3.5. At the higher pH of 3.5, arginine was required to maintain adequate recovery.

[0454] The results are summarized in Table 17. Compared with the levozo monoclonal antibody variants (constructs 128-131), the novel IgG1 and IgG4 variants demonstrated greater monomer purity obtained directly from affinity capture under optimized elution conditions.

[0455] Table 17. Purity of Anti-IL-13 Antibody Monomer

[0456] *See the constructor sequence in Table 2-8.

[0457] Example 5. Accelerated Stability This embodiment demonstrates that novel variants in the IgG1 constructs exhibit a lower tendency to aggregate and are more resistant to changes in basic species under various stress conditions, as shown in Table 18. The proportion of basic species was determined by capillary isoelectric focusing (ciEF) as known in the art. Compared to novel IgG1 variants (e.g., constructs 132, 133, 136, 137, 140, 141, and 144), the variants associated with lerezo monoclonal antibodies (constructs 128-131) and IgG4 variants (constructs 134, 135, 142, and 143) as described in Examples 1-7 are more prone to aggregation and affected by changes in basic species.

[0458] Table 18. Changes in the stability of anti-IL-13 antibodies

[0459] *See the constructor sequence in Table 2-8.

[0460] For stability at 40°C, the changes in monomer purity and basic species of the clone were assessed on days 0 and 14; and for stability at pH 3.5, the changes were assessed on days 0 and 2.

[0461] NT - Untested.

[0462] Example 6: Safety, tolerability, and pharmacokinetics of anti-IL-13 antibodies in healthy subjects: a phase 1, randomized, double-blind, placebo-controlled, single-dose escalation and multiple-dose escalation first-in-human study. Research Design and Methods This is a phase 1, randomized, double-blind, placebo-controlled, parallel-group, first-in-human (FIH) study of the anti-IL-13 antibody presented in this article, conducted in healthy subjects. The anti-IL-13 antibody was administered subcutaneously (SC) in single-dose escalation and multiple-dose escalation (SAD and MAD) administrations, respectively. Up to five SAD cohorts and two MAD cohorts were studied in this study. Each cohort consisted of eight healthy subjects who were randomized in a 6:2 ratio to receive either the anti-IL-13 antibody or placebo.

[0463] Subjects were screened for eligibility to the study within 42 days prior to dosing. For each dose of anti-IL-13 antibody administered, subjects resided at the clinical research unit (CRU) for 5 consecutive days (1 day before dosing, 1 day after dosing, and 3 days after dosing). All SAD cohorts employed sentinel dosing in a 2-subject (1 active agent, 1 placebo) configuration. Outpatient surveillance continued until the end of the study (EOS) visit (day 337).

[0464] SAD queue Recruit up to 5 SAD cohorts using 4 escalating dose levels (150 mg, 300 mg, 600 mg and 1200 mg); Figure 1 Alternatively, the starting dose in the first SAD cohort is 300 mg. Figure 4 Each SAD cohort enrolled 8 participants. Participants were randomly assigned in a blinded 6:2 ratio to receive either anti-IL-13 antibody or placebo. The first 2 participants in each cohort (sentinel participants) were randomly assigned in a blinded 1:1 ratio (active agent: placebo) and followed for at least 24 hours post-dose before the remaining participants in the treatment cohort. The remaining 6 participants were randomly assigned in a 5:1 ratio (active agent: placebo). (Illustration provided) Figure 1 middle.

[0465] Subjects entered the CRU one day prior to dosing (Day -1). On Day 1 (dose day), subjects received either the SC dose of anti-IL-13 antibody or placebo. On Day 4 (72 hours after dosing), subjects left the CRU after completing all clinical assessments that day. CRU dwell time for Cohort 2 and subsequent cohorts was adjusted based on newly emerging data from previous cohorts.

[0466] The starting dose in the first SAD cohort was 150 mg; this dose reflects a safety margin of >10 times the human equivalent dose in a good laboratory-standard 28-day non-human primate toxicology study in subjects weighing at least 60 kg, where no adverse events were observed. Alternatively, the starting dose in the first SAD cohort was 300 mg.

[0467] Following SAD cohort 1, the evaluated doses included 300 mg, 600 mg, and 1200 mg (or 600 mg and 1200 mg). Figure 4 However, dose escalation and actual dose increases / decreases are determined by the Safety Review Committee (SRC). The SRC makes its determination based on safety data from at least 14 days of dosing from previous dose levels. Specifically, the SRC determines whether any protocol-defined dose-limiting toxicities (DLTs) have occurred in subjects receiving the anti-IL-13 antibody in the current cohort by day 15, and whether any termination rules have been met. At least 6 out of 8 subjects in the cohort have day 15 safety data available for focused study by the SRC. Additionally, available tail pharmacokinetic (PK) results are reviewed to assess the appropriateness of the next planned dose and, if necessary, to guide revisions to the assessed next dose. Dose escalations in subsequent cohorts do not exceed a 2-fold increase. The highest single dose tested does not exceed 1200 mg.

[0468] On day 1, subjects received either an SC dose of anti-IL-13 antibody or placebo at the CRU. Vital signs, electrocardiograms (ECGs), adverse events (AEs), and blood draws were continuously recorded for pharmacokinetic (PK) and safety laboratory testing. After completion of CRU confinement (by day 4), subjects returned to the outpatient clinic 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, covering approximately five half-lives. Follow-up time, PK sampling time, and study duration were adjusted based on safety and PK outcomes from previous cohorts.

[0469] MAD queue Up to three cohorts will be recruited, with two escalating dose levels (150 mg [Q4W] x 2 doses every 4 weeks; the starting dose; and 300 mg Q4W x 2 doses) and other doses determined by the SRC and sponsor. Alternatively, two multiple-dose (MD) cohorts will be studied in this study, where subjects receive 720 mg construct 133 at weeks 0 and 2 and 360 mg construct 133 at weeks 4 and 12 (induction phase). During the maintenance phase, subjects receive 360 ​​mg construct 133 every 3 months (Q12W) or 6 months (Q24W); see [link to study]. Figure 4 Based on available data from the SAD cohort, including available PK data, the SRC ultimately determines the actual starting dose and dosing frequency. The first cohort is recruited after the SRC has reviewed at least 14 days of safety and PK data from the SAD cohort, and the total dose in the SAD cohort is at least equal to the total dose given to subjects in the MAD cohort (i.e., completion of a single 300 mg SAD safety review allows the opening of the MAD cohort with 150 mg Q4W × 2 doses, equivalent to a total dose of 300 mg).

[0470] Following MAD cohort 1, escalation and actual dose increases / decreases are determined by the SRC. Specifically, the SRC determines whether any protocol-defined dose-limiting toxicities (DLTs) occurred in subjects receiving the anti-IL-13 antibody in the current cohort within 14 days after the last dose of the study drug, and whether any termination rules were met. At least 5 of the 8 subjects in the cohort must have day 43 (i.e., 14 days after the second dose given on day 29) safety data available for focused study by the SRC. Additionally, available tail PK results are reviewed to assess the appropriateness of the next planned dose and, if necessary, to guide revisions to the assessed next dose. Dose escalations in subsequent cohorts do not exceed a 2-fold increase. The highest MAD dose tested does not exceed a total of 1200 mg during the dosing period.

[0471] Subjects received two separate sub-sitives (SC) doses of anti-IL-13 antibody at the CRU: one on day 1 and one on day 29. Subjects remained at the CRU for 72 hours after each dose, and subsequent cohorts were adjusted based on emerging data. Vital signs, electrocardiograms (ECGs), adverse event assessments, and blood draws were continuously obtained for pharmacokinetic (PK) and safety laboratory testing.

[0472] After completing CRU confinement, subjects returned to the outpatient clinic on days 8, 15, and 22 after the first dose of study drug, and on days 50, 57, 85, 113, 141, 169, 197, 225, 253, 281, and 309 after the second dose of study drug. An EOS follow-up was conducted on day 337, which was expected to cover approximately five half-lives. Follow-up timelines, pharmacokinetic (PK) sampling time, and study duration were adjusted based on safety and PK results from previous cohorts.

[0473] Study duration The duration of any individual subject can be as long as 378 days.

[0474] Number of subjects Up to 64 participants (up to 8 cohorts, with 8 participants in each cohort).

[0475] Key compliance standards Inclusion criteria Inclusion criteria included: healthy men and non-pregnant women identified through physical examination and laboratory screening tests; aged 18 to 65 (inclusive), with a body mass index of 18 kg / m². 2 Up to 34 kg / m 2 (including 18 kg / m 2 and 34 kg / m 2 The patient is willing to use appropriate contraception from admission until 6 months or 5 half-lives (whichever is longer) after the last administration of the study drug; and the patient is willing to use appropriate contraception from admission until 6 months or 5 half-lives (whichever is longer) after the last administration of the study drug; and the injection site is suitable for SC injection and is not tattooed. Exclusion criteria Exclusion criteria include: evidence of clinically significant abnormalities or diseases, including (but not limited to) the following: hemoglobin A1c ≥ 6.5% and / or a diagnosis of diabetes; a positive human immunodeficiency virus (HIV) antibody test; acute or chronic hepatitis B or hepatitis C as demonstrated by hepatitis B surface antigen (HBsAg) and / or hepatitis C antibody (HCV Ab); signs of infection or remission after vaccination are permissible in the presence of antibodies or evidence of the absence of viral deoxyribonucleic acid (DNA) for polymerase chain reaction; a positive blood test for pulmonary tuberculosis at the time of screening; a diagnosed or suspected diagnosis of immunodeficiency or autoimmune disease, or prior to the trial of immunosuppressive therapy such as chemotherapy or radiotherapy for cancer, or systemic corticosteroid therapy within the past 120 days; any other laboratory, vital sign, ECG abnormalities, clinically significant medical conditions or findings that, in the investigator's view, may adversely alter the risk-benefit of study participation, confound the results of the study, or interfere with the conduct or compliance of the study. Other exclusion criteria include fever within 7 days prior to administration of the study drug; a known history of drug abuse and / or alcoholism within 2 years prior to screening; a positive drug abuse screening at screening or admission to the CRU; or regular daily use of >5 cigarettes (or equivalent amounts of nicotine-containing products); a history of severe allergic reactions, or allergy to any component of the anti-IL-13 antibody or placebo; if female, breastfeeding, lactating, pregnant, or planning to become pregnant within 6 months of an EOS visit; donation or loss of ≥1 unit (450 mL) of blood within 1 month prior to administration; use of any prescription or over-the-counter medication within 7 days prior to administration (exceptions: up to 2 g of birth control pills or acetaminophen per day prior to administration is permitted); and use of any investigational drug therapy within 30 days or 5 half-lives (whichever is longer) prior to administration of the study drug and within 30 days or 5 half-lives (whichever is longer) after the last dose of the study drug.

[0476] Study products, dosage, and administration methods. The anti-IL-13 antibody described in this example is a high-affinity IgG1 humanized monoclonal antibody that binds to IL-13. The anti-IL-13 antibody solution will be administered via subcutaneous (SC) injection.

[0477] In the SAD portion of the study, the starting dose was 150 mg; the expected escalation doses were 300 mg, 600 mg, and 1200 mg. In the MAD portion of the study, the doses were 150 mg and 300 mg every 4 weeks (Q4W), for a total of two doses. Except for the starting dose (150 mg in the SAD study), dose levels and regimens were determined based on newly emerging safety data reviewed by the SRC. No subject received a single dose >1200 mg in the SAD portion of the study; and no subject received a total dose >1200 mg in the MAD portion of the study. In the alternative MAD portion of the study, the dose was 300 mg on days 1 and 29, or on days 1 and 15.

[0478] Evaluation criteria Pharmacokinetics The following p-values ​​were determined for both the SAD and MAD portions of the study: the observed maximum concentration (C0). max ), reaching C max Time (T) max ), terminal elimination rate constant (λ) z ) and terminal half-life (T 1 / 2 ).

[0479] In SAD studies, the following additional PK parameter is measured: the area under the concentration-time curve (AUC) from time zero to the last quantifiable time point. 0-最后 Apparent clearance rate (CL / F) and apparent distribution volume (V) z / F).

[0480] In the MAD study, the following additional PK parameters were measured: AUC (AUC0-τ) at the dosing interval after the first and last doses, cumulative ratio (RAUC), CL / F, and V. z / F.

[0481] Table 19 below describes the pharmacokinetic properties used in this article.

[0482] Table 19. PK Parameters

[0483] Anti-drug antibodies The presence of ADA and its PK effect on ADA against IL-13 antibodies.

[0484] Pharmacodynamics Changes in pSTAT6 and other blood biomarkers (including, for example, TARC and IgE) over time.

[0485] Security Safety assessment includes evaluation of treatment-induced adverse events (TEAEs), clinical laboratory tests (e.g., hematology, serology, and urinalysis), vital signs, ECG, and physical examination.

[0486] Statistical methods Analysis of groups This study defined the following three analytical cohorts: (1) the safety cohort, defined as all subjects who received at least one dose of the study drug and underwent at least one post-baseline safety assessment. (2) the PK cohort, defined as all enrolled subjects for whom at least one PK parameter of interest was calculated. Typically, on a parameter-by-parameter basis, if there is insufficient data available for individual subjects to calculate the specific parameter in question, the data of that subject are excluded from the analysis. (3) the full analytical cohort, defined as all randomly assigned subjects who completed the study without experiencing significant protocol deviations or violations.

[0487] Sample size The sample size is typical for FIH studies and allows for preliminary determination of tolerability, safety, and efficacy, as well as comprehensive determination of single-dose and multi-dose pharmacokinetics in healthy subjects.

[0488] Pharmacokinetic analysis Plasma anti-IL-13 antibody concentrations were summarized by dose and time point using descriptive statistics of the PK population. Mean and individual plasma anti-IL-13 antibody concentrations over time are presented in the graphs using linear and semi-logarithmic scales. PK parameters were calculated using non-compartmental analysis and summarized by dose. AUC and C2 were tested across dose levels. max To verify dose proportionality; calculate steady-state AUC and C0. max The accumulation.

[0489] Security Analysis Safety data will be summarized using descriptive statistics. All subjects who received treatment, regardless of duration, will be included in the safety data summary. TEAEs will be coded using the Medical Dictionary for Regulatory Activities and the incidence of TEAEs in subjects will be summarized by treatment, dose, system organ class, and preferred items. The incidence of TEAEs in subjects will also be summarized by severity and relationship to the investigational drug.

[0490] Goals and End Points The target and endpoint are provided in Table 20 below: Table 20. Objectives and endpoints of multiple dose escalation studies

[0491] Abbreviations: ADA = Anti-drug antibody; AE = Adverse event; AUC 0-∞ =Area under the plasma concentration-time curve extrapolated from time zero to infinity; AUC 0-最后 =AUC (Area under the plasma concentration-time curve from time zero to the last quantifiable time point) 0-τ =Plasma concentration-time area under the curve at the dosing interval; CL / F = Apparent clearance; C max = Observed maximum plasma concentration; PK = Pharmacokinetics; RAUC = Cumulative ratio; T max =Time to reach maximum plasma concentration; T 1 / 2 =Terminal elimination half-life; V z / F = apparent volume distribution; λ z =Terminal elimination rate constant Example 7: A Phase 1, randomized, double-blind, placebo-controlled first-in-human study of the safety, tolerability, and pharmacokinetics of anti-IL-13 antibodies in healthy subjects, involving single-dose escalation and multiple-dose escalation. Research Design and Methods This is 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). Three SAD cohorts and one MAD cohort were investigated in this study.

[0492] Evaluation criteria Key compliance standards Inclusion criteria See the description in Example 6.

[0493] Exclusion criteria See the description in Example 6.

[0494] Pharmacokinetics See the description in Example 6.

[0495] Anti-drug antibodies See the description in Example 6.

[0496] Pharmacodynamics See the description in Example 6.

[0497] Security See the description in Example 6.

[0498] Statistical methods Analysis of groups See the description in Example 6.

[0499] Sample size See the description in Example 6.

[0500] Pharmacokinetic analysis See the description in Example 6.

[0501] Security Analysis See the description in Example 6.

[0502] Goals and End Points See the description in Example 6.

[0503] SAD queue Twenty-four participants were enrolled in SAD cohorts 1 through 3. The three SAD cohorts included three escalating dose levels (300 mg, 600 mg, and 1200 mg). Eight subjects were enrolled in each SAD cohort. Subjects were randomly assigned in a blinded 6:2 ratio to receive either anti-IL-13 antibody or placebo. The first two participants in each cohort (sentinel participants) were randomly assigned in a blinded 1:1 ratio (active agent: placebo) and followed for at least 24 hours post-dose before the remaining participants in the treatment cohort. The remaining six participants were randomly assigned in a 5:1 ratio (active agent: placebo). (Illustration provided) Figure 4 middle.

[0504] On day 1, subjects received either an SC dose of construct 133 or a placebo at the CRU. Vital signs, ECG, AE assessment, and blood draws were obtained for pharmacokinetic and safety laboratory testing. After completing CRU confinement (by day 4), subjects returned to the outpatient clinic.

[0505] Data spanning 113 days indicated that construct 133 was well tolerated, with no serious adverse events (SAEs), Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 events, or dose-limiting toxicities (DLTs). Table 21 lists the most freque...

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 induction dose 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, the maintenance doses beginning administration 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, wherein 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 induction dose, a third induction dose, a fourth induction dose, and / or a 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 weeks to about 16 weeks after the first induction dose.

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

8. The method of any one of claims 1-4, comprising administering a second induction dose, a third induction dose, a fourth induction dose, and / or a 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 weeks 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 once every 3 months, once 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 once 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 once 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 once 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 once 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 once every 3 months, once every 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 once every 2 months or every 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 once 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 once 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 once 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 a 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 a withdrawable 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 features in the patient at baseline and during and after an 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: administering to the patient an anti-IL-13 antibody subcutaneously for an induction period of 4 weeks to 17 weeks, wherein during the induction period the anti-IL-13 antibody is administered as follows: at a loading dose of about 100 mg to about 1200 mg or a dose listed in any of Tables 11-13, once or twice, and optionally at least once at half or a quarter of the loading dose; and administering to the patient the anti-IL-13 antibody subcutaneously at a dose of 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 having 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 VHcomprises 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 VLcomprises 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.

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 half or quarter dose is administered at week 8, week 12, and week 16.

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

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

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

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

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

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

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

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

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

47. The method of any one of claims 31-36, wherein during the induction period, the half or quarter dose is administered at week 2, week 4, and week 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 once every 3 months, once 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 once every 2 months or once every 8 weeks.

51. The method of any one of claims 31-48, wherein during the maintenance period, the anti-IL-13 antibody is administered once every 16 weeks or 3 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 once 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 once 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.

56. 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: a) two loading doses of 720 mg of the 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 that begins administration 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.

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

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

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

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

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

62. 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: a) a loading dose of 720 mg of the 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 that begins administration 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.

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

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

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

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

67. 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, which begins administration 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.

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

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

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

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

72. 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.

73. The method of claim 71, wherein the composition is a unit dose having a withdrawable volume of 2 mL, 2.25 mL, or 2.7 mL.

74. The method of claim 72, wherein the composition is a unit dose having a withdrawable volume of 2 mL.

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

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

77. 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’s Global Assessment (IGA) score of > 3, and (c) a body surface area (BSA) of > 10%.

78. The method of any one of claims 31-76, further comprising measuring one or more of the following features in the patient at baseline and during and after the induction period: Eczema Area and Severity Index (EASI), Investigator’s Global Assessment (IGA), body surface area (BSA), Itch 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), Sinus Outcomes Test 22-item version (SNOT-22).

79. 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.

80. The composition of claim 78, wherein the composition is a unit dose having a withdrawable volume of 2 mL, 2.25 mL, or 2.7 mL.

81. The composition of claim 79, wherein the composition is a unit dose having a withdrawable volume of 2 mL.

82. An auto-injector configured for delivering 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.

83. The auto-injector of claim 81, wherein the composition is a unit dose having a withdrawable volume of 2 mL, 2.25 mL, or 2.7 mL.

84. The method, composition, or auto-injector 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.

85. The method, composition, or auto-injector 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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