WO2024264003A2

WO2024264003A2 - Antibodies that bind interleukin 13 and tslp or tslpr and methods of use

Info

Publication number: WO2024264003A2
Application number: PCT/US2024/035140
Authority: WO
Inventors: Jacob Cole MILLIGAN; Eric Franklin Zhu; Hussam Hisham Shaheen
Original assignee: Paragon Therapeutics Inc
Current assignee: Paragon Therapeutics Inc
Priority date: 2023-06-22
Filing date: 2024-06-21
Publication date: 2024-12-26
Anticipated expiration: 2025-12-22
Also published as: WO2024264003A3; AU2024313862A1

Abstract

Described herein are novel bispecific antibodies that bind Interleukin 13 (IL-13) and TSLP or TSLPR and methods of use thereof. In certain aspects, described herein are methods of inhibiting IL-13 and TSLP or TSLPR biological activities. In certain aspects, described herein are pharmaceutical compositions comprising the bispecific antibodies that bind Interleukin 13 (IL-13) and TSLP or TSLPR. In certain aspects, the antibodies and methods described herein are used for treatment of an inflammatory disease or disorder associated with elevated levels of IL-13, and/or IgE, and TSLP or TSLPR

Description

Attorney Docket No. PRG-013WO ANTIBODIES THAT BIND INTERLEUKIN 13 AND TSLP OR TSLPR AND METHODS OF USE Cross-reference to related applications [0001] This application claims the benefit and priority to U.S. Provisional Patent Application No.63/522,631, filed June 22, 2023. Background [0002] Interleukin (IL)-13 is a T helper cell subclass 2 (Th2) cytokine and belongs to a family of type I cytokines, exhibiting pleiotropic effects across multiple cellular pathways. IL-13 is involved in the differentiation of naïve T cells into Th2 cells. IL-13 promotes B-cell proliferation and induces immunoglobulin isotype class switching to IgG4 and IgE when co- stimulated with CD40/CD40L. It also up-regulates Fc^RI, and thus, helps in IgE priming of mast cells. In monocytes/macrophages, IL-13 up-regulates expression of CD23 and MHC class I and class II antigens, down-regulates the expression of CD14, inhibits antibody- dependent cytotoxicity, and promotes eosinophil survival, activation, and recruitment. IL-13 also manifests important functions on nonhematopoietic cells, such as smooth muscle cells, epithelial cells, endothelial cells, and fibroblast cells. IL-13 enhances proliferation and cholinergic-induced contractions of smooth muscles. In epithelial cells, IL-13 is a potent inducer of chemokine production, alters mucociliary differentiation, decreases ciliary beat frequency of ciliated epithelial cells, and results in goblet cell metaplasia. In endothelial cells, IL-13 is a potent inducer of vascular cell adhesion molecule 1 (VCAM-1), which is important for recruitment of eosinophils. In epithelial keratinocytes, IL-13 reduces the expression of barrier integrity molecules, such as filaggrin and loricrin, while stimulating CCL26 and CCL2 secretion responsible for the recruitment of several inflammatory cells of myeloid lineages. In human dermal fibroblasts, IL-13 induces type 1 collagen synthesis in human dermal fibroblasts. [0003] Thymic stromal lymphopoietin (TSLP) is an epithelial cell derived cytokine produced in response to pro-inflammatory stimuli. TSLP has been discovered to promote allergic inflammatory responses primarily through its activity on dendritic and mast cells. Human TSLP expression has been reported to be increased in asthmatic airways correlating to disease severity. In addition, TSLP protein levels are detectable in the concentrated bronchoalveolar lavage (BAL) fluid of asthma patients, and other patients suffering from allergic disorders. In addition, TSLP has also been found to promote fibrosis. ^{IPTS/128623945.3} 1 Attorney Docket No. PRG-013WO [0004] TSLP binds to a heterodimeric receptor consisting of the TSLP receptor (TSLPR) and an IL-7 receptor ^ chain (IL-7R ^) in dendritic cells, thereby activating the dendritic cells. Upon activation, the dendritic cells express inflammatory chemokines such as thymus and activation regulated chemokines (TARC (CCL17)), macrophage-derived chemokines (MDC (CCL22)), and the like. [0005] Activation of dendritic cells by TSLP through the TSLP receptor is associated with disease pathology, including allergic inflammatory diseases, such as asthma, and autoimmune disease, such as systemic sclerosis. [0006] Accordingly, there is a need in the art for antagonists to IL-13 and TSLP or the TSLP receptor (TSLPR) for preventing and treating diseases in which human IL-13, TSLP, and human TSLP receptor are involved in the disease pathology, such as inflammatory and fibrotic disorders. Summary [0007] In one aspect, provided herein is a bispecific antibody, wherein the bispecific antibody comprises a first antigen binding site and a second antigen binding site, wherein the first antigen binding site binds Interleukin 13 (IL-13) and comprises a first variable heavy (VH) chain sequence comprising three first heavy chain CDR sequences, a first CDR-H1, a first CDR-H2, and a first CDR-H3; and a first variable light (VL) chain sequence comprising three first light chain CDR sequences, a first CDR-L1, a first CDR-L2, and a first CDR-L3; wherein: the first CDR-H1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 58-99 and 121;the first CDR-H2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 100-111;the first CDR-H3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 112-120 and 130-140, the first CDR- L1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 141-144 and 149-152, the first CDR-L2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 153-158 and LAS; and the first CDR-L3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 165-172; and wherein the second antigen binding site binds TSLP or TSLPR and comprises a second variable heavy (VH) chain sequence comprising three second heavy chain CDR sequences, a second CDR-H1, a second CDR-H2, and a second CDR-H3; and a second variable light (VL) chain sequence comprising three second light chain CDR sequences, a second CDR-L1, a second CDR-L2, and a second CDR-L3; wherein: the second CDR-H1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 610-618; the second CDR-H2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 619-627; the second CDR-H3 comprises a sequence ^{IPTS/128623945.3} 2 Attorney Docket No. PRG-013WO selected from the sequences set forth in SEQ ID NOs: 628-636, the second CDR-L1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 637-645., the second CDR-L2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 646-651; and the second CDR-L3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 652-657. [0008] In some embodiments, the first CDR-H1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 58, 68, and 85; the first CDR-H2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 100, 104; and 108; the first CDR-H3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 112 and 130; the first CDR-L1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 141 and 589; the first CDR-L2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 153 and LAS; and the first CDR-L3 comprises a sequence set forth in SEQ ID NOs: 165; and the second CDR-H1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 610-618; the second CDR-H2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 619-627; the second CDR-H3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 628-636; the second CDR-L1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 637-645; the second CDR-L2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 646-651; and the second CDR-L3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 652-657. [0009] In some embodiments, the antibody comprises a first VH sequence selected from SEQ ID NOs: 1-32, 470, and 688 and a second VH sequence selected from SEQ ID NOs: 659-661, 682, 684, 686, and 688. [0010] In some embodiments, the antibody comprises a first VH sequence comprising SEQ ID NO: 3 and a second VH sequence selected from SEQ ID NOs: 659-661, 682, 684, 686, and 688. [0011] In some embodiments, the antibody comprises a first VL sequence selected from SEQ ID NOs: 33-57, 471, and 687 and a second VL sequence selected from SEQ ID NOs: 662-664, 681, 683, and 685. [0012] In some embodiments, the bispecific antibody comprises a first VL comprises a first VL sequence comprising SEQ ID NO: 39 and a second VL sequence selected from SEQ ID NOs: 662-664, 681, 683, and 685. [0013] In some embodiments, the bispecific antibody comprises a first VH sequence selected from SEQ ID NOs: 1-32, 470, and 688 and a second VH sequence selected from ^{IPTS/128623945.3} 3 Attorney Docket No. PRG-013WO SEQ ID NOs: 659-661, 682, 684, 686, and 688; and a first VL sequence selected from SEQ ID NOs: 33-57, 471, and 687 and a second VL sequence selected from SEQ ID NOs: 662- 664, 681, 683, and 685. [0014] In some embodiments, the bispecific antibody comprises a first VH sequence comprising SEQ ID NOs: 3 and a second VH sequence selected from SEQ ID NOs: 659-661, 682, 684, 686, and 688; and a first VL sequence comprising SEQ ID NOs: 39 and a second VL sequence selected from SEQ ID NOs: 662-664, 681, 683, and 685. [0015] In some embodiments, the bispecific antibody is a humanized, human, or chimeric antibody. [0016] In some embodiments, the bispecific antibody is a humanized antibody. [0017] In some embodiments, the bispecific antibody comprises a heavy chain human constant region of a class selected from IgG, IgA, IgD, IgE, and IgM. [0018] In some embodiments, the human Fc region comprises a human heavy chain constant region of the class IgG and a subclass selected from IgG1, IgG2, IgG3, and IgG4. [0019] In some embodiments, the human Fc region comprises a human IgG1 Fc. [0020] In some embodiments, the human Fc region comprises a human IgG4 Fc. [0021] In some embodiments, the human Fc region comprises a human IgG2 Fc. [0022] In some embodiments, the heavy chain comprises an Fc sequence selected from the sequences set forth in SEQ ID NOs: 425-468, 484-539, 670-680, 689-691, and 693-804. [0023] In some embodiments, the heavy chain comprises a constant heavy chain sequence set forth in SEQ ID NO: 439. [0024] In some embodiments, the bispecific antibody comprises a heavy chain/chain A from Table 11a or Table 11b, a light chain/chain B from Table 12a or Table 12b, and, optionally, an Fc sequence from Table 13 (SEQ ID NOs: 425-468, 484-539, 670-680, 689- 691, and 693-804). [0025] In some embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions result in a change in antibody half-life, ADCC activity, ADCP activity, or CDC activity as compared to an otherwise equivalent antibody comprising an Fc without the one or more substitutions. [0026] In some embodiments, the change is (a) an increase in antibody half-life and (b) a decrease in ADCC activity, ADCP activity, or CDC activity as compared to an otherwise equivalent antibody comprising an Fc without the one or more substitutions. [0027] In some embodiments, the one or more amino acid substitutions results in increased antibody half-life compared to an antibody comprising a wild-type Fc region. ^{IPTS/128623945.3} 4 Attorney Docket No. PRG-013WO [0028] In some embodiments, any of the isolated bispecific antibody described herein are for use in the treatment of an inflammatory disorder or disease. [0029] In one aspect, provided herein is an isolated polynucleotide or set of polynucleotides encoding the bispecific antibody of any of the above claims, a VH thereof, a VL thereof, a light chain thereof, a heavy chain thereof, or an antigen-binding portion thereof, and optionally, wherein the polynucleotide or set of polynucleotides comprises cDNA. [0030] In one aspect, provided herein is vector or set of vectors comprising the polynucleotide or set of polynucleotides described herein. [0031] In one aspect, provided herein is a host cell comprising the polynucleotide or set of polynucleotides or the vector or set of vectors described herein. [0032] In one aspect, provided herein is a method of producing an antibody, the method comprising expressing the bispecific antibody with the host cell described herein and isolating the expressed bispecific antibody. [0033] In one aspect, provided herein is a pharmaceutical composition comprising the bispecific antibody of any one of the bispecific antibodies described herein and a pharmaceutically acceptable excipient. [0034] In one aspect, provided herein is a kit comprising the bispecific antibody of any one of the bispecific antibodies described herein or a pharmaceutical composition described herein and instructions for use. [0035] In one aspect, provided herein is a method for treating an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount the bispecific antibody of any one of the bispecific antibodies described herein or a pharmaceutical composition described herein. [0036] In certain embodiments, the isolated bispecific antibody is used in the treatment of an inflammatory disorder or disease. In certain embodiments, the isolated bispecific antibody is used in the treatment of atopic dermatitis. In certain embodiments, the treatment reduces disease severity in a subject and wherein disease severity is assessed by an Atopic Dermatitis Disease Severity Outcome Measure. In certain embodiments, the isolated bispecific antibody is used in the treatment of asthma. In certain embodiments, the isolated bispecific antibody is used in the treatment of idiopathic pulmonary fibrosis. In certain embodiments, the isolated bispecific antibody is used in the treatment of alopecia areata. In certain embodiments, the isolated bispecific antibody is used in the treatment of chronic sinusitis with nasal polyps. In certain embodiments, the isolated bispecific antibody is used in the treatment of Chronic ^{IPTS/128623945.3} 5 Attorney Docket No. PRG-013WO Rhinosinusitis without Nasal Polyps (CRSsNP). In certain embodiments, the isolated bispecific antibody is used in the treatment of eosinophilic esophagitis (EoE). In certain embodiments, the isolated bispecific antibody is used in the treatment of an Eosinophilic gastrointestinal disorder or disease (ENID) selected from the group consisting of Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), and Eosinophilic Gastroenteritis (EGE). In certain embodiments, the isolated bispecific antibody is used in the treatment of Churg-Strauss syndrome/Eosinophilic granulomatosis with polyangiitis (EGPA). In certain embodiments, the isolated bispecific antibody is used in the treatment of Prurigo Nodularis (PN). In certain embodiments, the isolated bispecific antibody is used in the treatment of Chronic Spontaneous Urticaria (CSU). In certain embodiments, the isolated bispecific antibody is used in the treatment of Chronic Pruritis of Unknown Origin (CPUO). In certain embodiments, the isolated bispecific antibody is used in the treatment of Bullous Pemphigoid (BP). In certain embodiments, the isolated bispecific antibody is used in the treatment of Cold Inducible Urticaria (ColdU). In certain embodiments, the isolated bispecific antibody is used in the treatment of Allergic Fungal Rhinosinusitis (AFRS). In certain embodiments, the isolated bispecific antibody is used in the treatment of Allergic Bronchopulmonary Aspergillosis (ABPA). In certain embodiments, the isolated bispecific antibody is used in the treatment of Chronic Obstructive Pulmonary Disease (COPD). In certain embodiments, the isolated bispecific antibody is used in the treatment of inflammatory bowel disease, such as Crohn disease or ulcerative colitis. In certain embodiments, the isolated bispecific antibody is used in the treatment of psoriasis. In certain embodiments, the isolated bispecific antibody is used in the treatment of lupus. In certain embodiments, the isolated bispecific antibody is used in the treatment of rheumatoid arthritis. [0037] In certain aspects, described herein is an isolated polynucleotide or set of polynucleotides encoding an antibody described herein, a VH thereof, a VL thereof, a light chain thereof, a heavy chain thereof, or an antigen-binding portion thereof, and optionally, wherein the polynucleotide or set of polynucleotides comprises cDNA. In certain aspects, described herein is a vector or set of vectors comprising the polynucleotide or set of polynucleotides. In certain aspects, described herein is a host cell comprising the polynucleotide or set of polynucleotides or the vector or set of vectors. [0038] In certain aspects, described herein is a method of producing an antibody, the method comprising expressing the antibody with the host cell described herein and isolating the expressed antibody. ^{IPTS/128623945.3} 6 Attorney Docket No. PRG-013WO [0039] In certain aspects, described herein is a pharmaceutical composition comprising a bispecific antibody described herein and a pharmaceutically acceptable excipient. [0040] In certain aspects, described herein is a kit comprising a bispecific antibody described herein or a pharmaceutical composition described herein and instructions for use. [0041] In certain aspects, described herein is a method for treating an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount a bispecific antibody described herein or a pharmaceutical composition described herein. In certain embodiments of the methods described herein, 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. In certain embodiments, the inflammatory disorder or disease is alopecia areata. In certain embodiments, the inflammatory disorder or disease is chronic sinusitis with nasal polyps. In certain embodiments, the inflammatory disorder or disease is Chronic Rhinosinusitis without Nasal Polyps (CRSsNP). In certain embodiments, the inflammatory disorder or disease is eosinophilic esophagitis (EoE). In certain embodiments, the inflammatory disorder or disease is an Eosinophilic gastrointestinal disorder or disease (ENID) selected from the group consisting of Eosinophilic Gastritis (EoG), Eosinophilic enteritis (EoN), Eosinophilic colitis (EoC), and Eosinophilic Gastroenteritis (EGE). In certain embodiments, the inflammatory disorder or disease is Churg-Strauss syndrome/Eosinophilic granulomatosis with polyangiitis (EGPA). In certain embodiments, the inflammatory disorder or disease is Prurigo Nodularis (PN). In certain embodiments, the inflammatory disorder or disease is Chronic Spontaneous Urticaria (CSU). In certain embodiments, the inflammatory disorder or disease is Chronic Pruritis of Unknown Origin (CPUO). In certain embodiments, the inflammatory disorder or disease is Bullous Pemphigoid (BP). In certain embodiments, the inflammatory disorder or disease is Cold Inducible Urticaria (ColdU). In certain embodiments, the inflammatory disorder or disease is Allergic Fungal Rhinosinusitis (AFRS). In certain embodiments, the inflammatory disorder or disease is Allergic Bronchopulmonary Aspergillosis (ABPA). In certain embodiments, the inflammatory disorder or disease is Chronic Obstructive Pulmonary Disease (COPD). In certain embodiments, the inflammatory disorder or disease is inflammatory bowel disease, such as Crohn disease or ulcerative colitis. In certain embodiments, the inflammatory disorder or disease is psoriasis. In certain embodiments, the inflammatory disorder or disease is lupus. In certain embodiments, the inflammatory disorder or disease is rheumatoid arthritis. ^{IPTS/128623945.3} 7 Attorney Docket No. PRG-013WO [0042] In certain aspects, described herein is a method for treating a pathology associated with elevated levels of IL-13 in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of a bispecific antibody described herein or a pharmaceutical composition described herein. [0043] In certain aspects, described herein is a method of reducing biological activity of IL-13 in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount a bispecific antibody described herein or a pharmaceutical composition described herein. [0044] In certain aspects, described herein is a method of inhibiting the TH2 type allergic response in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of a bispecific antibody described herein or a pharmaceutical composition described herein. [0045] In certain aspects, described herein is a method of reducing levels of Thymus and Activation Regulated Chemokine (TARC)/CCL17 in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of a bispecific antibody described herein or a pharmaceutical composition described herein. [0046] In certain aspects, described herein is a method of preventing an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of a bispecific antibody of described herein or a pharmaceutical composition described herein. Brief Description of the Drawings [0047] These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description, and accompanying drawing, where: [0048] Figure 1 depicts an exemplary IgG-scFv bispecific antibody format. [0049] Figure 2 depicts an exemplary DVD-Ig bispecific antibody format. [0050] Figure 3 depicts an exemplary CrossMab bispecific antibody format. Detailed Description [0051] The instant disclosure relates, in part, to antibodies (e.g., bispecific antibodies) that bind (1) IL-13 and (2) either TSLP or a TSLP receptor (TSLPR). Definitions ^{IPTS/128623945.3} 8 Attorney Docket No. PRG-013WO [0052] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art, such as, for example, the widely utilized molecular cloning methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 4th ed. (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer-defined protocols and conditions unless otherwise noted. [0053] As used herein, the singular form “a,” “an,” and “the” includes plural references unless indicated otherwise. [0054] It is understood that aspects and embodiments of the invention described herein include “comprising,” “consisting,” and “consisting essentially of” aspects and embodiments. [0055] For all compositions described herein, and all methods using a composition described herein, the compositions can either comprise the listed components or steps, or can “consist essentially of” the listed components or steps. When a composition is described as “consisting essentially of” the listed components, the composition contains the components listed, and may contain other components which do not substantially affect the condition being treated, but do not contain any other components which substantially affect the condition being treated other than those components expressly listed; or, if the composition does contain extra components other than those listed which substantially affect the condition being treated, the composition does not contain a sufficient concentration or amount of the extra components to substantially affect the condition being treated. When a method is described as “consisting essentially of” the listed steps, the method contains the steps listed, and may contain other steps that do not substantially affect the condition being treated, but the method does not contain any other steps which substantially affect the condition being treated other than those steps expressly listed. As a non-limiting specific example, when a composition is described as “consisting essentially of” a component, the composition may additionally contain any amount of pharmaceutically acceptable carriers, vehicles, or diluents and other such components which do not substantially affect the condition being treated. ^{IPTS/128623945.3} 9 Attorney Docket No. PRG-013WO [0056] The term “vector,” as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a self- replicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as “expression vectors.” [0057] The terms “host cell,” “host cell line,” and “host cell culture” are used interchangeably and refer to cells into which an exogenous nucleic acid has been introduced, and the progeny of such cells. Host cells include “transformants” (or “transformed cells”) and “transfectants” (or “transfected cells”), which each include the primary transformed or transfected cell and progeny derived therefrom. Such progeny may not be completely identical in nucleic acid content to a parent cell, and may contain mutations. A “recombinant host cell” or “host cell” refers to a cell that includes an exogenous polynucleotide, regardless of the method used for insertion, for example, direct uptake, transduction, f-mating, or other methods known in the art to create recombinant host cells. [0058] As used herein, the term “eukaryote” refers to organisms belonging to the phylogenetic domain Eucarya such as animals (including but not limited to, mammals, insects, reptiles, birds, etc.), ciliates, plants (including but not limited to, monocots, dicots, algae, etc.), fungi, yeasts, flagellates, microsporidia, protists, etc. [0059] As used herein, the term “prokaryote” refers to prokaryotic organisms. For example, a non-eukaryotic organism can belong to the Eubacteria (including but not limited to, Escherichia coli, Thermus thermophilus, Bacillus stearothermophilus, Pseudomonas fluorescens, Pseudomonas aeruginosa, Pseudomonas putida, etc.) phylogenetic domain, or the Archaea (including but not limited to, Methanococcus jannaschii, Methanobacterium thermoautotrophicum, Halobacterium such as Haloferax volcanii and Halobacterium species NRC-1, Archaeoglobus fulgidus, Pyrococcus furiosus, Pyrococcus horikoshii, Aeuropyrum pernix, etc.) phylogenetic domain. [0060] An “effective amount” or “therapeutically effective amount” as used herein refers to an amount of therapeutic compound, such as an anti-IL-13 antibody, administered to an individual, either as a single dose or as part of a series of doses, which is effective to produce or contribute to a desired therapeutic effect, either alone or in combination with another therapeutic modality. Examples of a desired therapeutic effect is enhancing an immune response, slowing or delaying tumor development; stabilization of disease; amelioration of one or more symptoms. An effective amount may be given in one or more dosages. ^{IPTS/128623945.3} 10 Attorney Docket No. PRG-013WO [0061] The term “treating” (and variations thereof such as “treat” or “treatment”) refers to clinical intervention in an attempt to alter the natural course of a disease or condition in a subject in need thereof. Treatment can be performed during the course of clinical pathology. Desirable effects of treatment include preventing recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. [0062] The term “sufficient amount” means an amount sufficient to produce a desired effect, e.g., an amount sufficient to modulate an immune response in a subject. [0063] As used herein, the term “subject” or “individual” means a mammalian subject. Exemplary subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, and sheep. In certain embodiments, the subject is a human. In some embodiments the subject has a disease or condition that can be treated with an antibody provided herein. In some embodiments, the disease or condition is a cancer. In some embodiments, the disease or condition is a viral infection. [0064] The term “in vitro” refers to processes that occur in a living cell growing separate from a living organism, e.g., growing in tissue culture. [0065] The term “in vivo” refers to processes that occur in a living organism. [0066] The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic or diagnostic products (e.g., kits) that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and/or warnings concerning the use of such therapeutic or diagnostic products. [0067] The term “pharmaceutical composition” refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective in treating a subject, and which contains no additional components which are unacceptably toxic to the subject in the amounts provided in the pharmaceutical composition. [0068] The terms “co-administration,” “co-administer,” and “in combination with” include the administration of two or more therapeutic agents either simultaneously, concurrently or sequentially within no specific time limits. In one embodiment, the agents are present in the cell or in the subject's body at the same time or exert their biological or therapeutic effect at the same time. In one embodiment, the therapeutic agents are in the same composition or unit dosage form. In other embodiments, the therapeutic agents are in separate ^{IPTS/128623945.3} 11 Attorney Docket No. PRG-013WO compositions or unit dosage forms. In certain embodiments, a first agent can be administered prior to the administration of a second therapeutic agent. [0069] The terms “modulate” and “modulation” refer to reducing or inhibiting or, alternatively, activating or increasing, a recited variable. [0070] The terms “increase” and “activate” refer to an increase of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or greater in a recited variable. [0071] The terms “reduce” and “inhibit” refer to a decrease of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or greater in a recited variable. [0072] The term “about” indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term “about” indicates the designated value ± 10%, ± 5%, or ± 1%. In certain embodiments, where applicable, the term “about” indicates the designated value(s) ± one standard deviation of that value(s). [0073] The term “agonize” refers to the activation of receptor signaling to induce a biological response associated with activation of the receptor. An “agonist” is an entity that binds to and agonizes a receptor. [0074] The term “antagonize” refers to the inhibition of receptor signaling to inhibit a biological response associated with activation of the receptor. An “antagonist” is an entity that binds to and antagonizes a receptor. [0075] For any of the structural and functional characteristics described herein, methods of determining these characteristics are known in the art. [0076] The term “optionally” is meant, when used sequentially, to include from one to all of the enumerated combinations and contemplates all sub-combinations. [0077] The term “amino acid” refers to the twenty common naturally occurring amino acids. Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C); glutamic acid (Glu; E), glutamine (Gln; Q), Glycine (Gly; G); histidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V). [0078] The term “affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen or epitope). Unless indicated otherwise, as used herein, “affinity” ^{IPTS/128623945.3} 12 Attorney Docket No. PRG-013WO refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen or epitope). [0079] The term “kd” (sec-1), as used herein, refers to the dissociation rate constant of a particular antibody-antigen interaction. This value is also referred to as the koff value. [0080] The term “ka” (M-1×sec-1), as used herein, refers to the association rate constant of a particular antibody-antigen interaction. This value is also referred to as the kon value. [0081] The term “KD” (M), as used herein, refers to the dissociation equilibrium constant of a particular antibody-antigen interaction. KD = kd/ka. In some embodiments, the affinity of an antibody is described in terms of the KD for an interaction between such antibody and its antigen. For clarity, as known in the art, a smaller KD value indicates a higher affinity interaction, while a larger KD value indicates a lower affinity interaction. [0082] The term “KA” (M-1), as used herein, refers to the association equilibrium constant of a particular antibody-antigen interaction. KA = ka/kd. [0083] The term “antibody” is used herein in its broadest sense and includes certain types of immunoglobulin molecules comprising one or more antigen-binding domains that specifically bind to an antigen or epitope. An antibody specifically includes intact antibodies (e.g., intact immunoglobulins), antibody fragments, and multi-specific antibodies. [0084] A “anti-IL-13 antibody,” “IL-13 antibody,” or “IL-13 specific antibody” is an antibody, as provided herein, which specifically binds to the antigen IL-13. [0085] The term “epitope” means a portion of an antigen that specifically binds to an antibody. [0086] The term “hypervariable region” or “HVR,” as used herein, refers to each of the regions of an antibody variable domain which are hypervariable in sequence and/or form structurally defined loops (“hypervariable loops”). [0087] The term “antigen-binding domain” means the portion of an antibody that is capable of specifically binding to an antigen or epitope. [0088] The term “chimeric antibody” refers to an antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species. [0089] The term “human antibody” refers to an antibody which possesses an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies. ^{IPTS/128623945.3} 13 Attorney Docket No. PRG-013WO [0090] The term “humanized antibody” refers to a protein having a sequence that differs from the sequence of an antibody derived from a non-human species by one or more amino acid substitutions, deletions, and/or additions, such that the humanized antibody is less likely to induce an immune response, and/or induces a less severe immune response, as compared to the non-human species antibody, when it is administered to a human subject. [0091] The term “multispecific antibody” refers to an antibody that comprises two or more different antigen-binding domains that collectively specifically bind two or more different epitopes. [0092] A “bispecific antibody” is an antibody that comprises two different antigen binding domains that each bind different epitopes. [0093] A “monospecific antibody” is an antibody that comprises one or more binding sites that specifically bind to a single epitope. An example of a monospecific antibody is a naturally occurring IgG molecule which, while divalent (i.e., having two antigen-binding domains), recognizes the same epitope at each of the two antigen-binding domains. The binding specificity may be present in any suitable valency. [0094] The term “monoclonal antibody” refers to an antibody from a population of substantially homogeneous antibodies. A population of substantially homogeneous antibodies comprises antibodies that are substantially similar and that bind the same epitope(s), except for variants that may normally arise during production of the monoclonal antibody. Such variants are generally present in only minor amounts. A monoclonal antibody is typically obtained by a process that includes the selection of a single antibody from a plurality of antibodies. For example, the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody can be further altered, for example, to improve affinity for the target (“affinity maturation”), to humanize the antibody, to improve its production in cell culture, and/or to reduce its immunogenicity in a subject. [0095] The term “single-chain” refers to a molecule comprising amino acid monomers linearly linked by peptide bonds. In a particular such embodiment, the C-terminus of the Fab light chain is connected to the N-terminus of the Fab heavy chain in the single-chain Fab molecule. As described in more detail herein, an scFv has a variable domain of light chain (VL) connected from its C-terminus to the N-terminal end of a variable domain of heavy chain (VH) by a polypeptide chain. Alternately the scFv comprises of polypeptide chain where in the C-terminal end of the VH is connected to the N-terminal end of VL by a polypeptide chain. ^{IPTS/128623945.3} 14 Attorney Docket No. PRG-013WO [0096] The “Fab fragment” (also referred to as fragment antigen-binding) contains the constant domain (CL) of the light chain and the first constant domain (CH1) of the heavy chain along with the variable domains VL and VH on the light and heavy chains respectively. The variable domains comprise the complementarity determining loops (CDR, also referred to as hypervariable region) that are involved in antigen-binding. Fab^ fragments differ from Fab fragments by the addition of a few residues at the carboxy terminus of the heavy chain CH1 domain including one or more cysteines from the antibody hinge region. [0097] “F(ab’)2” fragments contain two Fab’ fragments joined, near the hinge region, by disulfide bonds. F(ab’)2 fragments may be generated, for example, by recombinant methods or by pepsin digestion of an intact antibody. The F(ab’) fragments can be dissociated, for example, by treatment with ß-mercaptoethanol. [0098] “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain. [0099] “Single-chain Fv” or “sFv” or “scFv” includes the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain. In one embodiment, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen-binding. For a review of scFv see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol.113, Rosenburg and Moore eds., Springer-Verlag, New York, pp.269-315 (1994). HER2 antibody scFv fragments are described in WO93/16185; U.S. Pat. No.5,571,894; and U.S. Pat. No. 5,587,458. [00100] “scFv-Fc” fragments comprise an scFv attached to an Fc domain. For example, an Fc domain may be attached to the C-terminal of the scFv. The Fc domain may follow the VH or VL, depending on the orientation of the variable domains in the scFv (i.e., VH-VL or VL- VH ). Any suitable Fc domain known in the art or described herein may be used. In some cases, the Fc domain comprises an IgG4 Fc domain. [00101] The term “single domain antibody” or “sdAb” refers to a molecule in which one variable domain of an antibody specifically binds to an antigen without the presence of the other variable domain. Single domain antibodies, and fragments thereof, are described in Arabi Ghahroudi et al. (1998) FEBS Letters 414:521-526 and Muyldermans et al. (2001) Trends in Biochem. Sci.26:230-245, each of which is incorporated by reference in its entirety. Single domain antibodies are also known as sdAbs or nanobodies. Sdabs are fairly stable and easy to express as fusion partner with the Fc chain of an antibody (Harmsen MM, ^{IPTS/128623945.3} 15 Attorney Docket No. PRG-013WO De Haard HJ (2007) “Properties, production, and applications of camelid single-domain antibody fragments” Appl. Microbiol Biotechnol.77(1): 13-22). [00102] The terms “full length antibody,” “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a naturally occurring antibody structure and having heavy chains that comprise an Fc region. For example, when used to refer to an IgG molecule, a “full length antibody” is an antibody that comprises two heavy chains and two light chains. [00103] The term “antibody fragment” refers to an antibody that comprises a portion of an intact antibody, such as the antigen-binding or variable region of an intact antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab’)2 fragments, Fab’ fragments, scFv (sFv) fragments, and scFv-Fc fragments. [00104] The term “Fc domain” or “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. [00105] The term “substantially purified” refers to a construct described herein, or variant thereof that may be substantially or essentially free of components that normally accompany or interact with the protein as found in its naturally occurring environment, i.e. a native cell, or host cell in the case of recombinantly produced antibody that in certain embodiments, is substantially free of cellular material includes preparations of protein having less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% (by dry weight) of contaminating protein. [00106] The term “percent identity,” in the context of two or more nucleic acid or polypeptide sequences, refer to two or more sequences or subsequences that have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned for maximum correspondence, as measured using one of the sequence comparison algorithms described below (e.g., using publicly available computer software such as BLAST, BLASTP, BLASTN, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE software or other algorithms available to persons of skill) or by visual inspection. Software for performing BLAST analyses (Altschul et al. (1990) J. Mol. Biol.215:403-410) is publicly available through the National Center for Biotechnology Information (ncbi.nlm.nih.gov). Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Depending on the application, the percent ^{IPTS/128623945.3} 16 Attorney Docket No. PRG-013WO “identity” can exist over a region of the sequence being compared, e.g., over a functional domain, or, alternatively, exist over the full length of the two sequences to be compared. [00107] For sequence comparison, typically one sequence acts as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters. [00108] Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman (1981) Adv. Appl. Math.2:482, by the homology alignment algorithm of Needleman & Wunsch (1970) J. Mol. Biol.48:443, by the search for similarity method of Pearson & Lipman (1988) Proc. Nat’l. Acad. Sci. USA 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (see generally Ausubel et al., infra). [00109] Ranges recited herein are understood to be shorthand for all of the values within the range, inclusive of the recited endpoints. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50. [00110] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Bispecific Anti-IL-13/TSLP Antibodies Basic Antibody Structure [00111] The recognized immunoglobulin (antibody) genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. The “class” of an antibody or immunoglobulin refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains ^{IPTS/128623945.3} 17 Attorney Docket No. PRG-013WO that correspond to the different classes of immunoglobulins are called ^, ^, ^, ^, and ^, respectively. [00112] An exemplary immunoglobulin structural unit is composed of two pairs of polypeptide chains, each pair having one “light” (about 25 kD) and one “heavy” chain (about 50-70 kD). The N-terminal domain of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (VL) and variable heavy chain (VH) refer to these light and heavy chain domains respectively. The IgG1 heavy chain comprises of the VH, CH1, CH2, and CH3 domains respectively from the N- to C-terminus. The light chain comprises of the VL and CL domains from N- to C-terminus. The IgG1 heavy chain comprises a hinge between the CH1 and CH2 domains. In certain embodiments, the immunoglobulin constructs comprise at least one immunoglobulin domain from IgG, IgM, IgA, IgD, or IgE connected to a therapeutic polypeptide. In some embodiments, the immunoglobulin domain found in an antibody provided herein, is from or derived from an immunoglobulin based construct such as a diabody or a nanobody. In certain embodiments, the immunoglobulin constructs described herein comprise at least one immunoglobulin domain from a heavy chain antibody such as a camelid antibody. In certain embodiments, the immunoglobulin constructs provided herein comprise at least one immunoglobulin domain from a mammalian antibody such as a bovine antibody, a human antibody, a camelid antibody, a mouse antibody, or any chimeric antibody. [00113] In some embodiments, the antibodies provided herein comprise a heavy chain. In one embodiment, the heavy chain is an IgA. In one embodiment, the heavy chain is an IgD. In one embodiment, the heavy chain is an IgE. In one embodiment, the heavy chain is an IgG. In one embodiment, the heavy chain is an IgM. In one embodiment, the heavy chain is an IgG1. In one embodiment, the heavy chain is an IgG2. In one embodiment, the heavy chain is an IgG3. In one embodiment, the heavy chain is an IgG4. In one embodiment, the heavy chain is an IgA1. In one embodiment, the heavy chain is an IgA2. [00114] In some embodiments, an antibody is an IgG1 antibody. In some embodiments, an antibody is an IgG3 antibody. In some embodiments, an antibody is an IgG2 antibody. In some embodiments, an antibody is an IgG4 antibody. [00115] Generally, native four-chain antibodies comprise six hypervariable regions (HVRs); three in the VH (H1, H2, and H3), and three in the VL (L1, L2, and L3). HVRs generally comprise amino acid residues from the hypervariable loops and/or from the complementarity determining regions (CDRs), the latter being of highest sequence variability and/or involved in antigen recognition. With the exception of CDR1 in VH, CDRs generally ^{IPTS/128623945.3} 18 Attorney Docket No. PRG-013WO comprise the amino acid residues that form the hypervariable loops. HVRs are also referred to as CDRs, and these terms are used herein interchangeably in reference to portions of the variable region that form the antigen-binding regions. This particular region has been described by Kabat et al. (1983) U.S. Dept. of Health and Human Services, Sequences of Proteins of Immunological Interest and by Chothia et al. (1987) J Mol Biol 196:901-917, where the definitions include overlapping or subsets of amino acid residues when compared against each other. Nevertheless, application of either definition to refer to a CDR of an antibody or variants thereof is intended to be within the scope of the term as defined and used herein. The exact residue numbers which encompass a particular CDR will vary depending on the sequence and size of the CDR. Those skilled in the art can routinely determine which residues comprise a particular CDR given the variable region amino acid sequence of the antibody. [00116] The amino acid sequence boundaries of a CDR can be determined by one of skill in the art using any of a number of known numbering schemes, including those described by Kabat et al., supra (“Kabat” numbering scheme); Al-Lazikani et al. (1997) J. Mol. Biol., 273:927-948 (“Chothia” numbering scheme); MacCallum et al. (1996) J. Mol. Biol.262:732- 745 (“Contact” numbering scheme); Lefranc et al. (2003) Dev. Comp. Immunol.27:55-77 (“IMGT” numbering scheme); and Honegge and Plückthun (2001) J. Mol. Biol.309:657-70 (“AHo” numbering scheme); each of which is incorporated by reference in its entirety. [00117] Table 1 provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR- H2, and CDR-H3 as identified by the Kabat and Chothia schemes. For CDR-H1, residue numbering is provided using both the Kabat and Chothia numbering schemes. [00118] CDRs may be assigned, for example, using antibody numbering software, such as Abnum, available at www.bioinf.org.uk/abs/abnum/, and described in Abhinandan and Martin (2008) Immunology, 45:3832-3839, incorporated by reference in its entirety. Table 1. Residues in CDRs according to Kabat and Chothia numbering schemes.

^{IPTS/128623945.3} 19 Attorney Docket No. PRG-013WO

* The C-terminus of CDR-H1, when numbered using the Kabat numbering convention, varies between H32 and H34, depending on the length of the CDR. [00119] The “EU numbering scheme” is generally used when referring to a residue in an antibody heavy chain constant region (e.g., as reported in Kabat et al., supra). Unless stated otherwise, the EU numbering scheme is used to refer to residues in antibody heavy chain constant regions described herein. [00120] One example of an antigen-binding domain is an antigen-binding domain formed by a VH-VL dimer of an antibody. Another example of an antigen-binding domain is an antigen-binding domain formed by diversification of certain loops from the tenth fibronectin type III domain of an Adnectin. An antigen-binding domain can include CDRs 1, 2, and 3 from a heavy chain in that order; and CDRs 1, 2, and 3 from a light chain in that order. [00121] Epitopes frequently consist of surface-accessible amino acid residues and/or sugar side chains and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter may be lost in the presence of denaturing solvents. An epitope may comprise amino acid residues that are directly involved in the binding and other amino acid residues, which are not directly involved in the binding. The epitope to which an antibody binds can be determined using known techniques for epitope determination such as, for example, testing for antibody binding to IL-13 variants with different point-mutations or to chimeric IL-13 variants. [00122] To screen for antibodies which bind to an epitope on a target antigen bound by an antibody of interest (e.g., IL-13, TSLP, or TSLPR), a routine cross-blocking assay such as that described in Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1988), can be performed. Alternatively, or additionally, epitope mapping can be performed by methods known in the art. [00123] Chimeric antibodies are antibodies in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species. [00124] Human antibodies are antibodies which possesses an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a ^{IPTS/128623945.3} 20 Attorney Docket No. PRG-013WO non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies. [00125] A humanized antibody has a sequence that differs from the sequence of an antibody derived from a non-human species by one or more amino acid substitutions, deletions, and/or additions, such that the humanized antibody is less likely to induce an immune response, and/or induces a less severe immune response, as compared to the non- human species antibody, when it is administered to a human subject. In one embodiment, certain amino acids in the framework and constant domains of the heavy and/or light chains of the non-human species antibody are mutated to produce the humanized antibody. In another embodiment, the constant domain(s) from a human antibody are fused to the variable domain(s) of a non-human species. In another embodiment, one or more amino acid residues in one or more CDR sequences of a non-human antibody are changed to reduce the likely immunogenicity of the non-human antibody when it is administered to a human subject, wherein the changed amino acid residues either are not critical for immunospecific binding of the antibody to its antigen, or the changes to the amino acid sequence that are made are conservative changes, such that the binding of the humanized antibody to the antigen is not significantly worse than the binding of the non-human antibody to the antigen. Examples of how to make humanized antibodies can be found in U.S. Pat. Nos.6,054,297, 5,886,152 and 5,877,293. For further details, see Jones et al. (1986) Nature 321:522-525; Riechmann et al. (1988) Nature 332:323-329; and Presta (1992) Curr. Op. Struct. Biol.2:593-596, each of which is incorporated by reference in its entirety. [00126] The two or more different epitopes may be epitopes on the same antigen (e.g., a single IL-13) or on different antigens (e.g., different IL-13 molecules, or a IL-13 molecule and a non- IL-13 molecule). In some embodiments, a multi-specific antibody binds two different epitopes (i.e., a “bispecific antibody”). In some embodiments, a multi-specific antibody binds three different epitopes (i.e., a “trispecific antibody”). [00127] Anti-IL-13/TSLP or TSLPR antibodies can include those described herein such as the clones set forth in the drawings and/or tables. In some embodiments, the bispecific antibody comprises an alternative scaffold. In some embodiments, the bispecific antibody consists of an alternative scaffold. In some embodiments, the bispecific antibody consists essentially of an alternative scaffold. In some embodiments, the bispecific antibody comprises an antibody fragment. In some embodiments, the bispecific antibody consists of an ^{IPTS/128623945.3} 21 Attorney Docket No. PRG-013WO antibody fragment. In some embodiments, the bispecific antibody consists essentially of an antibody fragment. [00128] In some embodiments the bispecific antibodies are monoclonal antibodies. [00129] In some embodiments the bispecific antibodies are polyclonal antibodies. [00130] In some embodiments the bispecific antibodies are produced by hybridomas. In other embodiments, the bispecific antibodies are produced by recombinant cells engineered to express the desired variable and constant domains. [00131] In some embodiments the bispecific antibodies may be single chain antibodies or other antibody derivatives retaining the antigen specificity and the lower hinge region or a variant thereof. [00132] In some embodiments the bispecific antibodies may be polyfunctional antibodies, recombinant antibodies, human antibodies, humanized antibodies, fragments or variants thereof. In particular embodiments, the antibody fragment or a derivative thereof is selected from a Fab fragment, a Fab^2 fragment, a CDR, and scFv. [00133] In some embodiments, the bispecific antibodies are capable of forming an immune complex. For example, an immune complex can be a tumor cell covered by bispecific antibodies. [00134] For sequence comparison, typically one sequence acts as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters. Bispecific Antibody Structure [00135] The present application provides antibodies and compositions comprising a bispecific antibody that binds IL-13 and TSLP or TSLPR. The bispecific antibodies disclosed here can be of any structure known in the art. [00136] The bispecific antibody can take any format shown in but not limited to the examples below. One format is a bispecific antibody that includes a first immunoglobulin heavy chain, a second immunoglobulin heavy chain and an immunoglobulin light chain. The first immunoglobulin heavy chain includes a first Fc (hinge-CH2-CH3) domain, a first variable heavy chain domain and an optional first CH1 heavy chain domain. The immunoglobulin light chain includes a variable light chain domain and a constant light chain ^{IPTS/128623945.3} 22 Attorney Docket No. PRG-013WO domain; together with the first immunoglobulin heavy chain, the immunoglobulin light chain forms an antigen-binding site that binds IL-13. The second immunoglobulin heavy chain comprises a second Fc (hinge-CH2-CH3) domain, a second variable heavy chain domain and a second CH1 heavy chain domain that may pair with an immunoglobulin light chain identical to the one that pairs with the first immunoglobulin heavy chain, except that when immunoglobulin light chain is paired with the second immunoglobulin heavy chain, the resulting antigen binding site binds to TSLP or TSLPR. [00137] Another exemplary format, as shown in Figure 1, involves a bispecific antibody that includes two sets of immunoglobulin light chain and immunoglobulin heavy chain pairs (IgG-scFv form). The first light chain/heavy chain pair includes a first immunoglobulin heavy chain, a immunoglobulin light chain and an scFv. The first immunoglobulin heavy chain includes, from N- to C-terminus, a first VH1 domain, a first CH1 domain, a first Fc (hinge-CH2-CH3) domain fused via either a linker or an antibody hinge to a single chain Fv (scFv). A variety of linkers can be used for linking the scFv to the first Fc domain (linker H2) or between the VL2 and the VH2 of the scFv itself (see black line connecting VH2 and VL2 of scFv in inset of Figure 1, referred to as linker H3 herein). The immunoglobulin light chain includes, from N- to C-terminus, a first variable light chain (VL1) domain and a first constant light chain (CL) domain. The first light chain/heavy chain pair binds to a second light chain/heavy chain pair to form two Fab regions and an Fc domain comprising the first Fc domain and a second Fc domain from the second heavy chain. The C-terminus of each of the first Fc domain and the second Fc domain is linked to an scFv. The Fab region can bind to IL-13 and the scFv region can bind to TSLP or TSLPR, or the Fab region can bind to TSLP or TSLPR, and the scFv region can bind to IL-13. [00138] In some embodiments, the bispecific antibody is in the dual-variable domain immunoglobulin (DVD-Ig™) form, as shown in Figure 2. The DVD-Ig™ combines the target binding domains of two monoclonal antibodies via flexible, naturally occurring linkers, and yields a tetravalent IgG-like molecule. The DVD-Ig format includes two sets of immunoglobulin light chain and immunoglobulin heavy chain pairs. The first heavy chain includes, from N- to C-terminus, a first heavy chain variable domain (VH1), a second heavy chain variable domain (VH’), and a first heavy chain constant domain (CH1-CH2-CH3). In certain embodiments, the VH1 and VH’ domains are connected by a linker. The first light chain includes, from N- to C-terminus, a first light chain variable domain (VL1), a second ^{IPTS/128623945.3} 23 Attorney Docket No. PRG-013WO light chain variable domain (VL’), and a constant light chain domain (CL). In certain embodiments, the VL’ is fused to the VL2 by a linker. [00139] In some embodiments, the bispecific antibody is in the CrossMab format, as shown in Figure 3. The CrossMab form is a bispecific antibody that includes two sets of immunoglobulin light chain and immunoglobulin heavy chain pairs. The first light chain/heavy chain pair includes a first immunoglobulin heavy chain (HC1) with an Fc domain and an immunoglobulin light chain (LC1). The first immunoglobulin heavy chain includes, from N- to C-terminus, a first VH domain (VH1) and a first constant heavy chain domain (CH1-CH2-CH3), and the first immunoglobulin light chain includes, from N- to C- terminus, a first VL domain and a first constant light chain (CL) domain. The second immunoglobulin heavy chain (HC2) includes, from N- to C-terminus, a second VH domain, (VH2) and a second constant heavy chain domain (CL’-CH2-CH3), and the second immunoglobulin light chain (LC2) includes a second VL domain (VL2) and a second constant heavy chain (CH1’) domain. The CH3 domains for the HC1 and HC2 can, in some embodiments, comprise mutations to promote heterodimerization (e.g., knob and hole mutations). [00140] In some embodiments, the bispecific antibody is in the Triomab form, which is a trifunctional, bispecific antibody that maintains an IgG-like shape. This chimera consists of two half antibodies, each with one light and one heavy chain, that originate from two parental antibodies. [00141] In some embodiments, the bispecific antibody is the KiH Common Light Chain (LC) form, which involves the knobs-into-holes (KIHs) technology. The KIH involves engineering C_H3 domains to create either a “knob” or a “hole” in each heavy chain to promote heterodimerization. The concept behind the “Knobs-into-Holes (KiH)” Fc technology was to introduce a “knob” in one CH3 domain (CH3A) by substitution of a small residue with a bulky one (e.g., T366W_CH3A in EU numbering). To accommodate the “knob,” a complementary “hole” surface was created on the other CH3 domain (CH3B) by replacing the closest neighboring residues to the knob with smaller ones (e.g., T366S/L368A/Y407VCH3B). The “hole” mutation was optimized by structured-guided phage library screening (Atwell et al. (1997) “Stable heterodimers from remodeling the domain interface of a homodimer using a phage display library,” J. Mol. Biol.270(1):26–35). X-ray crystal structures of KiH Fc variants (Elliott et al. (2014) “Antiparallel conformation of knob and hole aglycosylated half-antibody homodimers is mediated by a CH2-CH3 hydrophobic interaction,” J. Mol. Biol.426(9):1947–57; Mimoto et al. (2014) “Crystal structure of a novel ^{IPTS/128623945.3} 24 Attorney Docket No. PRG-013WO asymmetrically engineered Fc variant with improved affinity for FcgammaRs,” Mol. Immunol.58(1):132–8) demonstrated that heterodimerization is thermodynamically favored by hydrophobic interactions driven by steric complementarity at the inter-CH3 domain core interface, whereas the knob–knob and the hole–hole interfaces do not favor homodimerization owing to steric hindrance and disruption of the favorable interactions, respectively. [00142] In some embodiments, the bispecific antibody is in the Orthogonal Fab interface (Ortho-Fab) form. In the ortho-Fab IgG approach (Lewis et al. (2014) “Generation of bispecific IgG antibodies by structure-based design of an orthogonal Fab interface,” Nat. Biotechnol.32(2):191–8), structure-based regional design introduces complementary mutations at the LC and HC_VH-CH1 interface in only one Fab, without any changes being made to the other Fab. [00143] In some embodiments, the bispecific antibody is in the 2-in-1 Ig format. In some embodiments, the bispecific antibody is in the ES form, which is a heterodimeric construct containing two different Fabs binding to targets 1 and target 2 fused to the Fc. Heterodimerization is ensured by electrostatic steering mutations in the Fc. In some embodiments, the bispecific antibody is in the ^^-Body form, which is an heterodimeric constructs with two different Fabs fused to Fc stabilized by heterodimerization mutations: Fab1 targeting antigen 1 contains kappa LC, while second Fab targeting antigen 2 contains lambda LC. [00144] In some embodiments, the bispecific antibody is in Fab Arm Exchange form (antibodies that exchange Fab arms by swapping a heavy chain and attached light chain (half- molecule) with a heavy-light chain pair from another molecule, which results in bispecific antibodies). In some embodiments, the bispecific antibody is in the SEED Body form. The strand-exchange engineered domain (SEED) platform was designed to generate asymmetric and bispecific antibody-like molecules, a capability that expands therapeutic applications of natural antibodies. This protein engineered platform is based on exchanging structurally related sequences of immunoglobulin within the conserved CH3 domains. The SEED design allows efficient generation of AG/GA heterodimers, while disfavoring homodimerization of AG and GA SEED CH3 domains. (Muda M. et al. (2011) Protein Eng. Des. Sel.24(5):447- 54). In some embodiments, the bispecific antibody is in the LuZ-Y form, in which a leucine zipper is used to induce heterodimerization of two different HCs. (Wranik et al. (2012) J. Biol. Chem.287:43331-9). ^{IPTS/128623945.3} 25 Attorney Docket No. PRG-013WO [00145] In some embodiments, the bispecific antibody is in the Cov-X-Body form. In bispecific CovX-Bodies, two different peptides are joined together using a branched azetidinone linker and fused to the scaffold antibody under mild conditions in a site-specific manner. Whereas the pharmacophores are responsible for functional activities, the antibody scaffold imparts long half-life and Ig-like distribution. The pharmacophores can be chemically optimized or replaced with other pharmacophores to generate optimized or unique bispecific antibodies. (Doppalapudi et al. (2010) PNAS 107(52): 22611-22616). [00146] In some embodiments, the bispecific antibody is is in an Oasc-Fab heterodimeric form that includes Fab binding to target 1, and scFab binding to target 2 fused to Fc. Heterodimerization is ensured by mutations in the Fc. [00147] In some embodiments, the bispecific antibody is in a DuetMab form, which is an heterodimeric construct containing two different Fabs binding to antigens 1 and 2, and Fc stabilized by heterodimerization mutations. Fab 1 and 2 contain differential S-S bridges that ensure correct LC and HC pairing. [00148] In some embodiments, the bispecific antibody is in a CrossmAb form, which is an heterodimeric construct with two different Fabs binding to targets 1 and 2, fused to Fc stabilized by heterodimerization. CL and CH1 domains and VH and VL domains are switched, e.g., CH1 is fused in-line with VL, while CL is fused in-line with VH. [00149] In some embodiments, the bispecific antibody is n a Fit-Ig form, which is an homodimeric constructs where Fab binding to antigen 2 is fused to the N terminus of HC of Fab that binds to antigen 1. The construct contains wild-type Fc. [00150] Table 2 lists peptide sequences of heavy chain variable domains and light chain variable domains that, in combination, can bind to IL13. Table 1a lists peptide sequences of heavy chain variable domains and light chain variable domains that, in combination, can bind to TSLP or TSLPR. Sequences of Bispecific Anti-IL-13/TSLP or TSLPR Antibodies VH Domains [00151] In some embodiments, a bispecific antibody provided herein comprises a first VH sequence selected from SEQ ID NOs: 1-32, 470, and 688 and a second VH sequence selected from SEQ ID NOs: 659-661, 682, 684, 686, and 688. In some embodiments, a bispecific antibody provided herein comprises a first VH sequence comprising SEQ ID NO: 3 and a second VH sequence selected from SEQ ID NOs: 659-661, 682, 684, 686, and 688. ^{IPTS/128623945.3} 26 Attorney Docket No. PRG-013WO [00152] In some embodiments, a bispecific antibody provided herein comprises a first VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VH sequence selected from SEQ ID NOs: 1-32, 470, and 688 and a second VH sequence selected from SEQ ID NOs: 659-661, 682, 684, 686, and 688. In some embodiments, a bispecific antibody provided herein comprises a first VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VH sequence comprising SEQ ID NO: 3 and a second VH sequence selected from SEQ ID NOs: 659-661, 682, 684, 686, and 688. In some embodiments, a bispecific antibody provided herein comprises a first VH sequence selected from SEQ ID NOs: 1-32, 470, and 688 and a second VH sequence selected from SEQ ID NOs: 659-661, 682, 684, 686, and 688, with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions. In some embodiments, a bispecific antibody provided herein comprises a first VH sequence comprising SEQ ID NO: 3 and a second VH sequence selected from SEQ ID NOs: 659-661, 682, 684, 686, and 688, with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the bispecific antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining bispecific antibodies. VL Domains [00153] In some embodiments, a bispecific antibody provided herein comprises a first VL sequence selected from SEQ ID NOs: 33-57, 471, and 687 and a second VL sequence selected from 662-664, 681, 683, and 685. In some embodiments, a bispecific antibody provided herein comprises a first VL sequence comprising SEQ ID NO: 39 and a second VL sequence selected from SEQ ID NOs: 662-664, 681, 683, and 685. [00154] In some embodiments, a bispecific antibody provided herein comprises a first VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VL sequence selected from SEQ ID NOs: 33-57 , 471, and 687 and a second VL sequence selected from SEQ ID NOs: 662-664, 681, 683, and 685. In some embodiments, a bispecific antibody provided herein comprises a first VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VL ^{IPTS/128623945.3} 27 Attorney Docket No. PRG-013WO sequence comprising SEQ ID NO: 39 and a second VL sequence selected from SEQ ID NOs: 662-664, 681, 683, and 685. In some embodiments, a bispecific antibody provided herein comprises a first VL sequence selected from SEQ ID NOs: 33-57, 471, and 687, and a second VL sequence selected from SEQ ID NOs: 662-664, 681, 683, and 685, with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions. In some embodiments, a bispecific antibody provided herein comprises a first VL sequence comprising SEQ ID NO: 39 and a second VL sequence selected from SEQ ID NOs: 662-664, 681, 683, and 685, with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions. Table 1a. Sequences of TSLP or TSLPR binding heavy chain variable regions (VH) and light chain variable regions (VL) binding regions

VH-VL Combinations [00155] In some embodiments, a bispecific antibody provided herein comprises a first VH sequence selected from SEQ ID NOs: 1-32, 470, and 688 and a second VH sequence selected from 659-661, 682, 684, 686, and 688; and a first VL sequence selected from SEQ ID NOs: 33-57, 471, and 687, and a second VL sequence selected from SEQ ID NOs: 662-664, 681, ^{IPTS/128623945.3} 28 Attorney Docket No. PRG-013WO 683, and 685. In some embodiments, a bispecific antibody provided herein comprises a first VH sequence comprising SEQ ID NOs: 3 and a second VH sequence selected from 659-661, 682, 684, 686, and 688; and a first VL sequence comprising SEQ ID NOs: 39 and a second VL sequence selected from 662-664, 681, 683, and 685. [00156] In certain aspects, any of SEQ ID NOs: 1-32, 470, and 688 can be combined with any of SEQ ID NOs: 33-57, 471, and 687, and any of SEQ ID NOs: 659-661, 682, 684, 686, and 688 can be combined with any of SEQ ID NOs: 662-664, 681, 683, and 685. [00157] In some embodiments, a bispecific antibody provided herein comprises a first VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VH sequence provided in selected from SEQ ID NOs: 1-32, 470, and 688 and a second VH sequence selected from SEQ ID NOs: 659-661, 682, 684, 686, and 688; and a first VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VL sequence provided in SEQ ID NOs: 33-57, 471, and 687 and a second VL sequence selected from SEQ ID NOs: 662-664, 681, 683, and 685. In some embodiments, a bispecific antibody provided herein comprises a first VH sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VH sequence comprising SEQ ID NO: 3 and a second VH sequence selected from SEQ ID NOs 659-661, 682, 684, 686, and 688; and a first VL sequence having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a VL sequence comprising SEQ ID NO: 39 and a second VL sequence selected from SEQ ID NOs: 662-664, 681, 683, and 685. In some embodiments, a bispecific antibody provided herein comprises a first VH sequence provided in SEQ ID NOs: 1-32, 470, and 688 and a second VH sequence selected from SEQ ID NOs: 659-661, 682, 684, 686, and 688, with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions; and a first VL sequence provided in SEQ ID NOs: 33-57, 471, and 687 and a second VL sequence selected from SEQ ID NOs: 662-664, 681, 683, and 685, with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions. In some embodiments, a bispecific antibody provided herein comprises a first VH sequence comprising SEQ ID NO: 3 and a second VH sequence selected from SEQ ID NOs: 659-661, 682, 684, 686, and 688, with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions; and a first VL sequence comprising SEQ ID NO: 39 and a second VL sequence selected from SEQ ID NOs: 662-664, 681, 683, and 685, with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in ^{IPTS/128623945.3} 29 Attorney Docket No. PRG-013WO this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies. [00158] In certain embodiments, the isolated bispecific antibody comprises a heavy chain variable domain comprising a framework region sequence selected from a sequence set forth in SEQ ID NOs: 198-229, 255-256, 258-259, 261-285, 311-315, 317-342, 368-369, 371-399, and 540-580. In certain embodiments, the isolated bispecific antibody comprises a heavy chain variable domain comprising 1, 2, 3, or 4 framework region sequences selected from a sequence set forth in SEQ ID NOs: 198-229, 255-256, 258-259, 261-285, 311-315, 317-342, 368-369, 371-399, and 540-580. [00159] In certain embodiments, the isolated bispecific antibody comprises a light chain variable domain comprising a framework region sequence selected from a sequence set forth in SEQ ID NOs: 230-231, 233-235, 239, 241-254, 286, 288, 290-291, 293, 296-310, 343-345, 347, 400-424, and 581-609. In certain embodiments, the isolated bispecific antibody comprises a light chain variable domain comprising 1, 2, 3, or 4 framework region sequences selected from a sequence set forth in SEQ ID NOs: 230-231, 233-235, 239, 241-254, 286, 288, 290-291, 293, 296-310, 343-345, 347, 400-424, and 581-609. [00160] In certain embodiments, the isolated bispecific antibody comprises a heavy chain variable domain comprising 1, 2, 3, or 4 framework region sequences selected from a sequence set forth in SEQ ID NOs: 198-229, 255-256, 258-259, 261-285, 311-315, 317-342, 368-369, 371-399, and 540-580, and comprises a light chain variable domain comprising 1, 2, 3, or 4 framework region sequences selected from a sequence set forth in SEQ ID NOs: 230- 231, 233-235, 239, 241-254, 286, 288, 290-291, 293, 296-310, 343-345, 347, 400-424, and 581-609. Table 2. Anti-interleukin (IL)-13 antibody VH-VL sequences

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*Names correspond with name in informal sequence listing [00161] In some embodiments, such a IgG4-SP HC constant domain has the sequence: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS RLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 427). [00162] In some embodiments, such a hIgG1-LALA-YTE HC constant domain has the sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP EAAGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 439). ^{IPTS/128623945.3} 44 Attorney Docket No. PRG-013WO [00163] In some embodiments, such a hIgG1-LAGA YTE HC constant domain has the sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP ELAGAPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 440). [00164] In some embodiments, such a hIgG1-LALA-LS HC constant domain has the sequence: [00165] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG (SEQ ID NO: 446). [00166] In some embodiments, such a IgG4-YTE HC constant domain has the sequence: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLG GPSVFLFPPKPKDTLYITREPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS RLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 457). [00167] In some embodiments, such a IgG4-LS HC constant domain has the sequence: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS RLTVDKSRWQEGNVFSCSVLHEALHSYTQKSLSLSLGK (SEQ ID NO: 460). [00168] In some embodiments, such a human kappa LC constant domain has the sequence: ^{IPTS/128623945.3} 45 Attorney Docket No. PRG-013WO RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 469). CDRs [00169] In some embodiments, a bispecific antibody provided herein comprises a first antigen binding site comprising three CDRs of a first VH domain selected from SEQ ID NOs: 1-32, 470, and 688, such as any of the CDRs listed in Table 3, Table 4, or Table 5, below, and a second antigen binding site comprising three CDRs of a second VH domain selected from SEQ ID NOs: 659-661, 682, 684, 686, and 688, such as any of the CDRs listed in Table 3a. In some embodiments, the CDRs are Exemplary CDRs. In some embodiments, the CDRs are Kabat CDRs. In some embodiments, the CDRs are Chothia CDRs. In some embodiments, the CDRs are IMGT CDRs. In some embodiments, the CDRs are AbM CDRs. In some embodiments, the CDRs are Contact CDRs. [00170] In some embodiments, the first antigen binding site comprises CDRs having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with a CDR-H1, CDR-H2, or CDR-H3 of SEQ ID NOs: 58-140, and the second antigen binding site comprises CDRs having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with a CDR-H1, CDR-H2, or CDR-H3 of SEQ ID NOs: 610-636. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies. [00171] In some embodiments, a bispecific antibody provided herein comprises a first antigen binding site comprising one to three CDRs of a VL domain of SEQ ID NOs: 33-57, 471, and 687, such as any of the CDRs listed in Table 6, Table 7, or Table 8, and a second antigen binding comprising one to three CDRs of a VL domain of SEQ ID NOs: 662-664, 681, 683, and 685, such as any of the CDRs listed in Table 3a, below. In some embodiments, a bispecific antibody provided herein comprises a first antigen binding site comprising three CDRs of a VL domain of SEQ ID NOs: 33-57, 471, and 687, such as any of the CDRs listed ^{IPTS/128623945.3} 46 Attorney Docket No. PRG-013WO in Table 6, Table 7, or Table 8, and a second antigen binding comprising three CDRs of a VL domain of SEQ ID NOs: 662-664, 681, 683, and 685, such as any of the CDRs listed in Table 3a, below. In some embodiments, the CDRs are Exemplary CDRs. In some embodiments, the CDRs are Kabat CDRs. In some embodiments, the CDRs are Chothia CDRs. In some embodiments, the CDRs are IMGT CDRs. In some embodiments, the CDRs are AbM CDRs. In some embodiments, the CDRs are Contact CDRs. [00172] In some embodiments, the first antigen binding site comprises CDRs having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with a CDR-L1, CDR-L2, or CDR-L3 of SEQ ID NOs: 141-188, and the second antigen binding site comprises CDRs having at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with a CDR-L1, CDR-L2, or CDR-L3 of SEQ ID NOs: 637-657. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies. [00173] In some embodiments, a bispecific antibody provided herein comprises a first antigen binding site comprising three CDRs of a VH domain selected from SEQ ID NOs: 1- 32, 470, and 688 and three CDRs of a VL domain of SEQ ID NOs: 33-57, 471, and 687, and a second antigen binding site comprising three CDRs of a VH domain selected from SEQ ID NOs: 659-661, 682, 684, 686, and 688 and three CDRs of a VL domain of SEQ ID NOs: 662- 664, 681, 683, and 685. In some embodiments, a bispecific antibody provided herein comprises a first antigen binding site comprising three CDRs of a VH domain comprising SEQ ID NO: 3 and three CDRs of a VL domain comprising SEQ ID NO: 39, and a second antigen binding site comprising three CDRs of a VH domain selected from SEQ ID NOs: 659-661, 682, 684, 686, and 688 and three CDRs of a VL domain of SEQ ID NOs: 662-664, 681, 683, and 685. In some embodiments, the CDRs are Exemplary CDRs. In some embodiments, the CDRs are Kabat CDRs. In some embodiments, the CDRs are Chothia CDRs. In some embodiments, the CDRs are IMGT CDRs. In some embodiments, the CDRs are AbM CDRs. In some embodiments, the CDRs are Contact CDRs. ^{IPTS/128623945.3} 47 Attorney Docket No. PRG-013WO [00174] In some embodiments, a bispecific antibody provided herein comprises a first antigen binding site comprising a CDR-H3 selected from SEQ ID NOs: 112-120 and 130- 140, a CDR-H2 of SEQ ID NOs: 100-111, a CDR-H1 selected from SEQ ID NOs: 58-99 and 121, a CDR-L3 selected from SEQ ID NOs: 165-172, a CDR-L2 selected from SEQ ID NOs: 153-158 and LAS, and a CDR-L1 selected from SEQ ID NOs: 141-144 and 149-152, and a second antigen binding site comprising a CDR-H3 selected from SEQ ID NOs: 628-636, a CDR-H2 of SEQ ID NOs: 619-627, a CDR-H1 selected from SEQ ID NOs: 610-618, a CDR- L3 selected from SEQ ID NOs: 652-657, a CDR-L2 selected from SEQ ID NOs: 646-651, and a CDR-L1 selected from SEQ ID NOs: 637-645. In some embodiments, a bispecific antibody provided herein comprises a first antigen binding site comprising a CDR-H3 selected from SEQ ID NOs: 112 and 130, a CDR-H2 of SEQ ID NOs: 100, 104, 108, a CDR- H1 selected from SEQ ID NOs: 58, 68, and 85, a CDR-L3 comprising SEQ ID NO: 165, a CDR-L2 selected from SEQ ID NOs: 153 and LAS, and a CDR-L1 selected from SEQ ID NOs: 141 and 589, and a second antigen binding site comprising a CDR-H3 selected from SEQ ID NOs: 628-636, a CDR-H2 of SEQ ID NOs: 619-627, a CDR-H1 selected from SEQ ID NOs: 610-618, a CDR-L3 selected from SEQ ID NOs: 652-657, a CDR-L2 selected from SEQ ID NOs: 646-651, and a CDR-L1 selected from SEQ ID NOs: 637-645. [00175] In some embodiments, the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H3 selected from SEQ ID NOs: 112 and 130, the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of SEQ ID NOs: 100, 104, 108, the CDR- H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 selected from SEQ ID NOs: 58, 68, and 85, the CDR-L3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR- L3 comprising SEQ ID NOs: 165, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L2 selected from SEQ ID NOs: 153 and LAS, and the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L1 selected from SEQ ID NOs: 141 and 589 in the first antigen binding site, and the CDR-H3 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H3 selected from SEQ ID NOs: 628-636, the CDR-H2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H2 of SEQ ID NOs: 619-627, the CDR-H1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-H1 selected from SEQ ID NOs: 610-618, the CDR-L3 has at least about 80%, 90%, ^{IPTS/128623945.3} 48 Attorney Docket No. PRG-013WO 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L3 comprising SEQ ID NOs: 652-657, the CDR-L2 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L2 selected from SEQ ID NOs: 646-651, and the CDR-L1 has at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with a CDR-L1 selected from SEQ ID NOs: 637-645 in the second antigen binding site. [00176] In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this disclosure are referred to herein as “variants” or “clones”. In some embodiments, such variants or clones are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants or cones are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies. [00177] In certain aspects, the antibodies disclosed herein do not include antibodies disclosed in U.S. Pat. No.9,067,994. ^{IPTS/128623945.3} 49 Attorney Docket No. PRG-013WO Q_:

3 1-₎ L QKW Q W Q W I_{( 2} n ^{R R} _I G^E RK i _{F L} VG^E RK L VG^E W^P _P A^A _L W^P _P G^G _L W^P _{P L} G^G _L _k u_{e :} l _Q _r e_t ^E _S ^D _I O N⁸ ₅ ⁸ ₅ ⁸ ₅ n_I-i_t R S S S n D YN YN YN A C ₁ A V A V A V .₃ _{e Q :} l O_{0 8 8} _b ^E ^a _S ^D _I N⁴ ₅ ⁹ ₁ ⁹ ₁ _T R^A LS Q ^T Q ^T 1 ^L _{T P} ^T _P ^S K^T _L ^V _{T L} ^L _Q ^G _P ^S _{P I} ^G A^S _{L S} ^{N L} _Q ^G _P ^S _{P I} ^G A^S _{L S} ^N ^{R V}G S^{VT S} _F G ^VG ^S V T _L ^VG E_L ^S V Q^T _L _{F Q E L Q} ^C _{T Q} ^S _E ^V _{L Q C} ^S _{F Q} ^{S V} _C ^S _F u^z _{i C} *_e ^k _i H M r - 0 _ Hma _b e^b _{a C} ⁰ _C V N _L m H H t_c u_{r d} t ₁ _s ⁿ _a ³ no ^, ₁- C^D ₂ _I ^, ₈ ₁ ² _{1 3 4} ^{IPTS/128623945.3} 50 Attorney Docket No. PRG-013WO

Q_: E _S ^D _I O N⁸ ₅ ⁸ ₅ ⁸ ₅ ⁸ ₅ R S S S S D 1 YN YN YN YN C A V A V A V A V Q_: E _S ^D _I O₀ N⁰ _{1 2 3} ₂ ⁰ ₂ ⁰ ₂ ⁰ ₂ Q^G 1 ^L _QP ^S _PLS ^N VE A^G _PVS VE KA^N A^G _PVS VG S A^{N G} _PL A^N ^R GK^S _L ^V _{T L} ^L ^S F ^V _E ^S _E ^V _L ^T _E ^C _{T F Q}GK^V _L ^L S K^S _{F Q}GKK _L ^L VK^S _QG R GK^LA_L S G ^V _E ^S _QK ^C _S ^V _E ^S _QK^S _S ^C _{S F} ^V _E ^S _E ^V _{L S} ^C _{S F} V A G V G G G *_e Hma ¹ _C ² _C ³ _C ⁴ _C V N H H H H t_c u , , r ^{5 -} _{d 4} ⁶ , 7 , 8 ^t _{s 1}, ₃ 3ⁿ _a ⁴ _{1 1}, ¹ ₁ ₂ , ² ₁, ³ n ⁰ ₁ ^{, - 1 2} ₂ ³ ₂ o ₁ , _{6 1 1 d 1 d 1 d} C^D _I ^, ₅ ⁰ ₂ ³ ₁ ⁴ ₁ ^, ₆ ⁿ _a ^, ₇ ⁿ _a ^, ₈ ⁿ _a ^{IPTS/128623945.3} 51 Attorney Docket No. PRG-013WO

S ^D _I N⁸ ₅

_{5 5 5} R S S S N S D 1 YN YN Y YN C A V A V A W A V Q_: E O₄ 0 ₅ 0 ₆ 0 ₇ _S ^D _I N _{2 2 2} ⁰ ₂ LGGLS Q ^S S N Q S N LGGLS N A^{N G} _PL ^{L GS} _PL 1 ^L _QG G^P _QR LA_L ^L _QP K^S _L ^V _T ^L _{S QP} K^S _L ^V _T ^L _S ^L _QG^P _QRA^L _S _{F E E} ^V _{L S} ^CS ^VG S^{VT C} G S^{VT C V}G S^VLA R^VS _F G ^V G _S ^CY G _S G _{E E L E T} G _{Q E L E T} G _{E E L} G _S G * ₁ _e m 5 _ Hma _C ⁶ _C ⁷ _C ⁵ _C V N H H H H t_c u , r ⁹ ^t _{s 1} ^, , - ₂ -₇ n ⁰ ₉ ³ ₁ ³ ₁ o ⁴ ₁ , ^, _{4 d 0 5} C^D _I ^, ₉ ⁴ ₂ ⁰ ₁ ⁿ _a ⁴ ₁ ⁵ ₂ ⁶ ₂ ⁰ ₁ ^{IPTS/128623945.3} 52 Attorney Docket No. PRG-013WO

S ^D _I N⁸ ₅

_{5 5 5} R S S S S D 1 YN YN YN YN C A V A V A V A V Q_: E _S ^D _I O_{8 9 0 1} N⁰ ₂ ⁰ ₂ ¹ ₂ ¹ ₂ LGGLS ^R LGGLS LGGLS LGGLS 1 ^L _QG^P _QRA_L ^L _QG^P _QRA^H _L ^L _QG^P _QRA^D _L ^L _QG^PRA^Y _L R _F ^VG E ^S _E ^VL L_S A^S _F G^C _S G ^VG E ^S _E ^VL L_S A^S _F G^C _S G ^VG E ^{S L} E ^V _{L S} A^S _F G_Q ^L _S A^S _F G^C _S G ^V _E ^S _E ^V _L G^C _S G * _{2 3 4 5} _e m_ m_ m_ m_ Hma ⁵ _C ⁵ _C ⁵ _C ⁵ _C V N H H H H t_c u_r ^t _s no ₆ 0 ₇ 0 _{8 9} C^D _{I 1 1} ⁰ ₁ ⁰ ₁ ^{IPTS/128623945.3} 53 Attorney Docket No. PRG-013WO

S ^D _I N⁸ ₅

_{5 6 6} R S S S S D 1 YN YN YN YN C A V R V K V H V Q_: E _S ^D _I O_{2 4 4 4} N¹ ₂ ⁰ ₂ ⁰ ₂ ⁰ ₂ LGGLS ^S LGGLS LGGLS LGGLS 1 ^L _QG^P _QRA_L ^L _QG^P _QRA^N _L ^L _QG^P _QRA^N _L ^L _QG^PRA^N _L R _F ^VG E ^S _E ^VL L_S A^S _F G^C _S G ^VG E ^S _E ^VL L_S A^S _F G^C _S G ^VG E ^{S L} E ^V _{L S} A^S _F G_Q ^L _S A^S _F G^C _S G ^V _E ^S _E ^V _L G^C _S G * _{6 7 8 9} _e m_ m_ m_ m_ Hma ⁵ _C ⁵ _C ⁵ _C ⁵ _C V N H H H H t_c u_r ^t _s no ₀ 1 ₁ 1 _{2 3} C^D _{I 1 1} ¹ ₁ ¹ ₁ ^{IPTS/128623945.3} 54 Attorney Docket No. PRG-013WO

S ^D _I N ₆

_{6 6 6} R S S S S D 1 ^YN ^YN ^YN YN C _Q V _E V _S V Y V Q_: E O₄ 0 _{4 4 4} _S ^D _I N ₂ ⁰ ₂ ⁰ ₂ ⁰ ₂ LGGLS 1 ^L _QG^P _QRA^N LGGLS ^N LGGLS ^N LGGLS ^N A_L ^L _QG^P _QRA A_L ^L _QG^P _QRA_L ^L _QG^P _QRA_L R _F ^VG E ^S _E ^VL L_S ^S _F G^C _S G ^VG E ^S _E ^VL L_S ^S _F G^C _S G ^VG E ^S _E ^VL L_S A^S _F G^C _S G ^VG E ^S _E ^VL L_S A^S _F G^C _S G 1 1 1 1 *_e m_ m_ m_ m_ Hma ⁵ _C ⁵ _C ⁵ _C ⁵ _C V N H ₀ H ₁ H ₂ H ₃ t_c u_r ^t _s no ₄ 1 ₅ 1 _{6 7} C^D _{I 1 1} ¹ ₁ ¹ ₁ ^{IPTS/128623945.3} 55 Attorney Docket No. PRG-013WO

S ^D _I N⁶ ₆

_{5 5 5} R ^S S S S D _EN YN YN YN C ₁ A V A V A V A V Q_: E O_{4 4 4 4} _S ^D _I N⁰ ₂ ⁰ ₂ ⁰ ₂ ⁰ ₂ LGGLS ^N LGGLS ^N LGGLS ^N LGGLS 1 ^L _QG^P _QRA_L ^LG^PRA A _{Q Q L} ^L _QG^P _QRA_L ^L _QG^P _QRA^N _L R _F ^VG E ^S _E ^VL L_S ^S _F G^C _S G ^VG E ^S _E ^VL L_S A^S _F G^C _S G ^VG E ^S _E ^VL L_S A^S _F G^C _S G ^VG E ^{S L} E ^V _{L S} A^S _F G^C _S G 1 1 1 1 *_e m_ m_ m_ m Ha ^{5 5 5} _ m _{C C C} ⁵ H _{4 C} V N H ₅ H ₆ H ₇ t_c u_r ^t _s no ₈ 1 ₉ 1 _{0 1} C^D _{I 1 1} ² ₁ ² ₁ ^{IPTS/128623945.3} 56 Attorney Docket No. PRG-013WO

S ^D _I N⁸ ₅

_{5 5 5} R S S S S D YN YN YN YN C ₁ A V A V A V A V Q_: E O_{4 4 4 4} _S ^D _I N⁰ ₂ ⁰ ₂ ⁰ ₂ ⁰ ₂ LGGLS ^N LGGLS ^N LGGLS ^N LGGLS 1 ^L _QG^P _QRA_L ^LG^PRA A _{Q Q L} ^L _QG^P _QRA_L ^L _QG^P _QRA^N _L R _F ^VG E ^S _E ^VL L_S ^S _F G^C _S G ^VG E ^S _E ^VL L_S A^S _F G^C _S G ^VG E ^S _E ^VL L_S A^S _F G^C _S G ^VG E ^{S L} E ^V _{L S} A^S _F G^C _S G 1 1 2 2 *_e m_ m_ m_ m Ha ^{5 5 5} _ m _{C C C} ⁵ H _{8 C} V N H ₉ H ₀ H ₁ t_c u_r ^t _s no ₂ 2 ₃ 2 _{4 5} C^D _{I 1 1} ² ₁ ² ₁ ^{IPTS/128623945.3} 57 Attorney Docket No. PRG-013WO S_S V _T D A Q_L Y

_F R D _T M A V G R D^V _T

M A V G

Q_: E _I O_{0 0} _S ^D N⁰ ₁ ⁰ ₁ ₂ GI S R _S GI S _S D ^W _I KN GY^K _L ^W _I KN GY^K _L C M D V A M D V A Q_: E O₂ 6 ₂ _S ^D _I N ₂ ⁶ ₂ Q 2 RKW Q RKW R V^G F_P ^E _L V^GE W A G^G _{L P L} W A G^G _L . Q_{: g} n^E i_t _S ^D _I O N⁸ ₅ ⁸ ₅ ^si _l e R S S _c D YN ⁿ _e C ₁ YN A V A V ^u _q e :_s _Q ^l _a E _S ^D _I O₄ N⁰ ₄ ₂ ⁰ ₂ ^m _r o_f LGGLS LGGLS ⁿ _i ₁ ^L _QG^P _QRA^N _L ^L _QG^P _QRA^N _L ⁿ _i _e R _F ^VG E ^S _E ^VL L_S A G^CS S_F G ^VG E ^S _E ^VL L_S A G^CS S_F G ^m _an 2 2 ^ht_i *_e m_ m w _ m ⁵ _d _C ⁵ _C n Ha V N H ₂ H ₄ ^o _p ^s _e t_c ^r _r u_r ^o _c t_s ^s _e no C^D ₆ _I ² ₇ ₁ ^{2 m} _a ₁ N * ^{IPTS/128623945.3} 58 Attorney Docket No. PRG-013WO Q_: E O_{8 9 9} _S ^D _I N⁶ ₃ ⁶ ₃ ⁶ ₃

_e ^l _r e_t ^E _S ^D _I O N⁷ ₆ ⁸ ₆ ⁸ ₆ n_I-i ₁ _t R L S Y LY LY n D _F ^S _FA ^S _FA A . C G^A _S G N G N 4 _e ^l _{b Q : 2 3} a^E T_S ^D _I O N⁴ ₅ ⁴ ₃ ₅ ⁴ ₅ R^AT _PL_S Q^GS _P ^T _I Q^GS _P ^T _I ₁ ^L _{T P} K^{T V L} _QP ^S _S ^L _QP ^S _S VG _L T _T A VG _L S V A VG _LV R _{F Q} ^S _E ^V _{L Q} ^C _{T Q} ^S _E ^V _{L Q} ^T _{C Q} ^S _E ^V _L ^S _Q ^T _C *_e i - k_i ^b M Ha ^r _a _ m _b ^{0 0} ^e m L ^u _{C C C} V N _z H H H c u_{r d} t_s ⁿ ₁ _a ³ n ₁ o D ^, ^I ₂ -₈ C _t ^, ₁ ² _{1 3 4} ^{IPTS/128623945.3} 59 Attorney Docket No. PRG-013WO

W^G _P ^EM W^AGL W^AGL 2 N^P _L _QG^G _L N_Q R_QW_I M N_QQW_I R _F ^V _S R _I ^V _S ^G _P ^E _L ^V _S R^G _P ^E _LM K W V G V G Q_: E _S ^D _I O N⁸ ₆ ⁸ ₆ ⁸ ₆ ₁ R L S Y L S Y LY D _FA _FA ^S _FA C G N G N G N Q_: E _{4 5 6} _S ^D _I O N⁴ ₅ ⁴ ₅ ⁴ ₅ Q^GS _PL_S VE^G _PV_S VE^G _PV_S ₁ ^L _QP K^{S V} _T ^L _QAKKA ^L _QAKKA G _L G F_{E E L E T E Q}K^V _S K G VK R^{VS VT C VS} V A^C _S ^V _E ^S _QK V^S _S ^C _S *_e Hma ¹ _C ² _C ³ _C V N H H H c u , , , r ⁵ s₁ -_{3 d 4} ^{6 7} ^t , ⁿ _a ⁴ ₁, ¹ ₁ ² no D ⁰ ₁ ³ ₁, ^, ₁ ₆ -₁ ¹ _{1 2} , ₂ _d ² ₁ C ^{I , 0 3 4 , ,} _d _{t 5 2 1 1 6} ⁿ _{a 7} ⁿ _a ^{IPTS/128623945.3} 60 Attorney Docket No. PRG-013WO

^R _F ^V _S V^G _P ^E _L G ^V _S V^G _P ^E _L G ^V _S V G^W _E M Q_: E _S ^D _I O N⁸ ₆ ⁸ ₆ ⁹ ₆ ₁ R L S Y L S Y ^L _S Y D _FA _FA GA C G N G N G N Q_: E O₇ N⁴ _{8 4} _S ^D _{I 5} ⁴ ₅ ⁴ ₅ V LG QG^G _PL_S LGGL_S Q A A ^G _P ^S _PL_S ₁ R ^LG^PR ^{L S V} ^R GK^L F ^V _E ^S _E ^V _{L S} A _QG_Q G^C _S ^V _E ^S _E ^VL L_S A _QGK G^C _S ^V _E ^S _E ^V _L _L ^T _T _E ^C _T *_e Hma ⁴ _C ⁵ _C ⁶ _C V N H H H c u , , r ^{8 ,} ₂ -^t _{s 1} ⁹ , ³ ₁, - ₇ 0³ ₁ ³ n ³ _{1 2} ⁴ _{1 9} ^, ₁ o D ^{I ,} _d , _{4 d 0} C _{t 8} ⁿ _a ^, ₉ ⁴ ₂ ⁰ ₁ ⁿ _a ⁴ ₁ ⁵ ₂ ^{IPTS/128623945.3} 61 Attorney Docket No. PRG-013WO

^R _F ^W _S V G^W _E Y ^V _S V^G _P ^E _L G ^V _S V^G _P ^E _L G Q_: E _S ^D _I O N⁹ ₆ ¹ ₇ ² ₇ ₁ R ^L _S Y ^L _S Y LY D GA YA ^S _FA C G N G N G R Q_: E O_{9 8 8} _S ^D _I N⁴ ₅ ⁴ ₅ ⁴ ₅ Q ^S L_S LGGL_S LGGL_S ₁ ^L _Q ^G _{P P} GK^S _L ^V _T ^L _QG G^P _QRA A ^L _QG G^P _QRA A R _F ^V _Q ^S _E ^V _L ^T _E ^C _T ^V _E ^S _E ^VL L_S G^C _S ^V _E ^{S L} E ^V _{L S} G^C _S *_e m m Ha ⁷ _ 5 _ m _{C C} ⁵ H _{1 C} V N H H ₂ c u_r ^t _s no D ^{I 6} ₅ 0 ₆ C _{t 2 1} ⁰ ₁ ^{IPTS/128623945.3} 62 Attorney Docket No. PRG-013WO

Q_: E _S ^D _I O N³ ₇ ⁴ ₇ ⁵ ₇ ₁ R LY LY LY D ^S _FA ^S _FA ^S _FA C G H G D G Y Q_: E _{8 8} _S ^D _I O N⁴ ₅ ⁴ ₈ ₅ ⁴ ₅ L 1 ^LGGL_S LGGL_S LGGL_S _QG^P _QRA ^L _QG^P _QRA ^L _QG^PRA G A G A G_Q A R _F ^V _E ^S _E ^VL L_S G^C _S ^V _E ^S _E ^VL L_S G^C _S ^{V L} E ^S _E ^V _{L S} G^C _S *_e m_ m_ m Ha ^{5 5} _ m _{C C} ⁵ _C V N H ₃ H ₄ H ₅ c u_r ^t _s no D _{7 8 9} C ^I _t ⁰ ₁ ⁰ ₁ ⁰ ₁ ^{IPTS/128623945.3} 63 Attorney Docket No. PRG-013WO

Q_: E _S ^D _I O N⁷ ₆ ⁶ ₇ ⁷ ₇ ₁ R LY LY LY D ^S _F ^{A S} _FR ^S _FK C G _S G N G N Q_: E _{8 8} _S ^D _I O N⁴ ₅ ⁴ ₈ ₅ ⁴ ₅ L 1 ^LGGL_S LGGL_S LGGL_S _QG^P _QRA ^L _QG^P _QRA ^L _QG^PRA G A G A G_Q A R _F ^V _E ^S _E ^VL L_S G^C _S ^V _E ^S _E ^VL L_S G^C _S ^{V L} E ^S _E ^V _{L S} G^C _S *_e m_ m_ m Ha ^{5 5} _ m _{C C} ⁵ _C V N H ₆ H ₇ H ₈ c u_r ^t _s no D _{0 1 2} C ^I _t ¹ ₁ ¹ ₁ ¹ ₁ ^{IPTS/128623945.3} 64 Attorney Docket No. PRG-013WO

Q_: E _S ^D _I O N⁸ ₇ ⁹ ₇ ⁰ ₈ ₁ R L D ^S _FY L H ^S _F ^Y L Q ^S _F ^Y _E C G N G N G N Q_: E _{8 8} _S ^D _I O N⁴ ₅ ⁴ ₈ ₅ ⁴ ₅ L 1 ^LGGL_S LGGL_S LGGL_S _QG G^P _QRA ^LG^PRA ^LG^PRA LA _QG_Q A _QG_Q A R _F ^V _E ^S _E ^V _{L S} G^C _S ^V _E ^S _E ^VL L_S G^C _S ^V _E ^{S L} E ^V _{L S} G^C _S *_e m_ m_ m_ Hma ⁵ _C ⁵ V N H_{9 C} ⁵ H⁰ _{1 C} H¹ ₁ c u_r ^t _s no D _{3 4 5} C ^I _t ¹ ₁ ¹ ₁ ¹ ₁ ^{IPTS/128623945.3} 65 Attorney Docket No. PRG-013WO

Q_: E _S ^D _I O N¹ ₈ ² ₈ ³ ₈ ₁ R L S_F ^Y L S ^S _FY L S_{F E} D Y A C G N G N G N Q_: E _{8 8} _S ^D _I O N⁴ ₅ ⁴ ₈ ₅ ⁴ ₅ L 1 ^LGGL_S LGGL_S LGGL_S _QG G^P _QRA ^LG^PRA ^LG^PRA LA _QG_Q A _QG_Q A R _F ^V _E ^S _E ^V _{L S} G^C _S ^V _E ^S _E ^VL L_S G^C _S ^V _E ^{S L} E ^V _{L S} G^C _S *_e m_ m m 5 _ _ Hma _C ⁵ V N H² _{1 C} ⁵ H³ _{1 C} H⁴ ₁ c u_r ^t _s no D _{6 7 8} C ^I _t ¹ ₁ ¹ ₁ ¹ ₁ ^{IPTS/128623945.3} 66 Attorney Docket No. PRG-013WO

Q_: E _S ^D _I O N⁸ ₆ ⁸ ₆ ⁸ ₆ ₁ R LY LY LY D ^S _FA ^S _FA ^S _FA C G N G N G N Q_: E _{8 8} _S ^D _I O N⁴ ₅ ⁴ ₈ ₅ ⁴ ₅ L 1 ^LGGL_S LGGL_S LGGL_S _QG G^P _QRA ^LG^PRA ^LG^PRA LA _QG_Q A _QG_Q A R _F ^V _E ^S _E ^V _{L S} G^C _S ^V _E ^S _E ^VL L_S G^C _S ^V _E ^{S L} E ^V _{L S} G^C _S *_e m_ m m 5 _ _ Hma _C ⁵ V N H⁵ _{1 C} ⁵ H⁶ _{1 C} H⁷ ₁ c u_r ^t _s no D _{9 0 1} C ^I _t ¹ ₁ ² ₁ ² ₁ ^{IPTS/128623945.3} 67 Attorney Docket No. PRG-013WO

Q_: E _S ^D _I O N⁸ ₆ ⁸ ₆ ⁸ ₆ ₁ R LY LY LY D ^S _FA ^S _FA ^S _FA C G N G N G N Q_: E _{8 8} _S ^D _I O N⁴ ₅ ⁴ ₈ ₅ ⁴ ₅ L 1 ^LGGL_S LGGL_S LGGL_S _QG G^P _QRA ^LG^PRA ^LG^PRA LA _QG_Q A _QG_Q A R _F ^V _E ^S _E ^V _{L S} G^C _S ^V _E ^S _E ^VL L_S G^C _S ^V _E ^{S L} E ^V _{L S} G^C _S *_e m_ m m 5 _ _ Hma _C ⁵ V N H⁸ _{1 C} ⁵ H⁹ _{1 C} H⁰ ₂ c u_r ^t _s no D _{2 3 4} C ^I _t ² ₁ ² ₁ ² ₁ ^{IPTS/128623945.3} 68 Attorney Docket No. PRG-013WO V_T V _S N D M D KT R N^{QL A} _T ^A _C K_{L S} N^DY T _L ^S _S Y _EY V M A V G GL KW_I G _P ^E _LM G ^. _g

ⁿi E _S ^D _I O _t N⁸ ₆ ⁸ ₆ ⁸ ₆ ^si _l ₁ ^e _c R L ⁿ _e D ^S _FY L A ^S _FY L A ^S _FY A ^u _q C G N G N G N ^e _s _: ^l _a _Q E O₈ 4 ₈ ^m ⁴ _{8 r} _S ^D _I N _{5 5} ⁴ ₅ ^o _f n _i LG _S L _S L _S ⁿ _i L GL GGL GGL G^PRA ^LG^PRA A _e _{1 Q Q Q Q} ^L _QG^PR R^VG ^LA G ^LA G_Q A ^m E ^S _E ^V _{L S} G _S ^V _{E E L S} ^L _{S a} _F ^{C S V} G^C _S ^V _E ^S _E ^V _L G^C _S n ht_i *_e m w _ m m 5 _ _ _dn Hma _C ⁵ _C ⁵ _C V N H¹ ₂ H² ₂ H⁴ ₂ ^o _p ^s _e c ^r _r u_r ^o _c t_s ^s _e no D C ^I ₅ 2 ₆ 2 ₇ ^m _a _{t 1 1} ² ₁ N * ^{IPTS/128623945.3} 69 Attorney Docket No. PRG-013WO Q_: E O₈ N⁶ _{9 9} _S ^D _{I 3} ⁶ ₃ ⁶ ₃

u_{e 2} W_P ^E W^P _L ^G ^l _L W^P _L ^G _L _r ^R ^e _F N _LM N t V^P _Q V_QG N R K W V_QG A A R K W n_I-i _{Q :} _t ^E O n _S ^D _I N⁴ ₈ ⁵ ₈ ⁵ ₈ A .₅ _{e 1} ^S _L ^{N N} ^l _b R ^S _{S L} S _{S L} S _S a D _FY _FY _FY T C G A G A G A Q_: E O₂ N⁴ _{3 3} _S ^D _{I 5} ⁴ ₅ ⁴ ₅ R^ATL_S Q^{GS T} _I Q^{GS T} _I ₁ ^L _{T P P} ^T _L ^{V L} _{QP P} ^S _S ^L _{QP P} ^S _S R _F ^VGK Q^S _E ^V _L ^T _T A Q^C _T ^VG _L _Q ^S _E ^V _L ^S V A Q^T _C ^VG _L _Q ^S _E ^V _L ^S V Q^T _C *_e i k_i Ha ^{r b} _{a C} _ m _b m ^{0 0} N H _{C C} V ^e _L ^u _z - H H M t_c u_{r d 1} t_s ⁿ _a ³ ₁ no ^{, -} C^D ₂ _I ^, ₈ ₁ ² _{1 3 4} ^{IPTS/128623945.3} 70 Attorney Docket No. PRG-013WO

^E _S ^D _I N⁶ ₅ ⁶ ₅ ⁶ ₅ R_I KL V^G _P M V^G _P M 2 W^GW W ^E _L W ^E _L R _P ^E F N^P _LM N^A _Q ^G ^G _L N^A _Q ^G ^G _L V _Q G G V R _Q W V R _Q W Q_: E _S ^D _I O N⁵ ₈ ⁵ ₈ ⁵ ₈ ₁ ^{N N N} R _L S _{S L} S _{S L} S _S D _FY _FY _FY C G A G A G A Q_: E _S ^D _I O_{4 5 6} N⁴ ₅ ⁴ ₅ ⁴ ₅ Q _S VE V_S VE _S ₁ ^L _Q ^G _P ^S _PL GK^S _L ^V _T ^L _QA^G _PKA GK ^LA^G _PV KA K^V _S K _QGK KVK R _F ^V _E ^S _E ^V _L ^T _E ^C _T ^V _E ^S _Q V A^C _S ^V _E ^S _Q V^S _S ^C _S *_e Hma ¹ _C ² _C ³ _C V N H H H t_c , , , u_r ⁵ ^t _{1 d 6} ⁶ ₁ ⁷ ₁ _s , n ⁰ ₁ ⁿ _a ³ ₁- , ¹ 3 ¹ ₂ , 2² ₂ o C^D _I ^, , 5 ⁰ ₂ ³ ₁ ₁ ^, _{d 1 d} ₆ ⁿ _a ^, ₇ ⁿ _a ^{IPTS/128623945.3} 71 Attorney Docket No. PRG-013WO

^E _S ^D _I N⁷ ₅ ⁷ ₅ ⁶ ₅ V^G _P M V^G _P M V^G ^A _P M 2 W ^E _L W ^E _L W ^E _L R _F N_QG^G _L N^A _QG^G _L N^P _QG^G _L V R K W V R K W V R K W Q_: E _S ^D _I O N⁵ ₈ ⁵ ₈ ⁶ ₈ ₁ ^{N N} N R _L S _{S L} S _S ^L _{S S} D _FY _FY GY C G A G A G A Q_: E _S ^D _I O_{7 8 4} N⁴ ₅ ⁴ ₅ ⁴ ₅ VG _S LGG _S Q _S ₁ ^L _QG^G _PL L KRA ^L _QG^P _QRA ^L _Q ^G _P ^S _PL K^{S V} ^R G ^L _S A G ^L _S A G _{L T} _F ^V _E ^S _E ^V _L G^C _S ^V _E ^S _E ^V _L G^C _S ^V _E ^S _E ^V _L ^T _E ^C _T *_e Hma ⁴ _C ⁵ _C ⁶ _C V N H H H t_c , , ^, ^u _r ⁸ ^t ₁ ⁹ ₁ - ₂ -₇ _s , ³ no ³ _{1 2} , 4₁ ⁰ ₉ ³ ₁ ,³ 4₁ ₀ C^D _I ^, _d ₈ ⁿ _a ^, , 9 ⁴ ₂ ⁰ _d ₁ ⁿ _a ⁴ ₁ ⁵ ₂ ^{IPTS/128623945.3} 72 Attorney Docket No. PRG-013WO

^E _S ^D _I N⁷ ₅ ⁷ ₅ ⁷ ₅ V^G Y V^G _P M V^G _P M 2 W_P ^{E E E} ^R N^P _L _{F Q}G^G _L W N^A _L _QG^G _L W N^A _L _QG^G _L W R K W V R K W V R K W Q_: E _S ^D _I O N⁶ ₈ ⁷ ₈ ⁸ ₈ ₁ N N R ^L _{S S} ^L _{S S} ^R _L S_{F S} D GY YY Y C G A G A G A Q_: E _S ^D _I O₉ N⁴ ₈ ₅ ⁴ ₈ ₅ ⁴ ₅ Q 1 ^L _Q ^G _P ^S _PL_S LGGL_S LGGL_S GK^S _L ^V _T ^L _QG G^P _QRA ^LG^PRA L L_{E T E E L S} A _QG_Q ^LA R _F ^V _Q ^S _E ^{VT C VS V} G^C _S ^V _E ^S _E ^V _{L S} G^C _S *_e 7 _ _ Hma _C ⁵ _{C 1} ⁵ _{C 2} V N H H m H m t_c u_r ^t _s no _{5 6} C^D _I ⁶ ₂ ⁰ ₁ ⁰ ₁ ^{IPTS/128623945.3} 73 Attorney Docket No. PRG-013WO

^E _S ^D _I N⁷ ₅ ⁷ ₅ ⁷ ₅ V^G _P ^EM V^G V^G L_P ^EM _P ^EM 2 W R _F N^A _QG^G _L W N^A _L _QG^G _L W N^A _L _QG^G _L V R K W V R K W V R K W Q_: E _S ^D _I O N⁹ ₈ ⁰ ₉ ¹ ₉ ₁ ^{H D Y} R _L S _{S L S L S} D _FY ^S _FY ^S _FY C G A G A G A Q_: E _I O_{8 8 8} _S ^D N⁴ ₅ ⁴ ₅ ⁴ ₅ LGGL_S LGG _S LGG _S ₁ ^L _QG G^P _QR ^LG^PL L A RA ^LG^PRA L_S A _QG_Q ^L _S A _QG_Q ^L _S A R _F ^V _E ^S _E ^V _L G^C _S ^V _E ^S _E ^V _L G^C _S ^V _E ^S _E ^V _L G^C _S *_e _ Hma ⁵ _ C₃ ⁵ _ C₄ ⁵ _C5 V N H m H m H m t_c u_r ^t _s no C^D _{7 8 9} _I ⁰ ₁ ⁰ ₁ ⁰ ₁ ^{IPTS/128623945.3} 74 Attorney Docket No. PRG-013WO

^E _S ^D _I N⁷ ₅ ⁷ ₅ ⁷ ₅ V^G _P ^EM V^G V^G L_P ^EM _P ^EM 2 W R _F N^A _QG^G _L W N^A _L _QG^G _L W N^A _L _QG^G _L V R K W V R K W V R K W Q_: E _S ^D _I O N⁴ ₈ ³ ₉ ⁴ ₉ ₁ ^{S N N} R _L S _{S L S L S} D _FY ^S _FY ^S _FY C G A G R G K Q_: E _I O_{8 8 8} _S ^D N⁴ ₅ ⁴ ₅ ⁴ ₅ LGGL_S LGG _S LGG _S ₁ ^L _QG G^P _QR ^LG^PL L A RA ^LG^PRA L_S A _QG_Q ^L _S A _QG_Q ^L _S A R _F ^V _E ^S _E ^V _L G^C _S ^V _E ^S _E ^V _L G^C _S ^V _E ^S _E ^V _L G^C _S *_e _ Hma ⁵ _ C₆ ⁵ _ C₇ ⁵ _C8 V N H m H m H m t_c u_r ^t _s no C^D _{0 1 2} _I ¹ ₁ ¹ ₁ ¹ ₁ ^{IPTS/128623945.3} 75 Attorney Docket No. PRG-013WO

^E _S ^D _I N⁷ ₅ ⁷ ₅ ⁷ ₅ V^G _P ^EM V^G V^G L_P ^EM _P ^EM 2 W R _F N^A _QG^G _L W N^A _L _QG^G _L W N^A _L _QG^G _L V R K W V R K W V R K W Q_: E _S ^D _I O N⁵ ₉ ⁶ ₉ ⁷ ₉ ₁ ^{N N N} R _L D ^S _{F S L} Y ^S _{F S L} C G H G^{Y S} _S _{Q F} G^Y _E _{Q :} E O₈ N⁴ _{8 8} _S ^D _{I 5} ⁴ ₅ ⁴ ₅ LGGL_S LGGL_S LGG _S ₁ ^L _QG^PR ^LG^PR ^L L A A G^PRA G_Q A _{Q Q} A _{Q Q} A R^L F ^V _E ^S _E ^V _{L S} G G^{C L} S ^V _E ^S _E ^V _{L S} G G^C _S ^V _E ^S _E ^VL L_S G^C _S *_e _ Ha ⁵ _ C₉ ⁵ _ m _C ⁰ ₁ ⁵ _C ¹ ₁ V N H m H m H m t_c u_r ^t _s no C^D _{3 4 5} _I ¹ ₁ ¹ ₁ ¹ ₁ ^{IPTS/128623945.3} 76 Attorney Docket No. PRG-013WO

^E _S ^D _I N⁷ ₅ ⁷ ₅ ⁷ ₅ V^G _P ^EM V^G M V^G L_P ^E _{L P} ^EM 2 W R _F N^A _QG^G _L W N^A _QG^G _L W N^A _L _QG^G _L V R K W V R K W V R K W Q_: E _S ^D _I O₅ N⁶ ₅ ⁸ ₉ ⁹ ₉ ₁ ^{N N N} R _L D ^S _{F S L} Y^S _{S L} S S_FY ^S _{F E} C G G Y G A Q_: E O₈ N⁴ _{8 8} _S ^D _{I 5} ⁴ ₅ ⁴ ₅ LGGL_S LGGL_S LGG _S ₁ ^L _QG^P _QR ^LG^PR ^L L A A G^PRA G A _QG_Q A _{Q Q} A R _F ^{V L} E ^S _E ^V _{L S} G^{C L} S ^V _E ^S _E ^V _{L S} G G^C _S ^V _E ^S _E ^VL L_S G^C _S *_e _ _ _ Hma ⁵ _C ² ₁ ⁵ _C ³ ₁ ⁵ _C ⁴ ₁ V N H m H m H m t_c u_r ^t _s no C^D _{6 7 8} _I ¹ ₁ ¹ ₁ ¹ ₁ ^{IPTS/128623945.3} 77 Attorney Docket No. PRG-013WO

^E _S ^D _I N⁷ ₅ ⁷ ₅ ⁷ ₅ V^G _P ^EM V^G V^G L_P ^EM _P ^EM 2 W R _F N^A _QG^G _L W N^A _L _QG^G _L W N^A _L _QG^G _L V R K W V R K W V R K W Q_: E _S ^D _I O N⁵ ₈ ⁵ ₈ ⁵ ₈ ₁ ^{N N N} R _L S _{S L} S _{S L S} D _FY _FY ^S _FY C G A G A G A Q_: E O₈ N⁴ _{8 8} _S ^D _{I 5} ⁴ ₅ ⁴ ₅ LGGL_S LGGL_S LGG _S ₁ ^L _QG^P _QR ^LG^PR ^L L A A G^PRA G A _QG_Q A _{Q Q} A R _F ^{V L} E ^S _E ^V _{L S} G^{C L} S ^V _E ^S _E ^V _{L S} G G^C _S ^V _E ^S _E ^VL L_S G^C _S *_e _ _ _ Hma ⁵ _C ⁵ ₁ ⁵ _C ⁶ ₁ ⁵ _C ⁷ ₁ V N H m H m H m t_c u_r ^t _s no C^D _{9 0 1} _I ¹ ₁ ² ₁ ² ₁ ^{IPTS/128623945.3} 78 Attorney Docket No. PRG-013WO

^E _S ^D _I N⁷ ₅ ⁷ ₅ ⁷ ₅ V^G _P ^EM V^G V^G L_P ^EM _P ^EM 2 W R _F N^A _QG^G _L W N^A _L _QG^G _L W N^A _L _QG^G _L V R K W V R K W V R K W Q_: E _S ^D _I O N⁵ ₈ ⁵ ₈ ⁵ ₈ ₁ ^{N N N} R _L S _{S L} S _{S L S} D _FY _FY ^S _FY C G A G A G A Q_: E O₈ N⁴ _{8 8} _S ^D _{I 5} ⁴ ₅ ⁴ ₅ LGGL_S LGGL_S LGG _S ₁ ^L _QG^P _QR ^LG^PR ^L L A A G^PRA G A _QG_Q A _{Q Q} A R _F ^{V L} E ^S _E ^V _{L S} G^{C L} S ^V _E ^S _E ^V _{L S} G G^C _S ^V _E ^S _E ^VL L_S G^C _S *_e _ _ _ Hma ⁵ _C ⁸ ₁ ⁵ _C ⁹ ₁ ⁵ _C ⁰ ₂ V N H m H m H m t_c u_r ^t _s no C^D _{2 3 4} _I ² ₁ ² ₁ ² ₁ ^{IPTS/128623945.3} 79 Attorney Docket No. PRG-013WO

^E _S ^D _I N⁷ ₅ ⁷ ₅ ⁷ ₅ V^G _P V^{G G} ^AEM _P ^EM V_P ^EM 2 W _L ^G W _L ^G W _L ^. _g R _F N_QG_L N^A R K W V_QG_L N^A R K W V_QG^G _L ⁿi V R K W _t ^si _l _{Q :} ^e ^E _S ^D _I O _c N⁵ ₈ ⁵ ₈ ⁵ ₈ ⁿ _e u_q e_s ₁ ^N _L ^{N N l} _a R D ^S _{F S L} Y ^S _{F S L} Y ^S _{F S} Y ^m _r C G A G A G A ^o _f n _i _{Q :} ⁿ _i E _S ^D _I O₈ N⁴ ₈ ₅ ⁴ ₈ ₅ ⁴ _{5 e} m_an L 1 ^LGG _S LGG _S LGG _S _QG^PL L L QRA A ^L _QG^P _QRA A ^L _QG^P _QRA ^ht_i A w R G ^L F ^V _E ^S _E ^V _{L S} G G^{C L} S ^V _E ^S _E ^V _{L S} G G^{C L} S ^V _E ^S _E ^V _{L S} G^C _{S d}n o_p *_e ^s _ _e 5 _ 5 _ 5^r _r Hma _C ¹ _{2 C} ² _{2 C} ⁴ ₂ ^o _c V N H m H m H m ^s _e t_c ^m ^u _a _r N t_s * no C^D _{5 6 7} _I ² ₁ ² ₁ ² ₁ ^{IPTS/128623945.3} 80 Attorney Docket No. PRG-013WO Q_: E _S ^D _I O_{0 1 0} N⁰ ₄ ⁰ ₄ ⁰ ₄

₎ LI₍ n ^Q ⁱ _Q ^P _QI ^P k₂ ^{L Q} I Q_Q ^{L Q} _QK^L _L Y^G _L Y^G _L ^GK ^u _e ^R _P ^K _P ^K Y_{P P} ^Y ^l _F W K _P Y W K _P Y W K A _I _r e_t n _{Q :} _{I 1 1} -i ^E t_S ^D _I O N⁴ ₁ ₁ ⁴ ₁ ⁴ ₁ n A . GH G 6₁ S S H S GH K^Y _S M ^KY _S M ^KY _S M e R _S l^F b D AD_{S S} AD^F _{S S} AD^F _S a C R V N R V N R V N T Q_: E _S ^D _I O₁ N⁸ ₀ ₅ ³ ₁ ₂ ³ ₂ DS _C S ^L S 1 M^{P R T} _{L S} A ^T _L ^V _S V R _F ^V _{I S} ^V D^Q _{S E}N^{I A} T ^L _S ^G _{L T} ^V _{I P}V A N^{S RC} _S ^S _PAR^C _T _Q ^A _{L Q} G^I _T ^Q _I D^S _Q ^S _LD G^I _T *_e i k^b Lm _i a ^r _{b a 0 1} V N ^e m^C L ^u _{z L} - ^C _L ^C _L t_c u_{r d} t ₁ _s ⁿ _a ³ ₄ no ^, ₁- _d D _{2 8} ⁿ I ^, ₁ ² _a C _{1 3} -^{IPTS/128623945.3} 81 Attorney Docket No. PRG-013WO

F W K A^Y _I W K A^Y _I W K^Q _P Y W K _P Y Q_: E O₁ 4 ₁ 4 _{1 1} _S ^D _I N _{1 1} ⁴ ₁ ⁴ ₁ ₁ S GH S GH S GH S GH R ^K _S ^Y _S M A ^{F K} _S ^Y _S M A ^{F K} _S ^Y _S M A ^{F K} _S ^Y _S M D D_S D_S D_S AD^F _S C R V N R V N R V N R V N Q_: E O₁ 3 ₃ 3 ₄ 3 ₅ _S ^D _I N _{2 2 2} ³ ₂ S 1 ^T _LS S^V P_S V R^{C T}T L ^AP P_S A^{C T} _LS L^P P_TA ^T _LS ^L ^D _S _P A V _C R _F ^Q _I D^S A _T V V^R Q^S _LD G^I _T ^I _E ^S _Q ^S _{L E S} G^L _T ^V _I D^S V Q^{P P} L_{E C} G^S _I ^V _I D^S _Q ^AR L_EN G^I _T *_e _Lma ₂ C _{3 4 5} V N _L ^C _L ^C _L ^C _L t_c u_r ^t _s n ⁴ o ₁- C^D ₉ _I - ₅ ⁰ ₁ - -^{IPTS/128623945.3} 82 Attorney Docket No. PRG-013WO

F W K A^Y _I W K A^Y _I W K^Q _P Y W K _P Y Q_: E _S ^D _I O₁ N⁴ _{1 1 1} ₁ ⁴ ₁ ⁴ ₁ ⁴ ₁ ₁ S GH S GH S GH S GH R ^K _S ^Y _S M F^K _S ^Y _S M ^K _S ^Y _S M ^K _S ^Y _S M D AD_S AD^F _S AD^F _S AD^F _S C R V N R V N R V N R V N Q_: E _S ^D _I O₁ N³ ₃ ₂ ³ ₄ ₂ ³ ₉ ₂ ³ ₂ TS ^VV T^{P T}S ^PS ^TS ^P 1_L ^S _S R^{C T} _L ^A _S A^C _L ^L _TA _L ^A _S A R _F ^Q _{I P}A _T V_PV^R _S ^V _PV^P _C ^V _PV^RC _S D^S _Q ^S _LD G^I _T ^I _E ^S _Q ^S _{L E} G^L _{T I} D^S _Q ^P _{L E} G^S _{I I} D^S _Q ^A _{L E} G^I _T *_e _Lma ₆ C _{7 8 9} V N _L ^C _L ^C _L ^C _L t_c , u_r ⁰ ^t ₉ ^, ₇ -₂ _s , n ⁹ o ₁ ² ₁ ³ - - ₁ ⁴ ₂ C ⁵ ₅ 0 _{d 6} - D _{I 1 1} ⁿ _a ³ ₁ ⁰ ₂ - ⁵ ₂ ^{IPTS/128623945.3} 83 Attorney Docket No. PRG-013WO

Q_: E O₂ 4 _{3 4 1} _S ^D _I N ₁ ⁴ ₁ ⁴ ₁ ⁴ ₁ ₁ S G S GH S GH S GH R ^Q _S ^NH S ^L _F ^K _S ^Y _S M ^K _S ^Y _S M ^K _S ^Y _S M D ADN AD^R _S AD^S _S AD^F _S C R V N R V N R V N R V N Q_: E _S ^D _I O₉ N³ _{1 1 1} ₂ ³ ₂ ³ ₂ ³ ₂ TS ^P _S ^TS ^VV ^TS ^VV ^TS ^V 1_L ^A A _L ^S _S R _F ^V _{I P}V^RC _S ^Q _PAR^C _L _T ^S _{P S} AR^C _L _T ^S _{P S} V AR^C _T D^S _Q ^A _{L E} G^I _{T I} D^S _Q ^S _LD G^I _T ^Q _I D^S _Q ^S _LD G^I _T ^Q _I D^S _Q ^S _LD G^I _T *_e _Lm ⁰ m m m a ₁ ^_ ₆ ^{_ _} V N ^C _L ^C ₆ _{L 1} ^C ₆ _{L 2} ^C _{L 3} t_c u_r ^t _s no C^D _I ⁶ ₂ ¹ ₉ ² ₉ ³ ₉ ^{IPTS/128623945.3} 84 Attorney Docket No. PRG-013WO

Q_: E O₁ 4 _{1 1 1} _S ^D _I N ₁ ⁴ ₁ ⁴ ₁ ⁴ ₁ ₁ S GH S GH S GH S GH R ^K _S ^Y _S M ^KYM ^KYM ^KYM A ^F _{S S S S S S} D D_S AD^F _S AD^F _S AD^F _S C R V N R V N R V N R V N Q_: E O_{1 1 1 1} _S ^D _I N³ ₂ ³ ₂ ³ ₂ ³ ₂ ₁ ^T _LS S^V _S V ^TS ^VV ^TS ^VV ^TS ^VV R _F ^Q _{I P}AR^C _L _T ^S _S Q_PAR^C _L _T ^S _S Q_PAR^C _L _T ^S _{P S} AR^C _T D^S _Q ^S _LD G^I _{T I} D^S _Q ^S _LD G^I _{T I} D^S _Q ^S _LD G^I _T ^Q _I D^S _Q ^S _LD G^I _T *_e m Lm ^_ m m m a ₆ ^_ ₆ ^{_ _} V N ^C _{L 4} ^C ₆ _{L 5} ^C ₆ _{L 6} ^C _{L 7} t_c u_r ^t _s no C^D _I ⁴ ₉ ⁵ ₉ ⁶ ₉ ⁷ ₉ ^{IPTS/128623945.3} 85 Attorney Docket No. PRG-013WO

Q_: E O₁ 4 ₁ 4 ₁ 4 ₁ _S ^D _I N _{1 1 1} ⁴ ₁ ₁ S GH S GH S GH S GH R ^KY _S M ^KY _S M ^KY _S M ^KY _S M D _S AD^F _{S S} AD^F _{S S} AD^F _{S S} AD^F _S C R V N R V N R V N R V N Q_: E _{1 1} _S ^D _I O N³ ₂ ³ ₁ ₂ ³ ₁ ₂ ³ ₂ ₁ ^T _LS S^V _S V ^T _LS ^V _S V ^T _LS ^V _S V ^TS ^V _S V R _F ^Q _{I P}AR D^C _T ^S ^Q _{I P}AR D^C _T ^S ^Q _{I P}AR D^C _L _T ^S ^Q _{I P}AR D^C _T D^S _Q ^S _L G^I _T D^S _Q ^S _L G^I _T D^S _Q ^S _L G^I _T D^S _Q ^S _L G^I _T *_e m m m m Lm ^_ a ₆ ^_ V N ^C ₆ ^_ ₆ ^_ ₆ _{L 8} ^C _{L 9} ^C _L ⁰ ₁ ^C _L ¹ ₁ t_c u_r ^t ₀ _{s d} ⁴ n ⁿ ₁ o _a - C^D _I ⁸ _{7 0 1} ₉ ³ ₁ ⁹ ₉ ⁰ ₁ ⁰ ₁ ^{IPTS/128623945.3} 86 Attorney Docket No. PRG-013WO

C _{L L L L L L} _{Q :} E _S ^D _I O₈ N⁸ ₈ ₂ ⁸ ₈ ₂ ⁸ ₂ Q^{L Q L Q L} 2_QK_L K_L K_L G^K _{Q Q} R Y F_{P P} Y^G W K A^Y _{I P} ^K _P Y^GK W K A^Y _{I P P} W K A^Y _I ^. _g ni_t _{Q :} ^si _l E _S ^D _I O_{1 1 1} N⁴ ₁ ⁴ ₁ ⁴ ₁ ^e _c n_e ₁ S GH S GH S GH ^u _q R ^K D _S ^Y _S M AD^{F K} S_S ^Y _S M AD^{F K} S_S ^Y _S M ^e _s AD^F _S ^l _a C R V N R V N R V N ^m _r _{Q :} ^o _f E _S ^D _I O_{1 1 1} ⁿ _i N³ ₂ ³ ₂ ³ ₂ ⁿ _i _e ₁ ^T _LS S^V _S V ^T _LS ^V _S V ^T _LS ^V _S V ^m _an R _F ^Q _{I P} S AR^C _T ^S Q^S _LD^I _T ^Q _{I P} S AR^C _T ^S Q^S _LD^{I Q} _{I P} S AR^C ^S D_T ^{I h}t_i D G D G _T D _{Q L} G _T w d *_e m _ m _ m n _^o _p _Lma ₆ N ^C ₆ C ₆ ^s ^C _e V _L ² _{1 L} ³ _{1 L} ⁴ ₁ ^r _r o^t _c _c ^s ^u _e _r ^t _s ^m _a n _{2 3} N o ^{0 0} ₄ 0 * C^D _{I 1 1 1} ^{IPTS/128623945.3} 87 Attorney Docket No. PRG-013WO Q_: E O_{0 1 0} _S ^D _I N⁰ ₄ ⁰ ₄ ⁰ ₄

-₎ LI_{( 2} Q^G Y_P ^K ^{i K} _P ^Y Q^G _P ^KY Q^G _P ^K _P ^Y ^P _I Y _{P I} Y A_I n k ^R _F W _{Q Q} ^L _L W^K _Q ^P _Q ^L _L W^K _Q K^L _L u_e ^l _{r Q :} e_t ^E O_{1 1 1} n _S ^D _I N⁴ ₁ ⁴ ₁ ⁴ ₁ _I-i_{t 1} R ^K _S S S S S N ^K _S S ^K _S S n H NH NH D DG D D A . A 7 ^{V M} A^VG Y^M A R^VG C R _S Y _F R _{S F S} Y^M _F _e ^l _b a _{Q :} _T ^E _S ^D _I O₁ N⁸ _{0 1} ₅ ³ ₂ ³ ₂ ₁ M^P _S S GT L^PAGT L^{P S} GT R _F ^V _I D^QL T_S ^L _S A D V^R _C _E ^N _I ^V _{I S} N^QL T_S ^L _S A A V^R _C _Q ^S _I ^Q _{I S} D^Q _L ^VV_C _T ^S _{S S} R A D^T _I u *_e ^z _i ^C ^k _{i L} r - Lma _b V N ^{e b} _{a 0} _L m ^C ₁ _L ^C _L t_c u_{r d 1} t_s ⁿ _a ³ ₄ no ^, ₁- _d D _{2 8} ⁿ I ^, ₁ ² _a C _{1 3} - ^{IPTS/128623945.3} 88 Attorney Docket No. PRG-013WO

Q_: E O_{1 1 1 1} _S ^D _I N⁴ ₁ ⁴ ₁ ⁴ ₁ ⁴ ₁ ₁ S S S S S R ^K _S NH ^K _S S NH ^K _S S NH ^K _S S AD D NH D ^VG D D M A G A G A G C R _S Y _F R^V _S Y^M _F R^V _S Y^M _F R^V _S Y^M _F _{Q :} E _S ^D _I O₁ N³ ₃ ₂ ³ ₄ ₂ ³ ₅ ₂ ³ ₂ ₁ L^P GT S GT G^I _S AGT R _F ^Q _{I S} ^S D^Q _L ^VV_C L^P V_S ^{L P}A_CL^P T ^S _{S S} R A D^T _I ^I _E ^Q _{T T S} A V^R _E ^S _L ^V _{I S} ^P D^Q _L ^PA L^P T ^S _{L T} V^P _E ^C _S ^V _{I S} D^QL T_S ^L _S A D V^R _C _E ^N _I *_e _Lma _{2 3} V N ^C _L ^C ₄ _L ^C ₅ _L ^C _L t_c u_r ^t _s n ⁴ o _{9 1}- C^D _I - ₅ ⁰ ₁ - - ^{IPTS/128623945.3} 89 Attorney Docket No. PRG-013WO

Q_: E O₁ 4 ₁ 4 ₁ 4 ₁ _S ^D _I N _{1 1 1} ⁴ ₁ ₁ ^KS S S S S S S S R _S DNH ^K _S DNH ^K _S DNH ^K _S DNH D A C R^V _S G Y^M _F A R^V _S G Y^M _F A R^V _S G Y^M _F A R^V _S G Y^M _F _{Q :} E _{1 3} _S ^D _I O N³ ₂ ³ ₄ ₂ ³ ₉ ₂ ³ ₂ GT ^I 1 L^P _S ^S L^PS GT L^{P P}G_S L^PAGT R^Q _I ^Q _L ^V _S V R_C V_S I^QL _T ^P _S A R_{C S} S^V _{I L} ^P _TA ^V _{I S} ^L _S ^P _S A_C _F D _T ^S _S A D^T _{I E T} A V _{E L} D^Q _T ^S _L V^P _E ^C _S D^Q _T A V^R _E ^S _I *_e _Lma _{6 7 8} V N ^C ₉ _L ^C _L ^C _L ^C _L t_c , u_r ⁰ ₉ ^, ^t _s , ₇ -² ₂ ₁ ³ n ⁹ o ₁- -_{5 1} ⁴ ₂ C^D _I ⁵ ₁ ⁰ _{d 6} ₁ ⁿ _a ³ - 1 ⁰ ₂ - ⁵ ₂ ^{IPTS/128623945.3} 90 Attorney Docket No. PRG-013WO

_Q E O₂ 4 ₃ 4 _{4 1} _S ^D _I N _{1 1} ⁴ ₁ ⁴ ₁ ₁ S S S S S S S R ^Q _S H DN ^K _S NH ^K _S NH ^K _S NH D A^VG^L _F AD VGM AD VG ADG C R _S N N R _S Y R R _S Y^M _S R^V _S Y^M _F _{Q :} E _S ^D _I O₉ N³ _{1 1 1} ₂ ³ ₂ ³ ₂ ³ ₂ ₁ L^PAGT L^P GT L GT L GT R _F ^V _{I S} ^L _S ^P _S A_C ^Q _{I S} ^S _L ^V _S V_C ^P ^Q _{I S} ^S _L ^VV_C ^P ^Q _S ^S _L ^VV_C D^Q _T A V^R _E ^S _I D^Q _T ^S _S R A D^T _I D^Q _T ^S _{S S} R A D^T _{I I} D^Q _T ^S _{S S} R A D^T _I * _{1 2 3} _e ⁰ m _ m _ m Lma ₁ C _{6 6} ^_ ₆ V N _L ^C _L ^C _L ^C _L t_c u_r ^t _s no C^D _I ⁶ ₂ ¹ ₉ ² ₉ ³ ₉ ^{IPTS/128623945.3} 91 Attorney Docket No. PRG-013WO

_Q E O₁ 4 ₁ 4 _{1 1} _S ^D _I N _{1 1} ⁴ ₁ ⁴ ₁ ₁ S S S S S S S R ^K _S DNH ^K _S NH ^K _S NH ^K _S S NH D A^VG D M A^VG D M A^VG D M A G C R _S Y _F R _S Y _F R _S Y _F R^V _S Y^M _F _{Q :} E _S ^D _I O₁ N³ _{1 1 1} ₂ ³ ₂ ³ ₂ ³ ₂ ₁ L^P GT L^P GT L^P GT L^P GT R _F ^Q _{I S} ^S _L ^V _S V_C ^Q _{I S} ^S _L ^V _S V_C ^Q _{I S} ^S _L ^V _S V_C ^Q _{I S} ^S _L ^VV_C D^Q _T ^S _S R A D^T _I D^Q _T ^S _S R A D^T _I D^Q _T ^S _S R A D^T _I D^Q _T ^S _{S S} R A D^T _I * _{4 5 6 7} _e m _ m _ m m Lma _{6 6} ^_ ₆ ^_ ₆ V N ^C _L ^C _L ^C _L ^C _L t_c u_r ^t _s no C^D _I ⁴ ₉ ⁵ ₉ ⁶ ₉ ⁷ ₉ ^{IPTS/128623945.3} 92 Attorney Docket No. PRG-013WO

_Q E _S ^D _I O₁ N⁴ ₁ ₁ ⁴ ₁ ₁ ⁴ ₁ ₁ ⁴ ₁ ₁ ^KS S ^KS S S S S S R _S DNH _S DNH ^K _S DNH ^K _S DNH D A C R^V _S G Y^M _F A R^V _S G Y^M _F A R^V _S G Y^M _F A R^V _S G Y^M _F _{Q :} E _{1 1} _S ^D _I O N³ ₂ ³ ₁ ₂ ³ ₁ ₂ ³ ₂ ₁ L^P _S ^S GT T T V L^{P S} G L^{P S} G L^{P S} GT R^Q _I ^Q _L ^V _S R_C ^Q _{I S} Q_L ^V _S V R_C ^Q _{I S} Q_L ^V _S V R_C ^Q _{I S L} ^V _S V R_C _F D _T ^S _S A D^T _I D _T ^S _S A D^T _I D _T ^S _S A D^T _I D^Q _T ^S _S A D^T _I * _{8 9} 1 1 e m Lm ^_ m _ m _ m _ a ₆ C ₆ C ₆ C ₆ V N _{L L L 0} ^C _{L 1} t_c u_{r 4} t_{s d} ⁴ ₁ n ⁿ o _a - C^D _I ⁸ _{7 0 1} ₉ ³ ₁ ⁹ ₉ ⁰ ₁ ⁰ ₁ ^{IPTS/128623945.3} 93 Attorney Docket No. PRG-013WO

Q_: E _S ^D _I O_{8 8 8} N⁸ ₂ ⁸ ₂ ⁸ ₂ ₂ Q^G ^R Y_P ^K _P ^Y _I Q^G _P ^K _P ^Y _I Q^G _P ^K _P ^Y _I _F W^K _QA K^L Y L W^K _QA K^L Y L W^K _QA K^L _L ^. _g _{Q : 1 1} ⁿi_t E _S ^D _I O N⁴ ₁ ₁ ⁴ ₁ ⁴ ₁ ^si _l e_c ₁ R ^K D _S S S ^{K n} _e _S S S ^K _S S S u ADNH DNH DNH C R^V _S G Y^M _F A R^V _S G A G _q Y^M _F R^V _S Y^M _F ^e _s l _a _{Q : 1} ^m _r E _S ^D _I O N³ _{1 1} ₂ ³ ₂ ³ ₂ ^o _f n _i T T ⁿ _i ₁ L^P _S ^S G L V L^P _S ^S G L V L^P _S ^S GT V _e R _F ^Q _I D^{Q V} T ^S _{S S} R_C ^Q _I ^V _S R_C ^Q _{I L} ^V _S R_C A D^T _I D^Q _T ^S _S A D^T _I D^Q _T ^S _S A D^T _I ^m _an ht 1 1 1 _i *_e m _ m _ m w _ _dn Lma ₆ V N ^C ₆ _{L 2} ^C ₆ _{L 3} ^C _{L 4} ^o _p ^s _e ^r ^t _r _c ^o ^u _c _r ^t _s ^s _e no ^m C^D _{2 3 4 a} _I ⁰ ₁ ⁰ ₁ ⁰ ₁ N * ^{IPTS/128623945.3} 94 Attorney Docket No. PRG-013WO Q_: E O₀ N⁰ ₁ 0 _{0 0} _S ^D _{I 4 4} ⁰ ₄ ⁰ ₄

u_e ^l _{Q :} _r e_t ^E _S ^D _I O₉ N⁴ ₉ ₁ ⁴ ₉ ₁ ⁴ ₉ ₁ ⁴ ₁ n_i-i S t₁ D^F _S S D^F _S S D^F _S S D^F _S n R ^V _S N ^VN ^VN ^VN A D G . _S G _S G _S G 8 C K Y K Y K Y K Y e^l _b a _{Q :} _T ^E _S ^D _I O₂ N⁸ _{3 4 4} ₅ ⁸ ₅ ⁸ ₅ ⁸ ₅ T^L _S E GC QAQ^C _S Q^S D^C Q^S D^C 1 M^D N P ^L _S ^I _{T S} ^T _L ^L _S G A^{L I} _{T S} ^T _{L L} S G_T _S ^VI _{T S} ^T _{L L} S G_T _S ^VI _{T S} R _F ^V _I D^S _Q ^V _S AA ^V _{I S} AA ^Q _{I S} VA ^Q _{I S} VA R R N^P _S V R R D^P _S A R R D^P _S A R R *_e i k_i ^b _a _Lma ^r _b m^C _{L 0 1 2} V N ^e _L ^u _z - ^C _L ^C _L ^C _L c u_{r d} t_s ⁿ ₁ _a ³ ₄ no D ^, ₁ C ^I ₂ -_{8 d} n_{a 9} _t ^, ₁ ² _{1 3} - - ₅ ^{IPTS/128623945.3} 95 Attorney Docket No. PRG-013WO

₂ WK^R _P WK^Q _P WK^K _P WK^K _P ^R H _F M^Q _Q ^AY Q^I H L M^Q _L ^S Y Q^I H L M^Q _Q ^PY Q^I H L M^Q _QAY K^I _L _{Q :} ^E _{9 9 9 9} _S ^D _I O N⁴ ₁ ⁴ ₁ ⁴ ₁ ⁴ ₁ ₁ S ^F _S S ^F _S S ^F _S S ^F _SR DN D D D V_S ^V _S N ^V _S N ^V _S ND G G G G C K Y K Y K Y K Y _{Q :} ^E O_{5 6 7 4} _S ^D _I N⁸ ₅ ⁸ ₅ ⁸ ₅ ⁸ ₅ QS ^RR Q ^P QA^RR Q T^L _E ^C _S ^{T P} _{L E}R C^{T L} _{E C} ^{T S} _LD^C G_T _{1 L T}G L _L ^S _LG P _{S L S} GN^I _L ^S _S ^I _{T S} ^R VA^P _F ^I _E ^P _{S S T S} ^V _{I T} ^I _{S S} ^V _I D^L _{S T S} ^Q _I ^V V A A D^P _S V A A D^P _S ^P _{S S} VA V A A D A R R *_e _Lma ₃ V N ^C _{4 5 6} _L ^C _L ^C _L ^C _L c ^u _r -^t _sn ⁴ , 9 _{5 d 6} 0₁ ⁿ _a ³ ₁o D ₁ C ^I - ₁- , ^, ₇ -₂ _t ⁰ ₁ - - ⁵ ₁ ⁰ ₉ ² ₁ ³ ₁ ^{IPTS/128623945.3} 96 Attorney Docket No. PRG-013WO

₂ WK^R _P WK^Q _P WK^K K^K ^R H^QAY^I H^QS Y^I H^Q _P PY W Q_P PY _F M _{Q Q L} M _{L Q L} M _{Q Q} ^I _L ^H _{L Q Q} ^I _L _{Q :} ^E O₉ 4 ₉ 4 ₉ 4 ₀ _S ^D _I N _{1 1 1} ⁵ ₁ ₁ S ^F _S S ^F _S S ^F _S S D D D DNR N N N VND ^V _S G ^V _S G ^V _S G K Y K Y K Y ^S _QG C N _F _{Q :} ^E O₅ 8 _{6 8 8} _S ^D _I N ₅ ⁸ ₅ ⁸ ₅ ⁸ ₅ QS ^R _ER Q^{P P} _ER QA^R _ER QA^R _ER ₁ ^T _L ^L _TG^C _S ^T _{L L}G^{C T} _L ^L _S G^{C T L} _S ^C ^R V _F ^I A E ^{P P} S_S ^L _{T S} ^V _I ^S _L ^P _S _T ^I _{S S} ^V _I A^P _S _S ^I _L G T_S ^V _I A^P _S _S ^I _{T S} V A A D^P _S V A A D^P _S V A A D^P _S V A A *_e _Lma ₇ V N ^C _{8 9} ⁰ ₁ _L ^C _L ^C _L ^C _L c ^u _r ^t _s n ⁴ o D ₂ C ^I - t ⁰ ₂ - ⁵ ₂ ⁶ ₂ ^{IPTS/128623945.3} 97 Attorney Docket No. PRG-013WO

₂ WK^K _P WK^K _P WK^K _P W ^K _P ^R H^QAY^I H^QAY^I H^QAR HK QA_F _F M _Q K _L M _Q K _L M _Q K^I _L M _Q K^I _L _{Q :} ^E ₁ _S ^D _I O N⁵ ₂ ₁ ⁵ ₉ ₁ ⁴ ₉ ₁ ⁴ ₁ ₁ S S S S DS D^S _S ^F _S ^F _SR N N D D V^{V V}N ^VND _S G _S G _S G _S G C K Y R K Y K Y K Y _{Q :} ^E _S ^D _I O₄ N⁸ ₄ ₅ ⁸ ₄ ₅ ⁸ ₄ ₅ ⁸ ₅ Q Q Q Q ₁ ^T _L ^S _LD^C ^Q _I ^S G_T ^S S ^VI _LD^C _T ^S _LD^C _T ^S _LD^C _T _{T S} ^T _L Q_I ^S G S ^VI _{T S} ^T _L Q^S G S ^VI _{T S} ^T _L Q^S G S ^VI _{T S} ^R _F ^P _{S S} VA ^P _{S S} VA _I ^P _S VA _I ^P _S VA D A R R D A R R D _S A R R D _S A R R *_e m m _Lm ^{_ _} m m a ₆ V N ^C ₆ ^_ ₆ ^_ ₆ _{L 1} ^C _{L 2} ^C _{L 3} ^C _{L 4}c ^u _r ^t _s no D C ^I _t ¹ ₉ ² ₉ ³ ₉ ⁴ ₉ ^{IPTS/128623945.3} 98 Attorney Docket No. PRG-013WO

₂ WK^K _P WK^K _P WK^K _P WK^K _P ^R H _F M^Q _QAY K^I H L M^Q _QAY K^I H L M^Q _QAY K^I H L M^Q _QAY K^I _L _{Q :} ^E O_{9 9 9} N^{4 4} ₉ _S ^D _{I 1 1} ⁴ ₁ ⁴ ₁ ₁ S D^F _S S D^F _S S D^F _S S D^F _SR ^V _S N ^V _S N ^V _S N ^VND G G G _S G C K Y K Y K Y K Y _{Q :} ^E _S ^D _I O_{4 4 4 4} N⁸ ₅ ⁸ ₅ ⁸ ₅ ⁸ ₅ Q T^S _LD^C Q ^C Q ^C Q ^C G_T ^{T S} _LD G_T ^{T S} _LD G_T ^{T S} _LD_T _{1 L} ^{S I} _{T S L} ^{S I} _{T S L} ^{S I} _{T S L} ^S G^I _{T S} ^R _F ^Q _{I S} ^V _S VA ^Q _{I S} ^V _S ^Q _{I S} ^V _S ^Q _{I S} ^V _S D^P _S A R R D^P _S VA A ^P _S VA ^P _S VA R R D A R R D A R R *_e m _Lm ^_ m m m a ₆ ^_ ₆ ^{_ _} V N ^C _{6 6} _{L 5} ^C _{L 6} ^C _{L 7} ^C _{L 8}c ^u _r ^t ₄ _{s d} ⁴n ⁿo D C ^I _{a 1}-₇ _t ⁵ ₉ ⁶ ₉ ⁷ ₉ ⁸ ₉ ³ ₁ ^{IPTS/128623945.3} 99 Attorney Docket No. PRG-013WO

₂ WK^K _P WK^K _P WK^K _P WK^K _P ^R H _F M^Q _QAY K^I H L M^Q _QAY K^I H L M^Q _QAY K^I H L M^Q _QAY K^I _L _{Q :} ^E O_{9 9 9} N⁴ ₁ ⁴ ₉ _S ^D _{I 1} ⁴ ₁ ⁴ ₁ ₁ S D^F _S S D^F _S S S D^F _S D^F _SR ^V _S N ^V _S N ^VN ^VND G G _S G _S G C K Y K Y K Y K Y _{Q :} ^E _{4 4 4 4} _S ^D _I O N⁸ ₅ ⁸ ₅ ⁸ ₅ ⁸ ₅ Q ^C Q ^C Q ^C Q ^C ₁ ^T _L ^S _LD Q_I ^S G_T _S ^VI S_{T S} ^T _L ^S _LD Q_I ^S G_T _S ^VI S_{T S} ^T _L ^S _LD Q_I ^S G_T _S ^VI S_{T S} ^T _L ^S _LD Q_I ^S G_T _S ^VI S_{T S} ^R _F D^P _S VA A R R ^P _S VA ^P _S VA ^P _S VA D A R R D A R R D A R R *_e m _ m _ m _ m_Lma ₆ V N ^C ₆ C ₆ ^_ ^C ₆ _{L 9 L} ⁰ _{1 L} ¹ ₁ ^C _L ² ₁c ^u _r ^t _s no D C ^{I 9} _{0 1 2} _{t 9} ⁰ ₁ ⁰ ₁ ⁰ ₁ ^{IPTS/128623945.3} 100 Attorney Docket No. PRG-013WO

VS F S ^I ^GG L^A ^{S DS} _{S F} VGFL C ^{G A} ^{S DS} _{S F C} ¹ L L N^V _{S P}H _{3 S} ^{R E} _{F T} R^GI _T ^D _EY_S E _{F T} R^GI _T ^D _EY R N^{K Q} S_S ^V _S _{F L} N^S _{P S} G^L _T ^P _Q ^Y _{T L} N^S _{P S} G^L _T ^P _Q ^Y D G A T C G G H R^I _S ₂ ORD _{S S g Q}N_{7 8} C ^A n L ^A _L ⁱ _r ^E ^e _S ^D _I ³ ₆ ³ ₆ _b _S

N ^s _{i l c} GD T D ₁ S ^N ^F S ^{F e} _c ⁿ _e u ₂ DA Y ^L _{L Q}R D_S D_S ⁿ ^V _{e q} H Y N S N ^VN ^{u e} _S R HG D ^W _I KK^P _I YD G _S G C K Y K Y _q e_s R C V N V^F _T ^D _S l D _{Q : a} _{4 4} ^m C O ^E _S ^D _I O N⁸ _r ₅ ⁸ ₅ ^o _f ^R _QN_{9 0} n _P _i L ^E _S ^D _I ¹ ₆ ² ₆ Q ^S ₁ ^T _L ^S _LD^C G_T Q^S D^C ^{I T} _{L L}G_T ⁿ _{i T} I _e -i_{t 1} H M M^R _F ^Q _I ^S _S ^V _{S T S} ^S VA ^Q _{I S} ^V _{S T S} VA ^m _a n R G A D^P _S A R R D^P _S A R R n A D Y ht_{i r} ^Y o C _T H D H *_e m m w _P O _Lm ^_ a ₆ ^_ V N ^C _{6 d} L n ^S L ³ ₁ ^C _L ⁴ ₁ ^o _{p T Q}N_{0 1} s_e -_i ^E _S ^D _I ¹ ₆ ¹ ₆c ^r _t _r n A ^u _r ^o _c . ^y ^t _s ^{s a} _do ^y _d ^y o _don _{e 3}o D _e ^bi_t ^bi_t ^bi_t C ^I _{3 4} _t ⁰ ₁ ⁰ ₁ ^m _a ^l N _b n n n A A ₁ A ₂ * ^a _T ^{IPTS/128623945.3} 101 Attorney Docket No. PRG-013WO

^R _S GY ^a _i H _E ^D _F ^H N h_t R W^A _TD^R _{S T} H ^Q _PV A^L _I G^{Y G} _E ^D _F _E ^D _F ^o G R _E ^DM_S G _h D _EVMG D R _FR C ^Q _P H G V G D^M _I C A W A A^H _TAKG D V R C O O 0_QN_{1 2 Q}N 3^E ₃ E _{4 5 6} _{6 S} ^D _I ³ ₆ ³ ₆ ³ _{6 S} ^D _I ³ ₆ ³ ₆ ³ ₆ AS D ^{N N} _S ^S _T G G_S A _{2 S} G G _T G A A ₂ G ^{D G} S Y G H D D L^G H D _{L S}G ^Y _TK R Y _{L S} R Y ^L _P ^G _S K^V _S D G V C W ^P _I ^G _S D C ^W _I K ^I _F V _T O O 1_QN _QN 2^E ₂ 2 ₃ 2 ₄ 2^E ₅ 2 _{6 7} _{6 S} ^D _{I 6 6 6 S} ^D _{I 6} ² ₆ ² ₆ ₁ M H ^R _F T F_I ^R ₁ _F H ^R _F T F_I ^R A _F A R ^{T T} R ^TG S _S D _F H C G^Y _TYY_F D _F YY ^T _FA G D G^S _S C G^Y _T G D G^S _S O O 2_QN_{3 Q}N 1₆ ^E _S ^D _I ¹ ₄ ₆ ¹ ₅ ₆ ¹ ₆ ^E ₆ _S ^D _I ¹ ₇ ₆ ¹ ₈ ₆ ¹ ₆ y_d ^y _d ^y _d ^y _d ^{y y} _d ^{y y y} o o _d o _{d d d} bi_t ^b o o o o o o i_t ^bi_t ^bi ^bi ^bi_t ^bi ^bi ^bi n n _{t t t t t} A ₃ n A A ₁ n A ₂ n A ₃ n n A A ₁ n A ₂ n A ₃ ^{IPTS/128623945.3} 102 Attorney Docket No. PRG-013WO [00178] In some embodiments, the format of the bispecific antibodies disclosed herein have any of the bispecific antibody formats described herein. In some embodiments, the format of the bispecific antibodies disclosed herein is selected from the group consisting of (a) Single chain Fv (scFv), (b) tandem scFv format of bispecific T cell engager (BiTE), (c) disulfide-linked diabody format of dual affinity retargeting (DART) bsAb, (d) tandem diabody (TandAb), (e) conventional immunoglobulin G (IgG), (f) IgGs with additional binding units such as scFv, (g) dual variable domain immunoglobulin (DVD-Ig), (h) quadromab bsAb, (i) knobs-into-holes (KiH) bsAb with a common light chain, (j) KiH- CrossMabCH1-CL, and (k) bsAb by controlled Fab arm exchange (cFAE). (see Shim et al. (2020) Biomolecules 26;10(3):360.) In some embodiments, the format of the bispecific antibodies disclosed herein is selected from the group consisting of IgG-scFv and DVD-Ig. In some embodiments, the format of the bispecific antibodies disclosed herein is IgG-scFv. In some embodiments, the format of the bispecific antibodies disclosed herein is DVD-Ig. In some embodiments, the format of the bispecific antibodies disclosed herein is kiH- CrossMabCH1-CL. [00179] In some embodiments, a Heavy Chain/Chain A construct in Table 11a or Table 11b with an alias and construct number is combined with the Light Chain/Chain B construct having the same alias and construct number in Table 12a or Table 12b. [00180] The abbreviations used to describe the first VH sequence, heavy chain constant region, first VL sequence, second VH sequence, linkers, and light chain constant domain in the paragraphs below correspond to the abbreviations used in column titles of Table 11a, Table 11b, Table 12a, and Table 12b. [00181] In some embodiments, the format of the bispecific antibodies disclosed herein is IgG-scFv. In some embodiments, the bispecific format comprises a first VH sequence (VH1) comprising SEQ ID NO: 3, a heavy chain constant region (CH(1-3)) comprising SEQ ID NO: 439, and linker H2 comprising SEQ ID NO: 665, a first VL sequence (VL1) comprising SEQ ID NO: 662, a linker H3 comprising SEQ ID NO: 666, a second VH (VH2) sequence comprising SEQ ID NO: 659, a second VL sequence (VL2) comprising SEQ ID NO: 39, and a light chain constant domain (CL) comprising SEQ ID NO: 469. ^{IPTS/128623945.3} 103 Attorney Docket No. PRG-013WO [00182] In some embodiments, the bispecific format comprises a first VH sequence (VH1) comprising SEQ ID NO: 3, a heavy chain constant region (CH(1-3)) comprising SEQ ID NO: 439, and linker H2 comprising SEQ ID NO: 665, a first VL sequence (VL2) comprising SEQ ID NO: 663, a linker H3 comprising SEQ ID NO: 666, a second VH (VH2) sequence comprising SEQ ID NO: 660, a second VL sequence (VL1) comprising SEQ ID NO: 39, and a light chain constant domain (CL) comprising SEQ ID NO: 469. [00183] In some embodiments, the bispecific format comprises a first VH sequence (VH1) comprising SEQ ID NO: 3, a heavy chain constant region (CH(1-3)) comprising SEQ ID NO: 439, and linker H2 comprising SEQ ID NO: 665, a first VL sequence (VL2) comprising SEQ ID NO: 664, a linker H3 comprising SEQ ID NO: 666, a second VH (VH2) sequence comprising SEQ ID NO: 661, a second VL sequence (VL1) comprising SEQ ID NO: 39, and a light chain constant domain (CL) comprising SEQ ID NO: 469. [00184] In some embodiments, the bispecific format comprises a first VH sequence (VH1) comprising SEQ ID NO: 659, a heavy chain constant region (CH(1-3)) comprising SEQ ID NO: 439, and linker H2 comprising SEQ ID NO: 665, a first VL sequence (VL2) comprising SEQ ID NO: 39, a linker H3 comprising SEQ ID NO: 666, a second VH (VH2) sequence comprising SEQ ID NO: 3, a second VL sequence (VL1) comprising SEQ ID NO: 662, and a light chain constant domain (CL) comprising SEQ ID NO: 669. [00185] In some embodiments, the bispecific format comprises a first VH sequence (VH1) comprising SEQ ID NO: 660, a heavy chain constant region (CH(1-3)) comprising SEQ ID NO: 439, and linker H2 comprising SEQ ID NO: 665, a first VL sequence (VL2) comprising SEQ ID NO: 39, a linker H3 comprising SEQ ID NO: 666, a second VH (VH2) sequence comprising SEQ ID NO: 3, a second VL sequence (VL1) comprising SEQ ID NO: 663, and a light chain constant domain (CL) comprising SEQ ID NO: 469. [00186] In some embodiments, the bispecific format comprises a first VH sequence (VH1) comprising SEQ ID NO: 661, a heavy chain constant region (CH(1-3)) comprising SEQ ID NO: 439, and linker H2 comprising SEQ ID NO: 665, a first VL sequence (VL2) comprising SEQ ID NO: 39, a linker H3 comprising SEQ ID NO: 666, a second VH (VH2) sequence comprising SEQ ID NO: 3, a second VL sequence (VL1) comprising SEQ ID NO: 664, and a light chain constant domain (CL) comprising SEQ ID NO: 469. ^{IPTS/128623945.3} 104 Attorney Docket No. PRG-013WO [00187] In some embodiments, the bispecific format comprises a first VH sequence (VL’) comprising SEQ ID NO: 3, a linker comprising SEQ ID NO: 667, a second VH sequence (VL1) comprising SEQ ID NO: LAS, a heavy chain constant region (CH(1-3)) comprising SEQ ID NO: 439, and a first VL sequence (VL’) comprising SEQ ID NO: 39, a linker comprising SEQ ID NO: 668, a second VL (VL1) sequence comprising SEQ ID NO: 662, and a light chain constant domain (CL) comprising SEQ ID NO: 469. [00188] In some embodiments, the bispecific format comprises a first VH sequence (VL’) comprising SEQ ID NO: 3, a linker comprising SEQ ID NO: 667, a second VH sequence (VL1) comprising SEQ ID NO: 660, and a heavy chain constant region (CH(1-3)) comprising SEQ ID NO: 439, and a first VL sequence (VL’) comprising SEQ ID NO: 39, a linker comprising SEQ ID NO: 668, a second VL (VL1) sequence comprising SEQ ID NO: 663, and a light chain constant domain (CL) comprising SEQ ID NO: 469. [00189] In some embodiments, the bispecific format comprises a first VH sequence (VL’) comprising SEQ ID NO: 3, a linker comprising SEQ ID NO: 667, a second VH sequence (VL1) comprising SEQ ID NO: 661, a heavy chain constant region (CH(1-3)) comprising SEQ ID NO: 439, and a first VL sequence (VL’) comprising SEQ ID NO: 39, a linker comprising SEQ ID NO: 668, a second VL (VL1) sequence comprising SEQ ID NO: 664, and a light chain constant domain (CL) comprising SEQ ID NO: 469.. [00190] In some embodiments, the bispecific format comprises a first VH sequence (VL’) comprising SEQ ID NO: 659, a linker comprising SEQ ID NO: 667, a second VH sequence (VL1) comprising SEQ ID NO: 3, a heavy chain constant region (CH(1-3)) comprising SEQ ID NO: 439, and a first VL sequence (VL’) comprising SEQ ID NO: 662, a linker comprising SEQ ID NO: 668, a second VL (VL1) sequence comprising SEQ ID NO:39, and a light chain constant domain (CL) comprising SEQ ID NO: 469. [00191] In some embodiments, the bispecific format comprises a first VH sequence (VL’) comprising SEQ ID NO: 660, a linker comprising SEQ ID NO: 667, a second VH sequence (VL1) comprising SEQ ID NO: 3, a heavy chain constant region (CH(1-3)) comprising SEQ ID NO: 439, and a first VL sequence (VL’) comprising SEQ ID NO: 663, a linker comprising SEQ ID NO: 668, a second VL (VL1) sequence comprising SEQ ID NO: 39, and a light chain constant domain (CL) comprising SEQ ID NO: 469. ^{IPTS/128623945.3} 105 Attorney Docket No. PRG-013WO [00192] In some embodiments, the bispecific format comprises a first VH sequence (VL’) comprising SEQ ID NO: 661, a linker comprising SEQ ID NO: 667, a second VH sequence (VL1) comprising SEQ ID NO: 3, a heavy chain constant region (CH(1-3)) comprising SEQ ID NO: 439, and a first VL sequence (VL’) comprising SEQ ID NO: 664, a linker comprising SEQ ID NO: 668, a second VL (VL1) sequence comprising SEQ ID NO: 39, and a light chain constant domain (CL) comprising SEQ ID NO: 469. [00193] In some embodiments, the format of the bispecific antibodies disclosed herein is IgG-scFv. In some embodiments, the bispecific format comprises a first VH sequence (VH1) comprising SEQ ID NO: 3, a heavy chain constant region (CH(1-3)) comprising SEQ ID NO: 439, and linker H2 comprising SEQ ID NO: 665, a first VL sequence (VL2) comprising SEQ ID NO: 681, a linker H3 comprising SEQ ID NO: 666, a second VH (VH2) sequence comprising SEQ ID NO: 682, a second VL sequence (VL1) comprising SEQ ID NO: 39, and a light chain constant domain (CL) comprising SEQ ID NO: 469. [00194] In some embodiments, the bispecific format comprises a first VH sequence (VH1) comprising SEQ ID NO: 3, a heavy chain constant region (CH(1-3)) comprising SEQ ID NO: 439, and linker H2 comprising SEQ ID NO: 665, a first VL sequence (VL2) comprising SEQ ID NO: 683, a linker H3 comprising SEQ ID NO: 666, a second VH (VH2) sequence comprising SEQ ID NO: 684, a second VL sequence (VL1) comprising SEQ ID NO: 39, and a light chain constant domain (CL) comprising SEQ ID NO: 469. [00195] In some embodiments, the bispecific format comprises a first VH sequence (VH1) comprising SEQ ID NO: 3, a heavy chain constant region (CH(1-3)) comprising SEQ ID NO: 439, and linker H2 comprising SEQ ID NO: 665, a first VL sequence (VL2) comprising SEQ ID NO: 685, a linker H3 comprising SEQ ID NO: 666, a second VH (VH2) sequence comprising SEQ ID NO: 686, a second VL sequence (VL1) comprising SEQ ID NO: 39, and a light chain constant domain (CL) comprising SEQ ID NO: 469. [00196] In some embodiments, the bispecific format comprises a first VH sequence (VH1) comprising SEQ ID NO: 659, a heavy chain constant region (CH(1-3)) comprising SEQ ID NO: 439, and linker H2 comprising SEQ ID NO: 665, a first VL sequence (VL2) comprising SEQ ID NO: 687, a linker H3 comprising SEQ ID NO: 666, a second VH (VH2) sequence comprising SEQ ID NO: 688, a second VL sequence (VL1) comprising SEQ ID NO: 662, and a light chain constant domain (CL) comprising SEQ ID NO: 669. ^{IPTS/128623945.3} 106 Attorney Docket No. PRG-013WO [00197] In some embodiments, the bispecific format comprises a first VH sequence (VH1) comprising SEQ ID NO: 660, a heavy chain constant region (CH(1-3)) comprising SEQ ID NO: 439, and linker H2 comprising SEQ ID NO: 665, a first VL sequence (VL2) comprising SEQ ID NO: 687, a linker H3 comprising SEQ ID NO: 666, a second VH (VH2) sequence comprising SEQ ID NO: 688, a second VL sequence (VL1) comprising SEQ ID NO: 663, and a light chain constant domain (CL) comprising SEQ ID NO: 469. [00198] In some embodiments, the bispecific format comprises a first VH sequence (VH1) comprising SEQ ID NO: 661, a heavy chain constant region (CH(1-3)) comprising SEQ ID NO: 439, and linker H2 comprising SEQ ID NO: 665, a first VL sequence (VL2) comprising SEQ ID NO: 687, a linker H3 comprising SEQ ID NO: 666, a second VH (VH2) sequence comprising SEQ ID NO: 688, a second VL sequence (VL1) comprising SEQ ID NO: 664, and a light chain constant domain (CL) comprising SEQ ID NO: 469. [00199] In some embodiments, the bispecific format comprises a first VH sequence (VH1) comprising SEQ ID NO: 3, a heavy chain constant region (CH(1-3)) comprising SEQ ID NO: 689, a first VL sequence (VL1) comprising SEQ ID NO: 39, and a light chain constant domain (CL) comprising SEQ ID NO: 469, a second VH sequence (VH2) comprising SEQ ID NO: 659, a heavy chain constant domain (CH2) comprising SEQ ID NO: 690, a second VL sequence (VL2) comprising SEQ ID NO: 662, and a second light chain constant domain comprising SEQ ID NO: 692. [00200] In some embodiments, the bispecific format comprises a first VH sequence (VH1) comprising SEQ ID NO: 3, a heavy chain constant region (CH(1-3)) comprising SEQ ID NO: 689, a first VL sequence (VL1) comprising SEQ ID NO: 39, and a light chain constant domain (CL) comprising SEQ ID NO: 469, a second VH sequence (VH2) comprising SEQ ID NO: 660, a heavy chain constant domain (CH2) comprising SEQ ID NO: 691, a second VL sequence (VL2) comprising SEQ ID NO: 663, and a second light chain constant domain comprising SEQ ID NO: 692. [00201] In some embodiments, the bispecific format comprises a first VH sequence (VH1) comprising SEQ ID NO: 659, a heavy chain constant region (CH(1-3)) comprising SEQ ID NO: 689, a first VL sequence (VL1) comprising SEQ ID NO: 662, and a light chain constant domain (CL) comprising SEQ ID NO: 669, a second VH sequence (VH2) comprising SEQ ID NO: 3, a heavy chain constant domain (CH2) comprising SEQ ID NO: 691, a second VL sequence (VL2) comprising SEQ ID NO: 39, and a second light chain constant domain comprising SEQ ID NO: 692. ^{IPTS/128623945.3} 107 Attorney Docket No. PRG-013WO [00202] In some embodiments, the bispecific format comprises a first VH sequence (VH1) comprising SEQ ID NO: 660, a heavy chain constant region (CH(1-3)) comprising SEQ ID NO: 689, a first VL sequence (VL1) comprising SEQ ID NO: 663, and a light chain constant domain (CL) comprising SEQ ID NO: 469, a second VH sequence (VH2) comprising SEQ ID NO: 3, a heavy chain constant domain (CH2) comprising SEQ ID NO: 691, a second VL sequence (VL2) comprising SEQ ID NO: 39, and a second light chain constant domain comprising SEQ ID NO: 692. ^{IPTS/128623945.3} 108 Attorney Docket No. PRG-013WO

n_i a C G^G K_S Y _P V ^L D^G _F ^E S ^Q _L ^VVK^P _P V_R ^H _S D_{E L E}AR^L ^{R V}K^{P P} _EK^S _{E P} ^K ^T _S G^H _LG^D _I _h ^T _S K V_TNK^{C T} _I VV_{P S} G_{L Q} ^DV _{L T} ^{YQ P} _S ^Q ^C _/ ^T _S n_i A^K _S ^VN L V^C _I D_T ^S _P W^A _P V Y V H G^Y _LDY V W^K _TV V^N _LAG_R ^W K K^S _P ^C _{T E}K_L V Y^F _Q ^A F_E W H^L _E _S ^S ₍ a_h I PLK D T C K y K^S _F ^G _P GKTG D^G D^S _I ^V _S G_Q v ^V ^a _L _e ^G _S ^P _QG^T _L ^{S A}G ) H ₁ ^G _P – H ^{VR W} _{L C}W ₃ G_{T I I} ^R _S K LYN _: D O s V _S ^C t ^E _TWM^K _{L S} Y a _Q ^LN^G _L ^VVM N A^S _S ^D r ^L _S ^V _S W^A _{S Q} ^A N_{T I} m _Q ^L _TY^ENKD^Y _P ^V _T ^Q ^o _F ^V _E ^E _S A_LY N G V^S _S AY A Y^V _E _T ^S ₍ y_do ^e ₁ b _k i_t nⁱ HA n _{L r} N A cⁱf_i c _' _e H p_s V i _B A . N a 1₁ ^t _c - n - ₁ - e_s l_b ^ai_l ^u _r G- t_s ^g _I ^A _{_} ^y H a _T A n ^{_ A} ^o _{3 L} ^E _d V^v C ³ ₁ ^A _{L T}o - Y^bi _{t L F} V^c _{s 1} ^{IPTS/128623945.3} 109 Attorney Docket No. PRG-013WO

K^S ^V _F ^G _PG L ^VD^G _Q K^S _F ^G ^GPD^S _{I P} G ^V G^T _S GG ^V _L ^GP D^S _I G^T _S _{S Q L} ^S _L ^{A )} _{S Q L} ^S 1 ^G _P ^{V W} _CW ₃ ^G _{P L} H ^R ^G _{T I I} ^R _S KYN _: ^VR O _{T I} ^W _I ^R _S K V _S ^C ^E _TWM^K _L ^L _S YD N ^G _S ^C _TWM^KL _S _Q ^LN^G _L ^VVM Q A^S _S ^{D E} _Q ^LN^G _{L L} ^V ^L _S ^V _S _Q ^L W^A _S ^A N_T ^YV _I L _S ^V _S W^A _{S Q} N V_TY N D_P _E ^E _S A^E _LYK _T ^Q _{E Q} ^L _TY^E _LNK N G V^S _S AY A Y^V _T ^S ₍ ^V _E ^E _S A Y N G V^S _S e_{k 1} nⁱ H L_r A A N N ' H V A A N N - s ai_l ^T _S G- n - - - n -^T _C ^g _I ^AA ₂ _{_} ^y _d H ^T G- ₃ V _S ^{T g} _I ^AA _{_} ^y _d A N ^_ ^OU _{3 L} ^E _To -_L ^v _F N_C ^_ _{3 L} ^E _To C_R ³ ₁ ^A _L Y^bi _t V^c _{s 2} ^O _C ^U _R ³ ₁ ^A _L Y^bi _t ^{IPTS/128623945.3} 110 Attorney Docket No. PRG-013WO

G Q D^G V_F AD YR^QY^AS G_Q G V^G _S ^Q _LY_{E S} K H ⁾ 1 ^AG CW ⁾ ₃ GA_R ^W V_I NV ^V V^{VL A}V_{T 9} 5 H YN _: G G^A _CWA_{S T} DN_T ^L _EV_6: YD O ^S HVA ^D _E ^M _TO V VM A_TA^S N ^S _{E L} ^K _S W N S ^D _I V^R _LMWY G^{E AQG} LHN D_{R P Q} ^D _I D^Y _P ^V _T ^L ^Q _Q ^{S Y}GK^{R L} _S AG R AY^V _E ^M _R G_TK^N _{S T} ^I N^AW _I ^Q _E A Y _T ^S _{( Q P} ^R _F G G _T M _C D^S ₍ e_{k 1} nⁱ H L_r A N ' H V A N s - ^y ^a _d O - - i_l H o - - V G^AC _{_} ^U _R ³ ₃ H V A -_L ^v _F ^bi _t ^g _{I L} ^E _T ^T _S ^{1 - v} _F V^c _{s 3} n A^_ ₁ ^A _L Y N^T _{C L} V^c _{s 4} ^{IPTS/128623945.3} 111 Attorney Docket No. PRG-013WO

K ^L KY _E V^GA _QL P_I ^V _{R C}A MYD E_S ₁ AAR G Y ⁾ ₀ KV^F _T ^KY M ⁶ H G^C _S WG_F ^A _TVV^S _{S 6:} HM^{NS A} _T ^Y _S ^V _TO V ^S _QV _Q MWN_T S D^H _TVN V LKA^E _LY_T ^D D_S V^L _T ^D _I _Q ^V _S Y D D^{GS T} _T ^R _LG^GQ ^VA _QT G G D M^S _QE _Q ^T _{F R} ^M _R G^S ₍ e_{k 1} nⁱ H L_r A N ' H V A N s ^y _d - - O U- 3 - a_il o b G^A _L ^C _{_ R 3} H 1 V A ⁱ _tn ^g _I ^E _T ^T _S ^{T -} _L ^v _F A^_ ₂ ^A _L Y N _C V^c _{s 5} ^{IPTS/128623945.3} 112 Attorney Docket No. PRG-013WO

^P _Q ^{T G} ^V _{F P} ^G _TM ^G L ^G _S A_S ^{F V} _{C Q} ) 1 GA^QG _{S R} ^Q G G_LY ₁ 6 H GA_R VVKYYW VY _6: G^CW^S _S ^V _S ^L _T ^AD _F O V _S E _S LHVDN K_T G^S _S N L L _RMWA Q^L _S ^A Y_P ^D S ^K _L N_E ^R _S ^V ^Y _T ^D _I D^A _RGV^Q ^VG G^S G_T K G ^G _E _{E R} ^R _S ^L _{S E} ^L _T ^S ₍ e_{k 1} nⁱ H L_r A N ' H V A N s ^y _d - - O U- 3 - a_il o b G^A _L ^C _{_ R 3} H 1 V A ⁱ _tn ^g _I ^E _T ^T _S ^{T -} _L ^v _F A^_ ₃ ^A _L Y N _C V^c _{s 6} ^{IPTS/128623945.3} 113 Attorney Docket No. PRG-013WO

Q V_F AD YR G^Q _LY^A _E ^S _S V^G _S ^Q Y KN ⁾ GA_R ^W _I VH^V _{T 9} ₁ G VV^V _S ^L _T ^A _TVV⁵ ₆ H G^A ^S _C S WADN ^L _{E :} HVA^KD _E ^M _TO V _{E L}MWY_S W A^QGN V^R ^L _LG^EHN_{R P Q} ^D _I _Q ^S ^M _R ^Y _L _TGKD^L ^N _S AG Q^G _P ^R _FK_S ^R _TNR^W _I ^Q _E G G^I _T M^A _C D^S ₍ e_{k 1} K nⁱ H ^Q _: ⁾ L_r ^T _S A^P _E G_{S (} ^D _I O₇ N⁶ ₆ S P ^C I I S Y V E _T ^N _L G ^V _I S ^L Y '_QK^{L S} WKMK^K _LD_S ^A _TYYN^T VGD_T H ^V _{S F}NG^GG ^{KV D} _I V ^L _QL G_P ^L _T ^G _S ^V _S ^P _LD^A _S ^I _Q ^V _S ^ADM^G _Q ^{S )} ₃ Y_PWG_S N_TN^S _{L T}G D AG_S ^Q _{E :} V _E G^E _S ^V _T ^Q _R ^E _L ^L _R ^K _S ^A _C ^Y _P ^V _T ^S ₍ O A W Y K A W N s ^y ^a _d - ^g i_l ^T _S ^T o - G^A _I- A N_C -^O ₃ ^bi _t ^g _{I L} ^ED C ^U _R ³ ₁ n ^{_ A} _TV A _{1 L} Y D ₇ ^{IPTS/128623945.3} 114 Attorney Docket No. PRG-013WO

K KY V^GA _L ^V _{E C}A E_{S Q} ^P _{I R}MYD ⁾ ₀ ₁ AAR KV^F G T ^KYYM F ^AVV^S _S ⁶ ₆ H G^CWG N_T ^A _T ^YV _: O V ^S _QS HM V _Q ^S MWN_T S D_{S T}N L _T ^DH _TV VKA^E Q^V _S Y_LY _S V^L _T ^D _I GDD T^RG ^Q ^VAD_Q ^S _{T T L} ^G ^S _QE _Q G^T _F G D M _R ^M _R G^S ₍ e_{k 1} K nⁱ H L_r ^T _S ^Q _: ⁾ ₇ A^P _E G_{S (} ^D _I O N⁶ ₆ S P ^NI I S YY V ' ^C ^E _QK_{T L} L^S WG ^V F NKM_I S K^K _LD^L _S ^A _TYYN^T VGD_T H ^V _S G^GG ^K V ^L _S ^{V D} _I _QL ⁾ ^VG E_P ^L _T ^G _S ^V _S ^P _LD^A _S ^I _Q ^V _S ^A _TDM^G _Q ^S ₃ Y_P G^E _S ^V _T A^QWG R ^E _L N_TN^S _L G D AG_S ^Q _{E :} O W Y^L _R ^K _S K A^A _C ^Y _P W^V _T ^S ₍ N s ^y ^a _d - ^g i _I _l ^T _S ^T o - b G^A - A N_C -₃ ⁱ _t ^g _{I L} ^ED O _C ^U _R ³ ₁ n ^_ ₂ ^A _TV A _L Y D ₈ ^{IPTS/128623945.3} 115 Attorney Docket No. PRG-013WO

P_Q ^{T G I} _T K^G ^V _{F P} ^G M L ^G _S A_S ^{F V} _{C Q} )^QG _{S R} ^Q _LYG ₁ ₁ GA_R G VKYYW ⁶ ₆ H GAV^S _S ^VL _TVY _: G_S ^C _S W _S N^A _T ^D _F O V E^LHVD^KDG^S _S N L L _RMWA_{P E} ^R Q^L _S ^A _S ^VD _I _S ^K _LYN YD^A _T _RGV^Q ^VG^S G_{T E} _E G _R K G^R _S ^L _S ^G _E ^L _T ^S ₍ e_{k 1} K nⁱ H ^T _S ^Q _{E :} O⁾ ₇ _{L r} A^P G_{S (} ^D _I N⁶ ₆ S P I I S YY V ' ^C ^E _QK_T ^N _L L^S WGM^V _I S D^L _S ^A NK K^K _{L T}YYN^T VGD_T H ^V _{S F} G^GG ^{KV D} _I V ^L _QL ⁾ ^VG E_P ^L _T ^G _S ^V _S ^P _LD^A _S _S ^I _Q ^V _S ^ADM^G _Q ^S ₃ Y_P WGN_TN^S _{L T}G D AG_S ^Q _{E :} O G^E _S ^V _T A^Q _R ^E _L W Y^L _R ^K _S K A^A _C ^Y _P W^V _T ^S ₍ N s ^y ^a _d - ^g i _I _l ^T _S ^T o - b G^A - A N_C -₃ ⁱ _t ^g _{I L} ^ED O _C ^U _R ³ ₁ n ^_ ₃ ^A _TV A _L Y D ₉ ^{IPTS/128623945.3} 116 Attorney Docket No. PRG-013WO

K^{S G}GKTG D^G ^V _{F P} _L ^G _S ^P D^S _I ^V _S G_Q _QG^T G 1 ^G _P H ^VR _L ^S _L ^A ^G _{T I} ⁾ ^W _I ^R _CW _3: M_S K LYN YD O V _S ^C ^E _TW Q^LN^GK L_{L S} VVM N Q^AA^S _S ^D ^L _S ^V _S W^A _S N_T ^YV _I _Q ^L ^V _TY^ENKD_{P T} ^Q _E _E ^E _S A_LY N G V^S _S AY A Y^V _T ^S ₍ e_{k 1} K nⁱ H ^T _S ^Q _: ⁾ ^P _E O₇ _{L r} A G_{S (} ^D _I N⁶ ₆ _' ^S _E ^P _QC S_LF ^GAS S ^T _I TS H ^V ^TH_P AVGD^TNN^A _T ^A _RVG_T ⁾ H VVR_F M WDA_F ^KM^DA V ^L _QV _C ^L _E ^W _I V ^D _{I 9} 5 G^L ^M _QG_S ^G _S G^Q _R ^E _L YYR_S ^Q _E ^DM _{T 6:} RAYV HGN G^W _I KK _LAY YW_F ^Q _EO G G A^T _R W K V N V^D _R ^N _L ^R _L V^Q _P ^A _E ^G _Q ^S _S ^S ₍ N s ^y ^a _d ^T _S - i ^g l o b N^T A ⁱ _tn O_C - - ^A _I D A- ₃ G_L ^E 1 ^C _{_} ^U _R ³ ₁ ^g _I _ ^A _{L T}V Y D ⁰ ₁ ^{IPTS/128623945.3} 117 Attorney Docket No. PRG-013WO

G ^Q V ^P D G P_S ^QK^TD^G _{S L} ^V _TNK_PV_R T _S V^{R V} _S K^{P P DV} _E ^{T Y} _LG P^L _E ^T S ^S _{( S S} K A^K NV S ^V _L W^A _P V^C _I K D^C _T ^S _{P I} V V Y V H G^Y Y_P G_{L QR L} ^W _{T L} ^Q _Q ^A _S ^Q _E _LD V W^K _TV V^N _LAG K K^S _P ^C _{T E}K V Y^F _{F E} W H^L _S ^S ₍ I P LKKD T K^S KTG^G ^V _F ^G _PG D L ^G D^S _I ^V _S G_Q G 1 ^G _S ^P _QG^T P_L ^S _L ^A _CW ⁾ ₃ H ^V _T ^R _I ^W _I ^R _S KYN _: O V ^G _S ^C ^E _TWM ^L Q^LN^GK _{L S} YD V N L _S ^V _{S L} ^AV M Q^AA^S _S ^D _I _Q ^LYW_S NN_T D^Y _P ^V _T V_T _E ^E _S A^E _LYK ^Q N G V^S _S AY A Y^V _E _T ^S ₍ e_{k 1} K nⁱ H ^T _S ^Q _{E :} O⁾ ₇ _{L r} A^P G_{S (} ^D _I N⁶ ₆ S PS ^F _I ^G D^N T^{S Y}G '_QKV H_P M H VK Y V ^L K MA ^L _{L Q} ^M _T ^S _{T R} ^AR_S ^V ^L _T ^HW_T ⁾ ₀ _Q ^V _E ^VG S_S A^QW NV AY_R ^E _L ^P _I YR^S G_{T E}D^A M^D _{C T}AV S YVD^{L D} _I _T ⁶ ^Q _6: V _QAA V G G^K _C ^D _T W^GF Q_TD DY YGM G^S _T ^K _F ^T _T A^R _L V M V^G _E _Q ^S _S ^S ₍ O N s ^y _d ^T ^ai_l o _S - b N^T A ⁱ _tn O_C - - ^g ^A _I _L D -^U ₃ G g _I ^AE _TV A₂ ^C _{_ R} ³ ₁ _ _L Y D ¹ ₁ ^{IPTS/128623945.3} 118 Attorney Docket No. PRG-013WO

₁₍ V_{T E} ^TG^S KKA^PV _E ^Y _L K^K _{E Q} ^KY _FG_L ^T _FY O H ^S _P G^P _S H^P _F ^{E D}V_QV ^P _T V_LVH N G_{F L} ^S YA_S ^S _E _P NV^P _C ^L _P E _EG^{E T} _L ^Y _E ^I _{P E} ^LGN S^{P K}NN C G K_S D^GQ _L ^VVK^P _{P F} V_R ^H _S D_E AR VK^{P P} _EK _{E P} T _S G^H _LG^D _I T_S ^T _S K_S VNV_TNK V^C _I D^C _T ^S _P ^T _I VV^R _{P S} G_{L Q} ^D W V Y V H G^YDY V W^KV V^NAG_R ^V _L ^W _{E T} ^Y K_L ^Q _Q ^A _E ^P _S ^Q _E A^K _{S L} ^A _{P L T L} K K^S _P ^C _T V Y^F _F W H^L _S ^S ₍ I P LK D T S K K V_F ^G _P GKTG L ^S ^G _I ^VD^G _Q _S ^P D QG^T _S G 1 ^G _{P L} ^S G L ^AW ⁾ ₃ H ^VR ^G _{T I} ^W _I ^R _C _S KYN _: O V _S ^CWM E _TN^GK _L ^L _S YD VM N Q^L _L ^V _Q A^S _S ^D ^L _S ^V _S W^A _S ^A _{T I} _Q ^L ^V _TY NND^Y _P ^V E ^E _S A^E _LYKA _T ^Q _E N G V^S _S Y A Y^V _T ^S ₍ e_{k 1} K nⁱ H L_r ^T _S ^Q A^P _{E :} ⁾ G_{S (} ^D _I O₇ N⁶ ₆ S ^P S H^GS S ^S _I TS E ^L ' H ^E _Q ^T L ^VL _{F P}VAD R ^GMAW^G _S A^T _F NN^A M_TK^D ^V _{F T} G^{G D} _I ⁾ ₁ V ^L _{L S} A QG^L _S ^Q YR^K _P ^D A^S _R ^K _L ^G G ^Q _{L E C Q} ^S Y^R _S G_S ⁶ _6: V _EGG _S VG_S ^Y _T N K AYGW^V _T ^Q _EO G G^A _C ^R _F W K^V _S G V^D _R ^Y _L ^R _L V G Y V^S ₍ N s ^y ^a _d i_l o ^T _S - b N^T - ^g _I A ⁱ _tn O_C -₃ G^A _L ^E _TD A-₃ ^C _{_} ^U _R ³ ₁ ^g _I _ ^A _L V Y D ² ₁ ^{IPTS/128623945.3} 119 Attorney Docket No. PRG-013WO

KF^P S S V V_L ^G _{S Q} ^W ^R _I ^K _L ^V A^V Q^AY _T V GV_I M^A _S N_T D_P Y^T _T ⁾ ₃ _{1 P} ^T H ^G _CW N^G _L K N^S AY^G _: O V _S E^T _L ^VWY_S ^AG D_TD_Q N Q^S _S L _LY^E _L ^V _I K^V AGK^S _{I S} GG AW ^D _I _Q ^T KG ^S _{L C}N ^Q ^V _EN E ^S _P ^L _S ^G _PD^T G_L R^K _LYD Y M^S _E _S ^S ₍ e_{k 1} nⁱ H L_r A N ' H V A N s ^t _c - n - - -^e _d ai_l ^u _r G t_s ^g _I - ^A ₁ _^A _{L _} ^y _d H _d V- ⁱ ^v _f ^e _z _l ^il _i A n 3₁ ^o ₃ _C ³ ₁ ^AE L_To - Y^bi _{t L F} ^u _s ^b V^c _s ⁱ _{d a} ^t _s ^{IPTS/128623945.3} 120 Attorney Docket No. PRG-013WO

KF^P S S V V_L ^G _{S Q} ^W _I ^K _L ^V A^V Q^AY _T V 1 ^G _PV^R _I M TW^GA _S N_T KD_P AY^T Y_T ⁾ ₃ H ^G _{S C} E^TN_LN^S _S ^AG^G _: _Q O V _L ^VWYD_TD N Q^S _S L _LY^E _L ^V _I K^V AGK^S _{I S} GG AW ^D _I _Q ^T KG ^S _{L C}N ^Q ^V _E _E ^S N P ^L _S ^G _PD^T G_L R^K _LYD Y M^S _E _S ^S ₍ e_{k 1} nⁱ H L_r A N ' H V A N - s G n -^ai_l ^T _S ^g ₂ - - N^T _{C I} - ^A ^{_ A} _{L _} ^e _d E^y _d H _d V- ⁱ ^v _f ^e _z _l ^il _i A ⁴ ₁ ^O _C ^U ₃ _R ³ ₁ ^A _{L T}o - Y^bi _{t L F} ^u _s ^b V^c _s ⁱ _{d a} ^t _s ^{IPTS/128623945.3} 121 Attorney Docket No. PRG-013WO

KF^P S S V ^V ^V _L ^G _{S Q} ^W _I ^K _L ^V A Q^A _T _T ^YV 1 ^G _PV^R _I M TW^GA _S ND_P Y^T _T ⁾ ₃ H ^G _{S C} TN_L K N WY^S A S ^AY TG^G _: _Q O V ^E _L ^V _S D DG N Q^S ^L _LY^E _L ^V _I K K ^VG Q^T _EAG ^S _{I S} W ^D _I NKG^{T S} _L ^A _CN ^Q ^VS D G_L R^K _LYD _E _{E P} ^L _S ^G _P Y M^S _S ^S ₍ e_{k 1} nⁱ H L_r A N ' H V A N - s G a - n -₃ - -^e _d _d ^e i_l ^T _S N^T _C ^g _I ^A ^_ _{_} ₃ ^A _L ^{E y} _d H- - ⁱ _{f z} ⁱ o V^{- v v} _l ^l _i A ⁵ ₁ ^O _C ^U _R ³ ₁ ^A _{L T} Y^bi _{t L F F} ^u _s V^c _s ^c _s ⁱ _d ^b _a ^t _s ^{IPTS/128623945.3} 122 Attorney Docket No. PRG-013WO

VS VAANRA VA V ^W YD^L _S R_I G W ^D _F ⁾ 1 G^A _CHWHRN G^S K^T _I ^A _C ^S _{S 9} 5 H ^S _LM^E M ^A G_L ^N _S ^T _F ^QY_E H^V ₆ _{T :} O V _ER V^{L Y}G _LY VN L _{S T}KGR QR^{R G} _PDGNVV L_T ^A _T ^L _E ^M _T ^D _I MG_F YK P^T _F ^A _Q ^W _I ^V _S N^DW^GQ ^K _E ^Q _QE _{Q Q} G R V D _S A _P G^S ₍ e_{k 1} nⁱ H L_r A N ' H V A N s ^y O - - -^e _d a _d i_l o - - b^C ⁱ _t G^A _{L _} ^U _R ³ ₃ H _d 1 V- ⁱ ^v _f ^e _z _l ^il _i A ⁶ ₁ n ^g _I A^_ ₁ ^AE L_T ^T _S Y N^{T -} C_{L F} ^u _s ^b V^c _s ⁱ _{d a} ^t _s ^{IPTS/128623945.3} 123 Attorney Docket No. PRG-013WO

KS G^NT V^G ^VAV EKWM_Q N^S _T ^D _{S Q} HW RGG YD M ⁾ ₀ ₁ A^C _S ^{T L} _S RW ⁶ H G S VM^E KA_LD G^S _T _T R^A ^ML _CA ₆ D _: O V _Q Y_{Q T E}Y ^S N V^V ^L _S ^D D YM_S _T ^GLVM V QA ^VD ^F _I _{I P} V^{G A} _L PRYV G ^Y _{S T} Q Q_PY K G_QI R^F A^A T ^K _F ^T _{S T} V D^H _T ^L _E _T ^S ₍ e_{k 1} nⁱ H L_r A N ' H V A N s ^y ^a _d O - - - i_l o - - b^C ⁱ _t G g^A _{L _} ^U _R ³ ₃ H ^e _d _d 1 V- ⁱ ^v _f ^e _z _l ^il _i A ⁷ ₁ n _I A^_ ₂ ^AE L_T ^T _S Y N^{T -} C_{L F} ^u _s ^b V^c _s ⁱ _{d a} ^t _s ^{IPTS/128623945.3} 124 Attorney Docket No. PRG-013WO

Q V_L ^G _S R^S S EG V_S D^KA ^L GA VA_PR^G _T ⁾ 1 G^AWWYN D^L _{S E} K^G _{Q 1} 6₆ H ^G _CH ^Y S ^S _L RN G M^K _T G^S _I M^V _{C :} O V ^E _LA LR^S G W A^T _F ^QY N YY L^L _S K^G _L ^{DS D} _I _{QS S} RYV G^R _{F S} _F ^G _P G G ^Q ^V _E ^G _P ^T _F ^AG Q_S K^L _T ^A _T ^V V V N D^R _{S T E} V^S ₍ e_{k 1} nⁱ H L_r A N ' H V A N s ^y ^a _d O - - - i_l o - - b^C ⁱ _t G g^A _{L _} ^U _R ³ ₃ H ^e _d _d 1 V- ⁱ ^v _f ^e _z _l ^il _i A ⁸ ₁ n _I A^_ ₃ ^AE L_T ^T _S Y N^{T -} C_{L F} ^u _s ^b V^c _s ⁱ _{d a} ^t _s ^{IPTS/128623945.3} 125 Attorney Docket No. PRG-013WO

C ₁ G y₍ K^G _LA^S _S K^C _{T P} ^H _S K N^T _L ^{L D} v ₁ ^{T N} _QC ^{P K} _S M _I G K^G _LA^S _S K^C _{T P} ^H _S K N^T _L ^N S A^G _S ^L _S H^H _T ^K _PVH^V _S ^P _EW_QYV ^Q _E ^TA^GLH^HK _PVH^V _S a_e H ^A _T N ^P _FD^V _{E S} V^R _P ^L _S G^L _F ^S _C ^G _P ^S _{( S} ^A _{T S S} N_T ^PD^V _S V H C A N Y V K V V K N A N Y V K _F V _E V K – s_t L NI ^T _LTP^S L I ^TTP^S a ^T _E _r ^VM ^V _S Y_S ^T _EN V _L M ^V _S Y_S m^S _{P S} ^R _S ^S Y^V _T ^S _{P S} ^R _S ^S Y^V _T o _F KY^G _L ^K _LG y^VAW_LKDV KY^G _L ^K _LG DV d_L ^{N A} G^T _T ^VAW_LKG^T _T o ^G _L ^E _S ^L _S _P ^S _LN^VA _L ^N C^G _Q ^{) G} _L ^{E A} _S ^L _S S _LN^VA _C ^G _Q ⁾ ^bi _FG t n ^G Y_QY S ^GK^V G_{3: P F}GY_QYG_3: _I NY O ^G _S ^GK^V _I NY O A c ^E _S ^G ⁱ _Q ^V _P _T ^PKKVWN ^E _S ^G _PKKVWN G^{S A}N f ^{L D} _Q ^V ^C _{Q T} ^{P S A}N D D_{S T}D _I ^L G C_QD_{S T}D _I _i c _{1 Q} _e H s ^V _T L^R _I D GKDM^Q _QT ^R ^S AA_{E I} D G DM^Q ^{S VL} K S AA_E p V i _{E S} W W _I A Y _{( E S} W W _I A Y^S ₍ _B ._b ^y _do ^E 1_T ^e _l ^y ^o _do ^{E e} _l 1^{y t} _c ^bi_t ^b _{a h} ^t _c ^bi _T ^b _a ^o _h _{e d} Y- - _t Y- - l o ^u b ^b _r i_t ^t n - s AG n -₃ ^{g A}M L ^s _s ⁿ _i ^{- u} _r _b ^t n - s AG n ^{- g A}Mⁿ _i _L ^s _s -_b a n ^{9 o 3} _I _^Ao^r o n^o _{3 I} Ao^r o T A _{1 C 1 1 L C k} ⁰ _{2 C} ³ ₁ ^_ _{2 L C} ⁿ _k ^{IPTS/128623945.3} 126 Attorney Docket No. PRG-013WO

RD ^{S P} _{L E Q} ^N D C^{S P} _PW RY H ) _{P F P} F^S _S KAR^N _F ^E _L ^K _E ^R _C ^{S P} _PW RY H ) P _P _P ^YT _{T S} N ₉ 8^A _LY D_T ^S D^E V_P ^T _I K_EW _P R^I _P ^{P T} _{T S} N ₉ 8^L _FKK D^H _6: ^P _FKH V_P KA PYV E _P ^D _QA_P ^Y ^L _FKK D^H _6: ) _TGY _L V ^V _{T T C} ^L _P ^{K P} _TGY _L ₃ YKNV^A O V ^G _S N _{T T} ^H _L KNV^A O VV^NT _{L E} N ^S _P ^L _C ^TV V^{S P} _PD^D _EK_L Y VA^VV^NT _{L E} N -_{1( Q} ^L _CE ^KH ^D _I G^G _{L L} ^S _P K^C _T ^K _P ^H _S A^TK_Q ^L _{C E} ^KH ^D _I ₁ ^P H _E ^P W_QS M K A_S YV ^Q A H^HK N_L _PVH ^N _S ^P _E ^P _S M W_QYV ^Q C ^R _P ^L _S G N^L _E ^T F ^S _C ^G _P ^S _{( S} A^AG T_S ^L _S N_T N Y V K^P _FD V^VV E_S V V K^R _P ^L _S G N^L _F ^S _C ^G _E _P ^S ₍ R GGV^VL^AG P W_S N_C _Q ^Y _T ^ED A^LY^W _I V^R _{L T}Y^D V_F YN G^TG V_F _FKH^K _S ^AA _E ⁾ G G^G _S ^G _PK NN_T D^S _EH^S ₉ _S ⁵ ₆ _EA^A _S D V QGRA^L _: _E ^V _TO V^A ^L _CRD^T _I R N V Y Q^S _L ^{T L} ^W _{F S} WV Q^MD _I ₁ H ^MRW H_I RN VG _{P T} ^Q M A K^MA _E V _Q ^L _{S Q} R^G _Q ^S ₍ - ₁ ^{E e} _l y_d ^y _d ^t _c - _T ^b ^u GY- _a ^o _h- o b o _r i_t ^b n ⁱ _t ^t _s ^g _I Mⁿ _i n ^_ ₃ ^A _L ^s _s - o _bo A ¹ ₂ n A^o _C ³ ₁ ^A _L ^r _C ⁿ _k ^{IPTS/128623945.3} 127 Attorney Docket No. PRG-013WO

T_LR C^GR_P E^F _T ^D _I 1_L V V ^I _{S P}D E ^L _T ^K _Q ^P _{I L}Y^Q G^R _S ^P _E _L ^S ₍ G LND^L VVCQ^{V F} _S ^S S G^W S_S G^C _I ^C _FV T^VS _S ^Y _S VVGRKG_Q ^S _EG_F ^L S_T ^{S C}DY^YKN^WDV_S N KV^Q _TK L ^Q S ^P _T ^P _{P T} _E V^T G^V _{S E}A^K _{T E S} G^L _S _EYNK^K _S ^LV^D _L ^QK S _EV P ^{P A} _P ^GVG LKA^P _EW^YG^I _E ^A _I V_Q ^Q ^N _Q ^N _{L T}DD^PW_T Y A_F _LY^{F S} _S KAR_F ^E D_T ^S D^E _P ^T _I K_EW^K _E ^R ^I _C ^S ^P _{P P} T_T ^R _S H ) N ₉ P_FKH_PVAYV^R _P ^D _{P P} ^Y _FKK VV^VK _T ^{P L E} _P ^K _QA P^LGYD^{H 8} ₆ _{L :} ) V 3 ^S _P ^L _C ^G _{S T}N_CT TV^{S P} _PD^D _T _E ^H K_{L L T} YKNV^A O VA V ^T _{L E} N -₁₍ G K^G _{L L}V_P A^S _S K^C _T ^K _P ^H _S A K^V N^T _L ^{L N} _E H ^D ^N _QC ^{P K} _S M _I ₁ H ^T _S A C A^AG T_S ^L _S H N^H _T ^K _PVH N Y V K^P _FD V^VV E_{S S} ^P V_EW_Q V K^R _P ^L _S GYV ^Q N^L _F ^S _C ^G _E _P ^S ₍ S AMGRR V G G PA ^LG^L YM^K _{F E}M_T K K^D _TW^NMR^G Y^A _Q V_E ^F _I ^E _{L Q} ^A _CG Y^GN_TYW ⁾ ₀ A G^G _QY^S _TYA ⁶ ₆ S _S ^G QA_PD S^S VD _: K^A _{T T} ^A D_TM O C V N V _QD S R^L _L ^TD T ^{DY D} _I ₁ ^L _QVV H K ^P _I ^M _{S S} ^S TR^H _{T S} ^Q _E V ^V _Q W V H^F _T V^L _S V^V _T ^S ₍ -^{E e} _l y ₂ _d ^y _d ^t _c - _T Y^b _a ^o _h- o ^u G- b o _r ⁿ ⁱ _t ^{bi t} _s ^g _I _^AM_i _L ^s _s -_b n _tn n A^o ₃ Ao^r o A ² _{2 C} ³ _{1 L C} ⁿ _k ^{IPTS/128623945.3} 128 Attorney Docket No. PRG-013WO

_h n C_t ⁱ _L h_g A A A i N N N L – s_t a m_r o _F y_d ^' o _L bi V t n A cⁱf_i c_e A A A p_s N N N i _B.a C- o - H C- o - H C o - H 2_{1 s} ^U _RG ^bi e ^a _i ^g _tn V^{- U} _RG ^bi_t - n V^{- U} _RG ^bi_tn V-^l _l ^T _I _S _b A ^_ - ^A _L ^g _I V ^T _S ^_ - ^A _L ^g _I V ^T _S ^_ - ^A _L V N₃ a^{3 A} _{L _} E^- ₁ ^v N₃ 3^A _{L _} E^- ₂ ^v N₃ 3^A _{L _} - ₃ ^v T ^O ₁ ^A _{T F} Y ^O ₁ _{L T F} Y _{d s 2} ^O ₁ ^E C_{T L T F} _{C T L} ^y _d ^c _{s 1 C T} ^{A y c A} Y^y _d ^c _s ^{IPTS/128623945.3} 129 Attorney Docket No. PRG-013WO

r e_k nⁱ _L A A N N '_L V A A N N S - ^v S - ^v s N³ _{3 F} c N³ _{3 F} c^a _il ^y _d - - O ¹ _s T- ^y _d - - O ¹ _s- o ^C ⁱ _{t _ C}H o ^{C T} _CH A ^b G^A V ^b G^A _{_} V 3 n ^g _{I L} ^E A^_ ₁ ^A _{L T}U-_L ⁱ _t ^g _{I L} ^E _TU-_L Y^R _T n V ₄ A^_ ₂ ^A _L Y^R _T V ₅ ^{IPTS/128623945.3} 130 Attorney Docket No. PRG-013WO

M ^{S DI D} _{L F} Q_I ^S _I D_{QE E} ^Q ^P V_E V^G _{L S} DGG^Q _E V^S ^I _I ^S ^P _I ^Q ^S DK^I _E D _Q ^L _{S Q} K^S ₍ ^Y _S N D^R _S ^G _F ^S _{( E Q Q} ^E _{P E} ^S ₍ )₈ ⁾ ⁶ ₈ 1 ₆ ⁶ ₆ _{L : :} _r O O e_k N N nⁱ _P A^D _{I P} A^D _I _L A^Q A A N ^V _E ^Q _E _T ^S ₍ ^V _T ^S ₍ I_T I ^I I VWL^{T D} _T L^{T D} RH^N _L _S ^T _E VW _{L E} _F N RH^N _S ^T _F N DM D F M G ^A _L ^{DN A} _L ^DN ^V _S _S N^Y _{I T Q} G^F ^{Q V} _S ^Y _{I T Q} Q ^' G L ^A _S ^{L G} L_{S C}K GY^I _S N E₎ ^A _S G^{L G} L_{S C}K GY^I _{E )} V ^L _S ^Y _S ^K _S ^YV⁹ ^S D_P ^G ₃ ^Y _S ^K _S ^YV⁹ ₃ _P ^VA_{S T} ^L ^K _{: S} D_P ^G ^{F A} _{F T}O ^S _P ^VA_{S T} A_F ^K _{T :} O S _S K Q^K _S ^G _R _P ^S DGN P ^EG ^S _S K^F ^D _Q ^K _S ^G _R _P ^S DGN P ^EG T_L ^AKV_P G _I ^T _L ^AKV_P G^D _I A ^Q _{I R} ^Q ^C _QG^Q ^S _L ^F ^S _T ^Q ^R _{E R} ^QG^Q _L ^F _T ^Q ^{S Q} _I ^C _Q ^{S S R} _E N D _T Y _{E S P (} D _T Y _{E S P} ^S ₍ S - s N³ ₃ ^v _F C c ^a _{i s} ^{U E} C T ^{U E} _T _l ^y _do - - O ¹ - _R ^y ^{C T}H ^T _d Y o - - ^g _R _I ^{T y} _d Y o - - ^g _I A ^bi _t G^A _{L _ C S} - UV N₃ ^bi _t G^A- _S _L - D N₃ ^bi G^A- LD n ^g _I ^E ^_ ₃ ^A _{L T} ^{R -} T_L ³ ₁ ₆ ^O _C n ^g _I ³ ^{_ A}V ^O _{1 t}n ^g _I _^AV A Y V _T A _{1 L} D _{7 C T} A _{2 L} D ₈ ^{IPTS/128623945.3} 131 Attorney Docket No. PRG-013WO

M^S _I ^{S DI} _{E L}D ^I G _LD ^I G Q_I D^D _QE ^Q _E _Q ^L _S ^P _QV K^S ₍ ^Q _I ^V _S ^Y _I D K^L _TG^Q L ^L _T ^G _E _F ^S ₍ ^Q _I ^V _S ^Y _I D K^L _TG^Q L ^L _T ^G _E _F ^S ₍ )₈ ⁾ ₈ ⁾ ⁶ ₈ 1 ₆ ⁶ ₆ ⁶ ₆ _{L : : :} _r O O O e_k N N N nⁱ _{P P} A^D _I ^D _{I P} ^D _I _L A A A^Q _E A^Q _E A^Q ^{VS V V} _E _{T ( T} ^S _{( T} ^S ₍ I_T I I I ^L F FT VWL^T _L ^D RH^N D _S M ^T _E RK G A A_F N ^{QW D} _{S T} ^G _P RD^G ^T _QS ^R _S ^S A S_L ^RKD^E _{P Q} D^N _QY^P _R ^I _TD _E ^Q _Q ^P _I ^E _LG G^F ^V _{S T Q} _S ^GW ^L G ^{G F} N^Y _I ^G _P ^D S ^Q _CK AH_{S T}W D V_L ^P _S Y_S R_T W^I _S ^S _I Y '_L ^A _S G^L S ^Y _L ^G _S Y^I _{E )} ^V ^{9 V} _{S S} D^A _T V⁾ N^Q _C ^T _{L 2} ^LH ^{P )} ⁶ _S ^Q _S ^T _{L L 3} V ^L _S ^K _P ^Y _TV₃ V^K ^S D _S Y Y ₆ ^{L V} _S ^S _F ⁶ ₆ _P ^VA^G _S ^K _: F^A _{F T}O ^S V P ^{G G} _S ^K L ^V Y_{T : T} O ^GI _S ^A ^I _F ^T _{F :} D^T _Q O S _S K Q^K _RDGN ^P ^T _S ^G _P ^{S E}G _QN_L ^N ^V _S DGN _{P P} ^Y _{I T} N PG^A _EG ^S _Q ^{QL GQ} _C _L ^AK_{P P}G^D _I ^TN Q_{I R} ^QV^QF _LG^A D^C _Q ^S _F D^G _F ^D _I V ^T _{S L S} _L ^AR _P ^GY ^D _I Y^I _E _{T Q}G Y^S _{L T} ^Q _E VG RG E ^S _S ^R _P ^S ₍ ^Y _S ^C _T ^G _P ^E _P ^A _EV^Q _E V_{R S} ^Q H^S ₍ ^I _E ^C _S ^A _Q ^G _S VV_E A K^S ₍ C - E^{- U Ag} _I - - U^Ag _I _s ^U _{T 1 R L}D _{2 R L}D a_{i R} _l ^{T y} A _S - _d Y N₃ o - - ^g _I ^y ^b - _do ^T _S - 3ⁱ ₃ ^A _LV ^y _d ^T- ^AV - t G^A _LD ^bi _t N ¹ G ^D o _S b³ ⁱ _{3 L}- t N ¹ G ^D ^O3 ₁ _{C T}n ^g _I V n ^O A^_ ₃ ^A _L D ₉ A _C _ ^T _C ^g _I ^E _T n ^O _ Y ⁰ ₁ A _C _ ^T _C ^g _I ^E _T _ Y ¹ ₁ ^{IPTS/128623945.3} 132 Attorney Docket No. PRG-013WO

)₈ 6 ¹ ₆ _{L :} _r O e_k N nⁱ _P A^D _I _L A^Q ^V _E _T ^S ₍ A A N N T V^G _PK^D R D^K _Q ^S _{P E} ^G V^P _Q _QG G^Q ^V _F ^GL _S ^F _T _{S S} W^QS _I ^P _P ' A_{L L} _L ^{S T} LY^S _{S L} ^Y _L ⁾ ₄ V ^S _S N S^AT _F N ⁶ ^Y ₆ P _{I T :} _S D ^D ^Y _Q _{I T} O Q_T ^Q _S ^L _S ^G _S ^Q _C N K A ^GY^{I D} _I M ^K _{P S} ^Y _E Q_I ^R _CAG_TV^Q _E A A D^T _I K^S _F ^A _F ^K _T ^S ₍ N N - ^g _I o - - H C- o H s - ₃ ^U _R ^A ^a _LD i_l ^y _do ^T _S - 3 ⁱ ₃ ^A _LV ^t _c - ^bi_t V - u_r G n - t ^g _L _I - ^{A e} _d ^UG ^bi_t V - V _d ^{i e} _R _z ^T _S ^g _I n -^_ - ^A _L ^e _d V _d ^{i e} _z A ^b N - ^{D t} _s ^A _{_} - - _fl ^il _{i 3} ^A _{_} - _fl ^il _i n ^O A _C ¹ G _ ^T _C ^g _I ^E _T n ^_ _ Y ² ₁ ³ ₁ ^o _{3 L} ^E ₁ ^v C ³ ₁ ^A _{L T} Y^y _F ^u _s _d ^c _s ⁱ _d ^b _a N³ _L ^{E -} ₂ ^v ^t _s ⁴ ₁ ^O ₁ _{C T} ^A _{L T F} ^u _s ^b Y^y _d ^c _s ⁱ _{d a} ^t _s ^{IPTS/128623945.3} 133 Attorney Docket No. PRG-013WO

nⁱ _L A A A N N N '_L V A A A N N N C o - S - S - - s ^UG ^bi_t H V- ³ - N₃ ³ - N₃ a_{i R} _l ^T _S ^g _I _ - n -^A _L ^v _F _{_} ^e _d V^c _{s d} ⁱ _f ^e _z ^y ⁱ _do - - O ¹ - C_{_} ^T _CH ^e _d _d ⁱ _f ^e _z ^y ⁱ _do - - O ¹ - - C_{_} ^T _CH ^e _d _d ⁱ _f ^e _z A N₃ 3 ⁵ ₁ ^A _L ^E 1 ^O _{C T} ^A _{L T} - ₃ - v _l _F ^u _s ^l _i b Y^y _d ^c _s ⁱ _{d a} ^bi _t G g ^t _I ^A _L ^E - s ⁶ ₁ n _TUV- _l ^l _i _L ^v _F ^u _s ^b A^_ ₁ ^A _L Y^R _T V^c _s ⁱ _{d a} ^bi _t G g ^t _I ^A _L ^E V- _l ^il _i _s ⁷ ₁ n _TU-_L ^v _F ^u _s ^b A^_ ₂ ^A _L Y^R _T V^c _s ⁱ _{d a} ^t _s ^{IPTS/128623945.3} 134 Attorney Docket No. PRG-013WO

AVDDVG R^D _I V^V T_S V R^AK^KKN^Q T_S H W D K^F _E _S ^S ₍ RI C F T ^{L Y} ^I _S _T ^KD _{T L} N V_P RA^G _S ^Y _Q DK^G G^G _S ^Q G_C 1^V _P _{L S} ^KS _FY Y A_Q V ^S _L ^QK_TK F ^S _P ^A _F ^I _E ⁾ ^S _S ^WVDV₄ 6₆ P _L _S Y^G _S ^E _P ^K _{T :} QN T ^S _I ^Q _L ^QGO N S _L S _Q MD_{S S} ^I G^D ^F _I Q_I ^Q _S ^A _{T T T Q} D A Y^L _T ^P _P ^E _{S (} 1_L _r e_k nⁱ _L A N '_L V A N S - s N³ ₃ a_il ^y _do - - O ¹ - -^e _d _d ^e ^{b C} ⁱ _t ^g _{_} ^T _CH ⁱ _z A G 8 _I ^A _L ^E - _fl ^il _i ₁ n _TUV-_L ^v _F ^u _s ^b A^_ ₃ ^A _L Y^R _T V^c _s ⁱ _{d a} ^t _s ^{IPTS/128623945.3} 135 Attorney Docket No. PRG-013WO

C _L N t ^C A_CV _E V^{P S} _S ^H _P CD_{P P} ^D _ED _P ^L _{QP P E} D^K _Q ^I _P ^RA _I ^D _LG^L _S ^D _L _I A^{L G} _{S T} ^CD_P K^D _Q ^I _P h ₍ _g ⁱ ₂ K^L _{T S} A_{T T} ^K _{P E T} ^HA_S D P^{S VQ} _QK A_C ^QS _S ^H _{T T} ^K _P ^D _{E T} ^HA L H ^P _Q GAV ADY ^H _TK^H _S K_L ^P _{L P P P} ^Q _T ^Q _E ^V _S V_L ^L _S V^H _TK^H _S K_L ^P _L – C G K A K^Q _C K^P _P A V N^V _T A^L _T ^Y _F ^P _TW R Y^S ₍ A^V _S A N Y^E _C K^P _P A V N^V _T A s_ta G LY TH_S LN^S ^m _r ^PT GH^K _S V^{V G} _P ^D _T ^GY_T S^A _TV^S _S o _Q ^R _F _F V^TKKN^D _E ^L _{E T} K^F _{I Q}D_TD^Y F ^GN _S DA V KY^GS _TD^D _S ^V _T y V _P _d G^G _S ^AGRRW^{M) VG} _PD^T D^T _I ^{L Q} _{P T 9 E S} ^AL _{T S} ^H R_TV V^L) ₀ o G bi_t GA_Q R Y^T _S _FNA^G5 ₆ AA_QL ^MLG_T ⁶ ₆ R_Q: GKR^P _{I T S} M^G _: n ^S _E ^A _CV^W _I RM GO ^{S C}V^FVR _QO A V^S WVG^QA _C ^WN _QS W_TR^L _ERGN cⁱf_i c ₂ ^L _L _QRHAK_{L I} ^D _I VVHGG ^A _CW^D _I MV^V _S NY^{D L} _QK M^K _FM A e H p_s V ^ML Q_S G R Y^W _ED^L _TY V_F ^Q A N A^A _E ^V E ^S ₍ ^V _QS M YY A A Y^W D^Q _E _E ^N _Q ^A _TY V M^S ⁱ ₍ _B ._b ^y _d 2 o ^E 1 ^y _T ^e _l ^y _do ^{E e} _l _d ^t _c ^bi_t ^{b o} _h ^{t b} _T ^{b o} _h n - Y- _a - _c i_t Y- _a - e^l o ^u _r _b ^bi _t ^t _s A- G^AMⁿ _i _L ^s _s ^{- u} _r _b ^t n - s A- G^AMⁿ _i _L ^s _s -_b a n n 9^o ₃ ^g _I Ao^r o n o ₃ ^g _I Ao^r o T A _{1 C} ³ ₁ ^_ _{1 L C} ⁿ _k ⁰ _{2 C} ³ ₁ ^_ _{2 L C} ⁿ _k ^{IPTS/128623945.3} 136 Attorney Docket No. PRG-013WO

)_L ’ _E V 3 ^L _S ^P _Q ^KH ^Q _EK^D _Q ^KF _S G_TDR Y_C ^P _L _Q ^{L P K} _E G_S D ^E _E G^V _EV^TK G_{S QS} H H ^V VM ^A _{E T}Y^K _TA Y_S ^Y _E ^VGVM C _QN^LV ^S _P VD A^P _EWN K_QN^LV -^’ ₂ N^S _{E F} F^S _C ⁾ G₁ ^P _F ^R _P ^S AV P^E _PR K N^Y A G^KN^S _{E F} ^S _C ⁾ G₁ H ^K _T C ^W _S ^S _F ^{P 9} _6: ^I _F ^Y _{F E} ^K _{S S} A^T _{I F Q} ^N _S ^{I K} _T ^F ^W _S ^S _F ^{P 9} _6: - ^L ^’ _{E E}G _S ^Q V L D ^DV^LO VN_S ^{L S} T_L ^P _CYK^E ^LV_{E L T} ^L _{E E}G _S DV^LO A_{I S} N_S LN ^S _P ^N _LN G^{L G} _Q ^P _{P T} ^E _P ^R _PW D^K _EDV A_{I S} N_S N C₍ ^R _S D^D _LG Q_S ^D _I A^L _{S T} D S^HC _T ^KDK _{T Q} ^I _P ^R _S D^D _LG^L ^Q _S ^D _I ₂ ^P H _P ^S C ^L _P ^V _{P Q}K A W^Q _T ^Q _C ^Q E ^V _S V_{L S T} A^L _S V R Y A N Y^{E H} _{P E} _TK^H _S K^H A_LA P_L ^P _P ^S _P ^V _{P Q}K W^Q _T ^Q _E _T ^Y _F ^P _T ^S ₍ ^V _{S C} K^P _P V N^V _T A^L _T ^Y _F ^P _T R Y^S ₍ E S S Y P Y AW^A _S ^V _Q W E_LN YN K^N NVD V_L _L ^S GYK G_FK^V _I ^S _S ^A _TM P ^GGKDDA Y^S _S ⁾ ₃ G_{S P} PGKA_P ^V _: _S ^V _QD^{S A}Y_TO E _T _Q ^CRG_I T _TYVN L _{T I} W^W _{I L} ^V ^R _S G^T ^S D_T ^D _I _{2 Q} ^L _S NM_{S L}G H ^G ^{VL GK A} _Q ^Q _E V _{E T} ^V _{S L L} ^K _{L C} G^S ₍ -^y ₁ ^E _T ^e _l _d ^o o ^y _d ^t _c - ^b ^u _{a h} b o _r GY- - n_i i_t ^bi _t ^t _s ^g _I _^AM L ^s _s -_b n n n A^o ₃ Ao^r o A ¹ _{2 C} ³ _{1 L C} ⁿ _k ^{IPTS/128623945.3} 137 Attorney Docket No. PRG-013WO

S_QRY C _S ^D W^A _TY^K _TN T _TH_L ^G _S ^Y _T ^D _I 2 _L ^I L ^Q _{I T} VM^Y _I G L^G _S ^A _FG^Q _E V D R^F _{S L} G D^G _F ^S ₍ A_TD D V^TA FDHLKC VGT KS H G_S K_S Y^C _E ^L _FV^VV _S ^N _{S Q}K K VYDN K_L ^WD Q^KVGVV_E _S KR VVVV^P _EANV^H _L ₎ HN^S _P ^CGV^KR^C _S ^N _E ^T _L ^A ^’ ₃ ^Q _EV K^D _Q ^KF _S G_TDR Y_C ^P _Q ^{L P} _E D^AE _E G A^V _EV^TK G_{S Q} ^KH G_S H C- ^S ^’ _{P E T}Y^K Y 2 ^P _F ^R _PVD_TA^P _S ^Y _EK^V _QNVM V S AV^E _E RWNKAN^{S L} _F ^{S )} ₁ H ^I _E ^P F ^Y _F ^K _{S S P} A^T _I ^N _F ^Y _QG N^K _{S E} ^F _CG⁹ ^{I K} _T ^W _S ^{S P} ₆ C VN^Q _S ^{L S} _L ^PYK^E _{E L T} ^L _EG_{F S :} -^{’ S} N_T ^G _C ^L _TV RW^K _EV^D _S V^L _S O L_P ^N _L ₍ ^GL _Q ^P _P ^E _{P P} ^D _ED^A _I N^LN C A^L _{S T} ^HCD D^K _Q ^I _P ^R _S ^D _LG_S ^D _I ₂ A_C ^QS H ^V _{S T T} ^K _{P E T} ^HA D S V_L ^L _S V^H _TK^HK_L ^{P P} _P ^S _P ^VQ P_QK Q^Q _E C A^V _S A N Y^E _C K^P _{P S} A V N^V _{T L} A^L _T ^Y _F ^P _TW_T R Y^S ₍ E S S Y PAW^AVYW E _S _LN_QYN K^N NVD V_L _L ^S GYK^A ^G _FK^V _I ^S _TM A P ^GGK_S DD^YS _S ⁾ ^G _{S P}G S ^VP _QDKA A_P Y^V ₃ _T: O E _T ^S Q^C ^L _T ^R _I G_I W^T _TYVN L ^V _S G^TD ^LW_I ^{R S} D_{T I} ₂ H _QS NM_{S L}G^GQ _E V ^V _E ^L _T ^V _S ^G _L ^K _L ^K _L ^A _CQ G^S ₍ -^e ^y ₂ ^E _{T l} _d ^y _d ^t _c - GY^{b o} _h - _a - o b o ^u _r i_t ^{b t} _s ^g _I ^AMⁿ _i _L ^s _s -_b n ⁱ _t A ² ₂ n n ^_ A^o ₃ o o C ³ ₁ ^A _L ^r _C ⁿ _k ^{IPTS/128623945.3} 138 Attorney Docket No. PRG-013WO Fc Modifications [00203] Described herein are bispecific antibodies that bind (1) IL-13 and (2) TSLP or TSLPR comprising modified Fc regions. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991. [00204] In some embodiments, the bispecific antibody comprises a modified Fc comprising one or more modifications. In some embodiments, the one or more modifications are located in a Fc from IgG1 (e.g., human IgG1 (hIgG1). In some embodiments, the one or more modifications are located in a Fc from IgG4 (e.g., human IgG4 (hIgG4). In some embodiments, the one or more modifications are located in a Fc from IgG2. In some embodiments, the one or more modifications promote selective binding of Fc-gamma receptors. In any embodiment, a constant heavy chain region can include a C-terminal lysine. [00205] Amino acid sequences of exemplary Fc regions are provided in Table 13. Table 13. Fc Sequences

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[00206] In some embodiments, any bispecific antibody described herein may comprise a Fc comprising one or more modifications with any one of the Fc modifications described herein. In some embodiments, any bispecific antibody described herein can comprise any one of the Fc sequences in Table 13 (SEQ ID NOs: 425-468, 484-539, 670-680, 689-691, and 693-804). In some embodiments, the CH(1-3) domain of a bispecific antibody in Table 11a or Table 11b is substituted with any one of the Fc sequences in Table 13(SEQ ID NOs: 425- 468, 484-539, 670-680, 689-691, and 693-804). [00207] In some embodiments, one or more modifications in the modified Fc is selected from the group consisting of: S298A, E333A, K334A, K326A, F243L, R292P, Y300L, V305I, P396L, F243L, R292P, Y300L, L235V, P396L, F243L, S239D, I332E, A330L, S267E, L328F, D265S, S239E, K326A, A327H, G237F, K326E, G236A, D270L, H268D, S324T, L234F, N325L, V266L, and S267D. In some embodiments, one or more modifications in the modified Fc is selected from the group consisting of S228P, M252Y, S254T, T256E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, ^{IPTS/128623945.3} 175 Attorney Docket No. PRG-013WO Q311V, A378V, E380A, M428L, N434A, N434S, N297A, D265A, L234A, L235A, and N434W. [00208] In some embodiments, the modified Fc comprises a specific combination of amino acid substitutions selected from the group consisting of: L234A/L235A; V234A/G237A; L235A/G237A/E318A; S228P/L236E; H268Q/V309L/A330S/A331S; C220S/C226S/C229S/P238S; C226S/C229S/E3233P/L235V/L235A; L234F/L235E/P331S; C226S/P230S; L234A/G237A; L234A/L235A/G237A; and L234A/L235A/P329G. [00209] In some embodiments, the modified Fc comprises a specific combination of amino acid substitutions selected from the group consisting of M428L/N434S (LS); M252Y/S254T/T256E (YTE); T250Q/M428L; T307A/E380A/N434A; T256D/T307Q (DQ); T256D/T307W (DW); M252Y/T256D (YD); T307Q/Q311V/A378V (QVV); T256D/H285D/T307R/Q311V/A378V (DDRVV); L309D/Q311H/N434S (DHS); S228P/L235E (SPLE); L234A/L235A (LALA); M428L/N434A (LA); L234A/G237A (LAGA); L234A/L235A/G237A (LALAGA); L234A/L235A/P329G (LALAPG); N297A/YTE; D265A/YTE; LALA/YTE; LAGA/YTE; LALAGA/YTE; LALAPG/YTE; N297A/LS; D265A/LS; LALA/LS; LAGA/LS; LALAGA/LS; LALAPG/LS; N297A/DHS; D265A/DHS; LALA/DHS; LAGA/DHS; LALAGA/DHS; LALAPG/DHS; SP/YTE; SPLE/YTE; SP/LS; SPLE/LS; SP/DHS; SPLE/DHS; N297A/LA; D265A/LA; LALA/LA; LAGA/LA; LALAGA/LA; LALAPG/LA; N297A/N434A; D265A/N434A; LALA/N434A; LAGA/N434A; LALAGA/N434A; LALAPG/N434A; N297A/N434W; D265A/N434W; LALA/N434W; LAGA/N434W; LALAGA/N434W; LALAPG/N434W; N297A/DQ; D265A/DQ; LALA/DQ; LAGA/DQ; LALAGA/DQ; LALAPG/DQ; N297A/DW; D265A/DW; LALA/DW; LAGA/DW; LALAGA/DW; LALAPG/DW; N297A/YD; D265A/YD; LALA/YD; LAGA/YD; LALAGA/YD; LALAPG/YD; N297A/QVV; D265A/QVV; LALA/QVV; LAGA/QVV, LALAGA/QVV; LALAPG/QVV; N297A/DDRVV; D265A/DDRVV; LALA/DDRVV; LAGA/DDRVV; LALAGA/DDRVV; and LALAPG/DDRVV. In some embodiments, the modified Fc comprises a specific combination of amino acid substitutions selected from the group consisting of M428L/N434S (LS) and M252Y/S254T/T256E (YTE). In some embodiments, the modified Fc comprises M428L/N434S (LS) (e.g., SEQ ID NO: 93 SEQ ID NO: 110, SEQ ID NO: 117) modifications. In some embodiments, the modified Fc comprises M252Y/S254T/T256E (YTE) modifications. [00210] In some embodiments, the bispecific antibodies described herein includes modifications to improve its ability to mediate effector function. Such modifications are ^{IPTS/128623945.3} 176 Attorney Docket No. PRG-013WO known in the art and include afucosylation, or engineering of the affinity of the Fc towards an activating receptor, mainly FCGR3a for antibody-dependent cellular cytotoxicity (ADCC), and towards C1q for complement-dependent cytotoxicity (CDC). [00211] In some aspects, the bispecific antibodies provided herein comprises a Fc domain (e.g., IgG1) with reduced fucose content at position Asn 297 (EU numbering) compared to a naturally occurring Fc domain. Such Fc domains are known to have improved ADCC. In some aspects, such antibodies do not comprise any fucose at position Asn 297. [00212] In some embodiments, the bispecific antibodies described herein comprises an Fc region with one or more amino acid substitutions which improve ADCC, such as a substitution at one or more of positions 298, 333, and 334 of the Fc region. In some embodiments, the bispecific antibodies provided herein comprises an Fc region with one or more amino acid substitutions at positions 239, 332, and 330. [00213] In some embodiments, the Fc comprises an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to any one of SEQ ID NOs in Table 13. In some embodiments, the Fc comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to any one of SEQ ID NOs in Table 13. In some embodiments, the Fc comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to any one of SEQ ID NOs in Table 13. In some embodiments, the Fc comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to any one of SEQ ID NOs in Table 13. In some embodiments, the Fc comprises an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to any one of SEQ ID NOs in Table 13. In some embodiments, the Fc comprises an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to any one of SEQ ID NOs in Table 13. In some embodiments, the Fc comprises an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to any one of SEQ ID NOs in Table 13. In some embodiments, the Fc comprises an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to any one of SEQ ID NOs in Table 13. In some embodiments, the Fc comprises the amino acid sequence according to any one of SEQ ID NOs in Table 13. [00214] In some embodiments, the bispecific antibodies described herein comprise an Fc region with at least one galactose residue in the oligosaccharide attached to the Fc region. Such variants may have improved CDC function. ^{IPTS/128623945.3} 177 Attorney Docket No. PRG-013WO [00215] In some embodiments, the bispecific antibodies described herein comprise one or more alterations that improves or diminishes C1q binding and/or CDC. [00216] In certain embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions result in an increase in one or more of antibody half-life, ADCC activity, ADCP activity, or CDC activity compared with the Fc without the one or more substitutions. In certain embodiments, the one or more amino acid substitutions results in increased antibody half-life at pH 6.0 compared to an antibody comprising a wild-type Fc region. In certain embodiments, the bispecific antibody has an increased half-life that is about 10,000-fold, 1,000-fold, 500-fold, 100-fold, 50-fold, 20-fold, 10-fold, 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4.5-fold, 4-fold, 3.5-fold, 3-fold, 2.5-fold, 2- fold, 1.95-fold, 1.9-fold, 1.85-fold, 1.8-fold, 1.75-fold, 1.7-fold, 1.65-fold, 1.6-fold, 1.55-fold, 1.50-fold, 1.45-fold, 1.4-fold, 1.35-fold, 1.3-fold, 1.25-fold, 1.2-fold, 1.15-fold, 1.1-fold, or 1.05-fold longer compared to an antibody comprising a wild-type Fc region. [00217] In certain embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions result in a decrease in one or more of ADCC activity, ADCP activity, or CDC activity compared with the Fc without the one or more substitutions. [00218] In certain embodiments, the Fc region binds an Fc^ Receptor selected from the group consisting of: Fc^RI, Fc^RIIa, Fc^RIIb, Fc^RIIc, Fc^RIIIa, and Fc^RIIIb. In certain embodiments, the Fc region binds an Fc^ Receptor with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region. [00219] In some embodiments, the bispecific antibodies described herein comprise an extended half-life (i.e., serum half-life). In some embodiments, the bispecific antibodies described herein comprise a half-life of at least about 14, 28, 42, 56, 70, 84, 96, or more than 96 weeks. In some embodiments, the TSLP or TSLPR binding protein described herein comprises a half-life in a range of about 14 days to about 96 days, about 14 days to about 84 days, about 14 days to about 70 days, about 14 days to about 56 days, about 14 days to about 42 days, about 14 days to about 28 days, of about 28 days to about 96 days, about 28 days to about 84 days, about 28 days to about 70 days, about 28 days to about 56 days, about 28 days to about 42 days, of about 42 days to about 96 days, about 42 days to about 84 days, about 42 days to about 70 days, or about 42 days to about 56 days. In some embodiments, the bispecific antibodies described herein comprise a half-life in a range of about 42 days to about 56 days. In some embodiments, the bispecific antibodies described herein comprise a half-life of at least about 50 days. In some embodiments, the bispecific antibodies described ^{IPTS/128623945.3} 178 Attorney Docket No. PRG-013WO herein comprise a half-life of about 50 days. Methods of measuring half-life are known in the art. In some embodiments, the half-life is measured in a non-human primate. In some embodiments, the half-life is measured in a human. In some embodiments, the half-life is measured following intravenous administration. In some embodiments, the half-life is measured following subcutaneous administration. [00220] In some embodiments, the bispecific antibodies described herein have a half-life that is at least 20% longer than a comparator antibody. In some embodiments, the comparator antibody comprises the same complementarity determining regions and variable regions but different Fc regions. In some embodiments, the half-life of the bispecific antibodies described herein is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% longer than the half-life of the comparator antibody. In some embodiments, the half-life of the bispecific antibodies described herein is longer than the half-life of the comparator antibody by at least 2 fold, at least 3 fold, at least 4 fold, at least 5 fold, at least 6 fold, at least 7 fold, at least 8 fold, at least 9 fold, or at least 10 fold. Binding [00221] The affinity of a molecule X for its partner Y can be represented by the dissociation equilibrium constant (K_D). The kinetic components that contribute to the dissociation equilibrium constant are described in more detail below. Affinity can be measured by common methods known in the art, including those described herein, such as surface plasmon resonance (SPR) technology (e.g., BIACORE®) or biolayer interferometry (e.g., FORTEBIO®). [00222] With regard to the binding of an antibody to a target molecule, the terms “bind,” “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction (e.g., with a non-target molecule). Specific binding can be measured, for example, by measuring binding to a target molecule (i.e., IL-13. TSLP, or TSLPR) and comparing it to binding to a non-target molecule. Specific binding can also be determined by competition with a control molecule that mimics the epitope recognized on the target molecule. In that case, specific binding is indicated if the binding of the antibody to the target molecule is competitively inhibited by the control molecule. In some embodiments, the affinity of a bispecific antibody disclosed here in for a non-target molecule is less than about 50% of the affinity for IL-13 TSLP, or TSLPR. In some embodiments, the affinity of a bispecific antibody disclosed here in for a non-target molecule is less than about 40% of the affinity for IL-13 TSLP, or TSLPR. ^{IPTS/128623945.3} 179 Attorney Docket No. PRG-013WO In some embodiments, the affinity of a bispecific antibody disclosed here in for a non-target molecule is less than about 40% of the affinity for IL-13 TSLP, or TSLPR. In some embodiments, the affinity of a bispecific antibody disclosed here in for a non-target molecule is less than about 20% of the affinity for IL-13 TSLP, or TSLPR. In some embodiments, the affinity of a bispecific antibody disclosed here in for a non-target molecule is less than about 10% of the affinity for IL-13 TSLP, or TSLPR. In some embodiments, the affinity of a bispecific antibody disclosed here in for a non-target molecule is less than about 1% of the affinity for IL-13 TSLP, or TSLPR. In some embodiments, the affinity of a bispecific antibody disclosed here in for a non-target molecule is less than about 0.1% of the affinity for IL-13 TSLP, or TSLPR. [00223] When used herein in the context of two or more antibodies, the term “competes with” or “cross-competes with” indicates that the two or more antibodies compete for binding to an antigen (e.g., IL-13). In one exemplary assay, IL-13 is coated on a surface and contacted with a first anti-IL-13 antibody, after which a second anti-IL-13 antibody is added. In another exemplary assay, a first anti-IL-13 antibody is coated on a surface and contacted with IL-13, and then a second anti-IL-13 antibody is added. If the presence of the first anti- IL-13 antibody reduces binding of the second anti-IL-13 antibody, in either assay, then the antibodies compete with each other. The term “competes with” also includes combinations of antibodies where one antibody reduces binding of another antibody, but where no competition is observed when the antibodies are added in the reverse order. However, in some embodiments, the first and second antibodies inhibit binding of each other, regardless of the order in which they are added. In some embodiments, one antibody reduces binding of another antibody to its antigen by at least 25%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% as measured in a competitive binding assay. A skilled artisan can select the concentrations of the antibodies used in the competition assays based on the affinities of the antibodies for IL-13 and the valency of the antibodies. The assays described in this definition are illustrative, and a skilled artisan can utilize any suitable assay to determine if antibodies compete with each other. Suitable assays are described, for example, in Cox et al., “Immunoassay Methods,” in Assay Guidance Manual [Internet], Updated December 24, 2014 (ncbi.nlm.nih.gov/books/NBK92434/; accessed September 29, 2015); Silman et al., Cytometry, 2001, 44:30-37; and Finco et al., J. Pharm. Biomed. Anal., 2011, 54:351-358; each of which is incorporated by reference in its entirety. ^{IPTS/128623945.3} 180 Attorney Docket No. PRG-013WO [00224] A test antibody competes with a reference antibody if an excess of a test antibody (e.g., at least 2x, 5x, 10x, 20x, or 100x) inhibits or blocks binding of the reference antibody by, e.g., at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as measured in a competitive binding assay. Antibodies identified by competition assay (competing antibody) include antibodies binding to the same epitope as the reference antibody and antibodies binding to an adjacent epitope sufficiently proximal to the epitope bound by the reference antibody for steric hindrance to occur. For example, a second, competing antibody can be identified that competes for binding to IL-13 with a first antibody described herein. In certain instances, the second antibody can block or inhibit binding of the first antibody by, e.g., at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as measured in a competitive binding assay. In certain instances, the second antibody can displace the first antibody by greater than 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. [00225] In certain embodiments, the antibody binds a human IL-13 and TSLP or TSLPR. [00226] In certain embodiments, the bispecific antibody binds an IL-13 sequence set forth in SEQ ID NOs: 472-475. [00227] In certain embodiments, the bispecific antibody is cross-reactive to cynomolgus monkey IL-13. [00228] In certain embodiments, the bispecific antibody is cross-reactive to cynomolgus monkey IL-13. [00229] In certain embodiments, the bispecific antibody binds to an IL-13 sequence set forth in SEQ ID NOs: 472-475 with a K_D of less than or equal to about 1, 2, 3, 4, 5, 6, 7, 8, 9 x 10^-9 M, as measured by SPR. In certain embodiments, the bispecific antibody binds to an IL-13 sequence set forth in SEQ ID NOs: 472-475 with a K_D of less than or equal to about 1 x 10^-10 M, as measured by SPR. In certain embodiments, the bispecific antibody binds to human IL-13 with a K_D of less than or equal to about 1 x 10^-9 M, as measured by SPR. [00230] In some embodiments, a bispecific antibody provided herein binds IL-13 with a K_D of less than or equal to about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.95, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 x 10^-8 M, as measured by ELISA or any other suitable method known in the art. In some embodiments, an antibody provided herein binds IL-13 with a K_D of less than or equal to about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.95, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 x 10^-9 M, as measured by ELISA or any other suitable method known in the art. ^{IPTS/128623945.3} 181 Attorney Docket No. PRG-013WO [00231] In some embodiments, the K_D of the antibody provided herein for the binding of IL-13, TSLP, or TSLPR is between about 0.001-0.01, 0.01-0.1, 0.01-0.05, 0.05-0.1, 0.1-0.5, 0.5-1, 0.25-0.75, 0.25-0.5, 0.5-0.75, 0.75-1, 0.75-2, 1.1-1.2, 1.2-1.3, 1.3-1.4, 1.4-1.5, 1.5-1.6, 1.6-1.7, 1.7-1.8, 1.8-1.9, 1.9-2, 1-2, 1-5, 2-7, 3-8, 3-5, 4-6, 5-7, 6-8, 7-9, 7-10, or 5-10 x 10^-8 M, as measured by ELISA or any other suitable method known in the art. In some embodiments, an antibody provided herein binds IL-13, TSLP, or TSLPR with a KD of less than or equal to about 1 x 10^-8 M, or less than or equal to above 1 x 10^-9 M as measured by ELISA or any other suitable method known in the art. [00232] In some embodiments, the antibody provided herein binds IL-13, TSLP, or TSLPR with a KD of less than or equal to about 10, 9, 8, 7, 6, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.98, 1.95, 1.9, 1.85, 1.8, 1.75, 1.7, 1.65, 1.6, 1.55, 1.50, 1.45, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.05, 0.01, 0.005, 0.001, 0.0005, or 0.0001 x 10^-8 M, or less, as measured by ELISA or any other suitable method known in the art . In some embodiments, the antibody provided herein binds IL-13, TSLP, or TSLPR with a K_D between 5-3, 4-2, 3-1, 1.9-1.8, 1.8-1.7, 1.7-1.6, 1.6-1.5, 1.9-1.5, 1.5-1, 1-0.8, 1-0.5, 0.9-0.6, 0.7-0.4, 0.6-0.2, 0.5-0.3, 0.3-0.2, 0.2-0.1, 0.1-0.01, 0.01-0.001, or 0.001-0.0001 x 10^-8 M as measured by ELISA or any other suitable method known in the art. Function [00233] “Effector functions” refer to those biological activities mediated by the Fc region of an antibody, which activities may vary depending on the antibody isotype. Examples of antibody effector functions include receptor ligand blocking, agonism, or antagonism, C1q binding to activate complement dependent cytotoxicity (CDC), Fc receptor binding to activate antibody-dependent cellular cytotoxicity (ADCC), and antibody dependent cellular phagocytosis (ADCP). In some embodiments, the effector function of the bispecific anti-IL- 13/TSLP or TSLPR antibodies described herein is antagonism and blocks the IL-13 receptor binding to IL-13 and/or blocks TSLP binding to TSLPR. Pharmaceutical compositions [00234] The present application provides compositions comprising the bispecific antibodies including pharmaceutical compositions comprising any one or more of the bispecific antibodies described herein with one or more pharmaceutically acceptable excipients. In some embodiments the composition is sterile. The pharmaceutical compositions generally comprise an effective amount of a bispecific antibody. [00235] These compositions can comprise, in addition to one or more of the bispecific antibodies disclosed herein, a pharmaceutically acceptable excipient, carrier, buffer, stabilizer ^{IPTS/128623945.3} 182 Attorney Docket No. PRG-013WO or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material can depend on the route of administration, e.g., oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal routes. [00236] Pharmaceutical compositions for oral administration can be in tablet, capsule, powder or liquid form. A tablet can include a solid carrier such as gelatin or an adjuvant. Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol can be included. [00237] For intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer’s Injection, Lactated Ringer’s Injection. Preservatives, stabilizers, buffers, antioxidants and/or other additives can be included, as required. [00238] The bispecific anti-IL-13/TSLP or TSLPR antibodies that is to be given to an individual, administration is preferably in a “therapeutically effective amount” or “prophylactically effective amount” (as the case can be, although prophylaxis can be considered therapy), this being sufficient to show benefit to the individual. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of protein aggregation disease being treated. Prescription of treatment, e.g., decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington’s Pharmaceutical Sciences, 16^th edition, Osol, A. (ed), 1980. [00239] A composition can be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated. Methods ^{IPTS/128623945.3} 183 Attorney Docket No. PRG-013WO Methods of Preparation [0001] Methods for making bispecific antibodies are known in the art. See Milstein and Cuello (1983) NATURE 305:537, International (PCT) Publication No. WO93/08829, and Traunecker et al. (1991) EMBO J., 10:3655. For further details of generating bispecific antibodies see, for example, Suresh et al. (1986) METHODS ENZYMOL.121:210. Bispecific antibodies include cross-linked or “heteroconjugate” or “heterodimer” antibodies. For example, one of the antibodies in the heterodimer can be coupled to avidin, the other to biotin. Heterodimer antibodies may be made using any convenient cross-linking method. Suitable cross-linking agents are well known in the art, and are disclosed in U.S. Pat. No. 4,676,980, along with a number of cross-linking techniques. [00240] For example, bispecific antibodies described herein can be produced using recombinant methods and compositions, e.g., as described in U.S. Pat. No.4,816,567. In one embodiment, an isolated nucleic acid encoding a bispecific antibody described herein is provided. Such a nucleic acid may encode an amino acid sequence comprising the VL sequence(s) and/or an amino acid sequence comprising the VH sequence(s) of the antibody (e.g., the light and/or heavy chains of the antibody). In a further embodiment, one or more vectors (e.g., expression vectors) comprising such nucleic acids are provided. In one embodiment, the nucleic acid is provided in a multicistronic vector. In a further embodiment, a host cell comprising such nucleic acid is provided. In one such embodiment, a host cell comprises (e.g., has been transformed with): (1) a vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL sequence(s) of the antibody and an amino acid sequence comprising the VH sequence(s) of the antigen-binding polypeptide construct, or (2) a first vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL sequence(s) of the antigen-binding polypeptide construct and a second vector comprising a nucleic acid that encodes an amino acid sequence comprising the VH sequence(s) of the antigen-binding polypeptide construct. In one embodiment, the host cell is eukaryotic, e.g., a Chinese Hamster Ovary (CHO) cell, or human embryonic kidney (HEK) cell, or lymphoid cell (e.g., Y0, NS0, Sp20 cell). In one embodiment, a method of making a bispecific antibody is provided, wherein the method comprises culturing a host cell comprising nucleic acid encoding the bispecific antibody, as provided above, under conditions suitable for expression of the antibody, and optionally recovering the antibody from the host cell (or host cell culture medium). ^{IPTS/128623945.3} 184 Attorney Docket No. PRG-013WO [00241] For recombinant production of the antibody, nucleic acid encoding an antibody, e.g., as described above, is isolated and inserted into one or more vectors for further cloning and/or expression in a host cell. Such nucleic acid may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody). [00242] When an antibody or variant thereof is recombinantly produced by the host cells, the protein in certain embodiments is present at about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, about 4%, about 3%, about 2%, or about 1% or less of the dry weight of the cells. When the antibody or variant thereof is recombinantly produced by the host cells, the protein, in certain embodiments, is present in the culture medium at about 5 g/L, about 4 g/L, about 3 g/L, about 2 g/L, about 1 g/L, about 750 mg/L, about 500 mg/L, about 250 mg/L, about 100 mg/L, about 50 mg/L, about 10 mg/L, or about 1 mg/L or less of the dry weight of the cells. In certain embodiments, “substantially purified” antibody produced by the methods described herein, has a purity level of at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, specifically, a purity level of at least about 75%, 80%, 85%, and more specifically, a purity level of at least about 90%, a purity level of at least about 95%, a purity level of at least about 99% or greater as determined by appropriate methods such as SDS/PAGE analysis, RP-HPLC, SEC, and capillary electrophoresis. [00243] Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells described herein. [00244] Recombinant host cells or host cells are cells that include an exogenous polynucleotide, regardless of the method used for insertion, for example, direct uptake, transduction, f-mating, or other methods known in the art to create recombinant host cells. The exogenous polynucleotide may be maintained as a nonintegrated vector, for example, a plasmid, or alternatively, may be integrated into the host genome. Host cells can include CHO, derivatives of CHO, NS0, Sp2O, CV-1, VERO-76, HeLa, HepG2, Per.C6, or BHK. [00245] For example, antibody may be produced in bacteria, in particular when glycosylation and Fc effector function are not needed. For expression of antibody fragments and polypeptides in bacteria, see, e.g., U.S. Pat. Nos.5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol.248 (B.K.C. Lo, ed., Humana Press, Totowa, N.J., 2003), pp.245-254, describing expression of antibody fragments in E. coli.) ^{IPTS/128623945.3} 185 Attorney Docket No. PRG-013WO After expression, the antibody may be isolated from the bacterial cell paste in a soluble fraction and can be further purified. [00246] In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for antibody-encoding vectors, including fungi and yeast strains whose glycosylation pathways have been “humanized,” resulting in the production of an antibody with a partially or fully human glycosylation pattern. See Gerngross, Nat. Biotech.22:1409-1414 (2004), and Li et al., Nat. Biotech.24:210-215 (2006). [00247] Suitable host cells for the expression of glycosylated antibodies are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Numerous baculoviral strains have been identified which may be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells. [00248] Plant cell cultures can also be utilized as hosts. See, e.g., U.S. Pat. Nos.5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing PLANTIBODIES™ technology for producing antibodies in transgenic plants). [00249] Vertebrate cells may also be used as hosts. For example, mammalian cell lines that are adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney line (293 or 293 cells as described, e.g., in Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells as described, e.g., in Mather, Biol. Reprod.23:243-251 (1980)); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., in Mather et al., Annals N.Y. Acad. Sci.383:44-68 (1982); MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR− CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines such as Y0, NS0 and Sp2/0. For a review of certain mammalian host cell lines suitable for antibody production, see, e.g., Yazaki and Wu, Methods in Molecular Biology, Vol.248 (B.K.C. Lo, ed., Humana Press, Totowa, N.J.), pp.255-268 (2003). [00250] In one embodiment, the antibodies described herein are produced in stable mammalian cells, by a method comprising: transfecting at least one stable mammalian cell with: nucleic acid encoding the antibody, in a predetermined ratio; and expressing the nucleic ^{IPTS/128623945.3} 186 Attorney Docket No. PRG-013WO acid in the at least one mammalian cell. In some embodiments, the predetermined ratio of nucleic acid is determined in transient transfection experiments to determine the relative ratio of input nucleic acids that results in the highest percentage of the antibody in the expressed product. [00251] In some embodiments, is the method of producing an antibody in stable mammalian cells as described herein wherein the expression product of the at least one stable mammalian cell comprises a larger percentage of the desired glycosylated antibody as compared to the monomeric heavy or light chain polypeptides, or other antibodies. [00252] In some embodiments, is the method of producing a glycosylated antibody in stable mammalian cells described herein, said method comprising identifying and purifying the desired glycosylated antibody. In some embodiments, the said identification is by one or both of liquid chromatography and mass spectrometry. [00253] If required, the antibodies can be purified or isolated after expression. Proteins may be isolated or purified in a variety of ways known to those skilled in the art. Standard purification methods include chromatographic techniques, including ion exchange, hydrophobic interaction, affinity, sizing or gel filtration, and reversed-phase, carried out at atmospheric pressure or at high pressure using systems such as FPLC and HPLC. Purification methods also include electrophoretic, immunological, precipitation, dialysis, and chromatofocusing techniques. Ultrafiltration and diafiltration techniques, in conjunction with protein concentration, are also useful. As is well known in the art, a variety of natural proteins bind Fc and antibodies, and these proteins can find use in the present invention for purification of antibodies. For example, the bacterial proteins A and G bind to the Fc region. Likewise, the bacterial protein L binds to the Fab region of some antibodies. Purification can often be enabled by a particular fusion partner. For example, antibodies may be purified using glutathione resin if a GST fusion is employed, Ni⁺² affinity chromatography if a His-tag is employed or immobilized anti-flag antibody if a flag-tag is used. For general guidance in suitable purification techniques, see, e.g., incorporated entirely by reference Protein Purification: Principles and Practice, 3^rd Ed., Scopes, Springer-Verlag, NY, 1994, incorporated entirely by reference. The degree of purification necessary will vary depending on the use of the antibodies. In some instances, no purification is necessary. [00254] In certain embodiments, the antibodies are purified using Anion Exchange Chromatography including, but not limited to, chromatography on Q-sepharose, DEAE sepharose, poros HQ, poros DEAF, Toyopearl Q, Toyopearl QAE, Toyopearl DEAE, Resource/Source Q and DEAE, Fractogel Q and DEAE columns. ^{IPTS/128623945.3} 187 Attorney Docket No. PRG-013WO [00255] In specific embodiments, the proteins described herein are purified using Cation Exchange Chromatography including, but not limited to, SP-sepharose, CM sepharose, poros HS, poros CM, Toyopearl SP, Toyopearl CM, Resource/Source S and CM, Fractogel S and CM columns and their equivalents and comparables. [00256] In addition, antibodies described herein can be chemically synthesized using techniques known in the art (e.g., see Creighton, 1983, Proteins: Structures and Molecular Principles, W. H. Freeman & Co., N.Y and Hunkapiller et al., Nature, 310:105-111 (1984)). For example, a polypeptide corresponding to a fragment of a polypeptide can be synthesized by use of a peptide synthesizer. Furthermore, if desired, nonclassical amino acids or chemical amino acid analogs can be introduced as a substitution or addition into the polypeptide sequence. Non-classical amino acids include, but are not limited to, to the D-isomers of the common amino acids, 2,4diaminobutyric acid, alpha-amino isobutyric acid, 4aminobutyric acid, Abu, 2-amino butyric acid, g-Abu, e-Ahx, 6amino hexanoic acid, Aib, 2-amino isobutyric acid, 3-amino propionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, alanine, fluoro-amino acids, designer amino acids such as methyl amino acids, C-methyl amino acids, N-methyl amino acids, and amino acid analogs in general. Furthermore, the amino acid can be D (dextrorotary) or L (levorotary). [00257] In certain embodiments, an antibody described herein has an aggregation temperature greater than about 69 °C, greater than about 70 °C, greater than about 71 °C, greater than about 72 °C, greater than about 73 °C, greater than about 74 °C, greater than about 75 °C, or greater than about 76 °C, for example, between about 69 °C and about 77 °C, between about 70 °C and about 76 °C, between about 71 °C and about 75 °C. In certain embodiments, aggregation temperature is measured using DSF. [00258] In certain embodiments, an antibody described herein has reduced hydrophobicity as compared to lebrikizumab as measured by hydrophobic interaction chromatography (HIC). In certain embodiments, the antibody exhibits an HIC retention time that is less than about 15.2 min. In certain embodiments, the antibody exhibits an HIC retention time that is between about 13 min and about 15 min. Methods of Use [00259] In an aspect, the present application provides methods of contacting IL-13 with an bispecific antibody described herein, which results in inhibition of IL-13 binding to an IL-13 receptor expressed on a cell and/or the inhibition of TSLP binding to TSLPR on a cell. ^{IPTS/128623945.3} 188 Attorney Docket No. PRG-013WO [00260] In an aspect, the present application provides methods of using the bispecific antibodies described herein for treatment of a disorder or disease in a subject. In certain aspects, described herein is a method for treating a subject in need thereof with a bispecific antibody, the method comprising administering to a mammalian subject a therapeutically effective amount of a bispecific antibody or pharmaceutical composition comprising a bispecific antibody described herein. In certain embodiments, the present application provides methods of treating a disorder or disease associated with elevated levels of IL-13 and/or IgE and/or TSLP in a subject. [00261] In certain aspects, described herein are methods for treating a pathology associated with IL-13 and/or TSLP activity, the method comprising administering to a mammalian subject a therapeutically effective amount a bispecific antibody or a pharmaceutical composition comprising a bispecific antibody described herein. [00262] In certain aspects, described herein is a method for treating an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount an antibody described herein or a pharmaceutical composition described herein. In certain embodiments of the methods described herein, 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. In certain embodiments of the methods described herein, the inflammatory disorder or disease is alopecia areata. In certain embodiments, the inflammatory disorder or disease is chronic sinusitis with nasal polyps. In certain embodiments, the inflammatory disorder or disease is Chronic Rhinosinusitis without Nasal Polyps (CRSsNP). In certain embodiments, the inflammatory disorder or disease is eosinophilic esophagitis (EoE). In certain embodiments, the inflammatory disorder or disease is an Eosinophilic gastrointestinal disorder or disease (ENID) selected from the group consisting of Eosinophilic Gastritis (EoG), Eosinophilic enteritis (EoN), Eosinophilic colitis (EoC), and Eosinophilic Gastroenteritis (EGE). In certain embodiments, the inflammatory disorder or disease is Churg-Strauss syndrome/Eosinophilic granulomatosis with polyangiitis (EGPA). In certain embodiments, the inflammatory disorder or disease is Prurigo Nodularis (PN). In certain embodiments, the inflammatory disorder or disease is Chronic Spontaneous Urticaria (CSU). In certain embodiments, the inflammatory disorder or disease is Chronic Pruritis of Unknown Origin (CPUO). In certain embodiments, the inflammatory disorder or disease is Bullous Pemphigoid (BP). In certain embodiments, the inflammatory disorder or disease is Cold Inducible Urticaria (ColdU). In certain ^{IPTS/128623945.3} 189 Attorney Docket No. PRG-013WO embodiments, the inflammatory disorder or disease is Allergic Fungal Rhinosinusitis (AFRS). In certain embodiments, the inflammatory disorder or disease is Allergic Bronchopulmonary Aspergillosis (ABPA). In certain embodiments, the inflammatory disorder or disease is Chronic Obstructive Pulmonary Disease (COPD). In certain embodiments, the inflammatory disorder or disease is inflammatory bowel disease, such as Crohn disease or ulcerative colitis. In certain embodiments, the inflammatory disorder or disease is psoriasis. In certain embodiments, the inflammatory disorder or disease is lupus. In certain embodiments, the inflammatory disorder or disease is rheumatoid arthritis. [00263] In certain aspects, described herein are methods for treating a pathology associated with elevated levels of IL-13 in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount an antibody or a pharmaceutical composition described herein. [00264] In certain aspects, described herein are methods of reducing biological activity of IL-13 and/or TSLP in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount an antibody or a pharmaceutical composition described herein. [00265] In certain aspects, described herein are methods for inhibiting the TH2 type allergic response in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of a bispecific antibody or a pharmaceutical composition described herein. [00266] In certain aspects, described herein are methods for inhibiting IL-13-induced phosphorylation of STAT6 in a cell, the method comprising contacting the cell with an antibody described herein. [00267] In certain aspects, described herein are methods for inhibiting IL-13-induced CD23 expression in a cell, the method comprising contacting the cell with a bispecific antibody described herein. [00268] In certain aspects, described herein are methods for inhibiting IL-13-induced secretion of CCL2 and CCL26 from a cell, the method comprising contacting the cell with a bispecific antibody described herein. [00269] In certain aspects, described herein are methods for inhibiting IL-13-induced NTRK1 expression in a cell, the method comprising contacting the cell with a bispecific antibody described herein. [00270] In certain aspects, described herein are methods for reducing levels of Thymus and Activation Regulated Chemokine (TARC)/CCL17 in a mammalian subject in need ^{IPTS/128623945.3} 190 Attorney Docket No. PRG-013WO thereof, the method comprising administering to the mammalian subject a therapeutically effective amount a bispecific antibody or a pharmaceutical composition described herein. [00271] In certain aspects, described herein are methods of preventing an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount a bispecific antibody or a pharmaceutical composition described herein. Methods of Administration [00272] In some embodiments, the methods provided herein are useful for the treatment of a disease or disorder in an individual. In an embodiment, the individual is a human and the antibody is an anti-IL-13 antibody described herein. [00273] In some embodiments, an antibody is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. An effective amount of a bispecific antibody may be administered for the treatment of a disease or disorder. The appropriate dosage of a bispecific antibody may be determined based on the type of disease or disorder to be treated, the type of the bispecific antibody, the severity and course of the disease or disorder, the clinical condition of the individual, the individual’s clinical history and response to the treatment, and the discretion of the attending physician. [00274] In some embodiments, an antibody provided herein is administered with at least one additional therapeutic agent. Any suitable additional therapeutic or immunotherapeutic agent may be administered with an antibody provided herein. Additional therapeutic agents include agents that are used to treat or prevent a disease or disorder such as, but not limited to, an inflammatory disease or disorder associated with elevated levels of IL-13 and/or IgE and/or TSLP. [00275] The additional therapeutic agent can be administered by any suitable means. In some embodiments, an antibody provided herein and the additional therapeutic agent are included in the same pharmaceutical composition. In some embodiments, an antibody provided herein and the additional therapeutic agent are included in different pharmaceutical compositions. [00276] In embodiments where a bispecific antibody provided herein and the additional therapeutic agent are included in different pharmaceutical compositions, administration of the bispecific antibody can occur prior to, simultaneously, and/or following, administration of the additional therapeutic agent. In some embodiments, administration of an antibody provided herein and the additional therapeutic agent occur within about one month of each other. In ^{IPTS/128623945.3} 191 Attorney Docket No. PRG-013WO some embodiments, administration of a bispecific antibody provided herein and the additional therapeutic agent occur within about one week of each other. In some embodiments, administration of a bispecific antibody provided herein and the additional therapeutic agent occur within about one day of each other. In some embodiments, administration of a bispecific antibody provided herein and the additional therapeutic agent occur within about twelve hours of each other. In some embodiments, administration of a bispecific antibody provided herein and the additional therapeutic agent occur within about one hour of each other. Kits and Articles of Manufacture [00277] The present application provides kits comprising any one or more of the bispecific antibody compositions described herein and instructions for use. In some embodiments, the kits further contain a component selected from any of secondary antibodies, reagents for immunohistochemistry analysis, pharmaceutically acceptable excipient and instruction manual and any combination thereof. In one specific embodiment, the kit comprises a pharmaceutical composition comprising any one or more of the bispecific antibody compositions described herein, with one or more pharmaceutically acceptable excipients. [00278] The present application also provides articles of manufacture comprising any one of the bispecific antibody compositions or kits described herein. Examples of an article of manufacture include vials (including sealed vials). EXAMPLES [00279] Provided herein are examples of specific embodiments for carrying out the present invention. The examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should, of course, be allowed for. [00280] The practice of the present invention will employ, unless otherwise indicated, conventional methods of protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. See, e.g., T.E. Creighton, Proteins: Structures and Molecular Properties (W.H. Freeman and Company, 1993); A.L. Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Sambrook, et al., Molecular Cloning: A Laboratory Manual (2^nd Edition, 1989); Methods In Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.); Remington’s ^{IPTS/128623945.3} 192 Attorney Docket No. PRG-013WO Pharmaceutical Sciences, 18^th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry 3^rd Ed. (Plenum Press) Vols A and B(1992). Methods Gene synthesis and plasmid construction [00281] The coding sequences for HCs and LCs of the bispecific antibody were generated by DNA synthesis and PCR, subsequently subcloned into a plasmid for mammalian cell expression for protein expression in mammalian cell system. The gene sequences in the expression vectors were confirmed by DNA sequencing. Expression of antibody constructs [00282] Transient expression of bispecific antibodies was performed by co-transfection of paired HC and LC constructs into CHO cells using PEI method. Briefly, CHO cells at approximately 5.5×10⁶/mL in a shake flask were used as the host. Transfection was initiated by adding a mixture of 1 mg/L DNA and 7 mg/L PEI in OptiMEM™ medium (Invitrogen) to the cells followed by gentle mixing. Cells were then cultured in an incubator shaker at 120 rpm, 37°C, and 8% CO2, for 9 days. Feeding with peptone and glucose was carried out 24 h later and every 2-3 days thereafter depending on the cell density and viability. The cell culture was terminated on day 9 when cell viability reduced to <80%. The conditioned medium was harvested for protein purification. Purification of antibody construct [00283] Protein purification by affinity chromatography, and ion exchange chromatography was performed using an AKTA pure instrument (GE Lifesciences). Conditional medium expressing target bispecific antibody was harvested by centrifugation at 4000 rpm, 50 min, and filtered with a 0.22 µm filter. The harvested supernatants were loaded to a column of Mabselect™ SuRe™ (GE Healthcare). After washing column with Buffer A (PBS, PH 7.4), the protein was eluted with Buffer B (1 M Glycine, pH 2.7), and immediately neutralized with 1/10 volume of Buffer D (1 M sodium citrate, pH 6.0). The affinity purified antibody was then buffer exchanged into 20 mM sodium acetate pH 5.5. SEC-HPLC Analysis of Antibody Construct ^{IPTS/128623945.3} 193 Attorney Docket No. PRG-013WO [00284] Analytical SEC-HPLC was performed using Shimadzu LC-10 HPLC instrument (Shimadzu Corp.).20 µl sample on 1 mg/mL was loaded to a Superdex® 200 Increase 5/150GL column (GE Lifesciences). The mobile phase was 2*PBS with a flow rate of 0.3 mL/min, 15 min. Measuring Antibody-IL13 Binding Kinetics Using Surface Plasmon Resonance [00285] A Biacore 8K SPR system (GE HealthCare) equipped with Series S Sensor Chip Protein G (Cytiva, Cat.29179315) was used to determine the binding kinetic rate and affinity constants at 25˚C and in a running buffer of HBS-EP+ (10 mM HEPES pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.05% Surfactant P20). Following a stabilization period in running buffer, the bispecific constructs (diluted to 1 ^g/mL) were captured onto flow cell 2 (active) for 60 sec at a flow rate of 10 µL/min. Recombinant Human IL13, TSLP and/or TSLPR Protein, His Tag was prepared at concentrations of 0, 0.39, 0.78, 1.56, 3.13, 6.25, 12.5 and 0 nM and injected over flow cell 1 (reference) and flow cell 2 (active) for 180 sec at a flow rate of 30 ^L/min. Recombinant Cynomolgus IL13, TSLP and/or TSLPR Protein, His Tag was prepared at concentrations of 0, 0.39, 0.78, 1.56, 3.13, 6.25, 12.5, 25 and 0 nM and injected over flow cell 1 (reference) and flow cell 2 (active) for 180 sec at a flow rate of 30 ^L/min. Samples were injected in a multi-cycle manner over freshly captured bispecific antibody, by regenerating the capture surfaces with injection of glycine pH 1.5 for 30 sec at a flow rate of 30 ^L/min. The data was processed and analyzed with Biacore Insight Evaluation Software Version 2.0.15.12933 (GE Healthcare) as follows. Responses from flow cell 1 (reference) were subtracted from the responses from flow cell 2 (active). The responses from the two buffer blank injections were then subtracted from the reference subtracted data (2–1) to yield double-referenced data, which were fit to an 1:1 binding model to determine the apparent association (ka) and dissociation rate constants (kd). Their ratio provides the apparent equilibrium dissociation constant or affinity constant (KD = kd/ka). Assessing blockade by cell-line-based assays [00286] Multiple assays are used to assess blockade of the full signalling complex of IL- 13/IL4a and/or TSLP/TSLPR and prevention of downstream signalling. Briefly, HEK293 previously transduced to stably express both hIL-13/IL4a and/or hTSLP/TSLPR are cultured and harvested. Cells are seeded at 200,000 cells in 100 µL per well. Cells are washed and the supernatant is discarded. A 100 µL mixture of biotinylated hIL-13 and/or hTSLP and purified bispecific antibody (1:1 by volume) is made and incubated for 1 hour. The incubated mixture ^{IPTS/128623945.3} 194 Attorney Docket No. PRG-013WO is added to resuspend the cells, resulting in a final concentration of 0.05 ug/mL of hIL-13 and/or hTSLP and 0-100 nM of purified bispecific antibody. The cells are stained in this mixture at 4 °C for 1 hour. Cells are then washed and stained with 100 µL of Alexa Fluor 488-conjugated streptavidin at a 1:1000 dilution to detect binding of biotinylated hIL-13 on the cell surface. Cells are incubated at 4 °C for 1 hour, protected from light. Cells are then washed and the median fluorescence intensity (MFI) of cells in each well are recorded by FACS using a BD FACSCanto II. Subsequent data are analyzed using GraphPad Prism. IC₅₀ values are determined as the concentration of bispecific antibody required to inhibit 50% of the maximum MFI of biotinylated hIL-13 or hTSLP surface detected with incubation of 0.05 ug/mL of hIL-13 or hTSLP alone. Assessing blockade by ELISA [00287] 96-well plates (Costar #9018) are coated with TSLP R at 2ug/ml in PBS pH7.4 at 4°C overnight and then blocked with PBST+1% BSA for 2h at 37°C. Serial diluted test articles (duplicate, 1/5 diluted from 10 nM, 7 dose + Blank) are mixed with 5 ng/ml Biotin- TSLP for 30 min at RT. Then, test antibody (TA)-TSLP mixture is added to blocked plates and incubated for 1 h at 37°C. After washing, plates are incubated with Streptavidin-HRP for 1 h at 37°C. After wash, TMB is added to each well and incubated at room temperature until color developed (approximately 10 min). Reactions are stopped by addition of 1N HCl and optical density (OD) is read at 450 nm. Inhibition% is calculated as 1- (OD450 of sample/OD450 of ‘Ligand only’). IC50 of TAs is calculated through non-linear regression Inhibition of IL-13 or TSLP Binding to IL-13/IL4a or TSLP/TSLPR Overexpressing Cells [00288] IL-13 and/or TSLP binding to cells overexpressing IL-13/IL4R^ and/or TSLP/TSLPR is used to evaluate the functional blockade of antibodies against this binding interaction. It is expected that the cell-line-based assays will show that the bispecific antibodies will exhibit a low IC50 and inhibit IL-13 and/or TSLP binding on an IL-13/IL4R^ or TSLP/TSLPR overexpression cell line. Example 1: Engineered bispecific antibodies exhibit improved affinity and potency of blockade of IL-13/IL4a and/or TSLP/TSLPR Results ^{IPTS/128623945.3} 195 Attorney Docket No. PRG-013WO Determination of Antibody Affinity to IL-13 and/or TSLP or TSLPR [00289] Using the methods described above, the affinity of bispecific antibodies to IL-13 and/or TSLP/TSLPR and the binding kinetics thereof were assessed using surface plasmon resonance (SPR). [00290] As measure by SPR, the bispecific antibodies bound to human IL-13 and/or TSLP with sub-nanomolar affinity. The results are summarized in Table 14. Table 14.

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Claims

Attorney Docket No. PRG-013WO Claims 1. A bispecific antibody, wherein the bispecific antibody comprises a first antigen binding site and a second antigen binding site, wherein a) the first antigen binding site binds Interleukin 13 (IL-13) and comprises a first variable heavy (VH) chain sequence comprising three first heavy chain CDR sequences, a first CDR- H1, a first CDR-H2, and a first CDR-H3; and a first variable light (VL) chain sequence comprising three first light chain CDR sequences, a first CDR-L1, a first CDR-L2, and a first CDR-L3; wherein: i. the first CDR-H1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 58-99 and 121; ii. the first CDR-H2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 100-111; iii. the first CDR-H3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 112-120 and 130-140, iv. the first CDR-L1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 141-144 and 149-152, v. the first CDR-L2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 153-158 and LAS; and vi. the first CDR-L3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 165-172; and b) wherein the second antigen binding site binds TSLP or TSLPR and comprises a second variable heavy (VH) chain sequence comprising three second heavy chain CDR sequences, a second CDR-H1, a second CDR-H2, and a second CDR-H3; and a second variable light (VL) chain sequence comprising three second light chain CDR sequences, a second CDR-L1, a second CDR-L2, and a second CDR-L3; wherein: vii. the second CDR-H1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 610-618; viii. the second CDR-H2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 619-627; ix. the second CDR-H3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 628-636, x. the second CDR-L1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 637-645., IPTS/128623945.3 Attorney Docket No. PRG-013WO xi. the second CDR-L2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 646-651; and xii. the second CDR-L3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 652-657. 2. The isolated bispecific antibody of claim 1, wherein i. the first CDR-H1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 58, 68, and 85; ii. the first CDR-H2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 100, 104; and 108; iii. the first CDR-H3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 112 and 130; iv. the first CDR-L1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 141 and 589; v. the first CDR-L2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 153 and LAS; and vi. the first CDR-L3 comprises a sequence set forth in SEQ ID NOs: 165; and vii. the second CDR-H1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 610-618; viii. the second CDR-H2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 619-627; ix. the second CDR-H3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 628-636; x. the second CDR-L1 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 637-645; xi. the second CDR-L2 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 646-651; and xii. the second CDR-L3 comprises a sequence selected from the sequences set forth in SEQ ID NOs: 652-657. 3. The isolated bispecific antibody of claim 1 or 2, wherein the antibody comprises a first VH sequence selected from SEQ ID NOs: 1-32, 470, and 688 and a second VH sequence selected from SEQ ID NOs: 659-661, 682, 684, 686, and 688. IPTS/128623945.3 Attorney Docket No. PRG-013WO 4. The isolated bispecific antibody of any one of claims 1-3, wherein the antibody comprises a first VH sequence comprising SEQ ID NO: 3 and a second VH sequence selected from SEQ ID NOs: 659-661, 682, 684, 686, and 688. 5. The isolated bispecific antibody of any one of claims 1-4, wherein the antibody comprises a first VL sequence selected from SEQ ID NOs: 33-57, 471, and 687 and a second VL sequence selected from SEQ ID NOs: 662-664, 681, 683, and 685. 6. The isolated bispecific antibody of any one of claims 1-5, wherein the bispecific antibody comprises a first VL sequence comprising SEQ ID NO: 39 and a second VL sequence selected from SEQ ID NOs: 662-664, 681, 683, and 685. 7. The isolated bispecific antibody of any one of claims 1-3, wherein the bispecific antibody comprises a first VH sequence selected from SEQ ID NOs: 1-32, 470, and 688 and a second VH sequence selected from SEQ ID NOs: 659-661, 682, 684, 686, and 688; and a first VL sequence selected from SEQ ID NOs: 33-57, 471, and 687 and a second VL sequence selected from SEQ ID NOs: 662-664, 681, 683, and 685. 8. The isolated bispecific antibody of any one of claims 1-3 or 7, wherein the bispecific antibody comprises a first VH sequence comprising SEQ ID NOs: 3 and a second VH sequence selected from SEQ ID NOs: 659-661, 682, 684, 686, and 688; and a first VL sequence comprising SEQ ID NOs: 39 and a second VL sequence selected from SEQ ID NOs: 662-664, 681, 683, and 685. 9. The isolated bispecific antibody of any one of claims 1-8, wherein the bispecific antibody is a humanized, human, or chimeric antibody. 10. The isolated bispecific antibody of any one of claims 1-9, wherein the bispecific antibody is a humanized antibody. 11. The isolated bispecific antibody of any one of claims 1-10, wherein the bispecific antibody comprises a heavy chain human constant region of a class selected from IgG, IgA, IgD, IgE, and IgM. 12. The isolated bispecific antibody of claim 11, wherein the human Fc region comprises a human heavy chain constant region of the class IgG and a subclass selected from IgG1, IgG2, IgG3, and IgG4. 13. The isolated bispecific antibody of claim 12, wherein the human Fc region comprises a human IgG1 Fc. 14. The isolated bispecific antibody of claim 12, wherein the human Fc region comprises a human IgG4 Fc. IPTS/128623945.3 Attorney Docket No. PRG-013WO 15. The isolated bispecific antibody of claim 12, wherein the human Fc region comprises a human IgG2 Fc. 16. The isolated bispecific antibody of any one of claims 11-15, wherein the Fc region comprises a sequence selected from any one of the sequences set forth in SEQ ID NOs: 425- 468, 484-539, 670-680, 689-691, and 693-804. 17. The isolated bispecific antibody of any one of the claims 11-16, wherein the heavy chain comprises a constant heavy chain sequence set forth in SEQ ID NO: 439. 18. The isolated bispecific antibody of any one of claims 1-17, wherein the bispecific antibody comprises a heavy chain/chain A from Table 11a or Table 11b, a light chain/chain B from Table 12a or Table 12b, and, optionally, an Fc sequence from Table 13. 19. The isolated antibody of any one of claims 11-18, wherein the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions results in a change in antibody half-life, ADCC activity, ADCP activity, or CDC activity as compared to an otherwise equivalent antibody comprising an Fc without the one or more substitutions. 20. The isolated bispecific antibody of claim 19, wherein the change is (a) an increase in antibody half-life and (b) a decrease in ADCC activity, ADCP activity, or CDC activity as compared to an otherwise equivalent antibody comprising an Fc without the one or more substitutions. 21. The isolated bispecific antibody of claim 19, wherein the one or more amino acid substitutions results in increased antibody half-life compared to an antibody comprising a wild-type Fc region. 22. The isolated bispecific antibody of any one of claims 1-21 for use in the treatment of an inflammatory disorder or disease. 23. An isolated polynucleotide or set of polynucleotides encoding the bispecific antibody of any of claims 1-21, a VH thereof, a VL thereof, a light chain thereof, a heavy chain thereof, or an antigen-binding portion thereof, and optionally, wherein the polynucleotide or set of polynucleotides comprises cDNA. 24. A vector or set of vectors comprising the polynucleotide or set of polynucleotides of claim 23. 25. A host cell comprising the polynucleotide or set of polynucleotides of claim 23 or the vector or set of vectors of claim 24. 26. A method of producing an antibody, the method comprising expressing the bispecific antibody with the host cell of claim 25 and isolating the expressed bispecific antibody. IPTS/128623945.3 Attorney Docket No. PRG-013WO 27. A pharmaceutical composition comprising the bispecific antibody of any one of claims 1-21 and a pharmaceutically acceptable excipient. 28. A kit comprising the bispecific antibody of any one of claims 1-21 or a pharmaceutical composition of claim 27 and instructions for use. 29. A method for treating an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount the bispecific antibody of any one of claims 1-21 or a pharmaceutical composition of claim 27. IPTS/128623945.3