Method of administering antibodies that bind to interleukin-13

Abstract

This specification describes methods for administering and using antibodies that bind to interleukin-13 (IL-13). In certain embodiments, the methods described herein are for inhibiting the biological activity of IL-13. In certain embodiments, the antibodies and methods described herein are used for the treatment of inflammatory diseases or disorders. In certain embodiments, the methods described herein are for treating atopic dermatitis in patients requiring treatment.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests and priority of U.S. Provisional Applications No. 63 / 462,832 filed on 28 April 2023, No. 63 / 469,180 filed on 26 May 2023, No. 63 / 471,088 filed on 5 June 2023, No. 63 / 521,614 filed on 16 June 2023, No. 63 / 541,581 filed on 29 September 2023, No. 63 / 612,871 filed on 20 December 2023, No. 63 / 621,479 filed on 16 January 2024, and No. 63 / 561,097 filed on 4 March 2024, the entirety of each of these disclosures is incorporated herein by reference for all purposes. [Background technology]

[0002] Interleukin (IL)-13 is a T helper cell subclass 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, together with CD40 / CD40L co-stimulation, induces class switching to IgG4 and IgE (IL-13 upregulates FcεRI and thus helps in the priming of mast cells with IgE). In monocytes / macrophages, IL-13 upregulates the expression of CD23 as well as MHC class I and class II antigens, downregulates the expression of CD14, inhibits antibody-dependent cell cytotoxicity IL-13, and promotes the survival, activation, and recruitment of eosinophils. IL-13 also exhibits important functions on non-hematopoietic cells such as smooth muscle cells, epithelial cells, endothelial cells, and fibroblasts. IL-13 enhances smooth muscle proliferation and cholinergic-induced contraction. In epithelial cells, IL-13 potently induces chemokine production, alters mucociliary differentiation, decreases the frequency of ciliary movement of ciliated epithelial cells, and results in the metaplasia of goblet cells. In endothelial cells, IL-13 is a potent inducer of vascular cell adhesion molecule 1 (VCAM-1), which is important for eosinophil recruitment. In human skin fibroblasts, IL-13 induces the synthesis of type I collagen in human skin fibroblasts.

[0003] Inhibition of IL-13 can be used to treat or prevent inflammatory diseases and conditions, such as, but not limited to, those associated with elevated levels of IgE, including asthma, allergic rhinitis, urticaria, asthma, allergic rhinitis, urticaria, and allergic dermatitis or atopic dermatitis. Therefore, there is a need for the development of potent and specific inhibitors of IL-13, such as inhibitors that maintain activity for a longer period when administered to a subject, for the prevention and / or treatment of IL-13- and IgE-mediated diseases or conditions.

[0004] These and other features, aspects, and advantages of the present invention will be better understood in relation to the following description and the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0005] [Figure 1] Schematic diagram showing the design of single - and multiple - ascending dose (SAD and MAD, respectively) trials using the anti - IL - 13 antibody described herein. The bold arrows indicate equivalent doses between the SAD and MAD dosing schemes. Abbreviations: Q4wk, every 4 weeks; SRC, Safety Review Committee; SC, SQ, subcutaneous.

[0006] [Figure 2] Graph showing the serum concentration (ng / mL) over time (days after injection) of construct 133 and lebrikizumab in non - human primates (NHP). The half - life was 17 - 18 days for lebrikizumab, whereas it was 27.6 days for construct 133.

[0007] [Figure 3] Graph showing the normalized AUC0 - ∞ (C - normalized * days) from dosing to infinity, or the area under the curve (AUC) of antibodies with YTE substitution.

[0008] [Figure 4] Schematic diagram showing the design of single - and multiple - ascending dose (SAD and MAD, respectively) trials using construct 133 described herein. Abbreviations: PK, pharmacokinetics; ADA, anti - drug antibody, pSTAT6, phosphorylated signal transducer and activator of transcription 6, TARC, thymus and activation - regulated chemokine, SQ, subcutaneous.

[0009] [Figure 5] Series of graphs showing the serum concentration (μg / mL) over time (weeks after injection) of construct 133 in humans enrolled in the SAD (left panel) and MAD (right panel) trials described in Figure 4. Abbreviations: D1, day 1, 29, day 29.

[0010] [Figure 6]Figure 4 shows the median percentage change from baseline in inhibition of IL-13-induced phosphorylation of STAT6 (pSTAT6) in humans enrolled in the SAD trial. At approximately 3 months (week 12, upward arrow), which was the end of the follow-up period, pSTAT6 remained suppressed after a single dose of construct 133.

[0011] [Figure 7] Figure 4 shows a series of graphs comparing the median percentage change from baseline in inhibition of thymic and activating modulatory chemokine (TARC) IL-13-induced release in humans enrolled in the SAD trial (right panel) with that of subjects treated with Dupixent (right panel).

[0012] [Figure 8] This is a schematic diagram illustrating the design of a Phase 2 clinical trial using construct 133 described herein. [Overview of the project]

[0013] In certain embodiments, the method described herein is a method for treating atopic dermatitis in a patient requiring treatment, and the patient a) 1 to 5 or more induction doses of anti-IL-13 antibody selected from 100 mg, 125 mg, 150 mg, 180 mg, 200 mg, 250 mg, 300 mg, 360 mg, 400 mg, 450 mg, 600 mg, 720 mg, 800 mg, 900 mg, 1080 mg, or 1200 mg, or any of the doses listed in Tables 11 to 13, and b) Subcutaneous administration of one or more maintenance doses administered approximately 4 to 17 weeks or more 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. The method for producing an 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 acid represented by 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 acid represented by SEQ ID NO: 39.

[0014] In a particular embodiment, the method further comprises administering an initial dose before 1 to 5 or more induction doses, the initial dose being twice the induction dose.

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

[0016] In a particular embodiment, the first induction dose is 150 mg, 300 mg, 360 mg, or 600 mg. In a particular embodiment, the first induction dose is 360 mg.

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

[0018] In a particular embodiment, the second induction dose is administered approximately 2 to 16 weeks after the first induction dose.

[0019] In certain embodiments, the second induction dose is administered approximately 2 to 8 weeks after the first induction dose.

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

[0021] In a particular embodiment, the second induction dose is administered approximately 2 to 16 weeks after the first induction dose.

[0022] In a particular embodiment, the second induction dose is administered approximately 2 to 16 weeks after the first induction dose.

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

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

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

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

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

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

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

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

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

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

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

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

[0035] In certain 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.

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

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

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

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

[0040] In a particular embodiment, the patient has one or more of the following: (a) Eczema Area Severity Index (EASI) score of 10 or higher, (b) Global Assessment (IGA) scores by three or more investigators, (c) Body surface area (BSA) of 10% or more.

[0041] In certain embodiments, the method further includes determining one or more of the following characteristics of the patient at baseline, during the induction period, and after the induction period: Eczema Area Severity Index (EASI), Investigator General Assessment (IGA), Body Surface Area (BSA), Numerical Rating Scale for Pruritus (NRS), Numerical Rating Scale for Skin Pain (SP-NRS), Insomnia Scale, Scoring for Atopic Dermatitis (SCORAD), Patient Self-Assessment of Eczema (POEM), Quality of Life Index for Skin Disease (DLQI), 5-Item Asthma Control Questionnaire (ACQ-5), and 22-Item Sinus Outcome Test (SNOT-22).

[0042] In certain embodiments, the method described herein is a method for treating atopic dermatitis in a patient requiring treatment, and the patient The treatment involves subcutaneous administration of anti-IL-13 antibodies during an induction period of 4 to 17 weeks, and during the induction period, the anti-IL-13 antibodies... The drug is administered subcutaneously, with an initial dose of approximately 100 mg to approximately 1200 mg or one of the doses listed in Tables 11 to 13, administered once or twice, and optionally, at least once, half or one-quarter of the initial dose. During the maintenance period, the patient is subcutaneously administered an anti-IL-13 antibody at a dose of approximately 100 mg to approximately 1200 mg or the doses listed in Table 14. The anti-IL-13 antibody contains a heavy chain variable region (VH) with an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 3 (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%), and at least 90% sequence identity to SEQ ID NO: 39 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least A method comprising a light chain variable region (VL) having sequence identity of 97%, at least 98%, at least 99%, or 100%, wherein VH comprises 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 comprises 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.

[0043] In a particular embodiment, the initial dose during the induction period is approximately 100 mg, 150 mg, 180 mg, 200 mg, 300 mg, 360 mg, 400 mg, 450 mg, 600 mg, 720 mg, 800 mg, 900 mg, 1080 mg, or 1200 mg.

[0044] In a particular embodiment, the initial dose is administered during the induction period in weeks 0 and 2.

[0045] In a particular embodiment, the initial dose is administered during the induction period at weeks 0 and 4.

[0046] In a particular embodiment, the initial dose is administered during the induction period at weeks 0 and 8.

[0047] In a particular embodiment, the initial dose is administered during the induction period at week 0 and week 12.

[0048] In a particular embodiment, half or quarter doses are administered during the induction period at weeks 8, 12, and 16.

[0049] In a particular embodiment, half or quarter doses are administered during the induction period at weeks 4, 8, 12, and 16.

[0050] In a particular embodiment, half or one-quarter doses are administered during the induction period at weeks 4 and 12.

[0051] In a particular embodiment, half or quarter doses are administered during the induction period at weeks 2, 4, and 12.

[0052] In a particular embodiment, half or quarter doses are administered during the induction period at weeks 2 and 12.

[0053] In a particular embodiment, half or a quarter of the dose is administered at week 12 during the induction period.

[0054] In certain embodiments, half or quarter doses are administered during the induction period at weeks 8 and 16.

[0055] In a particular embodiment, half or a quarter of the dose is administered at week 16 during the induction period.

[0056] In a particular embodiment, half or quarter doses are administered during the induction period at weeks 4 and 14.

[0057] In a particular embodiment, half or a quarter of the dose is administered at week 14 during the induction period.

[0058] In a particular embodiment, half or quarter doses are administered during the induction period at weeks 2, 4, and 14.

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

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

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

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

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

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

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

[0066] In a particular embodiment, 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 acid represented by 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 acid represented by SEQ ID NO: 39.

[0067] In certain embodiments, the method described herein is a method for treating atopic dermatitis in a patient requiring treatment, and the patient a) Two initial doses of 720 mg of anti-IL-13 antibody prior to the two induction doses. b) Two induction doses of 360 mg of anti-IL-13 antibody, and c) Subcutaneous administration of one or more maintenance doses of 360 mg of anti-IL-13 antibody, which is started approximately 12 weeks or more after the first induction dose. The method for producing an 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 acid represented by 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 acid represented by SEQ ID NO: 39.

[0068] In a particular embodiment, the second initial dose is administered approximately two weeks after the first initial dose.

[0069] In a particular embodiment, the first induction dose is administered approximately two weeks after the second initial dose.

[0070] In a particular embodiment, the second induction dose is administered approximately 8 weeks after the first induction dose.

[0071] In a particular embodiment, the maintenance dose is administered every three months.

[0072] In a particular embodiment, the maintenance dose is administered every six months.

[0073] In certain embodiments, the method described herein is a method for treating atopic dermatitis in a patient requiring treatment, and the patient a) The initial dose of 720 mg of anti-IL-13 antibody prior to the two induction doses, b) Two induction doses of 360 mg of anti-IL-13 antibody, and c) A method comprising subcutaneously administering one or more maintenance doses of 360 mg of anti-IL-13 antibody, which are started approximately 12 weeks or more after the first induction dose, wherein 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 acid represented by 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 acid represented by SEQ ID NO: 39.

[0074] In a particular embodiment, the first induction dose is administered approximately four weeks after the initial dose.

[0075] In a particular embodiment, the second induction dose is administered approximately 8 weeks after the first induction dose.

[0076] In a particular embodiment, the maintenance dose is administered every three months.

[0077] In a particular embodiment, the maintenance dose is administered every six months.

[0078] In certain embodiments, the method described herein is a method for treating atopic dermatitis in a patient requiring treatment, and the patient a) The initial dose of 360 mg of anti-IL-13 antibody prior to the two induction doses, b) Two induction doses of 180 mg of anti-IL-13 antibody, and c) A method comprising subcutaneous administration of one or more maintenance doses of 180 mg of anti-IL-13 antibody, which is started approximately 12 weeks or more after the first induction dose, wherein 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 acid represented by 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 acid represented by SEQ ID NO: 39.

[0079] In a particular embodiment, the first induction dose is administered approximately four weeks after the initial dose.

[0080] In a particular embodiment, the second induction dose is administered approximately 8 weeks after the first induction dose.

[0081] In a particular embodiment, the maintenance dose is administered every three months.

[0082] In a particular embodiment, the maintenance dose is administered every six months.

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

[0084] In a particular embodiment, the composition has a unit dose of 2 mL of extractable volume.

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

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

[0087] In a particular embodiment, the patient has one or more of the following: (a) Eczema Area Severity Index (EASI) score of 10 or higher, (b) Global Assessment (IGA) scores by three or more investigators, (c) Body surface area (BSA) of 10% or more.

[0088] In certain embodiments, the method further includes determining one or more of the following characteristics of the patient at baseline, during the induction period, and after the induction period: Eczema Area Severity Index (EASI), Investigator General Assessment (IGA), Body Surface Area (BSA), Numerical Rating Scale for Pruritus (NRS), Numerical Rating Scale for Skin Pain (SP-NRS), Insomnia Scale, Scoring for Atopic Dermatitis (SCORAD), Patient Self-Assessment of Eczema (POEM), Quality of Life Index for Skin Disease (DLQI), 5-Item Asthma Control Questionnaire (ACQ-5), and 22-Item Sinus Outcome Test (SNOT-22).

[0089] In certain embodiments, the compositions described herein include 150 mg / mL, 180 mg / mL, or 200 mg / mL of anti-IL-13 antibody, wherein 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 acid represented by 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 acid represented by SEQ ID NO: 39.

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

[0091] In a particular embodiment, the autoinjector described herein is an autoinjector configured to deliver a composition comprising 150 mg / mL, 180 mg / mL, or 200 mg / mL of anti-IL-13 antibody, wherein 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 acid represented by 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 acid represented by SEQ ID NO: 39.

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

[0093] In certain embodiments, the methods, compositions, or autoinjectors described herein further comprise a heavy chain constant region of sequence number 439 or 624, or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity therewith.

[0094] In certain embodiments, the methods, compositions, or autoinjectors described herein further comprise a light chain constant region of sequence SEQ ID NO: 469, or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity therewith. [Modes for carrying out the invention]

[0095] definition Unless otherwise defined, all technical terms, notations, and other scientific terms used herein have meanings that are generally understood by those skilled in the art. Where applicable, terms that have generally understood meanings are defined herein for clarity and / or for immediate reference, and the inclusion of such definitions herein should not necessarily be construed as representing a difference beyond that which is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and are commonly employed by those skilled in the art using conventional methods, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual 4th ed. (2012), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. Where necessary, procedures involving the use of commercially available kits and reagents are generally carried out according to the protocols and conditions defined by the manufacturers, unless otherwise noted.

[0096] As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated.

[0097] It is understood that the aspects and embodiments of the present invention described herein include "including," "consisting of," and "essentially consisting of."

[0098] All compositions described herein, and all methods using such compositions, may include or "essentially consist of" the listed components or steps. Where a composition is described as "essentially consisting of" the listed components, it contains the listed components and may contain other components that do not substantially affect the condition being treated, but does not contain any other components that substantially affect the condition being treated, other than those explicitly listed. Alternatively, where a composition contains additional components other than those explicitly listed that substantially affect the condition being treated, it does not contain additional components in concentrations or amounts sufficient to substantially affect the condition being treated. Where a method is described as "essentially consisting of" the listed steps, it includes the listed steps and may contain other steps that do not substantially affect the condition being treated, but does not contain any other steps that substantially affect the condition being treated, other than those explicitly listed. As a non-limiting example, where a composition is described as "essentially composed of" a certain component, the composition may further contain any amount of pharmaceutically acceptable carriers, media, or diluents, and other such components that do not substantially affect the condition being treated.

[0099] As used herein, the term “vector” refers to a nucleic acid molecule capable of propagating another nucleic acid it is linked to. This term includes vectors as self-replicating nucleic acid structures, as well as vectors integrated into the genome of a host cell into which they are introduced. Certain vectors can operatively induce the expression of linked nucleic acids. Such vectors are referred to herein as “expression vectors.”

[0100] The terms “host cell,” “host cell line,” and “host cell culture” are used synonymously and refer to cells into which exogenous nucleic acids have been introduced, and the offspring of such cells. Host cells include “transformers” (or “transformed cells”) and “transferers” (or “transferred cells”), which include primary transformed cells or transferred cells and their offspring, respectively. Such offspring may not be completely identical to the parent cells in nucleic acid content and may contain mutations. “Recombinant host cell” or “host cell” refers to a cell containing exogenous polynucleotides, regardless of the method used for insertion, such as direct uptake, transduction, f-conjugation, or other methods known in the art to produce recombinant host cells.

[0101] As used herein, the term “eukaryote” refers to organisms belonging to the phylogenetic domain Eucarya, such as animals (including, but not limited to, mammals, insects, reptiles, and birds), ciliates, plants (including, but not limited to, monocots, dicots, and algae), fungi, yeasts, flagellates, microsporids, protists, and so on.

[0102] As used herein, the term “prokaryote” refers to a prokaryotic organism. For example, non-eukaryotes may belong to the phylogenetic domain of Eubacteria (including, but not limited to, Escherichia coli, Thermus thermophilus, Bacillus stearothermophilus, Pseudomonas fluorescens, Pseudomonas aeruginosa, Pseudomonas putida, etc.) or to the phylogenetic domain of Archaea (including, but not limited to, Halobacterium such as Methanococcus jannaschii, Methanobacterium thermoautotrophicum, Haloferax volcanii, and Halobacterium species NRC-1, Archaeeoglobus fulgidus, Pyrococcus furiosus, Pyrococcus horikoshii, Aeuropyrum pernix, etc.).

[0103] As used herein, “effective dose” or “therapeutic effective dose” refers to the amount of a therapeutic compound, such as an anti-IL-13R antibody, administered to an individual, either as a single dose or as part of a series of doses, which is effective in producing or contributing to a desired therapeutic effect, either alone or in combination with another mode of therapy. Examples of desired therapeutic effects include enhancing the immune response, slowing or delaying tumor development, stabilizing a disease, or improving one or more symptoms. An effective dose may be administered in one or more doses.

[0104] The term “to treat” (and its variations such as “to treat” or “to cure”) refers to a clinical intervention in an attempt to alter the natural course of a disease or condition in an object that requires such alteration. Treatment may be carried out in the course of clinicopathology. Desired effects of treatment include prevention of disease recurrence, relief of symptoms, reduction of any direct or indirect pathological consequences of the disease, prevention of metastasis, slowing of the rate of disease progression, recovery or reduction of the condition, and remission or improved prognosis.

[0105] The term "sufficient amount" means an amount sufficient to produce the desired effect, for example, an amount sufficient to alleviate the immune response in the subject.

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

[0107] The term "in vitro" refers to processes that occur in living cells that are growing independently of the living organism, such as growth in tissue culture.

[0108] The term "in vivo" refers to processes that occur in living organisms.

[0109] The term “package insert” is used to refer to the instructions typically included in the commercial packaging (e.g., a kit) of a therapeutic or diagnostic agent, which contain information about the indications, use, dosage, administration, combination therapy, contraindications, and / or warnings regarding its use.

[0110] The term "pharmaceutical composition" refers to a preparation in which the biological activity of the active ingredient contained in the preparation is effective in treating the target, and which does not contain any additional ingredients that are unacceptably toxic to the target in the amount provided in the pharmaceutical composition.

[0111] The terms “co-administration,” “co-administer,” and “combined” include administering two or more therapeutic agents simultaneously, concurrently, or consecutively within an unspecified time limit. In one embodiment, the agents are simultaneously present in cells or within the body of the subject, 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 different compositions or unit dosage forms. In certain embodiments, the first agent may be administered before the administration of the second therapeutic agent.

[0112] The terms "to regulate" and "to adjust" refer to reducing or inhibiting the listed variables, or activating or increasing them as an alternative.

[0113] The terms “increase” and “activate” refer to increases of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 2x, 3x, 4x, 5x, 10x, 20x, 50x, 100x, or more in the listed variables.

[0114] The terms “reduce” and “inhibit” refer to reductions of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 1 / 2, 1 / 3, 1 / 4, 1 / 5, 1 / 10, 1 / 20, 1 / 50, 1 / 100, or more in the listed variables.

[0115] The term "approximately" indicates and encompasses the given value and its upper and lower range. In certain embodiments, the term "approximately" indicates a specified value ± 10%, ± 5%, or ± 1%. In certain embodiments, where applicable, the term "approximately" indicates the specified value(s) ± one standard deviation of that value(s).

[0116] The term "stimulate" refers to the activation of receptor signaling pathways to induce a biological response associated with receptor activation. A "stimulant" is an entity that binds to and stimulates a receptor.

[0117] The term "antagonism" refers to the inhibition of receptor signaling, which inhibits biological responses related to receptor activation. An "antagonist" is an entity that binds to and antagonizes a receptor.

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

[0119] The term "by choice," when used consecutively, means to include all of the given combinations, taking into account all subcombinations.

[0120] The term "amino acid" refers to 20 common naturally occurring amino acids. These naturally occurring amino acids include alanine (Ala, A), arginine (Arg, R), asparagine (Asn, N), aspartic acid (Asp, D), cysteine ​​(Cys, C), glutamic acid (Glu, E), glutamine (Gln, Q), glycine (Gly, G), histidine (His, H), isoleucine (Ile, I), leucine (Leu, L), lysine (Lys, K), methionine (Met, M), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), and valine (Val, V).

[0121] The term "affinity" refers to the combined strength of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen or epitope). Unless otherwise indicated herein, "affinity" refers to the intrinsic binding affinity that reflects the 1:1 interaction between the members of a binding pair (e.g., an antibody and an antigen or epitope).

[0122] As used herein, the term "kd" (sec-1) refers to the dissociation rate constant of a particular antibody-antigen interaction. This value is also known as the koff value.

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

[0124] As used herein, the term "KD" (M) refers to the dissociation equilibrium constant of a particular antibody-antigen interaction. KD = kd / ka. In certain embodiments, the affinity of an antibody is described in terms of the KD of the interaction between such antibody and its antigen. For clarity, as is known in the art, a smaller KD value indicates a higher affinity interaction, and a larger KD value indicates a lower affinity interaction.

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

[0126] The term “antibody” is used herein in its broadest sense and includes certain types of immunoglobulin molecules that contain one or more antigen-binding domains that specifically bind to an antigen or epitope. Specifically, antibodies include intact antibodies (e.g., intact immunoglobulins), antibody fragments, and multispecific antibodies.

[0127] An "anti-IL-13 antibody," "IL-13 antibody," or "IL-13 specific antibody" is an antibody, such as those provided herein, that specifically binds to the antigen IL-13.

[0128] The term "epitope" refers to the portion of an antigen that specifically binds to an antibody.

[0129] The terms “hypervariable region” or “HVR,” as used herein, refer to each region of an antibody-variable domain that is hypervariable in the sequence and / or forms a structurally defined loop (“hypervariable loop”).

[0130] The term "antigen-binding domain" refers to the portion of an antibody that can specifically bind to an antigen or epitope.

[0131] The term "chimeric antibody" refers to an antibody in which part of the heavy chain and / or light chain originates from a specific source or species, while the rest of the heavy chain and / or light chain originates from a different source or species.

[0132] The term "human antibody" refers to an antibody that possesses an amino acid sequence corresponding to the amino acid sequence of an antibody produced by a human or human cell, or an antibody derived from a non-human source that utilizes the human antibody repertoire or (for example, obtained from a human source or newly designed) human antibody coding sequence. Strictly speaking, human antibodies exclude humanized antibodies.

[0133] The term "humanized antibody" refers to a protein that has a different sequence from that of an antibody derived from a non-human species, due to the substitution, deletion, and / or addition of one or more amino acids. As a result, when administered to a human subject, a humanized antibody is less likely to induce an immune response and / or induces a less severe immune response compared to an antibody from a non-human species.

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

[0135] A "monospecific antibody" is an antibody that contains 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 is bivalent (i.e., has two antigen-binding domains) but recognizes the same epitope in each of its two antigen-binding domains. Binding specificity can exist at any appropriate valency.

[0136] The term "monoclonal antibody" refers to an antibody from a population of substantially homogeneous antibodies. A population of substantially homogeneous antibodies is substantially similar, except for variants that may normally occur during the production of monoclonal antibodies, and includes antibodies that bind to the same epitope(s). Such variants are generally present only in small amounts. Monoclonal antibodies are typically obtained by a process involving the selection of a single antibody from multiple antibodies. For example, the selection process could be the selection of a specific clone from multiple clones, such as a hybridoma clone, phage clone, yeast clone, bacterial clone, or a pool of other recombinant DNA clones. The selected antibody can be further modified, for example, to improve its affinity for a target ("affinity maturation"), to humanize the antibody, to improve its production in cell culture, and / or to reduce its immunogenicity in a target.

[0137] The term "single-chain" refers to a molecule containing amino acid monomers linearly linked by peptide bonds. In certain such embodiments, the C-terminus of the Fab light chain is connected to the N-terminus of the Fab heavy chain in a single-chain Fab molecule. As described in more detail herein, scFv has a variable domain (VL) of the light chain connected from its C-terminus to the N-terminus of the variable domain (VH) of the heavy chain by a polypeptide chain. Alternatively, scFv includes a polypeptide chain, where the C-terminus of VH is connected to the N-terminus of VL by a polypeptide chain.

[0138] The "Fab fragment" (also called the antigen-binding fragment) includes the constant domain (CL) of the light chain and the first constant domain (CH1) of the heavy chain, as well as the variable domains VL and VH on the light and heavy chains, respectively. The variable domains contain the complementarity-determining loop (CDR, also called the hypervariable region) involved in antigen binding. The Fab' fragment differs from the Fab fragment in that several residues are added to the carboxyl terminus of the heavy chain CH1 domain, which contains one or more cysteines derived from the antibody hinge region.

[0139] The "F(ab')2" fragment contains two Fab' fragments linked by a disulfide bond near the hinge region. The F(ab')2 fragment can be generated, 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.

[0140] The "Fv" fragment contains a non-covalent dimer of one heavy chain variable domain and one light chain variable domain.

[0141] "Single-stranded Fv," "sFv," or "scFv" comprises the VH and VL domains of an antibody, where these domains reside within a single polypeptide chain. In one embodiment, the Fv polypeptide further includes a polypeptide linker between the VH and VL domains, which allows the scFv to form a structure desirable for antigen binding. For an overview of scFV, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994). HER2 antibody scFv fragments are described in WO93 / 16185, U.S. Patent No. 5,571,894, and U.S. Patent No. 5,587,458.

[0142] The “scFv-Fc” fragment comprises an scFv bound to an Fc domain. For example, the Fc domain may be bound to the C-terminus of the scFv. The Fc domain may follow VH or VL depending on the orientation of the variable domain of 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 includes an IgG4 Fc domain.

[0143] The term "single-domain antibody" or "sdAb" refers to a molecule in which one variable domain of the antibody specifically binds to an antigen in the absence of the other variable domain. Single-domain antibodies and their fragments are described in Arabi Ghahroudi et al., FEBS Letters, 1998, 414:521-526 and Muyldermans et al., Trends in Biochem. Sci., 2001, 26:230-245, which are respectively incorporated as wholes by reference. Single-domain antibodies are also known as sdAbs or nanobodies. sdAbs are fairly stable and readily expressed as fusion partners with the antibody's Fc chain (Harmsen MM, De Haard HJ (2007). "Properties, production, and applications of camelid single-domain antibody fragments". Appl. Microbiol Biotechnol. 77(1):13-22).

[0144] The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used herein synonymously to refer to antibodies having a structure substantially similar to that of naturally occurring antibodies and possessing a heavy chain containing an Fc region. For example, when used to refer to an IgG molecule, a “full-length antibody” is an antibody containing two heavy chains and two light chains.

[0145] The term "antibody fragment" refers to an antibody that contains a portion of an intact antibody, such as the antigen-binding region and / or variable region of the intact antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab')2 fragments, Fab' fragments, scFv(sFv) fragments, and scFv-Fc fragments.

[0146] In this specification, the terms “Fc domain” or “Fc region” are used to define the C-terminal region of an immunoglobulin heavy chain, which includes at least a portion of the constant region. This term includes both the native sequence Fc region and the mutant Fc region.

[0147] The term “substantially purified” means a construct or variant described herein that substantially or essentially does not contain components that normally accompany or interact with a protein, such as those found in its naturally occurring environment, i.e., in natural cells, or, in certain embodiments, in host cells, in recombinantly produced antibodies that substantially do not contain cellular material, and includes the preparation of proteins having contaminating proteins of 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 1% (by dry weight).

[0148] The term "identity" percentage refers to two or more nucleic acid sequences or polypeptide sequences that, in the context of two or more nucleic acid sequences or polypeptide sequences, have a certain percentage of identical nucleotide or amino acid residues when aligned and compared to maximize the match, measured using one of the following sequence comparison algorithms (e.g., publicly available computer software such as BLAST, BLASTP, BLASTN, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE software, or algorithms available to those skilled in the art) or by visual inspection. Software for performing BLAST analysis is generally available through the National Center for Biotechnology Information (ncbi.nlm.nih.gov). Those skilled in the art can determine appropriate parameters for sequence alignment, including any algorithm necessary to achieve maximum alignment over the full length of the sequences being compared. Depending on the application, the "identity" percentage may exist over a region of the sequences being compared, for example, over a functional domain, or alternatively, over the full length of both sequences being compared.

[0149] For sequence comparison, typically one sequence acts as a reference sequence, which is compared to the test sequence. When using a sequence comparison algorithm, the test sequence and reference sequence are entered into a computer, subsequence coordinates are specified as needed, and sequence algorithm program parameters are specified. The sequence comparison algorithm then calculates the sequence identity percentage of the test sequence(s) to the reference sequence based on the specified program parameters.

[0150] The optimal alignment of sequences for comparison may be performed, for example, by the local identity algorithm of Smith & Waterman, Adv.Appl.Math.2:482 (1981), by the identity alignment algorithm of Needleman & Wunsch, J.Mol.Biol.48:443 (1970), by the similarity search method of Pearson & Lipman, Proc.Nat'l.Acad.Sci.USA85:2444 (1988), by computer implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA included in the Wisconsin Genetics Software Package by Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection.

[0151] The ranges listed herein are understood to be abbreviated notations of all values ​​within that range, including the listed endpoints. For example, the range 1 to 50 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50.

[0152] It should be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless otherwise explicitly indicated by the context.

[0153] Anti-IL-13 antibody Antibody structure This application provides an antibody that binds to IL-13 and a composition containing the antibody.

[0154] The recognized immunoglobulin genes include kappa constant region genes, lambda constant region genes, alpha constant region genes, gamma constant region genes, delta constant region genes, epsilon constant region genes, and mu constant region genes, as well as a vast number of immunoglobulin variable region genes. The light chain is classified as either kappa or lambda. The "class" of an antibody or immunoglobulin refers to the type of constant domain or constant region held by its heavy chain. Antibodies have five main classes: IgA, IgD, IgE, IgG, and IgM, some of which can be further classified into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0155] The structural unit of an exemplary immunoglobulin (antibody) consists of two pairs of polypeptide chains, each having one “light” chain (approximately 25 kD) and one “heavy” chain (approximately 50–70 kD). The N-terminal domain of each chain defines a variable region of approximately 100–110 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 the VH domain, CH1 domain, CH2 domain, and CH3 domain from the N-terminus to the C-terminus, respectively. The light chain contains the VL domain and CL domain from the N-terminus to the C-terminus. The IgG1 heavy chain contains a hinge between the CH1 and CH2 domains. In certain embodiments, the immunoglobulin construct includes at least one immunoglobulin domain from IgG, IgM, IgA, IgD, or IgE linked to a therapeutic polypeptide. In some embodiments, the immunoglobulin domains found in the antibodies provided herein are from or derived from immunoglobulin-based constructs such as diabodies or nanobodies. In certain embodiments, the immunoglobulin constructs described herein include at least one immunoglobulin domain from a heavy chain antibody such as a camelid antibody. In certain embodiments, the immunoglobulin constructs provided herein include at least one immunoglobulin domain from a mammalian antibody such as a bovine antibody, human antibody, camelid antibody, mouse antibody, or any chimeric antibody.

[0156] In some embodiments, the antibodies provided herein include 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.

[0157] 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.

[0158] Generally, natural quadruple-chain antibodies contain six hypervariable regions (HVRs), three located in the VH (H1, H2, and H3) and three in the VL (L1, L2, and L3). HVRs generally contain amino acid residues from the hypervariable loop and / or complementarity-determining region (CDR), the latter of which has the highest sequence variability and / or is involved in antigen recognition. Except for CDR1 in the VH, CDRs generally contain amino acid residues that form the hypervariable loop. HVRs are also called CDRs, and these terms are used herein as synonymous to refer to the portion of the variable region that forms the antigen-binding region. This particular region is described in Kabat et al., USDept. of Health and Human Services, Sequences of Proteins of Immunological Interest (1983), and Chothia et al., J Mol Biol 196:901-917 (1987), where the definition includes overlaps or subsets of amino acid residues when compared to each other. Nevertheless, any application of definitions to refer to the CDR of an antibody or its variants is intended to be within the scope of the terms defined and used herein. The exact residue numbers that constitute a particular CDR vary depending on the sequence and size of the CDR. Those skilled in the art can routinely determine which residues constitute a particular CDR, given the variable region amino acid sequence of an antibody.

[0159] The amino acid sequence boundaries of the CDR can be determined by a person skilled in the art using any of several known numbering schemes, including those described by 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 Pluckthun, J.Mol.Biol., 2001, 309:657-70 ("AHo" numbering scheme) (each of these is incorporated as a whole by reference).

[0160] Table 1 shows 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 presented using both the Kabat and Chothia numbering schemes.

[0161] CDRs may be assigned using antibody numbering software, such as Abnum, described in Abhinandan and Martin, Immunology, 2008, 45:3832-3839, which is available, for example, at www.bioinf.org.uk / abs / abnum / and is incorporated in its entirety by reference. [Table 1]

[0162] The "EU numbering scheme" is generally used when referring to residues within the constant region of the antibody heavy chain (as reported, for example, in Kabat et al. (above)). Unless otherwise specified, the EU numbering scheme is used to refer to residues within the constant region of the antibody heavy chain as described herein.

[0163] One example of an antigen-binding domain is the one formed by the VH-VL dimer of an antibody. Another example of an antigen-binding domain is the one formed by the diversification of a specific loop from the tenth fibronectin type III domain of adnectin. The antigen-binding domain can contain CDR1, 2, and 3 from the heavy chain in that order, and CDR1, 2, and 3 from the light chain in that order.

[0164] Epitopes often consist of surface-accessible amino acid residues and / or sugar side chains and may possess specific three-dimensional structural and charge properties. The difference between conformational and non-conformational epitopes is that binding to the former is lost in the presence of a denaturing solvent, while binding to the latter is not. Epitopes may include amino acid residues directly involved in binding and other amino acid residues not directly involved in binding. The epitope to which an antibody binds can be determined using known techniques for epitope determination, such as antibody binding tests against IL-13 mutants with different point mutations or chimeric IL-13 mutants.

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

[0166] A chimeric antibody is an antibody in which a portion of the heavy chain and / or light chain originates from a specific source or species, while the remaining portion of the heavy chain and / or light chain originates from a different source or species.

[0167] Human antibodies are antibodies that possess amino acid sequences corresponding to the amino acid sequences of antibodies produced by humans or human cells, or antibodies derived from the human antibody repertoire or non-human sources that utilize human antibody coding sequences (e.g., obtained from human sources or newly designed). Strictly speaking, human antibodies exclude humanized antibodies.

[0168] Humanized antibodies have a sequence different from that of antibodies derived from non-human species by substituting, deleting, and / or adding one or more amino acids, and as a result, 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 produced by mutating certain amino acids in the heavy and / or light chain framework and constant domains of a non-human species antibody. In another embodiment, a constant domain(s) derived from a human antibody is fused to a variable domain(s) derived 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 modified to reduce the likelihood of immunogenicity of the non-human antibody when administered to a human subject, and none of the modified amino acid residues are important for the antibody's immune-specific binding to its antigen, or the amino acid sequence modification performed is a conservative modification, thereby ensuring that the binding of the humanized antibody to the antigen is not significantly worse than that of the non-human antibody to the antigen. Examples of methods for producing humanized antibodies can be found in U.S. Patents 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. These are each incorporated in their entirety by reference.

[0169] Two or more different epitopes may be epitopes on the same antigen (e.g., a single IL-13) or on different antigens (e.g., different IL-13 molecules, or an IL-13 molecule and a non-IL-13 molecule). In some embodiments, the multispecific antibody binds to two different epitopes (i.e., a "bispecific antibody"). In some embodiments, the multispecific antibody binds to three different epitopes (i.e., a "triplespecific antibody").

[0170] Anti-IL-13 antibodies may include those described herein, such as clones shown in the drawings and / or tables. In some embodiments, the antibody includes an alternative skeleton. In some embodiments, the antibody consists of an alternative skeleton. In some embodiments, the antibody is essentially made from an alternative skeleton. In some embodiments, the antibody includes an antibody fragment. In some embodiments, the antibody consists of an antibody fragment. In some embodiments, the antibody is essentially made from an antibody fragment.

[0171] In some embodiments, the antibody is a monoclonal antibody.

[0172] In some embodiments, the antibody is a polyclonal antibody.

[0173] In some embodiments, antibodies are produced by hybridomas. In other embodiments, antibodies are produced by recombinant cells engineered to express desired variable and constant domains.

[0174] In some embodiments, the antibody may be a single-chain antibody or other antibody derivative that retains antigen specificity and a lower hinge region or variants thereof.

[0175] In some embodiments, the antibody may be a polyfunctional antibody, a recombinant antibody, a human antibody, a humanized antibody, or a fragment or variant thereof. In certain embodiments, the antibody fragment or its derivative may be selected from Fab fragments, Fab'2 fragments, CDRs, and ScFvs.

[0176] In some embodiments, antibodies can form immune complexes. For example, the immune complex may be tumor cells covered by the antibody.

[0177] For sequence comparison, typically one sequence acts as a reference sequence, which is compared to the test sequence. When using a sequence comparison algorithm, the test sequence and reference sequence are entered into a computer, subsequence coordinates are specified as needed, and sequence algorithm program parameters are specified. The sequence comparison algorithm then calculates the sequence identity percentage of the test sequence(s) to the reference sequence based on the specified program parameters.

[0178] The optimal alignment of sequences for comparison can be performed, for example, by the local homology algorithm of Smith & Waterman, Adv.Appl.Math.2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J.Mol.Biol.48:443 (1970), by the similarity search method of Pearson & Lipman, Proc.Nat'l.Acad.Sci.USA85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA included in the Wisconsin Genetics Software Package by Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (generally see Ausubel et al., (below)).

[0179] One example of a suitable algorithm for determining sequence identity and sequence similarity percentages is the BLAST algorithm, described in Altschul et al., J.Mol.Biol.215:403-410 (1990). Software for performing BLAST analysis is generally available through the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov / ).

[0180] IL-13 antibody sequence VH domain In some embodiments, the antibodies provided herein include a VH sequence selected from SEQ ID NOs: 1 to 32.

[0181] In some embodiments, the antibodies provided herein contain 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 NOs: 1-32. In some embodiments, the antibodies provided herein contain a VH sequence 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 with the VH sequences provided in SEQ ID NOs: 1-32. H The sequence is included. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “mutants”. In some embodiments, such mutants are derived from the sequence provided herein by, for example, affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such mutants are not derived from the sequence provided herein and may be newly isolated, for example, according to a method provided herein to obtain an antibody.

[0182] VL domain In some embodiments, the antibodies provided herein include a VL sequence selected from SEQ ID NOs: 33-57.

[0183] In some embodiments, the antibodies provided herein include a VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the exemplary VL sequences provided in SEQ ID NOs. 33–57. In some embodiments, the antibodies provided herein include a VL sequence provided in SEQ ID NOs. 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 amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “mutants.” In some embodiments, such mutants are derived from the sequences provided herein by, for example, affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants may not be derived from sequences provided herein, but may be newly isolated, for example, according to methods provided herein for obtaining antibodies.

[0184] VH-VL combination In some embodiments, the antibodies provided herein include a VH sequence selected from SEQ ID NOs: 1-32 and a VL sequence selected from SEQ ID NOs: 33-57, for example, the VH-VL combinations described for constructs 3-127 and 132-144 in Table 2 below.

[0185] In a particular embodiment, any of sequence numbers 1 to 32 can be combined with any of sequence numbers 33 to 57.

[0186] In a particular embodiment, the antibody comprises a VH sequence selected from sequences represented by SEQ ID NOs: 1 to 32 and a VL sequence represented by SEQ ID NO: 49.

[0187] In a particular embodiment, the antibody comprises a VH sequence selected from sequences represented by SEQ ID NOs: 1 to 32 and a VL sequence represented by SEQ ID NO: 51.

[0188] In some embodiments, the antibodies provided herein include a VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the VH sequences provided in SEQ ID NOs: 1 to 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 sequences provided in SEQ ID NOs: 33 to 57. In some embodiments, the antibodies provided herein comprise a VH sequence provided in SEQ ID NOs: 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 a VL sequence provided in SEQ ID NOs: 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 conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “mutants”. In some embodiments, such mutants are derived from the sequences provided herein by, for example, affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants may not be derived from sequences provided herein, but may be newly isolated, for example, according to methods provided herein for obtaining antibodies.

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

[0190] In certain embodiments, the isolated antibody includes a heavy chain variable domain comprising a framework region sequence selected from sequences represented by SEQ ID NOs: 198-229, 255-256, 258-259, 261-285, 311-315, 317-342, 368-369, 371-399, and 540-580. In certain embodiments, the isolated antibody includes a heavy chain variable domain comprising one, two, three, or four framework region sequences selected from sequences represented by SEQ ID NOs: 198-229, 255-256, 258-259, 261-285, 311-315, 317-342, 368-369, 371-399, and 540-580.

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

[0192] In a particular embodiment, the isolated antibody comprises a heavy chain variable domain containing one, two, three, or four framework region sequences selected from sequences represented by SEQ ID NOs: 198-229, 255-256, 258-259, 261-285, 311-315, 317-342, 368-369, 371-399, and 540-580, and a light chain variable domain containing one, two, three, or four framework region sequences selected from sequences represented by SEQ ID NOs: 230-231, 233-235, 239, 241-254, 286, 288, 290-291, 293, 296-310, 343-345, 347, 400-424, and 581-609. [Table 2-1] Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17

[0193] In some embodiments, the VH domains listed for any one of constructs 3-127 and 132-144 in Table 2 can be combined with the heavy chain constant (HC) domains provided herein. In certain embodiments, the anti-IL-13 antibody comprises a VH domain selected from any one 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 thereto, and a heavy chain constant (HC) domain containing a sequence selected from any one of sequence numbers 425-468, 484-539, and 610-709, or an HC domain having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto. Any combination of (1) the VH / VL domains listed for constructs 3-127 and 132-144 in Table 2 and (2) the HC domain is intended herein. In some embodiments, the VH domains listed for any one of constructs 3-127 and 132-144 in Table 2 can be combined with the heavy chain constant (HC) domains provided herein. In certain embodiments, the anti-IL-13 antibody comprises a VH domain selected from any one 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 thereto, and an HC domain containing a sequence selected from any one of sequence numbers 610, 615-641, and 654-709, or an HC domain having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto. In certain embodiments, the HC domain is an IgG1 HC domain. In a particular embodiment, one of the VL domains from constructs 3-127 and 132-144 in Table 2 is combined with an IgG1 light chain constant (LC) domain.In a particular embodiment, one of the VL domains 3-127 and 132-144 of Table 2 is combined with an LC domain containing sequence number 469 or an LC domain having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto.

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

[0195] In some embodiments, such IgG4-SP HC constant domain has the following sequence: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (Sequence ID 427).

[0196] In some embodiments, such hIgG1-LALA-YTE HC constant domain has the following sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (Sequence ID 439).

[0197] In some embodiments, such hIgG1-LAGA YTE HC constant domain has the following sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELAGAPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (Sequence ID 440).

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

[0199] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG (Sequence ID 446).

[0200] In some embodiments, such IgG4-YTE HC constant domain has the following sequence: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (Sequence ID 457).

[0201] In some embodiments, such IgG4-LSHC constant domain has the following sequence: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHSYTQKSLSLSLGK (Sequence ID 460).

[0202] In some embodiments, such hIgG1-LALA-YTE HC C-terminal lysine variant constant domain has the following sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (Sequence ID 624).

[0203] In some embodiments, such hIgG1-LAGA YTE HC C-terminal lysine mutant constant domain has the following sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELAGAPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (Sequence ID 625).

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

[0205] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK (Sequence ID 631).

[0206] In certain embodiments, VL domains listed in constructs 3-127 and 132-144 of Table 2, or VL domains having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, can be combined with light chain stationary (LC) domains provided herein. In some embodiments, the LC domain is a human kappa LC stationary domain. In some embodiments, such a human kappa LC stationary domain has the following sequence: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Sequence ID 469).

[0207] CDR In some embodiments, the antibodies provided herein include one to three CDRs selected from SEQ ID NOs: 1 to 32, such as any of the CDRs listed in Tables 3, 4, or 5 below. In some embodiments, the antibodies provided herein include two to three CDRs selected from SEQ ID NOs: 1 to 32. In some embodiments, the antibodies provided herein include three CDRs selected from SEQ ID NOs: 1 to 32. In some embodiments, the CDR is an exemplary CDR. 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.

[0208] In some embodiments, 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 NOs. In some embodiments, CDR-H1 is a CDR-H1 of a VH domain selected from SEQ ID NOs. 1-32, having up to 1, 2, 3, 4, or 5 amino acid substitutions. In some embodiments, CDR-H2 is a CDR-H2 of a VH domain selected from SEQ ID NOs. 1-32, having up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, CDR-H3 is a CDR-H3 of a VH domain selected from SEQ ID NOs. 1-32, having up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “mutants.” In some embodiments, such mutants are derived from sequences provided herein by, for example, affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such mutants are not derived from sequences provided herein and may be newly isolated, for example, according to a method provided herein to obtain an antibody.

[0209] In some embodiments, the antibodies provided herein contain one to three CDRs from the VL domains of SEQ ID NOs. 33-57, such as any of the CDRs listed in Tables 6, 7, or 8 below. In some embodiments, the antibodies provided herein contain two to three CDRs from the VL domains of SEQ ID NOs. 33-57. In some embodiments, the antibodies provided herein contain three CDRs from the VL domains of SEQ ID NOs. 33-57. In some embodiments, the CDR is an exemplary CDR. 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.

[0210] In some embodiments, 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 NOs. 141–188. 201. CDR-L1 is a CDR-L1 of the VL domain of SEQ ID NOs. 33–57, having up to 1, 2, 3, 4, or 5 amino acid substitutions. 301. CDR-L2 is a CDR-L2 of the VL domain of SEQ ID NOs. 33–57, having up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. 401. CDR-L3 is a CDR-L3 of the VL domain of SEQ ID NOs. 33–57, having up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “mutants.” In some embodiments, such mutants are derived from sequences provided herein by, for example, affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such mutants are not derived from sequences provided herein and may be newly isolated, for example, according to a method provided herein to obtain an antibody.

[0211] In some embodiments, the antibodies provided herein include one to three CDRs from VH domains selected from SEQ ID NOs: 1 to 32 and one to three CDRs from VL domains from SEQ ID NOs: 33 to 57. In some embodiments, the antibodies provided herein include two to three CDRs from VH domains selected from SEQ ID NOs: 1 to 32 and two to three CDRs from VL domains from SEQ ID NOs: 33 to 57. In some embodiments, the antibodies provided herein include three CDRs from VH domains selected from SEQ ID NOs: 1 to 32 and three CDRs from VL domains from SEQ ID NOs: 33 to 57. In some embodiments, the CDR is an exemplary CDR. 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 NOs: 112-120 and 130-40. 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 of SEQ ID NOs: 112-120 or 130-40. In some embodiments, CDR-H3 is CDR-H3 selected from SEQ ID NOs: 112-120 and 130-40 having up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “mutants”. In some embodiments, such variants are derived from sequences provided herein by, for example, 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 sequences provided herein and may be newly isolated, for example, according to a method provided herein to obtain an antibody.

[0213] In some embodiments, the antibodies provided herein include CDR-H1 of SEQ ID NOs. 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 NOs. 58-99 or 121. In some embodiments, CDR-H1 is CDR-H1 of SEQ ID NOs. 58-99 or 121 having up to 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 by, for example, affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants may not be derived from sequences provided herein, but may be newly isolated, for example, according to methods provided herein for obtaining antibodies.

[0214] In some embodiments, the antibodies provided herein comprise one of the CDR-H2 sequences from SEQ ID NOs: 100 to 111. In some embodiments, the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with one of the CDR-H2 sequences from SEQ ID NOs: 100 to 111. In some embodiments, the CDR-H2 is one of the CDR-H2 sequences from SEQ ID NOs: 100 to 111, having up to 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 by, for example, affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants may not be derived from sequences provided herein, but may be newly isolated, for example, according to methods provided herein for obtaining antibodies.

[0215] In some embodiments, the antibodies provided herein comprise CDR-L3 selected from SEQ ID NOs: 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 NOs: 165–172. In some embodiments, CDR-L3 is CDR-L3 of SEQ ID NOs: 165–172 having up to 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 “mutants.” In some embodiments, such mutants are derived from sequences provided herein by, for example, affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants may not be derived from sequences provided herein, but may be newly isolated, for example, according to methods provided herein for obtaining antibodies.

[0216] In some embodiments, the antibodies provided herein comprise CDR-L2 selected from SEQ ID NOs. 153-158 and 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 NOs. 153-158 and amino acid sequence LAS. In some embodiments, CDR-L2 is CDR-L2 selected from SEQ ID NOs. 153-158 and amino acid sequence LAS having up to 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 sequences provided herein by, for example, affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants may not be derived from sequences provided herein, but may be newly isolated, for example, according to methods provided herein for obtaining antibodies.

[0217] In some embodiments, the antibodies provided herein comprise CDR-L1 selected from SEQ ID NOs: 141-144 and 149-152. In some embodiments, CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with CDR-L1 selected from SEQ ID NOs: 141-144 and 149-152. In some embodiments, CDR-L1 is CDR-L1 selected from SEQ ID NOs: 141-144 and 149-152 having up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “mutants”. In some embodiments, such variants are derived from sequences provided herein by, for example, 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 sequences provided herein and may be newly isolated, for example, according to a method provided herein to obtain an antibody.

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

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

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

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

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

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

[0224] In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in the present disclosure are referred to herein 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 clones are not derived from the sequences provided herein and may, for example, be newly isolated according to the methods provided herein for obtaining antibodies.

[0225] In certain aspects, the antibodies disclosed herein do not include the antibodies disclosed in U.S. Patent No. 9,067,994. [Table 3-1] [Table 3-2] [Table 3-3] Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8 Table 3-9 Table 4-1 Table 4-2 Table 4-3 Table 4-4 Table 4-5 Table 4-6 Table 4-7 Table 4-8 Table 4-9 Table 4-10 Table 4-11 Table 5-1 Table 5-2 Table 5-3 Table 5-4 Table 5-5 Table 5-6 Table 5-7 Table 5-8 Table 5-9 Table 5-10 Table 5-11 Table 6-1 Table 6-2 Table 6-3 Table 6-4 Table 6-5 Table 6-6 Table 6-7 Table 7-1 Table 7-2 Table 7-3 Table 7-4 Table 7-5 Table 7-6 Table 7-7 Table 8-1 Table 8-2 Table 8-3 Table 8-4 Table 8-5 Table 8-6 Table 8-7

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

[0227] Unless otherwise specified herein, the numbering of amino acid residues within the Fc region or constant region follows 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, the “Fc polypeptide” of dimeric Fc refers to one of the two polypeptides that form the dimeric Fc domain, i.e., the polypeptide containing the C-terminal constant region of an immunoglobulin heavy chain capable of stable self-assembly. For example, the Fc polypeptide of dimeric IgG Fc contains the constant domain sequences of IgG CH2 and IgG CH3. Fc may be of class IgA, IgD, IgE, IgG, and IgM, some of which may be further classified into subclasses (isotypes), e.g., 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 human FcR in its natural sequence. Generally, FcRs are those that bind to IgG antibodies (gamma receptors) and include the FcγRI, FcγRII, and FcγRIII subclasses of receptors, including allelic variants and splicing forms as alternatives of these receptors. The FcγRII receptor includes FcγRIIA ("activating receptor") and FcγRIIB ("inhibiting receptor"), which have similar amino acid sequences, mainly differing in their cytoplasmic domains. Other isotypes of immunoglobulins can also bind to 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 (ITAM) in its cytoplasmic domain. The inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine inhibitory motif (ITIM) in its cytoplasmic domain (discussed in Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs have been discussed in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991), Capel et al. Immunomethods 4:25-34 (1994), and de Haas et al. J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those to be identified in the future, are included in the term "FcR" as used herein. This term also includes FcRn, an embryonic receptor involved in the transfer of 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 FcR to Fc. Several amino acid modifications in the Fc region are known in the art to selectively alter the affinity of Fc to different Fc gamma receptors. In some embodiments, Fc includes one or more modifications to promote selective binding of Fc-gamma receptors.

[0230] The following are examples of mutations that alter the binding of FcR to Fc:

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

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

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

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

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

[0236] S239D / D265S / S298A / I332E, S239E / S298A / K326A / A327H, G237F / S298A / 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 variants listed in WO2011 / 120134 and WO2011 / 120135 incorporated herein by reference. Therapeutic Antibody Engineering (by William R. Strohl and Lila M. Strohl, Woodhead Publishing series in Biomedicine No. 11, ISBN 1 907568 37 9, Oct 2012) lists the mutations on page 283.

[0237] In certain embodiments, the antibodies described herein include modifications to improve their ability to mediate effector function. Such modifications are known in the art and include defucosylation or manipulation of the affinity of Fc to activating receptors, primarily FCGR3a for ADCC and C1q for CDC. Table 9 below summarizes various designs reported in the literature for effector function engineering.

[0238] Methods for producing antibodies with little to no fucose at the Fc glycosylation site (EU numbering of Asn297) without altering the amino acid sequence are well known in the art. GlymaX® technology (ProBioGen AG) is based on the introduction of genes into enzymes that deflect the cellular pathway of fucose biosynthesis into the cells used for antibody production. This prevents the antibody-producing cells from adding the sugar "fucose" to the carbohydrate portion of the N-binding antibody. (von Horsten et al. (2010) Glycobiology. 2010 Dec;20(12):1607-18.) Another approach to obtaining antibodies with reduced fucosylation levels can be found in U.S. Patent No. 8,409,572, which teaches that cell lines for antibody production can be completely defucosyled (meaning they do not contain detectable fucose) or partially defucosyled, i.e., the isolated antibodies may contain less than 95%, less than 85%, less than 75%, less than 65%, less than 55%, less than 45%, less than 35%, less than 25%, less than 15%, or less than 5% of the amount of fucose normally detected for similar antibodies produced by mammalian expression systems.

[0239] Accordingly, in one embodiment, the antibodies described herein may include a dimer Fc having one or more amino acid modifications listed in Table 9 that confer improved effector function. In another embodiment, the antibody may be defucosylated to improve effector function. [Table 9]

[0240] Fc modifications that reduce FcgR and / or complement binding and / or effector function are known in the art. Recent publications describe strategies used to manipulate antibodies with reduced or silenced effector activity (see Strohl, WR (2009), Curr Opin Biotech 20:685-691, and Strohl, WR and Strohl LM, “Antibody Fc engineering for optimal antibody performance,” In Therapeutic Antibody Engineering, Cambridge: Woodhead Publishing (2012), pp225-249). These strategies include reducing effector function through glycosylation modifications, using the IgG2 / IgG4 backbone, or introducing mutations in the Fc hinge or CH2 region. For example, U.S. Patent Publication 2011 / 0212087 (Strohl), International Patent Publication WO2006 / 105338 (Xencor), U.S. Patent Publication 2012 / 0225058 (Xencor), U.S. Patent Publication 2012 / 0251531 (Genentech), and Strop et al. ((2012) J.Mol.Biol.420:204-219) describe specific modifications for reducing complement binding to FcgR or Fc.

[0241] Specific, non-limiting examples of known amino acid modifications for reducing complement binding to FcgR or Fc are specified in Table 10 below. [Table 10]

[0242] Methods for producing antibodies with little to no fucose at the Fc glycosylation site (EU numbering of Asn297) without altering the amino acid sequence are well known in the art. GlymaxX® technology (ProBioGen AG) is based on the introduction of an enzyme gene that deflects the cellular pathway of fucose biosynthesis into the cells used for antibody production. This prevents the addition of the sugar "fucose" to the carbohydrate portion of N-linked antibodies by antibody-producing cells. (von Horsten et al. (2010) Glycobiology. 2010;20(12):1607-18.) Examples of cell lines capable of producing defucosylated antibodies include CHO-DG44 (see von Horsten et al., 2010 (above)), which stably overexpresses the bacterial oxidoreductase GDP-6-deoxy-D-lyxo-4-hexose reductase (RMD), or Lec13 CHO cells (Ripka et al.) which lack protein fucosylation. Examples include the alpha-1,6-fucosyltransferase gene or knockout cell lines such as 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 WO2003 / 085107; each of these is incorporated as a whole by reference). Another approach to 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 for antibody production based on their ability to elicit low levels of fucosylation in the antibody.

[0243] Examples of cell lines capable of producing defucosylated antibodies include CHO-DG44 (see von Horsten et al., 2010 (above)), which stably overexpresses the bacterial oxidoreductase GDP-6-deoxy-D-lyxo-4-hexose reductase (RMD), or Lec13 CHO cells lacking protein fucosylation (see Ripka et al., Arch. Biochem. Biophys., 1986, 249:533-545, U.S. Patent Publication No. 2003 / 0157108, WO2004 / 056312; each of these is incorporated as a whole by reference), and knockout cell lines such as alpha-1,6-fucosyltransferase gene or FUT8 knockout CHO cells (see Yamane-Ohnuki et al., Biotech. Bioeng., 2004, 87:614-622, Kanda et al. See al., Biotechnol. Bioeng., 2006, 94:680-688, and WO2003 / 085107 (each of these is incorporated as a whole by reference).

[0244] The antibody may be completely defucosylated (meaning it does not contain detectable fucose) or partially defucosylated, i.e., the isolated antibody contains less than 95%, less than 85%, less than 75%, less than 65%, less than 55%, less than 45%, less than 35%, less than 25%, less than 15%, or less than 5% of the amount of fucose normally detected for similar antibodies produced by mammalian expression systems.

[0245] In some embodiments, the antibodies provided herein contain an IgG1 domain in which the fucose content at position Asn297 is reduced compared to the naturally occurring IgG1 domain. Such Fc domains are known to improve ADCC. See Shields et al., J. Biol. Chem., 2002, 277:26733-26740, which is incorporated in its entirety by reference. In some embodiments, such antibodies contain no fucose at position Asn297. The amount of fucose can be determined using any suitable method, such as that described in WO2008 / 077546, which is incorporated in its entirety by reference.

[0246] In certain embodiments, the antibodies provided herein include an Fc region having one or more amino acid substitutions that improve ADCC, such as substitutions at one or more of the 298, 333, and 334 positions of the Fc region. In certain embodiments, the antibodies provided herein include an Fc region having one or more amino acid substitutions at the 239, 332, and 330 positions, as described in Lazar et al., Proc. Natl. Acad. Sci. USA, 2006, 103:4005-4010, which is incorporated in whole by reference.

[0247] Other exemplary glycosylated variants that may be incorporated into the antibodies provided herein include, for example, U.S. Patent Publications 2003 / 0157108, 2004 / 0093621, 2003 / 0157108, 2003 / 0115614, 2002 / 0164328, 2004 / 0093621, 2004 / 0132140, and 2004 / 011 These are described in publications 0704, 2004 / 0110282, 2004 / 0109865, International Patent Publications 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 its entirety by reference.

[0248] In certain embodiments, the antibodies provided herein include an Fc region having at least one galactose residue in an oligosaccharide conjugated to the Fc region. Such antibody variants may have improved CDC function. Examples of such antibody variants are described, for example, in WO1997 / 30087, WO1998 / 58964, and WO1999 / 22764, which are incorporated in their entirety by reference, respectively.

[0249] In certain embodiments, the antibodies provided herein include one or more modifications that improve or reduce C1q binding and / or CDC. See U.S. Patent No. 6,194,551, WO99 / 51642, and Idusogie et al., J.Immunol., 2000, 164:4178-4184, each incorporated in whole by reference.

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

[0251] In certain embodiments, the antibody provided herein includes a constant light chain (LC) region comprising the amino acid sequence represented by SEQ ID NO: 469.

[0252] In certain embodiments, the antibodies provided herein include (1) a constant heavy chain (HC) region comprising an amino acid sequence represented by 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, (1) a constant light chain (LC) region comprising an amino acid sequence represented by SEQ ID NO: 469, or at least 95%, 96%, or 97% sequence identity with SEQ ID NO: 469, (3) an LC region containing an amino acid sequence having 98%, 99%, or 100% sequence identity; (4) a VL containing an amino acid sequence representing SEQ ID NO: 3 or a VH having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 3; and (5) a VL containing an amino acid sequence representing an amino acid sequence representing SEQ ID NO: 39 or a VL having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 39.

[0253] In a particular embodiment, the isolated antibody comprises a heavy chain constant (HC) region containing an amino acid sequence represented by SEQ ID NO: 439 or 624, and a light chain constant (LC) region containing an amino acid sequence represented by SEQ ID NO: 469, wherein the antibody further comprises VH containing an amino acid sequence having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO: 3, and VL containing 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 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 comprises 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.

[0254] In certain embodiments, the Fc region contains one or more amino acid substitutions, and these substitutions result in an increased antibody half-life, increased ADCC activity, increased ADCP activity, or increased CDC activity compared to an Fc region without these substitutions. In certain embodiments, the one or more amino acid substitutions result in an increased antibody half-life at pH 6.0 compared to an antibody containing a wild-type Fc region.

[0255] In a particular embodiment, 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 a particular embodiment, one or more amino acid substitutions include multiple 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 / Q311 H / N434S(DHS);S228P / L235E(SPLE);L234A / L235A(LA), M428L / N434A, L234A / G237A(LALA), L23 4A / L235A / G237A, L234A / L235A / P329G, N297A, D265A / YTE, LALA / YTE, LAGA / YTE, LALAGA / YTE, L ALAPG / 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 / DH S;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, LA GA / QVV, LALAGA / QVV, LALAPG / QVV, DDRVV, N297A / DDRVV, D265A / DDRVV, LALA / DDRVV, LAGA / DDRVV, LALAGA / DDRVV, and LALAPG / DDRVV. ;

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

[0257] qualification YTE replacement In certain embodiments, the crystallized fragment region (Fc region) of the anti-IL-13 antibody described herein has a triple substitution M252Y / S254T / T256E (YTE) designed to extend 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 fetal Fc receptor (FcRn). IgG bound to FcRn is recycled via lysosomal salvage, resulting in the IgG returning to circulation. Thus, the YTE mutation confers greater FcRn-IgG binding compared to unmodified IgG, extending the serum half-life of IgG.

[0258] LALA replacement In certain embodiments, the anti-IL-13 antibodies described herein additionally retain the amino acid substitution L234A / L235A in the Fc region of the IgG1 heavy chain, commonly known as the LALA substitution or LALA mutation. These changes impair the binding of the Fc receptor to IgG and prevent the activation of undesirable effector cells.

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

[0260] While we do not wish to be bound by theory, it is thought that the binding of the anti-IL-13 antibodies described herein to IL-13 prevents the formation of IL-13Rα1 / IL-4Rα activating receptor heterodimers and subsequent IL-13-mediated signaling. Direct consequences of IL-13 signaling in atopic dermatitis (AD) lesions include skin thickening and CD4 + Increased T cell infiltration and disruption of the skin barrier are among the symptoms. Therefore, it is thought that preventing the formation of receptor heterodimers may reduce the clinical severity of Alzheimer's disease (AD).

[0261] The affinity of molecule X for its partner Y is given by the dissociation equilibrium constant (K D ) can be expressed as follows. The kinetic elements contributing to the dissociation equilibrium constant are described in more detail below. Affinity can be measured by common methods known in the art, including those described herein, such as surface plasmon resonance (SPR) techniques (e.g., BIACORE®) or biolayer interferometry (e.g., FORTEBIO®).

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

[0263] Where used herein in relation to two or more antibodies, the terms “compete with” or “cross-compete with” indicate that two or more antibodies compete for binding to an antigen (e.g., IL-13). In one exemplary assay, IL-13 is coated onto a surface, contacted with a first anti-IL-13 antibody, and then a second anti-IL-13 antibody is added. In another exemplary assay, a first anti-IL-13 antibody is coated onto a surface, contacted with IL-13, and then a second anti-IL-13 antibody is added. In either assay, the antibodies compete with each other if the presence of the first anti-IL-13 antibody reduces the binding of the second anti-IL-13 antibody. The term “compete with” also includes antibody combinations where one antibody reduces the binding of another, but no competition is observed when the antibodies are added in the reverse order. However, in certain embodiments, the first and second antibodies inhibit each other's binding, regardless of the order in which they are added. In certain embodiments, one 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% when measured in a competitive binding assay. Those skilled in the art can select the antibody concentrations used in the competitive assay based on the affinity of the antibody to IL-13 and the antibody titer. 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. Appropriate assays are described, for example, in Cox et al., “Immunoassay Methods,” in Assay Guidance Manual [Internet], Updated December 24, 2014 (ncbi.nlm.nih.gov / books / NBK92434 / ; accessed September 29, 2015), Silman et al., Cytometry, 2001, 44:30-37, and Finco et al., J. Pharm. Biomed. Anal., 2011, 54:351-358, each of which is incorporated by reference.

[0264] A test antibody competes with a reference antibody if, when measured in a competitive binding assay, an excess of the test antibody (e.g., at least 2-fold, 5-fold, 10-fold, 20-fold, or 100-fold) inhibits or blocks the binding of the reference antibody by, for example, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. Antibodies identified by a competition assay (competitive antibodies) include antibodies that bind to the same epitope as the reference antibody and antibodies that bind to an adjacent epitope close enough to the epitope to which the reference antibody binds to cause steric hindrance. For example, a second competitive antibody that competes with the binding of the first antibody described herein to IL-13 can be identified. In certain instances, 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% when measured in a competitive binding assay. In certain instances, the second antibody can displace the first antibody by more than 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.

[0265] In certain embodiments, the antibody binds to the IL-13 sequence represented by SEQ ID NOs: 472-475.

[0266] In certain embodiments, the antibody binds to the IL-13 sequence represented by SEQ ID NOs: 472-475 with a K of about 1, 2, 3, 4, 5, 6, 7, 8, 9×10 -9 M or less when measured by surface plasmon resonance (SPR). In certain embodiments, the antibody binds to the IL-13 sequence represented by SEQ ID NOs: 472-475 with a K of about 1×10 D M or less when measured by surface plasmon resonance (SPR). In certain embodiments, the antibody binds to human IL-13 with a K of about 1×10 -10 M or less when measured by surface plasmon resonance (SPR). D In certain embodiments, the antibody binds to human IL-13 with a K of about 1×10 -9 M or less when measured by surface plasmon resonance (SPR). D In certain embodiments, the antibody binds to human IL-13 with a K of about 1×10

[0267] In certain embodiments, the antibodies provided herein are IL-13 and, when measured by ELISA or any other suitable method known in the art, approximately 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.95, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 × 10 -8 K below M D It binds to IL-13. In certain embodiments, the antibodies provided herein, when measured by ELISA or any other suitable method known in the art, are approximately 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.95, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 × 10 -9 K below M D They are joined together.

[0268] In certain embodiments, the K of the antibody provided herein for IL-13 binding D When measured by ELISA or any other suitable method known in the art, the values ​​are 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 M is M. In certain embodiments, the antibody provided herein is IL-13 and, when measured by ELISA or any other suitable method known in the art, is approximately 1 × 10⁻⁶.-8 M or less, or approximately 1 × 10 -9 K below M D They are joined together.

[0269] In certain embodiments, the antibodies provided herein, when measured by ELISA or any other suitable method known in the art, are approximately 10, 9, 8, 7, 6, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.98, 1.95, 1.9, 1.85, 1.8, 1.75, 1.7, 1.65, 1.6, 1 0.55, 1.50, 1.45, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.05, 0.01, 0.005, 0.001, 0.0005, or 0.0001 × 10 -8 K is less than or equal to M. D It binds to IL-13. In certain embodiments, the antibodies provided herein, when measured by ELISA or any other suitable method known in the art, are 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 -8 M's K D They are joined together.

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

[0271] Pharmaceutical composition This application provides antibody-containing compositions, comprising a pharmaceutical composition containing one or more antibodies described herein together with one or more pharmaceutically acceptable excipients. In certain embodiments, the composition is sterile. The pharmaceutical composition generally contains an effective amount of antibody.

[0272] In certain embodiments, the composition comprises 150 mg / mL, 180 mg / mL, or 200 mg / mL of the anti-IL-13 antibody described herein. In certain embodiments, the anti-IL-13 antibody comprises a VH comprising an amino acid sequence such as that represented by SEQ ID NO: 3, and a VL comprising an amino acid sequence such as that represented by SEQ ID NO: 39. In certain embodiments, the anti-IL-13 antibody comprises a light chain variable domain comprising a framework region sequence selected from the sequences represented by SEQ ID NO: 439 or 624 and SEQ ID NO: 469, wherein the antibody comprises a VH comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 3, and at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, VL further comprises an amino acid sequence having 98%, 99%, or 100% sequence identity, wherein VH comprises 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 comprises 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.

[0273] These compositions may include, in addition to one or more of the antibodies disclosed herein, 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 detailed properties of the carrier or other materials may depend on the route of administration, e.g., oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, or intraperitoneal routes.

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

[0275] Pharmaceutical compositions for oral administration may be in the form of tablets, capsules, powders, or liquids. Tablets may contain a solid carrier such as gelatin or an adjuvant. Liquid pharmaceutical compositions generally contain a liquid carrier such as water, petroleum, animal or vegetable oil, mineral oil, or synthetic oil. They may also contain saline solution, dextrose or other sugar solutions, or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol.

[0276] For intravenous, cutaneous, or subcutaneous injection, or injection at a site of pain, the active ingredient is in the form of a parenterally acceptable aqueous solution that is pyrogen-free and has appropriate pH, isotonicity, and stability. Those skilled in the art can easily prepare a suitable solution using an isotonic vehicle such as sodium chloride injection, Ringer's injection, or Ringer's lactate injection. Preservatives, stabilizers, buffers, antioxidants, and / or other additives may be included as needed.

[0277] The administration of anti-IL-13 antibodies to an individual is preferably carried out in a “therapeutic effective dose” or “preventive effective dose” (in some cases, prevention may be considered therapeutic) sufficient to exert an effect on the individual. The actual amount administered, as well as the rate and duration of administration, depend on the nature and severity of the protein aggregation disorder being treated. The determination of the prescription of treatment, e.g., dosage, is the responsibility of the general practitioner and other physicians, and usually takes into account the disorder being treated, the individual patient’s condition, the site of delivery, the method of administration, and other factors known to the practitioner. Examples of the above techniques and protocols are found in Remington’s Pharmaceutical Sciences, 16 th It can be found in edition, Osol, A. (ed), 1980.

[0278] The compositions can be administered alone or in combination with other treatments, simultaneously or sequentially, depending on the condition being treated.

[0279] method Preparation method The antibodies described herein may be produced using, for example, the recombinant methods and compositions 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 containing the VL of the antibody and / or an amino acid sequence containing the VH (e.g., the light chain and / or heavy chain of the antibody), or an amino acid sequence containing the VH of a single-domain antibody. In a further embodiment, one or more vectors (e.g., expression vectors) containing such nucleic acid are provided. In one embodiment, the nucleic acid is provided in a multicistronic vector. In a further embodiment, a host cell containing such nucleic acid is provided. In such one embodiment, the host cell comprises (1) a vector containing a nucleic acid encoding an amino acid sequence containing the VL of the antibody and an amino acid sequence containing the VH of an antigen-binding polypeptide construct, or (2) a first vector containing a nucleic acid encoding an amino acid sequence containing the VL of an antigen-binding polypeptide construct, and a second vector containing a nucleic acid encoding an amino acid sequence containing the VH of an antigen-binding polypeptide construct (e.g., transformed with them). In one embodiment, the host cells are eukaryotic cells, such as Chinese hamster ovary (CHO) cells, or human embryonic kidney (HEK) cells, or lymphoid cells (e.g., Y0, NS0, Sp20 cells). In one embodiment, a method is provided for producing an antibody, which comprises culturing host cells containing nucleic acids encoding the antibody provided above under conditions suitable for antibody expression, and optionally recovering the antibody from the host cells (or host cell culture medium).

[0280] For recombinant antibody production, for example, the nucleic acid encoding the antibody, as described above, is isolated and inserted into one or more vectors for further cloning and / or expression in host cells. Such nucleic acids can be readily isolated and sequenced using conventional procedures (for example, by using oligonucleotide probes that can specifically bind to the genes encoding the heavy and light chains of the antibody).

[0281] When the antibody or its variant is recombinantly produced by the host cell, in certain embodiments the protein is present in the culture medium at a concentration of approximately 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, or less than 1% of the dry weight of the cell. When the antibody or its variant is recombinantly produced by the host cell, in certain embodiments the protein is present in the culture medium at a concentration of approximately 5 g / L, 4 g / L, 3 g / L, 2 g / L, 1 g / L, 750 mg / L, 500 mg / L, 250 mg / L, 100 mg / L, 50 mg / L, 10 mg / L, or less than 1 mg / L of the dry weight of the cell. In certain embodiments, the “substantially purified” antibodies produced by the methods described herein have purity levels 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%, and at least about 70%, specifically at least about 75%, 80%, and 85%, more specifically at least about 90%, at least about 95%, and at least about 99% or higher, as determined by appropriate methods such as SDS / PAGE analysis, RP-HPLC, SEC, and capillary electrophoresis.

[0282] Host cells suitable for cloning or expressing antibody-coding vectors include prokaryotic or eukaryotic cells as described herein.

[0283] Recombinant host cells or host cells are cells containing exogenous polynucleotides, regardless of the method used for insertion, such as direct uptake, transduction, f-conjugation, or other methods known in the art for producing recombinant host cells. The exogenous polynucleotides may be maintained as an unintegrated vector, e.g., a plasmid, or alternatively, integrated into the host genome. Host cells may contain CHO, derivatives of CHO, NS0, Sp2O, CV-1, VERO-76, HeLa, HepG2, Per.C6, or BHK.

[0284] For example, antibodies may be produced in bacteria, especially when glycosylation and Fc effector function are not required. For the expression of antibody fragments and polypeptides in bacteria, see, for example, U.S. Patents 5,648,237, 5,789,199, and 5,840,523. (Also see Charlton, Methods in Molecular Biology, Vol. 248 (BKCLo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, which describes the expression of antibody fragments in E. coli.) After expression, antibodies can be isolated from bacterial cell paste in the soluble fraction and further purified.

[0285] In addition to prokaryotes, eukaryotic microorganisms such as filamentous fungi or yeasts are suitable cloning or expression hosts for antibody-encoding vectors, including fungal and yeast strains whose glycosylation pathways have been "humanized," resulting in the production of antibodies with a partial or complete human glycosylation pattern. See Gerngross, Nat. Biotech. 22:1409-1414 (2004) and Li et al., Nat. Biotech. 24:210-215 (2006).

[0286] Host cells suitable for the expression of glycosylated antibodies can also be derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant cells and insect cells. In particular, numerous baculovirus strains have been identified that can be used in conjunction with insect cells for transduction of Spodoptera frugiperda cells.

[0287] Plant cell cultures can also be used as hosts. See, for example, U.S. Patents 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (which describe PLANTIBODIES® technology for antibody production in transgenic plants).

[0288] Vertebrate cells can also be used as hosts. For example, mammalian cell lines adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines include the CV1 monkey kidney cell line transformed with SV40 (COS-7), human embryonic kidney cells (e.g., 293 or 293 cells described in Graham et al., J. Gen Virol. 36:59 (1977)), neonatal hamster kidney cells (BHK), mouse Sertoli cells (e.g., TM4 cells described in Mather, Biol. Reprod. 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 hepatocytes (BRL 3A), human lung cells (W138), human hepatocytes (Hep G2), mouse mammary tumor cells (MMT060562), and TRI cells (e.g., Mather et al. Annals) These include MRC5 cells and FS4 cells (as described in NYAcad.Sci.383:44-68 (1982)). Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR-CHO cells (Urlaub et al., Proc.Natl.Acad.Sci.USA77:4216 (1980)), as well as myeloma cell lines such as Y0, NS0, and Sp2 / 0. For an overview of specific mammalian host cell lines suitable for antibody production, see, for example, Yazaki and Wu, Methods in Molecular Biology, Vol.248 (BKCLo, ed., Humana Press, Totowa, NJ), pp.255-268 (2003).

[0289] In one embodiment, the antibody described herein is produced by a method comprising transtransferring at least one stable mammalian cell with the nucleic acid encoding the antibody in a predetermined ratio into a stable mammalian cell, and expressing the nucleic acid in at least one mammalian cell. In a particular embodiment, the predetermined ratio of nucleic acids is determined by a transient transtransfer experiment to determine the relative ratio of input nucleic acids that yields the highest percentage of antibody in the expression product.

[0290] In a particular embodiment, the method for producing an antibody in stable mammalian cells described herein is provided, wherein the expression product of at least one stable mammalian cell contains a desired glycosylated antibody or other antibody in a high percentage compared to a monomeric weight chain polypeptide or monomeric light chain polypeptide.

[0291] In certain embodiments, a method for producing glycosylated antibodies in stable mammalian cells as described herein is provided, the method comprising identifying and purifying a desired glycosylated antibody. In certain embodiments, the identification is performed by either or both liquid chromatography and / or mass spectrometry.

[0292] If necessary, antibodies can be purified or isolated after expression. Proteins can be isolated or purified by various methods known to those skilled in the art. Standard purification methods include ion exchange, hydrophobic interaction, affinity, size exclusion or gel filtration, and chromatographic techniques, including reversed phase performed at atmospheric pressure or high pressure using systems such as FPLC and HPLC. Purification methods also include electrophoresis, immunological techniques, precipitation techniques, dialysis techniques, and chromatofocusing techniques. Ultrafiltration and dialysis techniques combined with protein concentration are also useful. As is well known in the art, various native proteins bind to Fc and antibodies, and these proteins may find applications in antibody purification in the present invention. 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 made possible by specific fusion partners. For example, antibodies can be purified using glutathione resin when a GST fusion is employed, or Ni when a His tag is employed. +2Purification can be performed using affinity chromatography or, if flag tags are used, using immobilized anti-flag antibodies. For general guidance on appropriate purification techniques, see, for example, Protein Purification: Principles and Practice, 3, which is incorporated as a whole by reference. rd See Ed., Scopes, Springer-Verlag, NY, 1994 (integrated as a whole by reference). The required degree of purification varies depending on the application of the antibody. In some cases, purification is not necessary.

[0293] In certain embodiments, antibodies are purified using Q-sepharose, DEAE sepharose, poros HQ, poros DEAF, Toyopearl Q, Toyopearl QAE, Toyopearl DEAE, Resource / Source Q, and anion exchange chromatography including, but not limited to, chromatography on DEAE, Fractogel Q, and DEAE columns.

[0294] In certain embodiments, the proteins described herein are purified using cation exchange chromatography, including but not limited to SP-sepharose, CM sepharose, poros HS, poros CM, Toyopearl SP, Toyopearl CM, Resource / Source S and CM, Fractogel S and CM columns, and their equivalents and equivalents.

[0295] 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, WH Freeman & Co., NY and Hunkapiller et al., Nature, 310:105-111 (1984)). For example, polypeptides corresponding to polypeptide fragments can be synthesized using a peptide synthesizer. In addition, non-classical amino acids or chemical amino acid analogs can be introduced as substitutions or additions to the polypeptide sequence, as needed. Non-classical amino acids, though not limited to them, commonly include D-isomers of amino acids such as 2,4-diaminobutyric acid, alpha-aminoisobutyric acid, 4-aminobutyric acid, Abu, 2-aminobutyric acid, g-Abu, e-Ahx, 6-aminohexanoic acid, Aib, 2-aminoisobutyric acid, 3-aminopropionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, alanine, fluoroamino acids, methylamino acids, artificially designed amino acids, C-methylamino acids, N-methylamino acids, and amino acid analogs. Furthermore, amino acids can be D (dextrorotatory) or L (levorotatory).

[0296] How to use This application provides a method for treating an inflammatory disorder or disease, such as atopic dermatitis, in a patient who requires treatment. In certain embodiments, the patient is diagnosed with moderate to severe atopic dermatitis. In certain embodiments, the patient has suffered from moderate to severe atopic dermatitis for at least one year. In certain embodiments, the patient is a pediatric patient.

[0297] In certain embodiments, the patient has one or more of the following: (a) an Eczema Area Severity Index (EASI) score of 10 or higher (e.g., an EASI of 16 or higher or an EASI of 10 or higher but less than 16), (b) an Investigator Global Assessment (IGA) score of 3 or higher, and (c) a Body Surface Area (BSA) of 10% or higher. In certain embodiments, the patient has an Eczema Area Severity Index (EASI) score of 10 or higher. In certain embodiments, the patient has an Eczema Area Severity Index (EASI) score of 16 or higher. In certain embodiments, the patient has an Eczema Area Severity Index (EASI) score of 10 or higher but less than 16. In certain embodiments, the patient has an Investigator Global Assessment (IGA) score of 3 or higher. In certain embodiments, the patient has a Body Surface Area (BSA) of 10% or higher.

[0298] The Investigator's Global Assessment (IGA), or "IGA," is a globally used assessment criterion for evaluating the severity of a patient's Alzheimer's disease (AD) (Simpson E, et al. J Am Acad Dermatol. 2020;83(3):839-846). It is based on a 5-point scale from 0 (no lesions) to 4 (severe), where the score is selected using the descriptor that best represents the overall appearance of the lesions at a given time point. Not all characteristics in the morphological description are required to be present. The IGA can be performed before the EASI and BSA assessments.

[0299] The Eczema Area Severity Index (EASI) is a standard used in clinical settings to assess the severity and extent of Alzheimer's disease (AD) (Hanifin et al., Exp Dermatol. 2001;10:11-18). The EASI is a composite index with a score ranging from 0 to 72, where higher values ​​indicate more severe and / or widespread disease. The severity of erythema, sclerosis / papules, exfoliation, and lichenification can be assessed by clinicians or other healthcare professionals on a scale of 0 (none) to 3 (severe) (0.5 points can also be used) for each of the four body regions: head and neck, trunk, upper extremities, and lower extremities. Furthermore, the extent of AD lesions 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 to 72) is assigned based on the sum of the scores for each of the four body regions. In a clinical trial setting, the terms "EASI-50," "EASI-75," and "EASI-90" refer to the percentage of patients whose EASI improved by 50, 75, and 90%, respectively.

[0300] The "Atopic Dermatitis Scoring" or "SCORAD" is an effective clinical tool developed by the European Task Force on Atopic Dermatitis to assess the extent and severity of AD (Consensus report of the European Task Force on Atopic Dermatitis. Dermatology. 1993;186(l):23-31). This assessment has three components: (i) assessing the extent of AD as a percentage of each designated body part and reporting the total of all parts as a score ranging from 0 to 100 (assigned "A" in the overall SCORAD calculation formula); and (ii) assessing the severity of the six symptoms of AD: redness, swelling, exudation / crusting, epidermal peeling, skin thickening / lichenification, and dryness. Each item is graded as follows: none (0), mild (1), moderate (2), or severe (3) (the highest total score of 18 points is assigned a "B" in the overall SCORAD formula), (iii) a subjective assessment of itching and insomnia is recorded for each symptom using a visual analog scale (VAS). 0 is no itching (or insomnia), 10 is the worst itching (or insomnia) imaginable, and the maximum possible score is 20 (assigned a "C" in the overall SCORAD formula). The SCORAD index formula is A / 5 + 7B / 2 + C. The maximum score on the SCORAD index is 103.

[0301] The Numerical Rating Scale for Pruritus (NRS) is an 11-point scale used by patients (with the assistance of a parent / caregiver, if applicable) to assess the severity of the worst itching in the past 24 hours, where 0 represents "no itching" and 10 represents "worst imaginable itching" (Phan NQ, et al. Acta Derm Venereol 2012;92:502-507). Assessments are recorded daily by the patient using an electronic diary. The baseline pruritus NRS is determined based on the mean of the daily pruritus NRS scores for the 7 days immediately preceding baseline. This calculation requires scores for at least 4 days within the 7 days immediately preceding baseline.

[0302] The insomnia scale assesses the patient's insomnia due to itching using a 5-point Likert scale (scores range from 0 [not at all], 1 [slightly], 2 [moderate], 3 [very difficult to sleep], and 4 [difficult to sleep at all]). Assessments are recorded daily by the patient using an electronic diary. In certain embodiments, the insomnia scale is the Atopic Dermatitis Sleep Scale (ADSS).

[0303] The Patient-Oriented Eczema Measure (POEM) is a seven-item valid questionnaire completed by the patient (and, if applicable, with the assistance of a parent / caregiver) to assess the symptoms of the disease over the past week (available at Centre of Evidence Based Dermatology.POEM-Patient Oriented Eczema Measure. www.nottingham.ac.uk / research / groups / cebd / resources / poem.aspx). Patients are asked to answer seven questions regarding dryness, itching, peeling, cracking, insomnia, bleeding, and wetness of the skin. All seven responses are equally weighted on a total assumed score of 0 to 28 (responses are scored as follows: none = 0, 1-2 days = 1, 3-4 days = 2, 5-6 days = 3, daily = 4). Higher scores indicate a reduced quality of life. POEM responses are taken weekly using an electronic diary.

[0304] The Quality of Life Index for Skin Diseases (DLQI) is a 10-item valid questionnaire completed by the patient or caregiver and used to assess the impact of skin disease on a patient's quality of life (Finlay, AY and Khan, GK 1994. Clinical and Experimental Dermatology 1993 Sep 23;19:210-216). The 10 questions cover the following topics: symptoms, timidity, shopping and housework, clothing, social and recreational activities, sports, work or learning, intimate relationships, sex life, and treatment in the previous week. Each question is scored from 0 to 3 ("never," "a little," "often," "very often"), and the total score is given from 0 to 30. A high score indicates a decline in quality of life.

[0305] In certain embodiments, the method described herein includes determining one or more of the following characteristics of a patient at baseline, during and after the induction period: Eczema Area Severity Index (EASI), Investigator General Assessment (IGA), Body Surface Area (BSA), Numerical Rating Scale for Pruritus (NRS), Insomnia Scale, Atopic Dermatitis Scoring (SCORAD), Patient Self-Assessment of Eczema (POEM), and Skin Disease Quality of Life Index (DLQI). In certain embodiments, the method described herein includes determining the following characteristics of a patient at baseline, during and after the induction period: Eczema Area Severity Index (EASI). In certain embodiments, the method described herein includes determining the following characteristics of a patient at baseline, during and after the induction period: Investigator General Assessment (IGA). In certain embodiments, the method described herein includes determining the following characteristics of a patient at baseline, during and after the induction period: Body Surface Area (BSA). In certain embodiments, the method described herein includes determining the following characteristics of a patient at baseline, during and after the induction period: Numerical Rating Scale (NRS). In certain embodiments, the method described herein includes determining the following characteristics of a patient at baseline, during and after the induction period: Insomnia Scale, Atopic Dermatitis Scoring (SCORAD). In certain embodiments, the method described herein includes determining the following characteristics of a patient at baseline, during and after the induction period: Patient Self-Assessment of Eczema (POEM). In certain embodiments, the method described herein includes determining the following characteristics of a patient at baseline, during and after the induction period: Quality of Life Index for Skin Disease (DLQI).

[0306] In certain embodiments, the patient described herein is determined to have one or more of the following patient characteristics at baseline, during the induction period, and after the induction period: Eczema Area Severity Index (EASI), Investigator General Assessment (IGA), Body Surface Area (BSA), Numerical Rating Scale for Pruritus (NRS), Numerical Rating Scale for Skin Pain (SP-NRS), Insomnia Scale, Scoring for Atopic Dermatitis (SCORAD), Patient Self-Assessment of Eczema (POEM), Quality of Life Index for Skin Disease (DLQI), 5-Item Asthma Control Questionnaire (ACQ-5) score, and 22-Item Sinus Outcome Test (SNOT-22) score. In certain embodiments, the patient described herein is determined to have a characteristic Eczema Area Severity Index (EASI) at baseline, during the induction period, and after the induction period. In certain embodiments, the patient described herein is determined to have a characteristic Investigator General Assessment (IGA) at baseline, during the induction period, and after the induction period. In certain embodiments, the patient herein is determined to have a characteristic body surface area (BSA) at baseline, during the induction period, and after the induction period. In certain embodiments, the patient herein is determined to have a characteristic numerical pruritus rating scale (NRS) at baseline, during the induction period, and after the induction period. In certain embodiments, the patient herein is determined to have a characteristic numerical skin pain rating scale (SP-NRS) at baseline, during the induction period, and after the induction period. In certain embodiments, the patient herein is determined to have a characteristic insomnia scale and atopic dermatitis scoring (SCORAD) at baseline, during the induction period, and after the induction period. In certain embodiments, the patient herein is determined to have a characteristic patient-reported eczema assessment (POEM) at baseline, during the induction period, and after the induction period. In certain embodiments, the patient herein is determined to have a characteristic quality of life index for skin disease (DLQI) at baseline, during the induction period, and after the induction period. In certain embodiments, the patient herein is determined to have a characteristic 5-item asthma control questionnaire (ACQ-5) score at baseline, during the induction period, and after the induction period.In certain embodiments, it is determined that the patient described herein has a characteristic 22-item sinus outcome test (SNOT-22) score at baseline, during the induction period, and after the induction period.

[0307] In one embodiment, the present application provides a method for contacting IL-13 with an anti-IL-13 antibody, such as a human antibody or a humanized antibody, which inhibits the binding of IL-13 to IL-13 receptors expressed on cells.

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

[0309] In certain embodiments, the methods described herein are methods for treating a medical condition related to IL-13 activity, 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.

[0310] In certain embodiments, the method described herein is a method for treating an inflammatory disorder or disease in a mammalian subject requiring treatment, comprising administering to the mammalian subject a therapeutically effective amount of the antibody or pharmaceutical composition described herein. In certain embodiments, the inflammatory disorder or disease is atopic dermatitis. In certain embodiments, the inflammatory disorder or disease is asthma. In certain embodiments, the inflammatory disorder or disease is idiopathic pulmonary fibrosis.

[0311] In certain embodiments, the method described herein is a method for treating a condition associated with elevated IL-13 levels in a mammalian subject, comprising administering to the mammalian subject a therapeutically effective amount of the antibody or pharmaceutical composition described herein.

[0312] In certain embodiments, the methods described herein are methods for doing so in a mammalian subject requiring a reduction in the biological activity of IL-13, and the methods include administering to the mammalian subject a therapeutically effective amount of the antibody or pharmaceutical composition described herein.

[0313] In certain embodiments, the methods described herein are methods for doing so in mammalian subjects requiring inhibition of a TH2 type allergic reaction, and include administering to the mammalian subject a therapeutically effective amount of the antibody or pharmaceutical composition described herein.

[0314] In certain embodiments, the method described herein is a method for doing so in a mammalian subject requiring a reduction in the levels of thymus and activated regulatory chemokine (TARC) / CCL17, and comprises administering to the mammalian subject a therapeutically effective amount of the antibody or pharmaceutical composition described herein.

[0315] In certain embodiments, the methods described herein are methods for doing so in a mammalian subject requiring the prevention of an inflammatory disorder or disease, and comprising administering to the mammalian subject a therapeutically effective amount of the antibody or pharmaceutical composition described herein.

[0316] Medication regimen In one embodiment, the present application provides a method for treating atopic dermatitis in a patient requiring treatment, the method comprising: a) administering to the patient 1 to 5 times (e.g., 2 to 3 times) or more (e.g., 6, 7, 8, 9, or 10 times) an anti-IL-13 antibody selected from doses 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 dose listed in any one of Tables 11 to 13. a) an induction dose, and b) one or more maintenance doses administered subcutaneously about 4 to 16 weeks (e.g., about 5 to 15, 6 to 14, 7 to 13, 8 to 12, 9 to 11, or 10) weeks or longer (e.g., 17, 18, 19, or 20 weeks) after the first induction dose, the maintenance dose being 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 of an anti-IL-13 antibody, or a dose listed in Table 14. The anti-IL-13 antibody may be selected from the anti-IL-13 antibodies disclosed herein. In a particular embodiment, the anti-IL-13 antibody comprises a heavy chain variable region (VH) containing an amino acid sequence such as that represented by SEQ ID NO: 3, or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region (VL) containing an amino acid sequence such as that represented by SEQ ID NO: 39, or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto. In a particular embodiment, 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.

[0317] In a particular embodiment, a dose of 1 to 5 or more introductory doses includes 2 to 3 introductory doses.

[0318] In certain embodiments, the 1 to 5 or more introductory doses include one introductory dose. In certain embodiments, the 1 to 5 or more introductory doses include two introductory doses. In certain embodiments, the 1 to 5 or more introductory doses include three introductory doses. In certain embodiments, the 1 to 5 or more introductory doses include four introductory doses. In certain embodiments, the 1 to 5 or more introductory doses include five introductory doses.

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

[0320] In a particular embodiment, each of the 1st to 5th induction doses is any dose of anti-IL-13 antibody listed in any one of Tables 11 to 13.

[0321] In certain embodiments, one or more of the 1st to 5th introductory doses is 100 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1st to 5th introductory doses is 125 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1st to 5th introductory doses is 150 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1st to 5th introductory doses is 180 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1st to 5th introductory doses is 200 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1st to 5th introductory doses is 250 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1st to 5th introductory doses is 300 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1st to 5th introductory doses is 350 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1st to 5th introductory doses is 360 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1st to 5th introductory doses is 400 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1st to 5th introductory doses is 450 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1st to 5th introductory doses is 500 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1st to 5th introductory doses is 550 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1st to 5th introductory doses is 600 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1st to 5th introductory doses is 650 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1st to 5th introductory doses is 700 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1st to 5th introductory doses is 720 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1st to 5th introductory doses is 750 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1st to 5th introductory doses is 800 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1st to 5th introductory doses is 850 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1st to 5th introductory doses is 900 mg of anti-IL-13 antibody.In certain embodiments, one or more of the 1 to 5 introductory doses is 950 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1 to 5 introductory doses is 1000 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1 to 5 introductory doses is 1050 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1 to 5 introductory doses is 1100 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1 to 5 introductory doses is 1150 mg of anti-IL-13 antibody. In certain embodiments, one or more of the 1 to 5 introductory doses is 1200 mg of anti-IL-13 antibody.

[0322] In a particular embodiment, one or more of the 1 to 5 induction doses are anti-IL-13 antibodies in doses listed in any one of Tables 11 to 13.

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

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

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

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

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

[0328] In certain embodiments, the second induction dose is administered approximately one week after the first induction dose. In certain embodiments, the second induction dose is administered approximately two weeks after the first induction dose. In certain embodiments, the second induction dose is administered approximately three weeks after the first induction dose. In certain embodiments, the second induction dose is administered approximately four weeks after the first induction dose. In certain embodiments, the second induction dose is administered approximately five weeks after the first induction dose. In certain embodiments, the second induction dose is administered approximately six weeks after the first induction dose. In certain embodiments, the second induction dose is administered approximately seven weeks after the first induction dose. In certain embodiments, the second induction dose is administered approximately eight weeks after the first induction dose. In certain embodiments, the second induction dose is administered approximately nine weeks after the first induction dose. In certain embodiments, the second induction dose is administered approximately ten weeks after the first induction dose. In certain embodiments, the second induction dose is administered approximately eleven weeks after the first induction dose. In certain embodiments, the second induction dose is administered approximately 12 weeks after the first induction dose. In certain embodiments, the second induction dose is administered approximately 13 weeks after the first induction dose. In certain embodiments, the second induction dose is administered approximately 14 weeks after the first induction dose. In certain embodiments, the second induction dose is administered approximately 15 weeks after the first induction dose. In certain embodiments, the second induction dose is administered approximately 16 weeks after the first induction dose.

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

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

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

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

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

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

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

[0336] In certain embodiments, the maintenance dose is administered every three months. In certain embodiments, the maintenance dose is administered every twelve weeks. In certain embodiments, the maintenance dose is administered four times a year.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0352] In certain embodiments, the maintenance dose is 360 mg, administered every two months or every eight weeks. In certain embodiments, the maintenance dose is 360 mg, administered every two months or every eight weeks. In certain embodiments, the maintenance dose is 360 mg, administered every two months. In certain embodiments, the maintenance dose is 360 mg, administered every eight weeks.

[0353] In certain embodiments, the maintenance dose is 600 mg, administered every two months or every eight weeks.

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

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

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

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

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

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

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

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

[0362] In a particular embodiment, the method includes administering an initial dose before one to four or more induction doses, the initial dose being twice the induction dose.

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

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

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

[0366] In one embodiment, the present application provides a method for treating atopic dermatitis in a patient requiring treatment, the method comprising subcutaneously administering an anti-IL-13 antibody to the patient during an induction period of 4 to 16 weeks (e.g., 5 to 15, 6 to 14, 7 to 13, 8 to 12, 9 to 11, or 10) weeks, during which the anti-IL-13 antibody is administered in an amount of approximately 150 mg to approximately 1200 mg (e.g., approximately 100 mg to approximately The initial dose is 1200mg, 150mg to approximately 1150mg, 200mg to approximately 1100mg, 250mg to approximately 1050mg, 300mg to approximately 1000mg, 350mg to approximately 950mg, 400mg to approximately 900mg, 450mg to approximately 850mg, 500mg to approximately 800mg, 550mg to approximately 750mg, 600mg to approximately 700mg, or approximately 650mg), administered once or twice, and optionally... , 1 / 2 (for example, 50mg, 62.5mg, 75mg, 100mg, 125mg, 150mg, 175mg, 180mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 360mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, or 600mg) or One-quarter (for example, 25mg, 31.25mg, 37.5mg, 50mg, 62.5mg, 75mg, 87.5mg, 90mg, 100mg, 112.5mg, 125mg, 137.5mg, 150mg, 162.5mg, 175mg, 180mg, 187.5mg, 200mg, 212.5mg, 225mg, 237.5mg, 250mg, 262.5mg, 275mg, 287mg).The initial dose is 5 mg or 300 mg, administered subcutaneously at least once (e.g., once, twice, or three times), and during the maintenance period, approximately 100 mg to approximately 1200 mg (e.g., approximately 100 mg to approximately 1200 mg, 150 mg to approximately 1150 mg, 200 mg to approximately 1100 mg, 250 mg to approximately 1050 mg, 300 mg to approximately 1000 mg, 350 mg to approximately 1200 mg) is administered subcutaneously, and during the maintenance period, approximately 100 mg to approximately 1200 mg (e.g., approximately 100 mg to approximately 1200 mg, 150 mg to approximately 1150 mg, 200 mg to approximately 1100 mg, 250 mg to approximately 1050 mg, 300 mg to approximately 1000 mg, 350 mg to approximately 1200 mg) is administered subcutaneously. The treatment involves subcutaneously administering anti-IL-13 antibodies to the patient in doses of approximately 950 mg, 400 mg to approximately 900 mg, 450 mg to approximately 850 mg, 500 mg to approximately 800 mg, 550 mg to approximately 750 mg, 600 mg to approximately 700 mg, or approximately 650 mg, wherein the anti-IL-13 antibodies are at least 90% (e.g., at least 91%, 92%, 93%, 94%) relative to SEQ ID NO: 3. The product comprises VH containing an amino acid sequence having sequence identity of 95%, 96%, 97%, 98%, 99%, or 100%, and VL containing an amino acid sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity to SEQ ID NO: 39. 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. 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.

[0367] In certain embodiments, the method includes subcutaneous administration of an anti-IL-13 antibody to a patient during an induction period of 4 to 16 weeks (e.g., 5 to 15, 6 to 14, 7 to 13, 8 to 12, 9 to 11, or 10 weeks). In certain embodiments, the method includes subcutaneous administration of an anti-IL-13 antibody to a patient during an induction period of 4 to 16 weeks. In certain embodiments, the method includes subcutaneous administration of an anti-IL-13 antibody to a patient during an induction period of 5 to 15 weeks. In certain embodiments, the method includes subcutaneous administration of an anti-IL-13 antibody to a patient during an induction period of 6 to 14 weeks. In certain embodiments, the method includes subcutaneous administration of an anti-IL-13 antibody to a patient during an induction period of 7 to 13 weeks. In certain embodiments, the method includes subcutaneous administration of an anti-IL-13 antibody to a patient during an induction period of 8 to 12 weeks. In certain embodiments, the method includes subcutaneous administration of an anti-IL-13 antibody to a patient during an induction period of 9 to 11 weeks. In a particular embodiment, the method includes subcutaneous administration of an anti-IL-13 antibody to a patient during a 10-week induction period.

[0368] In certain embodiments, the method includes subcutaneous administration of an anti-IL-13 antibody to a patient during a 4-week induction period. In certain embodiments, the method includes subcutaneous administration of an anti-IL-13 antibody to a patient during a 5-week induction period. In certain embodiments, the method includes subcutaneous administration of an anti-IL-13 antibody to a patient during a 6-week induction period. In certain embodiments, the method includes subcutaneous administration of an anti-IL-13 antibody to a patient during a 7-week induction period. In certain embodiments, the method includes subcutaneous administration of an anti-IL-13 antibody to a patient during an 8-week induction period. In certain embodiments, the method includes subcutaneous administration of an anti-IL-13 antibody to a patient during a 9-week induction period. In certain embodiments, the method includes subcutaneous administration of an anti-IL-13 antibody to a patient during a 10-week induction period. In certain embodiments, the method includes subcutaneous administration of an anti-IL-13 antibody to a patient during an 11-week induction period. In certain embodiments, the method includes subcutaneous administration of an anti-IL-13 antibody to a patient during a 12-week induction period. In certain embodiments, the method includes subcutaneous administration of an anti-IL-13 antibody to a patient during a 13-week induction period. In certain embodiments, the method includes subcutaneous administration of an anti-IL-13 antibody to a patient during a 14-week induction period. In certain embodiments, the method includes subcutaneous administration of an anti-IL-13 antibody to a patient during a 15-week induction period. In certain embodiments, the method includes subcutaneous administration of an anti-IL-13 antibody to a patient during a 16-week induction period.

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

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

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

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

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

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

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

[0376] In a particular embodiment, during the induction period, an initial dose (for example, approximately 100 mg to 1200 mg, 150 mg to 1150 mg, 200 mg to 1100 mg, 250 mg to 1050 mg, 300 mg to 1000 mg, 350 mg to 950 mg, 400 mg to 900 mg, 450 mg to 850 mg, 500 mg to 800 mg, 550 mg to 750 mg, 600 mg to 700 mg, or approximately 650 mg) is administered in weeks 0 and 2.

[0377] In a particular embodiment, during the induction period, an initial dose (for example, approximately 100 mg to 1200 mg, 150 mg to 1150 mg, 200 mg to 1100 mg, 250 mg to 1050 mg, 300 mg to 1000 mg, 350 mg to 950 mg, 400 mg to 900 mg, 450 mg to 850 mg, 500 mg to 800 mg, 550 mg to 750 mg, 600 mg to 700 mg, or approximately 650 mg) is administered in weeks 0 and 4.

[0378] In a particular embodiment, during the induction period, an initial dose (for example, approximately 100 mg to 1200 mg, 150 mg to 1150 mg, 200 mg to 1100 mg, 250 mg to 1050 mg, 300 mg to 1000 mg, 350 mg to 950 mg, 400 mg to 900 mg, 450 mg to 850 mg, 500 mg to 800 mg, 550 mg to 750 mg, 600 mg to 700 mg, or approximately 650 mg) is administered in weeks 0 and 8.

[0379] In a particular embodiment, during the induction period, an initial dose (for example, approximately 100 mg to 1200 mg, 150 mg to 1150 mg, 200 mg to 1100 mg, 250 mg to 1050 mg, 300 mg to 1000 mg, 350 mg to 950 mg, 400 mg to 900 mg, 450 mg to 850 mg, 500 mg to 800 mg, 550 mg to 750 mg, 600 mg to 700 mg, or approximately 650 mg) is administered at week 0 and week 12.

[0380] In a particular embodiment, 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., 2 Doses of 5 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 are administered at weeks 8, 12, and 16. In certain embodiments, half the dose is administered at weeks 8, 12, and 16 during the induction period. In certain embodiments, one-quarter of the dose is administered at weeks 8, 12, and 16 during the induction period.

[0381] In a particular embodiment, 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) is taken. Doses of 1 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 are administered at weeks 4, 8, 12, and 16. In certain embodiments, half the dose is administered at weeks 4, 8, 12, and 16 during the induction period. In certain embodiments, one-quarter of the dose is administered at weeks 4, 8, 12, and 16 during the induction period.

[0382] In a particular embodiment, 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., Doses of 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 are administered at weeks 4 and 12. In certain embodiments, half the dose is administered at weeks 4 and 12 during the induction period. In certain embodiments, one-quarter of the dose is administered at weeks 4 and 12 during the induction period.

[0383] In a particular embodiment, 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., Doses of 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 are administered at weeks 2, 4, and 12. In certain embodiments, half the dose is administered at weeks 2, 4, and 12 during the induction period. In certain embodiments, one-quarter of the dose is administered at weeks 2, 4, and 12 during the induction period.

[0384] In a particular embodiment, 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., Doses of 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 are administered at weeks 2 and 12. In certain embodiments, half the dose is administered at weeks 2 and 12 during the induction period. In certain embodiments, one-quarter of the dose is administered at weeks 2 and 12 during the induction period.

[0385] In a particular embodiment, during the infusion 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.) For example, doses of 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 are administered at week 12. In certain embodiments, half the dose is administered at week 12 during the induction period. In certain embodiments, one-quarter of the dose is administered at week 12 during the induction period.

[0386] In a particular embodiment, 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., Doses of 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 are administered at weeks 8 and 16. In certain embodiments, half the dose is administered at weeks 8 and 16 during the induction period. In certain embodiments, one-quarter of the dose is administered at weeks 8 and 16 during the induction period.

[0387] In a particular embodiment, during the infusion 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.) For example, doses of 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 are administered at week 16. In certain embodiments, half the dose is administered at week 16 during the induction period. In certain embodiments, one-quarter of the dose is administered at week 16 during the induction period.

[0388] In a particular embodiment, 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., Doses of 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 are administered at weeks 4 and 14. In certain embodiments, half the dose is administered at weeks 4 and 14 during the induction period. In certain embodiments, one-quarter of the dose is administered at weeks 4 and 14 during the induction period.

[0389] In a particular embodiment, during the infusion 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.) For example, doses of 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 are administered at week 14. In certain embodiments, half the dose is administered at week 14 during the induction period. In certain embodiments, one-quarter of the dose is administered at week 14 during the induction period.

[0390] In a particular embodiment, 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., Doses of 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 are administered at weeks 2, 4, and 14. In certain embodiments, half the dose is administered at weeks 2, 4, and 14 during the induction period. In certain embodiments, one-quarter of the dose is administered at weeks 2, 4, and 14 during the induction period.

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

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

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

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

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

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

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

[0398] The exemplary drug regimens described herein (e.g., induction and maintenance) include all regimens provided in Tables 11-14 below. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5] [Table 11-6] [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4] [Table 12-5] [Table 13-1] [Table 13-2] [Table 14]

[0399] In one aspect, the present disclosure relates to a method for treating atopic dermatitis in a patient who requires treatment, and to the patient, a) Two initial doses of 720 mg of anti-IL-13 antibody prior to the two induction doses. b) Two induction doses of 360 mg of anti-IL-13 antibody, and c) A method is provided which includes subcutaneous administration of one or more maintenance doses of 360 mg of anti-IL-13 antibody, which is started approximately 12 weeks or more after the first induction dose. Here, the anti-IL-13 antibody includes 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 acid represented by 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 acid represented by SEQ ID NO: 39.

[0400] In a particular embodiment, the second initial dose is administered approximately two weeks after the first initial dose.

[0401] In a particular embodiment, the first induction dose is administered approximately two weeks after the second initial dose.

[0402] In a particular embodiment, the second induction dose is administered approximately 8 weeks after the first induction dose.

[0403] In a particular embodiment, the maintenance dose is administered every three months.

[0404] In a particular embodiment, the maintenance dose is administered every six months.

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

[0406] In a particular embodiment, the composition has a unit dose of 2 mL of extractable volume.

[0407] In certain embodiments, the doses described herein are adjusted according to body weight, age, and / or body surface area.

[0408] In one aspect, the present disclosure relates to a method for treating atopic dermatitis in a patient who requires treatment, and to the patient, a) The initial dose of 720 mg of anti-IL-13 antibody prior to the two induction doses. b) Two induction doses of 360 mg of anti-IL-13 antibody, and c) A method is provided which includes subcutaneous administration of one or more maintenance doses of 360 mg of anti-IL-13 antibody, which is started approximately 12 weeks or more after the first induction dose. Here, the anti-IL-13 antibody includes 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 acid represented by 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 acid represented by SEQ ID NO: 39.

[0409] In a particular embodiment, the first induction dose is administered approximately four weeks after the initial dose.

[0410] In a particular embodiment, the second induction dose is administered approximately 8 weeks after the first induction dose.

[0411] In a particular embodiment, the maintenance dose is administered every three months.

[0412] In a particular embodiment, the maintenance dose is administered every six months.

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

[0414] In a particular embodiment, the composition has a unit dose of 2 mL of extractable volume.

[0415] In certain embodiments, the doses described herein are adjusted according to body weight, age, and / or body surface area.

[0416] In one aspect, the present disclosure relates to a method for treating atopic dermatitis in a patient who requires treatment, and to the patient, a) The initial dose of 360 mg of anti-IL-13 antibody prior to the two induction doses. b) Two induction doses of 180 mg of anti-IL-13 antibody, and c) A method is provided which includes subcutaneous administration of one or more maintenance doses of 180 mg of anti-IL-13 antibody, which is started approximately 12 weeks or more after the first induction dose. Here, the anti-IL-13 antibody includes 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 acid represented by 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 acid represented by SEQ ID NO: 39.

[0417] In a particular embodiment, the first induction dose is administered approximately four weeks after the initial dose.

[0418] In a particular embodiment, the second induction dose is administered approximately 8 weeks after the first induction dose.

[0419] In a particular embodiment, the maintenance dose is administered every three months.

[0420] In a particular embodiment, the maintenance dose is administered every six months.

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

[0422] In a particular embodiment, the composition has a unit dose of 2 mL of extractable volume.

[0423] In certain embodiments, the doses described herein are adjusted according to body weight, age, and / or body surface area.

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

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

[0426] In a particular embodiment, the autoinjector provided herein is an autoinjector configured to deliver a composition comprising an anti-IL-13 antibody in a concentration of 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, wherein the anti-IL-13 antibody comprises VH, which comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid represented by SEQ ID NO: 3, and VL, which comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid represented by SEQ ID NO: 39.

[0427] In certain embodiments, antibodies are administered intravenously, intramuscularly, subcutaneously, topically, orally, percutaneously, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or nasally. An effective dose of anti-IL-13 antibody may be administered for the treatment of a disease or disorder. The appropriate dosage of anti-IL-13 antibody may be determined based on the type of disease or disorder being treated, the type of anti-IL-13 antibody, the severity and course of the disease or disorder, the individual's clinical condition, the individual's clinical history and response to treatment, and the discretion of the attending physician.

[0428] In certain embodiments, the antibodies provided herein are administered together with at least one additional therapeutic agent. Any suitable additional therapeutic agent or immunotherapy agent may be administered together with the antibodies provided herein. Additional therapeutic agents include, but are not limited to, agents used to treat or prevent diseases or disorders, such as inflammatory diseases or disorders associated with elevated levels of IL-13 and / or IgE.

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

[0430] In embodiments in which the antibodies and additional therapeutic agents provided herein are included in different pharmaceutical compositions, the administration of the antibody may occur before, simultaneously with, and / or after, the administration of the additional therapeutic agent. In certain embodiments, the administration of the antibodies and additional therapeutic agents provided herein occurs within about one month of each other. In certain embodiments, the administration of the antibodies and additional therapeutic agents provided herein occurs within about one week of each other. In certain embodiments, the administration of the antibodies and additional therapeutic agents provided herein occurs within about one day of each other. In certain embodiments, the administration of the antibodies and additional therapeutic agents provided herein occurs within about 12 hours of each other. In certain embodiments, the administration of the antibodies and additional therapeutic agents provided herein occurs within about one hour of each other.

[0431] Kits and Products This application provides a kit comprising one or more antibody compositions described herein and instructions for use. In certain embodiments, the kit further comprises components selected from a secondary antibody, an immunohistochemical reagent, a pharmaceutically acceptable excipient, and instructions, as well as any combination thereof. In a particular embodiment, the kit comprises a pharmaceutical composition comprising one or more antibody compositions described herein together with one or more pharmaceutically acceptable excipients.

[0432] This application provides a manufactured product comprising one of the antibody compositions described herein or a kit thereof. An example of a manufactured product is a vial (including a sealed vial). [Examples]

[0433] The following are examples of specific embodiments for carrying out the present invention. These examples are presented for illustrative purposes only and are not intended in any way to limit the scope of the present invention. While efforts have been made to ensure accuracy of the numerical values ​​used (e.g., quantities, temperatures, etc.), some experimental error and deviation should naturally be permitted.

[0434] The practice of this invention will, unless otherwise indicated, utilize conventional methods of protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology within the scope of the skills of the art. Such techniques are fully described in the literature. For example, TECreighton, Proteins: Structures and Molecular Properties (WH Freeman and Company, 1993), ALLehninger, Biochemistry (Worth Publishers, Inc., current addition), Sambrook, et al., Molecular Cloning: A Laboratory Manual (2nd Edition, 1989), Methods In Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.), Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990), Carey and Sundberg Advanced Organic Chemistry 3. rd See Ed. (Plenum Press) Vols. A and B (1992).

[0435] Example 1: The manipulated anti-IL-13 antibody exhibits enhanced binding to human FcRn and cleavage of binding to the Fc receptor and C1q. Materials and methods Determination of antibody affinity for Fc receptor and C1q Binding affinity of antibodies to Fc receptor and C1q (K DThese were determined by surface plasmon resonance (SPR) using Biacore 8K and ELISA, respectively. Briefly, purified antibody normalized to 5 mg / mL was captured at a flow rate of 10 uL / min for 90 or 120 seconds using an SPR tip equipped with anti-kappa light chain antibody. A paired channel containing only buffer was used as a reference. Subsequently, recombinant human FcRn, FcγRI, FcγRIIa(H131), FcγRIIa(R131), FcγRIIb, FcγRIIIa(F158), FcγRIIIa(V158), and C1q at various concentrations were injected onto the surface along with the captured purified antibody and reference channel. The tip was regenerated with different antigen concentrations using 10 mM glycine HCl, pH 1.5, and the antibody was captured again. Subsequently, K D The association rate constant and dissociation rate constant were determined by fitting the derived values ​​using Biacore Insight Evaluation Software to either a 1:1 Langmuir coupled model or a steady-state analysis model, whichever was more appropriate.

[0436] result Antibody affinity for Fc receptor and C1q Construct 133 also showed a YTE-dependent increase in FcRn binding and LALA-dependent cleavage of Fc-dependent binding compared to the IgG1-positive control (Table 15). The functions of the YTE and LALA amino acid substitutions were confirmed by enhanced binding to human FcRn and cleavage of binding to the Fc receptor and C1q, respectively. [Table 15]

[0437] Example 2: The modified anti-IL13 antibody mutant demonstrated significant half-life extension and pSTAT6 inhibition in NHP. To demonstrate the potential of anti-IL13 antibody variants engineered to improve dosage compared to current and anticipated standard mAbs for the disease, particularly in Alzheimer's disease (AD), construct 133 (see construct 133 sequences in Tables 2-8), including SEQ ID NOs: 3, 39, 439, and 469, was tested in female non-human primates (NHPs) according to a single bolus dose of 3 mg / kg, assuming either IV or SQ. Furthermore, variant clones of construct 133, LS ("construct 133-LS"), with different FcRN-related half-life extension Fc modifications were evaluated. Blood samples were collected sequentially, starting with pre-administration samples, followed by samples at 0.167, 1, 4, 8, 24, 48, 96, 168, 336, 504, 674, 840, 1334, 1680, and 2160 hours post-administration. The PK parameter (C) of the highest measured serum concentration was measured. max ), time to reach the highest measured serum concentration (T max ), area under the serum concentration versus time curve (AUC) extrapolated from time 0 to infinity. 0-inf ), clearance (CL), distributed volume (V) in steady state ss ), half-life (T 1 / 2 The saturation point (SPR) and absolute subcutaneous bioavailability (F) were calculated (Table 16). The data were analyzed to show the mean serum concentration over time, including the standard deviation, and regression fitting was performed.

[0438] Inhibition of pSTAT6 in whole blood isolated from NHP administered via SC with construct 133-LS was evaluated ex vivo. [Table 16]

[0439] In direct comparative studies of construct 133 and leburikizumab in NHP, both the IV and SQ formulations of construct 133 showed significantly longer half-lives than leburikizumab. As shown in Figure 2, the mean half-life for construct 133 was 27.6 days for leburikizumab, compared to 17-18 days for leburikizumab. Furthermore, construct 133 showed a half-life of 1.45 mL / day in NHP. -1 kg -1The average clearance rate was shown. The steady-state distribution volume was 55.65 (mL / kg). -1 It was observed that ) was well absorbed, and subcutaneous bioavailability was determined to be 81.22%. Lebrikizumab was 2.93 (mL / day) in NHP. -1 kg -1 The average clearance rate was shown. The steady-state distribution volume was 52.10 (mL / kg). -1 It was observed that ) was well absorbed, and the subcutaneous bioavailability was determined to be 75.70%. Specifically, the t of levurikizumab 1 / 2 It is 18.0 days, C L 2.93 mL per day -1 kg -1 Therefore, Vss is 52.10 mL kg -1 Therefore, F was 75.70%.

[0440] Construct 133-LS or levukizumab at serum concentrations >5 μg / mL maintained complete inhibition of pSTAT6 in NHP whole blood. pSTAT6 inhibition was achieved by levukizumab (IC). 90 =27.9, IC 50 Compared to (IC = 48.9 days), the structure 133-LS lasted for a longer period. 90 = 56.8 days after administration, IC 50 (=92.6 days).

[0441] Structure 133 showed, t 1 / 2 Consistent with the YTE-dependent increase in exposure and the decrease in clearance, construct 133-LS (with a different FcRN-related amino acid substitution) inhibited pSTAT6 for a longer period compared to lebrikizumab. Construct 133 is expected to show a similar increase in the duration of pSTAT6 inhibition.

[0442] While not bound by theory, construct 133 was engineered to have a YTE amino acid substitution in the Fc region, which may extend the IgG half-life by increasing binding to the embryonic Fc receptor (FcRn) under acidic pH conditions. IgG bound to FcRn is recycled via lysosomal salvage, resulting in the IgG returning to circulation. The extended half-life of construct 133 may allow for reduced administration frequency compared to currently available therapies, thereby reducing the injection burden and improving compliance in patients living with atopic dermatitis and other IL-13-driven diseases.

[0443] In an indirect comparison with third-party NHP data, construct 133 had the highest normalized AUC among antibodies with YTE substitutions, as shown in Figure 3. 0-∞ (C 正規化*日 ), or the area of ​​curvature (AUC) from drug administration to infinity was shown. Therefore, the PK profile of construct 133 appears to provide the highest sustained concentration or drug level in blood flow compared to other antibodies with YTE substitution.

[0444] The extension of the half-life of mAbs with YTE amino acid substitutions depends on the type of target (receptor or soluble). Therefore, we tested converting NHP half-life data to human half-life data for mAbs with soluble targets, and found that the human half-life is approximately 3 to 4 times longer than the NHP half-life (mean: 3.5 times, median: 3.1x; data not shown).

[0445] Based on this NHP half-life data, construct 133 is expected to have a human half-life of approximately 80–110 days, based on an equivalent mAb with a YTE amino acid substitution.

[0446] Furthermore, based on PK modeling, with a human half-life of 33 days (which, to the best of the applicant's knowledge, is shorter than the shortest half-life of any mAb with YTE amino acid substitution reported to date), construct 133 is considered to be effectively administered on a maintenance dosing schedule every two months. With a half-life of 50 days, construct 133 is considered to be effectively administered on a maintenance dosing schedule every three months.

[0447] To understand the maintenance dosing schedule that construct 133 is expected to achieve, known PK parameters of lebrikizumab were used. These PK parameters helped to understand how lebrikizumab is distributed and eliminated systemically. Based on these known parameters, a two-compartment PK model with primary absorption, which is standard for mAbs, was constructed to predict the time-course concentrations or drug levels of both lebrikizumab and construct 133. Key parameters included a clearance (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%.

[0448] The effectiveness in inflammatory conditions such as AD is C トラフ It is thought that this depends on the minimum concentration of the mAb. Therefore, based on the model described above, target C of construct 133 トラフ In maintenance with monthly medication, lebrikizumab C トラフ It was set to be equal to 31.3 mg / L. Considering the overlapping epitopes of lebrikizumab and the specific antibodies disclosed herein, and the similarity of potency across multiple in vitro assays, the exposure required for the potential clinical activity of construct 133 can be predicted. To maintain the concentration of the disclosed antibody above 31.3 mg / L, K 消失By modeling the elimination rate constant or the percentage of the drug eliminated in a given time, and the half-life, it is determined that, assuming a dose of 300 mg, a half-life of at least 33 days is required to administer construct 133 every two months for maintenance, and a half-life of at least 50 days is required to administer construct 133 every three months for maintenance.

[0449] Therefore, with a human half-life of 33 days, construct 133 can be effectively administered with a maintenance dosing schedule every two months. With a half-life of 50 days, construct 133 can be effectively administered with a maintenance dosing schedule every three months.

[0450] Example 3: The GLP trial of multiple doses over 29 days in NHP was completed without adverse findings in all cohorts, including the best cohort tested, and was considered to be at a no-adverse-effect level (NOAEL). A GLP-compliant toxicity study was conducted in NHP (non-healthy pedicels) using repeated dosing over 29 days. NHP (3-5 animals per group, sex-specific) received construct 133 via SC administration at doses of 0, 30, 75, or 150 mg / kg / dose once weekly (a total of 5 doses). No adverse findings were observed up to the highest dose tested (150 mg / kg), which was considered the maximum feasible dose and thus the no-adverse-action level (NOAEL) in this study.

[0451] Example 4. Monomer purity after affinity capture from a stable pool. Monomer purity obtained by one-step affinity capture determines the final yield and unit cost of the antibody under cGMP production. To characterize this, briefly, a CHO stable pool was generated separately for each antibody in the workflow leading to the selection of a master cell bank for cGMP production. The affinity capture step was performed using a Mabselect SuRe column. Novel IgG1 variants (e.g., constructs 132, 133, 136, 137, 140, 141, and 144) maintained a clear solution with less than 15% aggregates after one-step purification. Novel IgG4 variants (constructs 134, 135, 138, 139, 142, and 143) exhibited a milky appearance with some precipitation and agglutination sensitivity (>68% agglutination) when eluted using 50 mM sodium citrate and 150 mM sodium chloride elution buffer at pH 3.0. The novel IgG4 variant exhibited lower aggregation levels when eluted with either 50 mM acetic acid at pH 2.8, or 100 mM sodium acetate and 800 mM arginine at pH 3.5. At higher pH levels of 3.5, arginine was required to maintain adequate recovery.

[0452] The results are summarized in Table 17. The novel IgG1 and IgG4 variants exhibit higher monomer purity obtained directly from affinity capture under optimized elution conditions compared to lebrikizumab variants (constructs 128-131). [Table 17]

[0453] Example 5. Acceleration Stability As demonstrated by this example, the novel mutants in the IgG1 constructs showed a lower tendency to aggregate and greater resistance to basic species changes under various stress conditions, as shown in Table 18. The proportion of basic species was determined by capillary isoelectric focusing (ciEF) performed as is known in the art. Lebrikizumab-related mutants (constructs 128-131) and IgG4 mutants (constructs 134, 135, 142, and 143; as described in Examples 1-7) were more susceptible to aggregation and basic species changes compared to the novel IgG1 mutants (e.g., constructs 132, 133, 136, 137, 140, 141, and 144). [Table 18]

[0454] Example 6: Phase 1 randomized, double-blind, placebo-controlled single-dose and multiple-dose escalation-dose human initial-dose study on the safety, tolerability, and pharmacokinetics of anti-IL-13 antibody in healthy subjects. Study design and methodology This is a phase 1 randomized, double-blind, placebo-controlled, parallel-group human first-dose (FIH) trial of the anti-IL-13 antibody as defined herein in healthy subjects. The anti-IL-13 antibody will be administered subcutaneously (SC) in single and multiple escalating doses (SAD and MAD, respectively). This trial will investigate up to five SAD cohorts and two MAD cohorts. Each cohort will consist of eight healthy subjects randomized in a 6:2 ratio to receive either the anti-IL-13 antibody or placebo.

[0455] Participants will be screened within 42 days prior to administration to assess their eligibility for trial participation. For each dose of anti-IL-13 antibody administered, participants will remain in the clinical research unit (CRU) for five consecutive days (one day before administration, the day of administration, and three days after administration). Sentinel dosing in two participants (one receiving the active drug and one receiving placebo) will be included in all SAD cohorts. In-hospital monitoring will continue until the end-of-study (EOS) visit (day 337).

[0456] SAD cohort Up to five SAD cohorts will be enrolled at four escalating dose levels (150, 300, 600, and 1200 mg, Figure 1). Alternatively, the starting dose in the first SAD cohort will be 300 mg (Figure 4). Each SAD cohort will enroll eight subjects. Subjects will be blinded and randomized in a 6:2 ratio to either anti-IL-13 antibody or placebo. The first two participants in each cohort (sentinel participants) will be blinded and randomized in a 1:1 ratio (active drug:placebo), followed for at least 24 hours after administration, and then the remaining cohort will be treated. The remaining six participants will be randomized in a 5:1 ratio (active drug:placebo). A schematic is shown in Figure 1.

[0457] Participants are admitted to the CRU one day prior to medication administration (-day 1). On day 1 (administration day), participants receive a small-scale dose of either an anti-IL-13 antibody or a placebo. On day 4 (72 hours after administration), participants are discharged from the CRU after completing all in-facility assessments for the day. The length of stay in the CRU will be adjusted for cohort 2 and beyond based on data obtained from previous cohorts.

[0458] The starting dose in the first SAD cohort is 150 mg. This dose reflects a safety margin of more than 10 times the human equivalent dose for at least 60 kg of subjects, based on the no-adverse-effect level (NOAEL) in a 28-day non-human primate toxicity study using best laboratory standards. Alternatively, the starting dose in the first SAD cohort is 300 mg.

[0459] Following SAD Cohort 1, evaluation doses include 300, 600, and 1200 mg (or alternatively, 600 and 1200 mg (Figure 4)). However, dose escalation and actual dose increases / decreases will be determined by the Safety Review Committee (SRC). The SRC will make its determination based on post-dose safety data for at least 14 days obtained from the previous dose level. Specifically, the SRC will determine whether any dose-limiting toxicity (DLT) defined in the protocol occurs by day 15 in subjects receiving anti-IL-13 antibodies in the current cohort, and whether any discontinuation rules apply. The SRC will convene when safety data for at least 6 of the 8 subjects in the cohort are available at day 15. Furthermore, available trailing pharmacokinetic (PK) results will be reviewed to assess the appropriateness of the next planned dose and guide any subsequent dose modifications to be evaluated. Dose escalations in subsequent cohorts will not exceed twofold. The maximum single dose tested will not exceed 1200 mg.

[0460] Participants will receive a small dose (SC) of either anti-IL-13 antibody or placebo in the CRU on day 1. Vital signs, electrocardiogram (ECG), adverse events (AEs), and blood samples for PK and safety clinical tests will be collected sequentially. After completion of CRU admission (up to day 4), participants will return for outpatient visits on days 8, 15, 22, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, and 309, followed by an end-of-surgery (EOS) visit on day 337, which covers approximately 5 half-lives. Follow-up visit dates, PK sampling times, and study duration will be adjusted based on the safety and PK results of the previous cohort.

[0461] MAD Cohort Up to three cohorts will be enrolled at two dose escalation levels (starting doses of 150 mg twice every four weeks [Q4W] and 300 mg twice every four weeks [Q4W]), and others will be enrolled at the discretion of the SRC and the sponsor based on new data. Alternatively, this study will investigate two multi-dose (MD) cohorts (induction phase) including subjects who received 720 mg of construct 133 at weeks 0 and 2, and 360 mg of construct 133 at weeks 4 and 12. In the maintenance phase, subjects will receive 360 ​​mg of construct 133 every three months (Q12W) or every six months (Q24W). See Figure 4. The actual starting dose and dosing frequency will be finally determined by the SRC based on available data from the SAD cohort, including available PK data. The first cohort will be enrolled after the SRC reviews safety and PK data from the SAD cohort for at least 14 days at a total dose at least equal to the total dose to be given to the MAD subjects (i.e., completing the safety review of SAD for a single dose of 300 mg will allow the initiation of the MAD cohort, which will be administered at a dose of 150 mg Q4W x 2, equivalent to a total dose of 300 mg).

[0462] Following MAD Cohort 1, the SRC will determine the increase and actual dose increase / decrease. Specifically, the SRC will determine whether any dose-limiting toxicity (DLT) as defined in the protocol occurs and whether any discontinuation rules apply to subjects receiving anti-IL-13 antibodies in the current cohort, throughout the 14 days following the final dose of the study drug. For the SRC to be held, at least 5 of the 8 subjects in the cohort must have safety data at day 43 (i.e., 14 days after the second dose was administered on day 29). Furthermore, available trailing PK results will be reviewed to assess the appropriateness of the next planned dose and guide any subsequent dose modifications to be assessed as necessary. Dose escalations in subsequent cohorts will not exceed a twofold increase. The maximum MAD dose tested will not exceed 1200 mg in total during the treatment period.

[0463] Participants will receive two small doses of anti-IL-13 antibody (SC) during the chronic rupture (CRU): one on day 1 and the other on day 29. Participants will remain in the CRU for 72 hours after each dose, which will be adjusted for subsequent cohorts based on new data. Vital signs, electrocardiograms (ECGs), adverse event (AE) assessments, and blood samples for pharmacokinetic (PK) and safety clinical tests will be collected sequentially.

[0464] Following completion of CRU admission, subjects will return for outpatient visits on days 8, 15, and 22 after the first dose of the study drug, and on days 50, 57, 85, 113, 141, 169, 197, 225, 253, 281, and 309 after the second dose of the study drug. The end-of-surgery (EOS) visit will be on day 337, which is expected to cover approximately five half-lives. Follow-up visit dates, PK sampling times, and study duration will be adjusted based on the safety and PK results of the previous cohort.

[0465] Exam period The maximum duration for each individual subject is 378 days.

[0466] Number of people Up to 64 participants (8 participants in each of up to 8 cohorts).

[0467] Main Eligibility Criteria Selection Criteria Selection criteria include: healthy men and non-pregnant women determined by physical examination and clinical screening tests; and a body mass index of 18-34 kg / m². 2 Applicants must be between 18 and 65 years of age (inclusive); willing to use appropriate contraception from admission until 6 months after the last dose of the study drug or 5 half-lives, whichever is longer; willing to use appropriate contraception from admission until 6 months after the last dose of the study drug or 5 half-lives, whichever is longer; and have a tattoo-free injection site suitable for SC injection.

[0468] Exclusion criteria Exclusion criteria include: evidence of a clinically significant abnormality or disease, including but not limited to: hemoglobin A1c ≥ 6.5% and / or a diagnosis of diabetes mellitus; a positive human immunodeficiency virus (HIV) antibody test; acute or chronic hepatitis B or C as demonstrated by hepatitis B surface antigen (HBsAg) and / or hepatitis C antibody (HCV Ab); evidence of a recovered infection or condition after vaccination, accompanied by the presence of antibodies or the demonstrated absence of viral deoxyribonucleic acid (DNA) in polymerase chain reaction; positive tuberculosis on a blood test at screening; a diagnosis or suspected diagnosis of immunodeficiency or autoimmune disease, or having received immunosuppressive therapy such as anticancer chemotherapy or radiotherapy prior to the study, or having received systemic corticosteroid treatment within the past 120 days; any other clinical trial, abnormal vital signs, ECG abnormalities, clinically significant medical condition, or, in the opinion of the principal investigator, is likely to negatively alter the risk-benefit of participation in the study, complicate the results of the study, or interfere with the conduct or compliance of the study. Additional exclusion criteria include: fever within 7 days prior to administration of the study drug; a known history of drug abuse and / or alcohol dependence within 2 years prior to screening; a positive drug abuse screening at the time of screening or admission to the CRU; or regular use of more than 5 cigarettes per day (or equivalent amounts of nicotine-containing products); a history of severe allergic reactions or allergies to either anti-IL-13 antibodies or any component of the placebo; for women, being breastfeeding, nursing, pregnant, or planning to become pregnant within 6 months of visiting the EOS; donation or loss of more than 1 unit (450 mL) of blood within 1 month prior to administration; use of any prescription or non-prescription medication within 7 days prior to administration (exceptions: contraceptives or acetaminophen up to 2 g per day prior to administration are permitted); and use of any investigational drug therapy from within 30 days or 5 half-lives (whichever is longer) prior to administration of the study drug to 30 days or 5 half-lives (whichever is longer) after the last dose of the study drug.

[0469] Investigational drug, dosage, and administration method The anti-IL-13 antibody described in the examples is a high-affinity IgG1 humanized monoclonal antibody that binds to IL-13. The anti-IL-13 antibody solution is administered by subcutaneous (SC) injection.

[0470] In the SAD part of this study, the starting dose is 150 mg, with expected dose increases of 300, 600, and 1200 mg. In the MAD part of this study, the dose is 150 mg and 300 mg every four weeks (Q4W), for a total of two doses. After the starting dose (150 mg in the SAD study), the dose level and regimen will be determined by the SRC based on the review of new safety data. In the SAD part of this study, no subjects will receive a single dose greater than 1200 mg, and in the MAD part of this study, no subjects will receive a total dose greater than 1200 mg. In the alternative MAD part of the study, the dose is 300 mg on days 1 and 29, or on days 1 and 15.

[0471] Evaluation Criteria Pharmacokinetics Determine the following PK parameters for both the SAD and MAD parts of the study: Maximum observed concentration (C max ), C max Time until (T max ), terminal disappearance rate constant (λ z ) and terminal half-life (T 1 / 2 ).

[0472] In the SAD trial, the following additional PK parameter is determined: Area under the concentration-time curve (AUC) from time zero to the last quantifiable time point. 0-last ), apparent clearance (CL / F), and apparent distribution volume (V z / F).

[0473] In the MAD trial, the following additional PK parameters are determined: AUC (AUC0-τ), accumulation ratio (RAUC), CL / F, and V for the interval between the first and last doses. z / F.

[0474] The pharmacokinetic properties used in this specification are described in Table 19 below. [Table 19]

[0475] Antidrug antibodies The presence of ADA and the effect of ADA on the PK of anti-IL-13 antibodies.

[0476] Pharmacodynamics Changes over time in pSTAT6 and other blood biomarkers (including TARC and IgE).

[0477] safety Safety assessment includes evaluation of adverse events (TEAEs) under investigational treatment, clinical laboratory tests (e.g., hematology, serology, and urinalysis), vital signs, ECG, and physical examination.

[0478] statistical methods Analysis group The following three analysis populations are defined for this study: (1) The safety population, defined as all subjects who received at least one dose of the study drug and had at least one post-baseline safety assessment. (2) The PK population, defined as all enrolled subjects for whom at least one PK parameter of interest was calculated. Generally, for each parameter, data from individual subjects are excluded from the analysis if sufficient data is not available from that subject to calculate the particular parameter in question. (3) The full analysis population, defined as all randomized subjects who completed the study without experiencing any significant protocol deviations or violations.

[0479] Sample size The sample size is specific to FIH trials 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.

[0480] Pharmacokinetic analysis Plasma concentrations of anti-IL-13 antibodies are summarized by dose and time point using descriptive statistics on the PK population. Mean and individual plasma anti-IL-13 antibody concentrations over time are presented in figures using linear and semi-logarithmic scales. PK parameters are calculated using non-compartmental analysis and summarized by dose. AUC and C max The proportionality of the dose is tested across the entire dose level. The accumulation of AUC and C in the steady state are examined. max Calculate the accumulation.

[0481] Safety analysis Safety data are summarized using descriptive statistics. All subjects undergoing treatment, regardless of the time period, are included in the safety data summary. TEAEs are coded using the Medical Dictionary for Regulatory Activities, and the incidence of TEAEs in subjects is summarized by treatment, dose, organ-specific classification, and basic terminology. The incidence of TEAEs in subjects is also summarized in relation to severity and the investigational drug.

[0482] Objectives and evaluation items The objectives and evaluation items are shown in Table 20 below. [Table 20]

[0483] Example 7: Phase 1 randomized, double-blind, placebo-controlled single-dose and multiple-dose escalation-dose hum...

Claims

1. A method for treating atopic dermatitis in a patient who requires treatment, wherein the patient: a) One to five or more induction doses of an anti-IL-13 antibody 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, respectively; and b) Subcutaneous administration of one or more maintenance doses administered approximately 4 to 17 weeks or more 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 the anti-IL-13 antibody. The method wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) containing an amino acid sequence having at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity with the sequence represented by SEQ ID NO: 3, and a light chain variable region (VL) containing an amino acid sequence having at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity with the sequence represented by SEQ ID NO:

39.

2. The method according to claim 1, further comprising administering an initial dose before the aforementioned 1 to 5 or more induction doses, wherein the initial dose is twice the induction dose.

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

4. The method according to any one of claims 1 to 3, wherein the first introductory dose is 150 mg, 300 mg, 360 mg, or 600 mg.

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

6. The method according to claim 5, wherein the second introductory dose is administered approximately 2 to 16 weeks after the first introductory dose.

7. The method according to claim 5, wherein the second introductory dose is administered approximately 2 to 8 weeks after the first introductory dose.

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

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

10. The method according to claim 8, wherein the second introductory dose is administered approximately two weeks after the first introductory dose.

11. The method according to any one of claims 1 to 10, wherein the maintenance dose is 150 mg, 200 mg, 300 mg, 360 mg, 400 mg, 600 mg, or 800 mg, and is administered every three months, every twelve weeks, or four times a year.

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

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

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

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

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

18. The method according to any one of claims 1 to 10, wherein the maintenance dose is 300 mg, 360 mg, or 600 mg, and is administered every two months or every eight weeks.

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

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

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

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

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

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

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

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

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

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

29. The method according to any one of claims 1 to 28, wherein the patient has one or more of the following: (a) Eczema Area Severity Index (EASI) score of 10 or higher, (b) Global Assessment (IGA) scores by three or more principal investigators, and (c) Body surface area (BSA) of 10% or more.

30. The method according to any one of claims 1 to 29, further comprising determining one or more of the following characteristics of the patient at baseline, during the induction period, and after the induction period: Eczema Area Severity Index (EASI), Investigator General Assessment (IGA), Body Surface Area (BSA), Numerical Rating Scale for Itch (NRS), Insomnia Scale, Scoring for Atopic Dermatitis (SCORAD), Patient Self-Assessment of Eczema (POEM), and Quality of Life Index for Skin Disease (DLQI).

31. A method for treating atopic dermatitis in patients who require treatment, The anti-IL-13 antibody is administered subcutaneously to the patient during an induction period of 4 to 17 weeks, and during the induction period, the anti-IL-13 antibody is The drug shall be administered subcutaneously, with an initial dose of approximately 100 mg to approximately 1200 mg or the dose listed in any one of Tables 11 to 13, administered once or twice, and optionally, at least once, administered at half or a quarter of the initial dose; During the maintenance period, the patient is subcutaneously administered the anti-IL-13 antibody in a dose of approximately 100 mg to approximately 1200 mg or the doses listed in Table 14; The anti-IL-13 antibody comprises a heavy chain variable region (VH) containing an amino acid sequence having at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity with SEQ ID NO: 3, and a light chain variable region containing an amino acid sequence having at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity with SEQ ID NO:

39. The method comprising a region (VL), wherein VH comprises HCDR1 including sequence number 58, sequence number 68, or sequence number 85, HCDR2 including sequence number 100, sequence number 104, or sequence number 108, and HCDR3 including sequence number 112 or sequence number 130, and VL comprises LCDR1 including sequence number 141 or sequence number 149, LCDR2 including sequence number 153 or sequence number 164, and LCDR3 including sequence number 165.

32. The method according to claim 31, wherein the initial dose is approximately 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 according to claim 31 or 32, wherein the initial dose is administered during the induction period in week 0 and week 2.

34. The method according to claim 31 or 32, wherein the initial dose is administered during the induction period in weeks 0 and 4.

35. The method according to claim 31 or 32, wherein the initial dose is administered during the induction period in weeks 0 and 8.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

55. The method according to any one of claims 31 to 54, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) containing the amino acid sequence represented by SEQ ID NO: 3 and a light chain variable region (VL) containing the amino acid sequence represented by SEQ ID NO:

39.

55. A method for treating atopic dermatitis in a patient who requires treatment, wherein the patient: a) Two initial doses of 720 mg of anti-IL-13 antibody prior to two induction doses; b) Two induction doses of 360 mg of the anti-IL-13 antibody; and c) Subcutaneous administration of one or more maintenance doses of 360 mg of the anti-IL-13 antibody, which is started approximately 12 weeks or more after the first induction dose. The method wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) containing the amino acid sequence represented by SEQ ID NO: 3 and a light chain variable region (VL) containing the amino acid sequence represented by SEQ ID NO:

39.

56. The method according to claim 55, wherein the second initial dose is administered approximately two weeks after the first initial dose.

57. The method according to claim 55 or 56, wherein the first introductory dose is administered approximately two weeks after the second initial dose.

58. The method according to any one of claims 55 to 57, wherein the second introductory dose is administered approximately eight weeks after the first introductory dose.

59. The method according to any one of claims 55 to 58, wherein the maintenance dose is administered every three months.

60. The method according to any one of claims 55 to 58, wherein the maintenance dose is administered every six months.

61. A method for treating atopic dermatitis in a patient who requires treatment, wherein the patient: a) Initial dose of 720 mg of anti-IL-13 antibody prior to two induction doses; b) Two induction doses of 360 mg of the anti-IL-13 antibody; and c) Subcutaneous administration of one or more maintenance doses of 360 mg of the anti-IL-13 antibody, which is started approximately 12 weeks or more after the first induction dose. The method wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) containing the amino acid sequence represented by SEQ ID NO: 3 and a light chain variable region (VL) containing the amino acid sequence represented by SEQ ID NO:

39.

62. The method according to claim 61, wherein the first introductory dose is administered approximately four weeks after the initial dose.

63. The method according to any one of claims 61 to 62, wherein the second induction dose is administered approximately eight weeks after the first induction dose.

64. The method according to any one of claims 61 to 63, wherein the maintenance dose is administered every three months.

65. The method according to any one of claims 61 to 64, wherein the maintenance dose is administered every six months.

66. A method for treating atopic dermatitis in a patient who requires treatment, wherein the patient: a) The initial dose of 360 mg of anti-IL-13 antibody prior to the two induction doses; b) Two induction doses of 180 mg of the anti-IL-13 antibody; and c) Subcutaneous administration of one or more maintenance doses of 180 mg of the anti-IL-13 antibody, which is started approximately 12 weeks or more after the first induction dose. The method wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) containing the amino acid sequence represented by SEQ ID NO: 3 and a light chain variable region (VL) containing the amino acid sequence represented by SEQ ID NO:

39.

67. The method according to claim 66, wherein the first introductory dose is administered approximately four weeks after the second initial dose.

68. The method according to any one of claims 66 to 67, wherein the second induction dose is administered approximately eight weeks after the first induction dose.

69. The method according to any one of claims 66 to 68, wherein the maintenance dose is administered every three months.

70. The method according to any one of claims 66 to 69, wherein the maintenance dose is administered every six months.

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

72. The method according to claim 71, wherein the composition has a unit dose of 2 mL, 2.25 mL, or 2.7 mL of extractable volume.

73. The method according to claim 72, wherein the composition has a unit dose of 2 mL of extractable volume.

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

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

76. The method according to any one of claims 31 to 75, wherein the patient has one or more of the following: (a) Eczema Area Severity Index (EASI) score of 10 or higher, (b) Global Assessment (IGA) scores by three or more principal investigators, and (c) Body surface area (BSA) of 10% or more.

77. The method according to any one of claims 31 to 76, further comprising determining one or more of the following characteristics of the patient at baseline, during the induction period, and after the induction period: Eczema Area Severity Index (EASI), Investigator General Assessment (IGA), Body Surface Area (BSA), Numerical Rating Scale for Pruritus (NRS), Numerical Rating Scale for Skin Pain (SP-NRS), Insomnia Scale, Scoring for Atopic Dermatitis (SCORAD), Patient Self-Assessment of Eczema (POEM), Quality of Life Index for Skin Disease (DLQI), 5-Item Asthma Control Questionnaire (ACQ-5), and 22-Item Sinus Outcome Study (SNOT-22).

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

39.

79. The composition according to claim 78, wherein the composition has a unit dose of 2 mL, 2.25 mL, or 2.7 mL of extractable volume.

80. The composition according to claim 79, wherein the composition has a unit dose of 2 mL of extractable volume.

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

39.

82. The autoinjector according to claim 81, wherein the composition has a unit dose of 2 mL, 2.25 mL, or 2.7 mL of extractable volume.

83. A method, composition, or autoinjector according to any of the prior claims, further comprising a heavy chain constant region of sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity thereto, or sequence 439 or sequence 624.

84. A method, composition, or autoinjector according to any of the prior claims, further comprising a light chain constant region of sequence 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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