Antibodies that bind tslp and tslpr and methods of use

Abstract

Provided herein are variant TSLP or TSLPR binding proteins and methods of use.

Description

ANTIBODIES THAT BIND TSLP AND TSLPR AND METHODS OF USECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit and priority to U.S. Provisional Patent Application No. 63 / 522,626, filed June 22, 2023.BACKGROUND

[0002] 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.

[0003] TSLP binds to a heterodimeric receptor consisting of the TSLP receptor (TSLPR) and an IL-7 receptor a chain (IL-7R a) 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.

[0004] 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.

[0005] Accordingly, there is a need in the art for antagonists to TSLP or the TSLP receptor (TSLPR) for preventing and treating diseases in which human TSLP and human TSLP receptor are involved in the disease pathology, such as inflammatory and fibrotic disorders.BRIEF DESCRIPTION OF THE FIGURES

[0001] FIG. 1 shows the ability of Antibody 1 wild-type and Antibody 1 YTE to inhibit the STAT5-induced expression of luciferase.

[0006] FIG. 2 shows the ability of Antibody 1 wild-type and Antibody 1 YTE to inhibit the proliferation of Baf3 cells.

[0007] FIG. 3A, FIG. 3B, and FIG. 3C the ability of the indicated antibodies to inhibit the STAT5-induced expression of luciferase in HEK293 cells.

[0008] FIG. 4A and FIG. 4B the ability of the indicated antibodies to inhibit the STAT5- induced expression of luciferase in Ba / F3 cells.

[0009] FIG. 5A and FIG. 5B shows the ability of the indicated antibodies to inhibit the proliferation of Baf3 cells.

[0010] FIG. 6A - FIG. 6C shows the ability of the indicated antibodies to inhibit the secretion of TARC from donor PMBC cells.

[0011] FIG. 7A - FIG. 7C shows the ability of the indicated antibodies to inhibit the secretion of TARC from donor isolated, monocyte cells.SUMMARY OF THE DISCLOSURE

[0012] The present disclosure provides antibodies to TSLP and TSLP receptor (TSLPR) and methods of treating diseases in which human TSLP and human TSLP receptor are involved in disease pathology. The antibodies of the disclosure can include Fc modifications and exhibit longer half-lives than an otherwise identical antibody that does not include the Fc modification, for example, certain anti-TSLP and anti-TSLPR antibodies known in the art.

[0013] In one aspect, provided herein is a TSLP or TSLPR binding protein comprising: (a) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence set forth in any one of SEQ ID NOs: 1-12, (ii) a CDR2 having an amino acid sequence set forth in any one of SEQ ID NOs: 13-24, and (iii) a CDR3 having an amino acid sequence set forth in any one of SEQ ID NOs: 25-36; (b) a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence set forth in any one of SEQ ID NOs: 37-48, (ii) a CDR2 having an amino acid sequence set forth in any one of SEQ ID NOs: 49-56, and (iii) a CDR3 having an amino acid sequence set forth in any one of SEQ ID NOs: 57-60; and (c) an Fc domain comprising at least one amino acid modification.

[0014] In some embodiments, the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 1, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO:13, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 25; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 37, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 49, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 57.

[0015] In some embodiments, the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 2, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO:14, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 26; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 38, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 50, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 58.

[0016] In some embodiments, the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 3, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO:15, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 27; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 39, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 51, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 59.

[0017] In some embodiments, the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 4, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO:16, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 28; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 40, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 52, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 60.

[0018] In some embodiments, the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 5, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO:17, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 29; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 41, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 53, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 61.

[0019] In some embodiments, the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 6, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO:18, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 30; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 42, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 54, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 62.

[0020] In some embodiments, the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 7, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO:19, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 31; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 43, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 55, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 63.

[0021] In some embodiments, the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 8, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO:20, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 32; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 44, (ii) a CDR2having an amino acid sequence set forth in SEQ ID NO: 56, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 60.

[0022] In some embodiments, the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 9, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 21, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 33; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 45, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 53, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 57.

[0023] In some embodiments, the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 10, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 22, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 34; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 46, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 54, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 58.

[0024] In some embodiments, the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 11, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 23, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 35; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 47, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 55, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 59.

[0025] In some embodiments, the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 12, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 24, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 36; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 48, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 56, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 60.

[0026] In some embodiments, the VH comprises a sequence having at least 80% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 65-69, and the VL comprises a sequence having at least 80% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 70-74.

[0027] In some embodiments, the VH comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 65 and the VL comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 70.

[0028] In some embodiments, the VH comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 66 and the VL comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 71.

[0029] In some embodiments, the VH comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 67 and the VL comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 72.

[0030] In some embodiments, the VH comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 68 and the VL comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 73.

[0031] In some embodiments, the VH comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 69 and the VL comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 74.

[0032] In some embodiments, the Fc is an IgGl, IgG2 or IgG4 immunoglobulin Fc domain.

[0033] In some embodiments, the Fc is an IgGl immunoglobulin domain, wherein the at least one modification comprises the modifications M252Y, S254T, and T256E (YTE).

[0034] In some embodiments, the Fc is an IgGl immunoglobulin domain, wherein the at least one modification comprises L234A / L235A (LALA).

[0035] In some embodiments, the Fc is an IgGl immunoglobulin domain, wherein the at least one modification comprises LALAGA and N434A.

[0036] In some embodiments, the Fc is an IgGl immunoglobulin domain, wherein the at least one modification comprises M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS).

[0037] In some embodiments, the Fc is an IgGl immunoglobulin domain, wherein the at least one modification comprises M252Y, S254T, and T256E (YTE) and L234A / L235A (LALA).

[0038] In some embodiments, the Fc is an IgG2 immunoglobulin domain.

[0039] In some embodiments, the Fc is an IgG4 immunoglobulin domain.

[0040] In one aspect, provided herein is a TSLP or TSLPR binding protein comprising: a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence set forth in any one of SEQ ID NOs: 1-12, (ii) a CDR2 having an amino acid sequence set forth in any one of SEQ ID NOs: 13-24, and (iii) a CDR3 having an amino acid sequence set forth in any one of SEQ ID NOs: 25-36; a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence set forth in any one of SEQ ID NOs: 37-48, (ii) a CDR2 having an amino acid sequence set forth in any one of SEQ ID NOs: 49-56, and (iii) a CDR3 having an amino acid sequence set forth in any one of SEQ ID NOs: 57-60; and a modified Fc that extends half-life of the TSLP or TSLPR binding protein as compared to a TSLP or TSLPR binding protein that does not comprise the modified Fc.

[0041] In one aspect, provided herein is a TSLP or TSLPR binding protein, wherein the TSLP or TSLPR binding protein specifically binds to an epitope of TSLP and comprises a Fc domain comprising amino acid modifications M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS).

[0042] In one aspect, provided herein is a method of treating an inflammatory disorder or disease in a patient in need thereof, the method comprising subcutaneously or intravenously administering to the patient an effective amount of an TSLP or TSLPR binding protein of any one of the TSLP or TSLPR binding protein described herein.

[0043] In some embodiments, the inflammatory disorder or disease is atopic dermatitis.

[0044] In some embodiments, the inflammatory disorder or disease is asthma.

[0045] In some embodiments, administration of the TSLP or TSLPR binding protein is subcutaneous.

[0046] In some embodiments, administration of the TSLP or TSLPR binding protein is intravenousDETAILED DESCRIPTION

[0047] To facilitate an understanding of the present disclosure, a number of terms and phrases are defined below.

[0048] As used herein, unless otherwise indicated, the term “antibody” is understood to mean an intact antibody (e.g., an intact monoclonal antibody), or a fragment thereof, such as a Fc fragment of an antibody (e.g., an Fc fragment of a monoclonal antibody), or an antigen-binding fragment of an antibody (e.g., an antigen-binding fragment of a monoclonal antibody), including an intact antibody, antigen-binding fragment, or Fc fragment that has been modified, engineered, or chemically conjugated. In general, antibodies are multimeric proteins that contain four polypeptide chains. Two of the polypeptide chains are called immunoglobulin heavy chains (H chains), and two of the polypeptide chains are called immunoglobulin light chains (L chains). The immunoglobulin heavy and light chains are connected by an interchain disulfide bond. The immunoglobulin heavy chains are connected by interchain disulfide bonds. A light chain consists of one variable region (VL) and one constant region (CL). The heavy chain consists of one variable region (VH) and at least three constant regions (CHI, CH2 and CH3). The variable regions determine the binding specificity of the antibody. Each variable region contains three hypervariable regions known as complementarity determining regions (CDRs) flanked by four relatively conserved regions known as framework regions (FRs). The extent of the FRs andCDRs has been defined (Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91- 3242; and Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917). The three CDRs, referred to as CDR1, CDR2, and CDR3, contribute to the antibody binding specificity. Naturally occurring antibodies have been used as starting material for engineered antibodies, such as chimeric antibodies and humanized antibodies. Examples of antibody -based antigen-binding fragments include Fab, Fab’, (Fab’)2, Fv, single chain antibodies (e.g., scFv), minibodies, and diabodies. Examples of antibodies that have been modified or engineered include chimeric antibodies, humanized antibodies, and multispecific antibodies (e.g., bispecific antibodies). An example of a chemically conjugated antibody is an antibody conjugated to a toxin moiety.

[0049] The terms “variable domain” and “variable region” are used interchangeably and refer to the portions of the antibody or immunoglobulin domains that exhibit variability in their sequence and that are involved in determining the specificity and binding affinity of a particular antibody. Variability is not evenly distributed throughout the variable domains of antibodies; it is concentrated in sub-domains of each of the heavy and light chain variable regions. These subdomains are called “hypervariable regions” or “complementarity determining regions” (CDRs). The more conserved (i.e., non-hypervariable) portions of the variable domains are called the “framework” regions (FRM or FR) and provide a scaffold for the six CDRs in three dimensional space to form an antigen-binding surface.

[0050] An “Fc polypeptide” of a dimeric Fc as used herein refers to one of the two polypeptides forming the dimeric Fc domain, i.e. a polypeptide comprising C-terminal constant regions of an immunoglobulin heavy chain, capable of stable self-association. For example, an Fc polypeptide of a dimeric IgG Fc comprises an IgG CH2 and an IgG CH3 constant domain sequence. An Fc can be of the class IgA, IgD, IgE, IgG, and IgM. These classes are also designated a, 8, s, y, and p, respectively. Several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

[0051] The terms “Fc receptor” and “FcR” are used to describe a receptor that binds to the Fc region of an antibody. For example, an FcR can be a native sequence human FcR. Generally, an FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and FcyRIII subclasses, including allelic variants and alternatively spliced forms of these receptors. FcyRII receptors include FcyRIIA (an “activating receptor”) and FcyRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. Immunoglobulins of other isotypes can also be bound by certain FcRs (see, e.g., Janeway et al., Immuno Biology, the immune system in health and disease, (Elsevier Science Ltd., NY) (4th ed., 1999)). Activating receptor FcyRIIA contains animmunoreceptor tyrosine-based activation motif (IT AM) in its cytoplasmic domain. Inhibiting receptor FcyRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain (reviewed in Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term “FcR” herein. The term also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976); and Kim et al., J. Immunol. 24:249 (1994)).

[0052] The terms “recipient”, “individual”, “subject”, “host”, and “patient”, are used interchangeably herein and in some embodiments, refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired, particularly humans. “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and laboratory, zoo, sports, or pet animals, such as dogs, horses, cats, cows, sheep, goats, pigs, mice, rats, rabbits, guinea pigs, monkeys etc. In some embodiments, the mammal is human. None of these terms require the supervision of medical personnel.

[0053] As used herein, the term “effective amount” refers to the amount of a compound (e.g., a compound of the present disclosure) sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

[0054] As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0055] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[0056] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate.

[0057] As used herein, all numerical values or numerical ranges include whole integers within or encompassing such ranges and fractions of the values or the integers within or encompassing ranges unless the context clearly indicates otherwise. Thus, for example, reference to a range of 90-100%, includes 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth. In another example, reference to a range of 1-5,000-fold includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, fold, etc., as well as 1.1, 1.2, 1.3, 1.4, 1.5, fold, etc., 2.1, 2.2, 2.3, 2.4, 2.5, fold, etc., and so forth.

[0058] “About” a number, as used herein, refers to range including the number and ranging from 10% below that number to 10% above that number. “About” a range refers to 10% below the lower limit of the range, spanning to 10% above the upper limit of the range.

[0059] “Percent (%) identity” refers to the extent to which two sequences (nucleotide or amino acid) have the same residue at the same positions in an alignment. For example, “an amino acid sequence is X% identical to SEQ ID NO: Y” refers to % identity of the amino acid sequence to SEQ ID NO: Y and is elaborated as X% of residues in the amino acid sequence are identical to the residues of sequence disclosed in SEQ ID NO: Y. Generally, computer programs are employed for such calculations. Exemplary programs that compare and align pairs of sequences, include ALIGN (Myers and Miller, 1988), FASTA (Pearson and Lipman, 1988; Pearson, 1990) and gapped BLAST (Altschul et al., 1997), BLASTP, BLASTN, or GCG (Devereux et al., 1984).

[0060] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present disclosure that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present disclosure that consist essentially of, or consist of, the recited processing steps.

[0061] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.TSLP Binding Proteins and TSLPR Binding Proteins

[0062] Provided herein are TSLP or TSLPR binding proteins that bind to TSLP or TSLPR, respectively. In certain embodiments, the TSLP or TSLPR binding protein is an antibody. In certain embodiments, the TSLP or TSLPR binding protein is an antibody comprising a modified Fc region. Described herein, in certain embodiments, are TSLP or TSLPR binding proteinscomprising a) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 1-12, (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 13-24, and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 25-36; b) a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 37-48, (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 49-56, and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 57-60; and c) a Fc domain comprising amino acid modifications M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS).

[0063] Further described herein, in certain embodiments, are TSLP or TSLPR binding proteins comprising: a) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 1-12, (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 13-24, and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 25-36; b) a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 37-48, (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 49-56, and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 57-60; and c) a modified Fc that extends half-life of the TSLP or TSLPR binding protein as compared to a TSLP or TSLPR binding protein that does not comprise the modified Fc.

[0064] Further described herein, in certain embodiments, are TSLP or TSLPR binding proteins, wherein the TSLP or TSLPR binding protein specifically binds to an epitope of TSLP and comprises a Fc domain comprising amino acid modifications M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS).

[0065] Amino acid sequences of exemplary CDRs of TSLP or TSLPR binding proteins are provided in Table 1.Table 1. Sequences of CDRs

[0066] In some embodiments, the TSLP or TSLPR binding protein comprises a heavy chain variable region comprising a CDR1, CDR2, and CDR3 as listed in Table 1. In some embodiments, the TSLP or TSLPR binding protein comprises a heavy chain variable region comprising (a) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 1- 12 (b) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 13 - 24, and (c) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 25 - 36.

[0067] In some embodiments, the TSLP or TSLPR binding protein comprises a light chain variable region comprising a CDR1, CDR2, and CDR3 as listed in Table 1. In some embodiments, the TSLP or TSLPR binding protein comprises a light chain variable region comprising (a) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 37- 48, (b) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 49 - 56, and (c) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 57 - 60.

[0068] In some embodiments, the TSLP or TSLPR binding protein comprises a heavy chain variable region comprising (a) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 1 - 12, (b) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 13 - 24, and (c) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 35 - 36; and a light chain variable region comprising (a) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 37 - 48, (b) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 49 - 56, and (c) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 57 - 60.

[0069] In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 1, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 13, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 25; and a light chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 37, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 49, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 57.

[0070] In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 2, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 14, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 26; and a light chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 38, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 50, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 58.

[0071] In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 3, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 15, and (c) a CDR3 having an amino acidsequence of SEQ ID NO: 27; and a light chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 39, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 51, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 59.

[0072] In some embodiments, the TSLPR binding protein comprises a heavy chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 4, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 16, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 28; and a light chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO 40, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 52, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 60.

[0073] In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 5, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 17, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 29; and a light chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 41, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 53, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 61.

[0074] In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 6, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 18, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 30; and a light chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 42, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 54, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 62.

[0075] In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 7, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 19, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 31; and a light chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 43, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 55, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 63.

[0076] In some embodiments, the TSLPR binding protein comprises a heavy chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 8, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 20, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 32; and a light chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 44, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 56, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 60.

[0077] In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 9, (b) a CDR2having an amino acid sequence of SEQ ID NO: 21, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 33; and a light chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 45, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 53, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 57.

[0078] In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 10, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 22, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 34; and a light chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 46, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 54, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 58.

[0079] In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 11, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 23, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 35; and a light chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 47, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 55, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 59.

[0080] In some embodiments, the TSLPR binding protein comprises a heavy chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 12, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 24, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 36; and a light chain variable region comprising (a) a CDR1 having an amino acid sequence of SEQ ID NO: 48, (b) a CDR2 having an amino acid sequence of SEQ ID NO: 56, and (c) a CDR3 having an amino acid sequence of SEQ ID NO: 60.

[0081] Amino acid sequences of exemplary heavy chain variable regions (VH) and light chain variable regions (VL) of TSLP or TSLPR binding proteins are provided in Table 2.Table 2. Sequences of heavy chain variable regions (VH) and light chain variable regions (VL) of TSLP or TSLPR binding proteins

[0082] In some embodiments, the TSLP or TSLPR binding protein comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 65-69. In some embodiments, the TSLP or TSLPR binding protein comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 65-69. In some embodiments, the TSLP or TSLPR binding protein comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 65-69. In some embodiments, the TSLP or TSLPR binding protein comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 65-69. In some embodiments, the TSLP or TSLPR binding protein comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 65-69. In some embodiments, the TSLP or TSLPR binding protein comprises a heavy chain comprising anamino acid sequence having at least 97 % sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 65-69. In some embodiments, the TSLP or TSLPR binding protein comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 65-69. In some embodiments, the TSLP or TSLPR binding protein comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 65-69. In some embodiments, the TSLP or TSLPR binding protein comprises a heavy chain variable region (VH) comprising an amino acid sequence having 100% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 65-69.

[0083] In some embodiments, the TSLP or TSLPR binding protein comprises a light chain variable region (VL) comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 70 - 74. In some embodiments, the TSLP or TSLPR binding protein comprises a light chain variable region (VL) comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 70 - 74. In some embodiments, the TSLP or TSLPR binding protein antibody comprises a light chain variable region (VL) comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 70 - 74. In some embodiments, the TSLP or TSLPR binding protein comprises a light chain variable region (VL) comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 70 - 74. In some embodiments, the TSLP or TSLPR binding protein comprises a light chain variable region (VL) comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 70 - 74. In some embodiments, the TSLP or TSLPR binding protein comprises a light chain variable region (VL) comprising an amino acid sequence having at least 97 % sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 70 - 74. In some embodiments, the TSLP or TSLPR binding protein comprises a light chain variable region (VL) comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 70 - 74. In some embodiments, the TSLP or TSLPR binding protein comprises a light chain variable region (VL) comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 70 - 74. In some embodiments, the TSLP or TSLPR binding protein comprises a light chain variable region (VL) comprising an amino acid sequence having 100% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 70 - 74

[0084] In some embodiments, the TSLP or TSLPR binding protein comprises a heavy chain variable region (VH) that comprises an amino acid sequence at least 60% (e.g., at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the heavy chain variable region (VH) of an TSLP or TSLPR binding protein disclosed in Table 2, and a light chain variable region (VL) that comprises an amino acid sequence at least 60% (e.g., at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to the light chain variable region (VL) of the same TSLP or TSLPR binding protein disclosed in Table 2.

[0085] In some embodiments, the TSLP or TSLPR binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 65-69; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 70 - 74. In some embodiments, the TSLP or TSLPR binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 65-69; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 70 - 74. In some embodiments, the TSLP or TSLPR binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 65-69; and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 70 - 74. In some embodiments, the TSLP or TSLPR binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 65-69; and a light chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 70 - 74. In some embodiments, the TSLP or TSLPR binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 65-69; and a light chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 70 - 74. In some embodiments, the TSLP or TSLPR binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 97 % sequence identity withan amino acid sequence according to any one of SEQ ID NOs: 65-69; and a light chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 70 - 74. In some embodiments, the TSLP or TSLPR binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 65-69; and a light chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 70 - 74. In some embodiments, the TSLP or TSLPR binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to any one of SEQ ID NOs: 65-69; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according any one of SEQ ID NOs: 70 - 74. In some embodiments, the TSLP or TSLPR binding protein comprises a heavy chain variable region comprising an amino acid sequence according to any one of SEQ ID NOs: 65-69; and a light chain variable region comprising an amino acid sequence according to any one of SEQ ID NOs: 70 - 74.

[0086] In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 65; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 70. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 65; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 70. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 65; and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 70. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 65; and a light chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 70. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 65; and a light chain variable region comprising an amino acid sequence having at least96% sequence identity with an amino acid sequence according to SEQ ID NO: 70. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 97 % sequence identity with an amino acid sequence according to SEQ ID NO: 65; and a light chain variable region comprising an amino acid sequence having at least 97 % sequence identity with an amino acid sequence according to SEQ ID NO: 70. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 65; and a light chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 70. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to SEQ ID NO: 65; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according SEQ ID NO: 70. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 65; and a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 70.

[0087] In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 66; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 71. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 66; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 71. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 66; and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 71. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 66; and a light chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 71. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acidsequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 66; and a light chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 71. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 97 % sequence identity with an amino acid sequence according to SEQ ID NO: 66; and a light chain variable region comprising an amino acid sequence having at least 97 % sequence identity with an amino acid sequence according to SEQ ID NO: 71. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 66; and a light chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 71. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to SEQ ID NO: 66; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according SEQ ID NO: 71. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 66; and a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 71.

[0088] In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 67; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 72. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 67; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 72. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 67; and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 72. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 67; and a light chain variable region comprising an amino acid sequence having at least 95% sequenceidentity with an amino acid sequence according to SEQ ID NO: 72. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 67; and a light chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 72. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 97 % sequence identity with an amino acid sequence according to SEQ ID NO: 67; and a light chain variable region comprising an amino acid sequence having at least 97 % sequence identity with an amino acid sequence according to SEQ ID NO: 72. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 67; and a light chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 72. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to SEQ ID NO: 67; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according SEQ ID NO: 72. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 67; and a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 72.

[0089] In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 68; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 73. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 68; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 73. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 68; and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 73. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having atleast 95% sequence identity with an amino acid sequence according to SEQ ID NO: 68; and a light chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 73. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 68; and a light chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 73. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 97 % sequence identity with an amino acid sequence according to SEQ ID NO: 68; and a light chain variable region comprising an amino acid sequence having at least 97 % sequence identity with an amino acid sequence according to SEQ ID NO: 73. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 68; and a light chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 73. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to SEQ ID NO: 68; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according SEQ ID NO: 73. In some embodiments, the TSLP binding protein comprises a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 68; and a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 73.

[0090] In some embodiments, the TSLPR binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 69; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 74. In some embodiments, the TSLPR binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 69; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 74. In some embodiments, the TSLPR binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 69; and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity withan amino acid sequence according to SEQ ID NO: 74. In some embodiments, the TSLPR binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 69; and a light chain variable region comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 74. In some embodiments, the TSLPR binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 69; and a light chain variable region comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 74. In some embodiments, the TSLPR binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 69; and a light chain variable region comprising an amino acid sequence having at least 97 % sequence identity with an amino acid sequence according to SEQ ID NO: 74. In some embodiments, the TSLPR binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 69; and a light chain variable region comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 74. In some embodiments, the TSLPR binding protein comprises a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to SEQ ID NO: 69; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according SEQ ID NO: 74. In some embodiments, the TSLPR binding protein comprises a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 69; and a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 74.Fc Modifications

[0065] Described herein are TSLP or TSLPR binding proteins 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.

[0066] In some embodiments, the TSLP or TSLPR binding proteins comprise a modified Fc comprising one or more modifications. In some embodiments, the one or more modifications are located in a Fc from IgGl (e.g., human IgGl (hlgGl). In some embodiments, the one or moremodifications are located in a Fc from IgG4 (e.g., human IgG4 (h!gG4). 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.

[0067] Amino acid sequences of exemplary Fc sequences are provided in Table 3. Table 3. Fc Sequences

[0068] In some embodiments, the TSLP or TSLPR binding protein comprises an Fc comprising one or more modifications in SEQ ID NO: 76. In some embodiments, the TSLP or TSLPR binding protein comprises a Fc comprising one or more modifications in SEQ ID NO: 77. In some embodiments, the TSLP or TSLPR binding protein comprises a Fc comprising oneor more modifications in SEQ ID NO: 82. 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: 76, 77, and 82. 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: 76, 77, and 82. 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: 76, 77, and 82. 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: 76, 77, and 82. 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: 76, 77, and 82. 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: 76, 77, and 82. 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: 76, 77, and 82. 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: 76, 77, and 82. In some embodiments, the Fc comprises the amino acid sequence according to any one of SEQ ID NOs: 76, 77, and 82.

[0069] 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, E309D, Q411H, Q311V, A378V, E380A, M428E, N434A, N434S, N297A, D265A, E234A, E235A, and N434W.

[0070] 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 / E236E; H268Q / V309E / A330S / A331S;C220S / C226S / C229S / P238S; C226S / C229S / E3233P / E235V / E235A; E234F / E235E / P331S; C226S / P230S; E234A / G237A; E234A / E235A / G237A; and E234A / E235A / P329G.

[0071] 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 / M428E; 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) (e.g., SEQ ID NO: 86, SEQ ID NO: 107, SEQ ID NO: 116) modifications.

[0072] In some embodiments, the TSLP or TSLPR binding protein described herein includes modifications to improve its ability to mediate effector function. Such modifications are known in the art and include afucosylation, or engineering of the affinity of the Fc towards an activating receptor, mainly FCGR3a for antibody-dependent cellular cytotoxicity (ADCC), and towards Clq for complement-dependent cytotoxicity (CDC).

[0073] In some aspects, the TSLP or TSLPR binding protein provided herein comprises a Fc domain (e.g., IgGl) 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.

[0074] In some embodiments, the TSLP or TSLPR binding protein 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 TSLP or TSLPR binding protein provided herein comprises an Fc region with one or more amino acid substitutions at positions 239, 332, and 330.

[0075] 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: 75-175 and 178-188. 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: 75- 175 and 178-188. 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: 75-175 and 178-188. 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: 75-175 and 178-188. 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: 75-175 and 178-188. 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: 75-175 and 178-188. 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: 75-175 and 178-188. 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: 75-175 and 178-188. In some embodiments, the Fc comprises the amino acid sequence according to any one of SEQ ID NOs: 75-175 and 178-188.

[0076] In some embodiments, the TSLP or TSLPR binding protein described herein comprises an Fc region with at least one galactose residue in the oligosaccharide attached to the Fc region. Such variants may have improved CDC function.

[0077] In some embodiments, the TSEP or TSLPR binding protein described herein comprises one or more alterations that improves or diminishes Clq binding and / or CDC.

[0078] 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 antibody has an increased halflife 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.

[0079] 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.

[0080] In certain embodiments, the Fc region binds an Fey Receptor selected from the group consisting of: FcyRI, FcyRIIa, FcyRIIb, FcyRIIc, FcyRIIIa, and FcyRIIIb. In certain embodiments, the Fc region binds an Fey Receptor with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.

[0081] In some embodiments, the TSLP or TSLPR binding protein described herein comprises an extended half-life (i.e., serum half-life). In some embodiments, the TSLP or TSLPR binding protein described herein comprises 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 TSLP or TSLPR binding proteins described herein comprise a half-life in a range of about 42 days to about 56 days. In some embodiments, the TSLP or TSLPR binding protein described herein comprises a half-life of at least about 50 days. In some embodiments, the TSLP or TSLPR binding protein described herein comprises 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.

[0082] In some embodiments, the TSLP or TSLPR binding proteins 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 TSLP or TSLPR binding protein 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 TSLP or TSLPR binding protein 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.Light Chain Constant Regions

[0083] Described herein are TSLP or TSLPR binding proteins comprising a light chain constant (LC) region. Unless otherwise specified herein, numbering of amino acid residues in the light chain 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, 5thEd. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0084] In some embodiments, the TSLP or TSLPR binding proteins comprise a light chain constant (LC) region disclosed herein. In some embodiments, the TSLP or TSLPR binding proteins comprise an LC region comprising SEQ ID NO: 176. In some embodiments, the TSLP or TSLPR binding proteins comprise an LC comprising SEQ ID NO: 177.

[0085] Amino acid sequences of exemplary Fc constant region sequences are provided in Table 4.Table 4. Light Chain Constant RegionsMETHODS OF TREATMENT

[0091] Described herein, in certain embodiments, the TSLP or TSLPR binding protein is used in the treatment of an inflammatory disorder or disease. In certain embodiments, the TSLP or TSLPR binding protein 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 TSLP or TSLPR binding protein is used in the treatment of asthma. In certain embodiments, the TSLP or TSLPR binding protein is used in the treatment of idiopathic pulmonary fibrosis. In certain embodiments, the TSLP or TSLPR binding protein is used in the treatment of alopecia areata. In certain embodiments, the TSLP or TSLPR binding protein is used in the treatment of chronic sinusitis with nasal polyps. In certain embodiments, the TSLP or TSLPR binding protein is used in the treatment of Chronic Rhinosinusitis without Nasal Polyps (CRSsNP). In certain embodiments, the TSLP or TSLPR binding protein is used in the treatment of eosinophilic esophagitis (EoE). In certain embodiments, the TSLP or TSLPR binding protein is used in thetreatment 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 TSLP or TSLPR binding protein is used in the treatment of Churg-Strauss syndrome / Eosinophilic granulomatosis with polyangiitis (EGPA). In certain embodiments, the TSLP or TSLPR binding protein is used in the treatment of Prurigo Nodularis (PN). In certain embodiments, the TSLP or TSLPR binding protein is used in the treatment of Chronic Spontaneous Urticaria (CSU). In certain embodiments, the TSLP or TSLPR binding protein is used in the treatment of Chronic Pruritis of Unknown Origin (CPUO). In certain embodiments, the TSLP or TSLPR binding protein is used in the treatment of Bullous Pemphigoid (BP). In certain embodiments, the TSLP or TSLPR binding protein is used in the treatment of Cold Inducible Urticaria (ColdU). In certain embodiments, the TSLP or TSLPR binding protein is used in the treatment of Allergic Fungal Rhinosinusitis (AFRS). In certain embodiments, the TSLP or TSLPR binding protein is used in the treatment of Allergic Bronchopulmonary Aspergillosis (ABPA). In certain embodiments, the TSLP or TSLPR binding protein is used in the treatment of Chronic Obstructive Pulmonary Disease (COPD). In certain embodiments, the TSLP or TSLPR binding protein is used in the treatment of inflammatory bowel disease, such as Crohn disease or ulcerative colitis. In certain embodiments, the TSLP or TSLPR binding protein is used in the treatment of psoriasis. In certain embodiments, the TSLP or TSLPR binding protein is used in the treatment of lupus. In certain embodiments, the isolated antibody is used in the treatment of rheumatoid arthritis.

[0092] 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 TSLP or TSLPR binding protein 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-Strausssyndrome / 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.

[0093] Described herein, in certain embodiments, are methods of treating an inflammatory disorder or disease in a patient in need thereof, the method comprising subcutaneously or intravenously administering to the patient an effective amount of an TSLP or TSLPR binding protein comprising a modified Fc region. Described herein, in certain embodiments, are methods of treating an inflammatory disorder or disease in a patient in need thereof, the method comprising subcutaneously or intravenously administering to the patient an effective amount of an TSEP or TSLPR binding protein comprising a) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 1- 12, (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 13-24, and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 25-36; b) a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 37-48, (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 49-56, and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 57-60; and c) a Fc domain comprising amino acid modifications M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS).

[0094] Further described herein, in certain embodiments, are methods of treating inflammatory disorder or disease in a patient in need thereof, the method comprising subcutaneously or intravenously administering to the patient an effective amount of an TSLP or TSLPR binding protein comprising: a) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 1-12, (ii) a CDR2having an amino acid sequence according to any one of SEQ ID NOs: 13-24, and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 25-36; b) a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NOs: 37-48, (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NOs: 49-56, and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NOs: 57-60; and c) a modified Fc that extends half-life of the TSLP or TSLPR binding protein as compared to a TSLP or TSLPR binding protein that does not comprise the modified Fc.

[0095] Further described herein, in certain embodiments, are methods of treating an inflammatory disorder or disease in a patient in need thereof, the method comprising subcutaneously or intravenously administering to the patient an effective amount of an TSLP or TSLPR binding protein, wherein the TSLP or TSLPR binding protein specifically binds to an epitope of TSLP and comprises a Fc domain comprising amino acid modifications M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS).

[0096] In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 75 mg to about 150 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 250 mg to about 750 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 300 mg to about 700 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 300 mg to about 600 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 300 mg to about 500 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 300 mg to about 400 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 400 mg to about 700 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 400 mg to about 600 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 300 mg to about 500 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 500 mg to about 700 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 500 mg to about 600 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 600 mg to about 700 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg.

[0097] In some embodiments, administration of the TSLP or TSLPR binding protein is intravenous, intratumoral, intramuscular, subcutaneous, intralesional, intraintestinal,intracolonic, intrarectal, intrapouch, or intraperitoneal. In some embodiments, administration of the TSLP or TSLPR binding protein is through a parenteral route such as intravenous, intramuscular, subcutaneous, intraarterial, or intraperitoneal administration. In some embodiments, administration of the TSLP or TSLPR binding protein is intravenous or subcutaneous. In some embodiments, administration of the TSLP or TSLPR binding protein is intravenous. In some embodiments, administration of the TSLP or TSLPR binding protein is subcutaneous.

[0098] Administration of the TSLP or TSLPR binding protein can occur at various intervals. In some embodiments, the TSLP or TSLPR binding protein is administered to the patient at least once at an interval more than 8 weeks. In some embodiments, the interval is about 12 to about 26 weeks. In some embodiments, the interval is about 12 to about 22 weeks. In some embodiments, the interval is about 12 to about 18 weeks. In some embodiments, the interval is about 12 to about 14 weeks. In some embodiments, the interval is about 16 to about 26 weeks. In some embodiments, the interval is about 16 to about 22 weeks. In some embodiments, the interval is about 16 to about 18 weeks. In some embodiments, the interval is about 20 to about 26 weeks. In some embodiments, the interval is about 20 to about 22 weeks. In some embodiments, the interval is about 12 weeks. In some embodiments, the interval is about 16 weeks. In some embodiments, the interval is about 26 weeks.PHARMACEUTICAL COMPOSITIONS

[0099] The present disclosure also features pharmaceutical compositions that contain a therapeutically effective amount of the TSLP or TSLPR binding proteins described herein. The composition can be formulated for use in a variety of drug delivery systems. One or more physiologically acceptable excipients or carriers can also be included in the composition for proper formulation. Suitable formulations for use in the present disclosure are found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 17th ed., 1985. For a brief review of methods for drug delivery, see, e.g., Langer (Science 249:1527-1533, 1990).

[0100] In some embodiments, a pharmaceutical composition may contain formulation materials for modifying, maintaining or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition. In such embodiments, suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen-sulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates or other organic acids);bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediamine tetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, betacyclodextrin or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose or dextrins); proteins (such as serum albumin, gelatin or immunoglobulins); coloring, flavoring and diluting agents; emulsifying agents; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; saltforming counterions (such as sodium); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid or hydrogen peroxide); solvents (such as glycerin, propylene glycol or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as pluronics, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate, triton, tromethamine, lecithin, cholesterol, tyloxapal); stability enhancing agents (such as sucrose or sorbitol); tonicity enhancing agents (such as alkali metal halides, preferably sodium or potassium chloride, mannitol sorbitol); delivery vehicles; diluents; excipients and / or pharmaceutical adjuvants (see, Remington ’s Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990)).

[0101] In some embodiments, a pharmaceutical composition is citrate-free.

[0102] In some embodiments, a pharmaceutical composition may contain nanoparticles, e.g., polymeric nanoparticles, liposomes, or micelles.

[0103] In some embodiments, a pharmaceutical composition may contain a sustained- or controlled-delivery formulation. Techniques for formulating sustained- or controlled-delivery means, such as liposome carriers, bio-erodible microparticles or porous beads and depot injections, are also known to those skilled in the art. Sustained-release preparations may include, e.g., porous polymeric microparticles or semipermeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained release matrices may include polyesters, hydrogels, polylactides, copolymers of L-glutamic acid and gamma ethyl-L-glutamate, poly (2- hydroxyethyl-inethacrylate), ethylene vinyl acetate, or poly-D(-)-3-hydroxybutyric acid. Sustained release compositions may also include liposomes that can be prepared by any of several methods known in the art.

[0104] Pharmaceutical compositions containing an TSLP or TSLPR binding protein disclosed herein can be presented in a dosage unit form and can be prepared by any suitable method. A pharmaceutical composition should be formulated to be compatible with its intended route of administration. Examples of routes of administration are intravenous (IV), intradermal, inhalation, transdermal, topical, transmucosal, intrathecal and rectal administration.. In some embodiments, the TSLP or TSLPR binding protein disclosed herein is administeredintravenously or subcutaneously. In some embodiments, the TSLP or TSLPR binding protein disclosed herein is administered intravenously. In some embodiments, the TSLP or TSLPR binding protein disclosed herein is administered subcutaneously.

[0105] Useful formulations can be prepared by methods known in the pharmaceutical art. For example, see Remington’s Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990). Formulation components suitable for parenteral administration include a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetates, citrates or phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose. In some embodiments, the formulation for parenteral administration is citrate-free.

[0106] For intravenous or subcutaneous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). The carrier should be stable under the conditions of manufacture and storage, and should be preserved against microorganisms. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol), and suitable mixtures thereof.

[0107] An intravenous or subcutaneous drug delivery formulation may be contained in a syringe, pen, or bag. In some embodiments, the bag is connected to a channel comprising a tube and / or a needle. In some embodiments, the formulation is a lyophilized formulation or a liquid formulation.

[0108] These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as -is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.

[0109] A polyol, which acts as a tonicifier and may stabilize the TSLP or TSLPR binding protein, may also be included in the formulation. The polyol is added to the formulation in an amount which may vary with respect to the desired isotonicity of the formulation. In some embodiments, the aqueous formulation is isotonic. The amount of polyol added may also be altered with respect to the molecular weight of the polyol. For example, a lower amount of a monosaccharide (e.g., mannitol) is added, compared to a disaccharide (such as trehalose). In some embodiments, the polyol which is used in the formulation as a tonicity agent is mannitol.

[0110] A detergent or surfactant may also be added to the formulation. Exemplary detergents include nonionic detergents such as polysorbates (e.g., polysorbates 20, 80 etc.) or poloxamerse.g., poloxamer 188). The amount of detergent added is such that it reduces aggregation of the formulated TSLP or TSLPR binding protein and / or minimizes the formation of particulates in the formulation and / or reduces adsorption. In some embodiments, the formulation may include a surfactant which is a polysorbate. In some embodiments, the formulation may contain the detergent polysorbate 80 or Tween 80. Tween 80 is a term used to describe polyoxyethylene (20) sorbitanmonooleate (see Fiedler, Lexikon der Hifsstoffe, Editio Cantor Verlag Aulendorf, 4th edi., 1996).

[0111] In embodiments, the protein product of the present disclosure is formulated as a liquid formulation. In some embodiments, the liquid formulation is prepared in combination with a sugar at stabilizing levels. In some embodiments, the liquid formulation is prepared in an aqueous carrier. In some embodiments, a stabilizer is added in an amount no greater than that which may result in a viscosity undesirable or unsuitable for intravenous administration. In some embodiments, the sugar is disaccharides, e.g., sucrose. In some embodiments, the liquid formulation may also include one or more of a buffering agent, a surfactant, and a preservative.

[0112] In some embodiments, the pH of the liquid formulation is set by addition of a pharmaceutically acceptable acid and / or base. In some embodiments, the pharmaceutically acceptable acid is hydrochloric acid. In some embodiments, the base is sodium hydroxide.

[0113] The aqueous carrier of interest herein is one which is pharmaceutically acceptable (safe and non-toxic for administration to a human) and is useful for the preparation of a liquid formulation. Illustrative carriers include sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), a pH buffered solution (e.g., phosphate-buffered saline), sterile saline solution, Ringer's solution or dextrose solution.

[0114] A preservative may be optionally added to the formulations herein to reduce bacterial action. The addition of a preservative may, for example, facilitate the production of a multi-use (multiple-dose) formulation.

[0115] The TSEP or TSLPR binding protein may be lyophilized to produce a lyophilized formulation including the proteins and a lyoprotectant. The lyoprotectant may be sugar, e.g., disaccharides. In some embodiments, the lyoprotectant is sucrose or maltose. The lyophilized formulation may also include one or more of a buffering agent, a surfactant, a bulking agent, and / or a preservative.

[0116] The amount of sucrose or maltose useful for stabilization of the lyophilized drug product may be in a weight ratio of at least 1 :2 protein to sucrose or maltose. In some embodiments, the protein to sucrose or maltose weight ratio is of from 1:2 to 1:5. In some embodiments, the pH of the formulation, prior to lyophilization, is set by addition of a pharmaceutically acceptable acid and / or base. In some embodiments, the pharmaceuticallyacceptable acid is hydrochloric acid. In some embodiments, the pharmaceutically acceptable base is sodium hydroxide.

[0117] In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 75 mg to about 150 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 250 mg to about 750 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 300 mg to about 700 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 300 mg to about 600 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 300 mg to about 500 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 300 mg to about 400 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 400 mg to about 700 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 400 mg to about 600 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 300 mg to about 500 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 500 mg to about 700 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 500 mg to about 600 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 600 mg to about 700 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg. In some embodiments, the TSLP or TSLPR binding protein is administered at a dose of about 300 mg. Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be about 250 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, or 700 mg so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0118] The specific dose can be a uniform dose for each patient of about 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg of protein. Alternatively, a patient’s dose can be tailored to the approximate body weight or surface area of the patient. Other factors in determining the appropriate dosage can include the disease or condition to be treated or prevented, the severity of the disease, the route of administration, and the age, sex, and medical condition of the patient. Further refinement of the calculations necessary to determine the appropriate dosage for treatment is routinely made by those skilled in the art, especially in light of the dosage information and assays disclosed herein. The dosage can also be determined through the use ofknown assays for determining dosages used in conjunction with appropriate dose-response data. An individual patient's dosage can be adjusted as the progress of the disease is monitored. Blood levels of the targetable construct or complex in a patient can be measured to see if the dosage needs to be adjusted to reach or maintain an effective concentration. Pharmacogenomics may be used to determine which targetable constructs and / or complexes, and dosages thereof, are most likely to be effective for a given individual (Schmitz et al., Clinica Chimica Acta 308: 43-53, 2001; Steimer et al., Clinica Chimica Acta 308: 33-41, 2001).METHODS OF PREPARATION

[0119] The TSLP or TSLPR binding proteins described above can be made using recombinant DNA technology well known to a skilled person in the art. For example, one or more isolated polynucleotides encoding the TSLP or TSLPR binding protein can be ligated to other appropriate nucleotide sequences, including, for example, constant region coding sequences, and expression control sequences, to produce conventional gene expression constructs (z.e., expression vectors) encoding the desired TSLP or TSLPR binding proteins. Production of defined gene constructs is within routine skill in the art.

[0120] Nucleic acids encoding desired TSLP or TSLPR binding proteins can be incorporated (ligated) into expression vectors, which can be introduced into host cells through conventional transfection or transformation techniques. Exemplary host cells are E. coli cells, Chinese hamster ovary (CHO) cells, human embryonic kidney 293 (HEK 293) cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), and myeloma cells that do not otherwise produce IgG protein. Transformed host cells can be grown under conditions that permit the host cells to express the genes that encode TSLP or TSLPR binding proteins.

[0121] Specific expression and purification conditions will vary depending upon the expression system employed. For example, if a gene is to be expressed in E. coli, it is first cloned into an expression vector by positioning the engineered gene downstream from a suitable bacterial promoter, e.g., Trp or Tac, and a prokaryotic signal sequence. The expressed protein may be secreted. The expressed protein may accumulate in refractile or inclusion bodies, which can be harvested after disruption of the cells by French press or sonication. The refractile bodies then are solubilized, and the protein may be refolded and / or cleaved by methods known in the art.

[0122] If the engineered gene is to be expressed in eukaryotic host cells, e.g., CHO cells, it is first inserted into an expression vector containing a suitable eukaryotic promoter, a secretion signal, a poly A sequence, and a stop codon. Optionally, the vector or gene construct maycontain enhancers and introns. In embodiments involving fusion proteins comprising an TSLP or TSLPR binding protein or portion thereof, the expression vector optionally contains sequences encoding all or part of a constant region, enabling an entire, or a part of, a heavy or light chain to be expressed. The gene construct can be introduced into eukaryotic host cells using conventional techniques.

[0123] In some embodiments, in order to express an TSLP or TSLPR binding protein, an N- terminal signal sequence is included in the protein construct. Exemplary N-terminal signal sequences include signal sequences from interleukin-2, CD-5, IgG kappa light chain, trypsinogen, serum albumin, and prolactin.

[0124] After transfection, single clones can be isolated for cell bank generation using methods known in the art, such as limited dilution, ELISA, FACS, microscopy, or Clonepix. Clones can be cultured under conditions suitable for bio-reactor scale-up and maintained expression of the TSLP or TSLPR binding proteins.

[0125] The TSLP or TSLPR binding proteins can be isolated and purified using methods known in the art including centrifugation, depth filtration, cell lysis, homogenization, freezethawing, affinity purification, gel filtration, ion exchange chromatography, hydrophobic interaction exchange chromatography, and mixed-mode chromatography.EXAMPLES

[0086] 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.

[0087] 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 (2ndEdition, 1989); Methods In Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.); Remington’s Pharmaceutical Sciences, 18thEdition (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry 3rdEd. (Plenum Press) Vols A and B(1992).MethodsGene synthesis and plasmid construction

[0088] The coding sequences for HC and LC of the 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

[0089] Transient expression of antibodies was performed by co-transfection of paired HC and LC constructs into CHO cells using PEI method. Briefly, CHO cells at approximately 5.5xlO6 / 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

[0090] Protein purification by affinity chromatography, and ion exchange chromatography was performed using an AKTA pure instrument (GE Lifesciences). Conditional medium expressing target antibody was harvested by centrifugation at 4000 rpm, 50 min, and filtered with a 0.22 pm 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

[0091] Analytical SEC-HPLC was performed using Shimadzu LC-10 HPLC instrument (Shimadzu Corp.). 20 pl 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 TSLP or TSLPR Binding Kinetics Using Surface Plasmon Resonance

[0092] A Biacore 8K SPR system (GE Healthcare) equipped with Series S Sensor Chip Protein G (Cytiva, Cat. 29179315) was used to determine the binding kinetic rate and affinity constants at 25°C and in a running buffer of HBS-EP+ (10 mM HEPES pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.05% Surfactant P20). Following a stabilization period in running buffer, the anti- TSLP mAb constructs (diluted to 1 pg / mL are captured onto flow cell 2 (active) for 60 sec at aflow rate of 10 uL / min. Recombinant Human TSLP 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 50 pL / min. Recombinant Cynomolgus TSLP Protein, His Tag is 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 50 pL / min. Samples were injected in a multi-cycle manner over freshly captured mAb, by regenerating the capture surfaces with injection of glycine pH 1.5 for 30 sec at a flow rate of 30 pL / 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 ELISA

[0093] 96-well plates (Costar #9018) are coated with TSLP R (Aero, TSR-H525a) 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 (Aero, TSP-H82Eb) for 30 min at RT. Then TA-TSLP mixture is added to blocked plates and incubated for 1 h at 37°C. After washing, plates are incubated with Streptavidin-HRP (SIGMA, 21140) 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 IN HC1 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.Example 1: Assessing the ability of engineered TSLP and TSLPR antibodies to improve affinity and potency of blockade of TSLP or TSLPRResultsDetermination of Antibody Affinity to TSLP or TSLPR

[0094] Using the methods described above, the affinity of anti-TSLP antibodies to TSLP and the binding kinetics thereof were assessed using surface plasmon resonance (SPR) as compared to control antibody, Antibody 1 (which contains an IgG2 Fc domain). An antibody based on Antibody 1, but with an IgGl Fc domain containing the modifications M252Y, S254T, andT256E (YTE), and L234A / L235A (LALA) (SEQ ID NO: 89), referred to as “Antibody 1 YTE” herein.

[0095] As measured by SPR, the antibodies exhibited strong affinity to TSLP. The antibodies were shown to bind to human TSLP with sub-nanomolar affinity and were cross- reactive to cynomolgus monkey TSLP with sub-nanomolar affinities as summarized in TABLE 5.Table 5.Antibody 1 4.62E-12Example 2: Inhibition of TSLP Binding to TSLPR and / or IL-7R «

[0096] The TSLP Responsive Luciferase Reporter Ba / F3 Cell Line is a murine Ba / F3 cell line engineered to express both TSLPR (also known as CRLF2, cytokine receptor like factor 2) and IL-7Ra separated by a self-cleaving P2A peptide. The construct was delivered by lentiviral transduction of STAT5 Luciferase Reporter Ba / F3 cells, which express a firefly luciferase reporter driven by STAT5 response elements located upstream of the promoter. After activation by TSLP, the endogenous transcription factor STAT5 binds to the response elements, inducing transcription of the luciferase reporter gene.

[0097] Inhibition of luciferase expression in BaF3 cells was used to evaluate the functional activity of antibodies to block TSLP induced biological activity. Briefly, BaF3 cells were collected and seeded at 50,000 cells per well in 50 pL. The cells were incubated at 37 C, 5% CO2 overnight. Meanwhile, serial dilutions of the antibody with TSLP were incubated in assay medium at 4C for 30 minutes. A 50 pL mixture of TSLP and purified antibody (1:1 by volume) was added to the wells. Cells were incubated at 37 °C for 6 hours. 100 pL of ONE-Glo Luciferase reagent was added to each well and rocked at room temperature for about 2 minutes to allow for cell lysis. The RLU of cells in each well were recorded by using a luminescence plate reader and subsequent data were analyzed using GraphPad Prism. IC50 values were determined as the concentration of antibody required to inhibit 50% of the maximum RLU of luciferase detected with incubation of TSLP alone. Relative IC50 values were determined against Antibody 1 as the reference antibody. Results are summarized in TABLE 6 and FIG. 1.Table 6.Antibody 1 0.10* 1 (0.1) 3.7 (0.4) 4.2 (0.23)*Average IC50 values (n> 11), (SEM)

[0098] Antibodies were generated based on the sequences of Antibody 2 and Antibody 3 a, and Antibody 2 and Antibody 3 with an IgGl Fc domain containing the modifications M252Y, S254T, and T256E (YTE) (SEQ ID NO: 86). These antibodies were tested for their ability to inhibit luciferase expression in BaF3 cells and HEK293 cells as described in this example, along with Antibody 1 and Antibody 1 YTE, which also has LALA modifications as indicated in Example 1. The results are summarized in Table 7, FIG. 3A - 3C (HEK293 cells), and FIG. 4A-4B (Ba / F3 cells). Antibody 4, an anti-TSLPR antibody, showed no significant inhibition of luciferase expression in HEK293 cells (FIG. 3C) and Ba / F3 cells (FIG. 4B). Table 7 ANTIBODY IC50HEK293 STAT5 IC50BAF3 IC50BAF3REPORTER (NM) STAT5 PROLIFERATIONREPORTER (NM)(NM)Antibody 1 YTEAntibody 2 l . l 0.07 1.2Antibody 2 YTE 1.2 0.06 0.9Antibody 3a 1.5 0.14 2.4Antibody 3a 1.9 0.15 2.9YTEAntibody 4 ND ND NDND = Not detected due to low signal.Example 3: Inhibition of Cell Proliferation in Ba / F3 Cells

[0099] The Ba / F3 cells were collected, plated, and washed twice with PBS. 5,000 cells / well were seeded in 96 -well culture plates in 50 pL of assay medium (1640 containing 10% FBS). Serial dilutions were prepared of the antibody (500nM, 1:5 dilution) with human TSLP protein (EC50) in assay medium. The mixture of antibody and TSLP protein in 50 pL of assay medium was added to the cells in the wells. Meanwhile, 50 pL of assay medium was added to the unstimulated control wells. The cells were incubated at 37°C with 5% CO2 for 72 hours. 100 pL of CellTiter-Glo reagent per well was added and rocked at room temperature for ~2 minutes to allow for cell lysis. The RLU of the plate was read using a luminescence plate reader and subsequent data were analyzed using GraphPad Prism. IC50 values were determined as the concentration of antibody required to inhibit 50% of the maximum RLU of luciferase detected with incubation of TSLP alone. Results are summarized in TABLE 6, TABLE 7, FIG. 2, and FIG. 5A-5B.Example 4: Inhibition of TSLP-Induced Release of TARC in PBMC Cells or Monocyte Cells

[0100] Inhibition of TARC secretion by peripheral blood mononuclear (PBMC) cells was used to evaluate the functional activity of antibodies to block TSLP-induced biological activity. Briefly, PBMC cells were seeded at 20,000 cells in 100 pL of DMEM + 10% FBS and cultured overnight at 37 °C. The next day, the cell culture media was discarded and cells were gently washed with fresh media. A 150 pL mixture of TSLP, purified antibody, and hTNFa (1:1:1 by volume) were added to the wells, resulting in a final concentration of 20 ng / mL TSLP, 0-100 nM purified antibody, and 200 ng / mL hTNFa OR 1.5 ng / mL hIL-4, 0-100 nM purified antibody, and 50 ng / mL TNFa. Cells were incubated in this mixture at 37 °C for 2 days. Following incubation, culture supernatant was collected and the amount of TARC present was analyzed using a commercial TARC ELISA kit, analyzed according to manufacturer’s instructions. The determined concentrations of TARC in each well were analyzed using GraphPad Prism. IC50 values were determined as the concentration of antibody required to inhibit 50% of the maximum TARC concentration detected with incubation of only 20 ng / mL of TSLP and 200 ng / mL hTNFa. Results are summarized in TABLE 6, TABLE 8, and FIGs. 6A-6C.

[0101] A similar assay was performed with monocyte cells. Monocyte cells were isolated from recovered PBMC (3 donors) using EasySep™ Human Monocyte Enrichment Kit. Isolated Monocytes were resuspended at 800,000 cells / ml with assay media and seeded 150 pl / well into assay plates (120,000 / well). 50 pl / well 4*TSLP (1 ng / ml) in assay medium was added to each well. Add 50 pl / well serial diluted 4* Antibody (1 / 3 diluted from 1,000 nM, 11 doses where onedose was a blank) was also added to each well in assay medium and incubated at 37°C, 5% CO2. After 2 days of incubation, the assay plate was centrifuged and 170 pl supernatant was collected for TARC detection. The amount of TARC in the culture supernatant was determined by ELISA, according to the manufacturer’s instructions. Results are summarized in TABLE 8 and FIGs. 7A-7C.Table 8EQUIVALENTS

[0126] The disclosure may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the disclosure described herein. Scope of the disclosure is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

CLAIMS1. A TSLP or TSLPR binding protein comprising: a) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence set forth in any one of SEQ ID NOs: 1-12, (ii) a CDR2 having an amino acid sequence set forth in any one of SEQ ID NOs: 13-24, and (iii) a CDR3 having an amino acid sequence set forth in any one of SEQ ID NOs: 25-36; b) a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence set forth in any one of SEQ ID NOs: 37-48, (ii) a CDR2 having an amino acid sequence set forth in any one of SEQ ID NOs: 49-56, and (iii) a CDR3 having an amino acid sequence set forth in any one of SEQ ID NOs: 57-60; and c) an Fc domain comprising at least one amino acid modification.

2. The TSLP binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 1, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 13, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 25; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 37, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 49, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 57.

3. The TSLP binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 2, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 14, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 26; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 38, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 50, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 58.

4. The TSLP binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 3, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 15, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 27; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 39, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 51, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 59.

5. The TSLPR binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 4, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 16, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 28; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ IDNO: 40, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 52, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 60.

6. The TSLP binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 5, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 17, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 29; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 41, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 53, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 61.

7. The TSLP binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 6, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 18, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 30; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 42, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 54, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 62.

8. The TSLP binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 7, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 19, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 31; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 43, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 55, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 63.

9. The TSLPR binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 8, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 20, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 32; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 44, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 56, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 60.

10. The TSLP binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 9, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 21, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 33; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 45, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 53, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 57.

11. The TSLP binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 10, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 22, and (iii) a CDR3 having an amino acid sequence set forth in SEQ IDNO: 34; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 46, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 54, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 58.

12. The TSLP binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 11, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 23, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 35; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 47, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 55, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 59.

13. The TSLPR binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 12, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 24, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 36; and the VL comprises (i) a CDR1 having an amino acid sequence set forth in SEQ ID NO: 48, (ii) a CDR2 having an amino acid sequence set forth in SEQ ID NO: 56, and (iii) a CDR3 having an amino acid sequence set forth in SEQ ID NO: 60.

14. The TSLP or TSLPR binding protein of any one of claims 1-13, wherein the VH comprises a sequence having at least 80% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 65-69, and the VL comprises a sequence having at least 80% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 70-74.

15. The TSLP binding protein of claim 14, wherein the VH comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 65 and the VL comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 70.

16. The TSLP binding protein of claim 14, wherein the VH comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 66 and the VL comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 71.

17. The TSLP binding protein of claim 14, wherein the VH comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 67 and the VL comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 72.

18. The TSLP binding protein of claim 14, wherein the VH comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 68 and the VL comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 73.

19. The TSLPR binding protein of claim 14, wherein the VH comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 69 and the VL comprises a sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 74.

20. The TSLP or TSLPR binding protein of any one of claims 1-18, wherein the Fc is an IgGl, IgG2 or IgG4 immunoglobulin Fc domain.

21. The TSLP or TSLPR binding protein of claim 20, wherein the Fc is an IgGl immunoglobulin domain, wherein the at least one modification comprises the modifications M252Y, S254T, and T256E (YTE).

22. The TSLP or TSLPR binding protein of claim 20, wherein the Fc is an IgGl immunoglobulin domain, wherein the at least one modification comprises L234A / L235A (LALA).

23. The TSLP or TSLPR binding protein of claim 20, wherein the Fc is an IgGl immunoglobulin domain, wherein the at least one modification comprises LALAGA and N434A.

24. The TSLP or TSLPR binding protein of claim 20, wherein the Fc is an IgGl immunoglobulin domain, wherein the at least one modification comprises M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS).

25. The TSLP or TSLPR binding protein of claim 20, wherein the Fc is an IgGl immunoglobulin domain, wherein the at least one modification comprises M252Y, S254T, and T256E (YTE) and L234A / L235A (LALA).

26. The TSLP or TSLPR binding protein of claim 20, wherein the Fc is an IgG2 immunoglobulin domain.

27. The TSLP or TSLPR binding protein of claim 20, wherein the Fc is an IgG4 immunoglobulin domain.

28. A TSLP or TSLPR binding protein comprising: a) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence set forth in any one of SEQ ID NOs: 1-12, (ii) a CDR2 having an amino acid sequence set forth in any one of SEQ ID NOs: 13-24, and (iii) a CDR3 having an amino acid sequence set forth in any one of SEQ ID NOs: 25-36; b) a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence set forth in any one of SEQ ID NOs: 37-48, (ii) a CDR2 having an amino acid sequence set forth in any one of SEQ ID NOs: 49-56, and (iii) a CDR3 having an amino acid sequence set forth in any one of SEQ ID NOs: 57-60; andc) a modified Fc that extends half-life of the TSLP or TSLPR binding protein as compared to a TSLP or TSLPR binding protein that does not comprise the modified Fc.

29. A TSLP or TSLPR binding protein, wherein the TSLP or TSLPR binding protein specifically binds to an epitope of TSLP and comprises a Fc domain comprising amino acid modifications M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS).

30. A method of treating an inflammatory disorder or disease in a patient in need thereof, the method comprising subcutaneously or intravenously administering to the patient an effective amount of an TSLP or TSLPR binding protein of any one of claims 1-29.

31. The method of claim 30, wherein the inflammatory disorder or disease is atopic dermatitis.

32. The method of claim 31, wherein the inflammatory disorder or disease is asthma.

33. The method of any one of claims 30-32, wherein administration of the TSLP or TSLPR binding protein is subcutaneous.

34. The method of any one of claims 30-32, wherein administration of the TSLP or TSLPR binding protein is intravenous.

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