Anti-wisp1 antibodies and methods of use

Abstract

Provided herein are antibodies and antibody fragments, which specifically bind WNT1-inducible-signaling pathway protein 1 (WISP1). The anti-WISP1 antibodies provided herein bind domain 2 of WISP1 protein and are shown to inhibit WISP1 protein activity. The anti-WISP1 antibodies are contemplated to be effective for treating and preventing fibrosis in a subject in need thereof. In embodiments, the fibrosis is liver fibrosis or lung fibrosis.

Description

PATENT Attorney Docket No.: 062698-505001WO ANTI-WISP1 ANTIBODIES AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No.63,625,877, filed January 26, 2024, which is hereby incorporated by reference in its entirety and for all purposes. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (062698- 505001WO_Sequence_Listing_ST26.xml; Size: 28,595 bytes; and Date of Creation: January 23, 2025) are hereby incorporated by reference in their entirety. BACKGROUND

[0003] Although the formation of fibrous tissue is part of the normal beneficial process of healing following injury, fibrosis is a condition characterized by an abnormal accumulation of a collagen matrix following injury or inflammation which alters the structure and function of various tissues. Progressive fibrosis in the kidney, liver, lung, heart, bone or bone marrow, and skin is a major cause of death. Many of the diseases associated with the proliferation of fibrous tissue are both chronic and often debilitating. Some, including lung fibrosis, are fatal due in part to the fact that the currently available treatments have significant side effects and are generally not efficacious in slowing or halting the progression of fibrosis.

[0004] WNT1-inducible-signaling pathway protein 1 (WISP1) expression is a hallmark of fibrosis progression. WISP1 includes 4 domains, and its expression leads to aberrant myofibroblast accumulation and excessive collagen deposition in fibrotic disorders. BRIEF SUMMARY

[0005] In an aspect is provided an anti-WNT1-inducible-signaling pathway protein 1 (WISP1) antibody, including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes: a CDR H1 as set forth in SEQ ID NO:1, a CDR H2 as set forth in SEQ ID NO:2 and a CDR H3 as set forth in SEQ ID NO:3; and wherein the light chain variable domain includes: a CDR L1 as set forth in SEQ ID NO:4, a CDR L2 including AAS, and a CDR L3 as set forth in SEQ ID NO:6.PATENT Attorney Docket No.: 062698-505001WO

[0006] In an aspect is provided an anti-WISP1 antibody, wherein the anti-WISP1 antibody binds the same epitope as an anti-WISP1 antibody including a heavy chain variable domain including: a CDR H1 as set forth in SEQ ID NO:1, a CDR H2 as set forth in SEQ ID NO:2 and a CDR H3 as set forth in SEQ ID NO:3; and a light chain variable domain including: a CDR L1 as set forth in SEQ ID NO:4, a CDR L2 including AAS, and a CDR L3 as set forth in SEQ ID NO:6.

[0007] In another aspect is provided an antibody that competes with an anti-WISP1 antibody for binding to a WISP1 protein, wherein the anti-WISP1 antibody includes: a heavy chain variable domain including: a CDR H1 as set forth in SEQ ID NO:1, a CDR H2 as set forth in SEQ ID NO:2 and a CDR H3 as set forth in SEQ ID NO:3; and a light chain variable domain including: a CDR L1 as set forth in SEQ ID NO:4, a CDR L2 including AAS, and a CDR L3 as set forth in SEQ ID NO:6.

[0008] In another aspect is provided an anti-WNT1-inducible-signaling pathway protein 1 (WISP1) antibody, wherein the antibody comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises CDR H1, CDR H2, and CDR H3, and the light chain variable domain comprises CDR L1, CDR L2, and CDR L3, wherein CDR H1 consists of SEQ ID NO:1, CDR H2 consists of SEQ ID NO:2, CDR H3 consists of SEQ ID NO:3, CDR L1 consists of SEQ ID NO:4, CDR L2 consists of the sequence AAS, and CDR L3 consists of SEQ ID NO:6.

[0009] In another aspect is provided an anti-WNT1-inducible-signaling pathway protein 1 (WISP1) antibody, wherein the antibody binds the same epitope as an anti-WISP1 antibody that comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises CDR H1, CDR H2, and CDR H3, and the light chain variable domain comprises CDR L1, CDR L2, and CDR L3, wherein CDR H1 consists of SEQ ID NO:1, CDR H2 consists of SEQ ID NO:2, CDR H3 consists of SEQ ID NO:3, CDR L1 consists of SEQ ID NO:4, CDR L2 consists of the sequence AAS, and CDR L3 consists of SEQ ID NO:6.

[0010] In another aspect is provided an antibody that competes with an anti-WISP1 antibody for binding to a WISP1 protein, wherein the anti-WISP1 antibody comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises CDR H1, CDR H2, and CDR H3, and the light chain variable domain comprises CDR L1, CDR L2, and CDR L3, wherein CDR H1 consists of SEQ ID NO:1, CDR H2 consists of SEQ ID NO:2, CDR H3PATENT Attorney Docket No.: 062698-505001WO consists of SEQ ID NO:3, CDR L1 consists of SEQ ID NO:4, CDR L2 consists of the sequence AAS, and CDR L3 consists of SEQ ID NO:6.

[0011] In an aspect is provided a method of treating fibrosis in a subject in need thereof, the method including administering to the subject a therapeutically effective amount of an antibody provided herein including embodiments thereof.

[0012] In an aspect is provided a method of treating fibrosis in a subject in need thereof, the method including: a) identifying in a biological sample obtained from the subject an elevated level of WISP1 relative to a standard control, an elevated level of α-Smooth Muscle Actin (α-SMA) relative to the standard control, an elevated level of collagen type I alpha 1 chain (Col1a1) relative to the standard control, an elevated level of tissue inhibitor of metalloproteinase 1 (Timp1) relative to the standard control, an elevated level of fibronectin (Fn1) relative to the standard control, an elevated level of interleukin 6 (IL-6) relative to the standard control, an elevated level of phosphorylated Small Mother Against Decapentaplegic 2 (pSMAD2) relative to the standard control, an elevated level of phosphorylated Small Mother Against Decapentaplegic 3 (pSMAD3) relative to the standard control, or a combination thereof; and b) administering to the subject a therapeutically effective amount of the anti-WISP1 antibody provided herein including embodiments thereof.

[0013] In an aspect is provided a method of inhibiting release of interleukin 6 (IL-6), phosphorylated Small Mother Against Decapentaplegic 2 (pSMAD2), phosphorylated Small Mother Against Decapentaplegic 3 (pSMAD3), or a combination thereof from a cell, the method comprising contacting the cell with the anti-WISP1 antibody provided herein including embodiments thereof.

[0014] In an aspect is provided a method of inhibiting migration of a WISP-1 receptor expressing cell, the method comprising contacting said cell with the anti-WISP1 antibody provided herein including embodiments thereof.

[0015] A method of detecting a WISP1-expressing cell, said method including i) contacting a WISP1-expressing cell with an antibody provided herein including embodiments thereof, and ii) detecting binding of the antibody to a WISP1 protein expressed by the cell. BRIEF DESCRIPTION OF THE DRAWINGSPATENT Attorney Docket No.: 062698-505001WO

[0016] FIG.1. Enzyme-linked immunosorbent assay (ELISA) results showing hybridoma- expressed antibodies binding to recombinant human WISP1 protein.

[0017] FIG.2. Analysis of the binding specificity of isolated anti-WISP1 antibody clones to human WISP1 protein.

[0018] FIG.3. SPR data showing binding kinetics of isolated anti-WISP1 antibody clones to human WISP1.

[0019] FIG.4. Binding of anti-WISP1 antibody clones to different domains of WISP1.

[0020] FIG.s 5A-5B. In vivo efficacy studies using anti-WISP1 antibody in the CarbonTetrachloride (CCL4) liver fibrosis model. FIG.5A) Data illustrating that anti-WISP1 suppresses liver fibrosis as measured by a decrease in hydroxyproline, an indication that collagen content in fibrotic tissue has decreased. Data expressed as Mean + / - SEM; *p<0.05 One-Way ANOVA with Dunnett’s multiple comparison vs +PBS. FIG.5B) Results show that anti-WISP1 antibody K4 decreases hydroxyproline by 76.5% and anti-WISP1 antibody M6-QYS decreases hydroxyproline by 79.7% compared to the vehicle control.

[0021] FIG.s 6A-6B. In vivo efficacy studies using anti-WISP1 antibody in the Bile Duct Ligation (BDL) liver fibrosis model illustrate that M6-QYS and K4 attenuated BDL-induced increases in liver α-SMA. FIG.6A) Administration of M6-QYS and K4 reduced α-SMA in the BDL liver fibrosis mouse model compared to vehicle-treated control. FIG.6B) Representative images of a-Smooth Muscle Actin (a-SMA) stained histological sections acquired at 100X magnification. Darker contrast stain reflects positive stain for a-SMA. The images show that BDL increased liver α-Smooth Muscle Actin (α-SMA) compared to sham treatment.

[0022] FIG.7. Anti-WISP1 antibody K4 reduces pSMAD2 in Normal Rat Kidney Fibroblasts (NRKF) treated with full-length (FL) WISP1. Inhibition of pSMAD2 by anti-WISP1 antibodiesvaried from 0% to 71%. Monoclonal antibody E8 reduced pSMAD2 by 44% while antibody K4reduced signal by 63%, comparable to reduction of pSMAD2 following treatment with polyclonal anti-WISP1 AF1627 antibody (65%; positive control).

[0023] FIG.8. Anti-WISP1 K4 antibody reduces primary Human Hepatic Stellate Cell (HHSC) chemotaxis / motility. Chemotaxis was inhibited starting at a concentration of 2 µg / mL monoclonalPATENT Attorney Docket No.: 062698-505001WO anti-WISP1 antibody K4 with increasing inhibition at higher doses (lower row). Treatment with a polyclonal anti-WISP1 antibody (R&D AF1627; positive control) also reduced WISP1-driven chemotaxis starting at 2 ^g / mL (middle row). IgG antibody treatment did not alter chemotaxis rates compared to wells receiving no antibody even at the highest concentration evaluated (top row). White cells are those that have migrated from the upper to the lower chamber of a transwell plate.

[0024] FIG.9. Anti-WISP1 K4 antibody reduces primary Human Hepatic Stellate Cell (HHSC) chemotaxis / motility. HHSC migration was quantified at 48 h. Conditions were as described in FIG. 8. The “Phase Area Bottom Normalized to Initial Top Value” metric was used for calculating chemotaxis. Significant HHSC chemotaxis occurred with a combination of WISP1 and 10% FBS, but not without FBS. Non-specific IgG antibody did not inhibit chemotaxis / cell migration even at the highest concentration (100 ^g / mL). Polyclonal anti-WISP1 antibody AF1627 inhibited chemotaxis starting at 2 ^g / mL and inhibition increased with higher antibody concentrations. Monoclonal anti-WISP1 antibody K4 also significantly inhibited chemotaxis starting at 2 ^g / mL and inhibition increased with antibody concentration. Significance is indicated relative to IgG at 100 ^g / mL with 10% FBS (p < 0.05).

[0025] FIG.10. IC50 for anti-WISP1 antibody K4. IC50 and IC80 values were determined using a python-based nonlinear regression curve-fit for dose response data from final timepoint (48h). Mediar monoclonal anti-WISP1 antibody K4 generates an IC50 of 1.8788 ^g / mL and IC80 of 4.7959 ^g / mL (left panel); polyclonal anti-WISP1 antibody AF1627 has an IC50 of 1.6629 ^g / mL and IC80 of 5.152 µg / mL (right panel). DETAILED DESCRIPTION

[0026] While various embodiments and aspects of the present invention are shown and described herein, it will be obvious to those skilled in the art that such embodiments and aspects are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention.PATENT Attorney Docket No.: 062698-505001WO

[0027] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, without limitation, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety for any purpose.

[0028] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0029] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. See, e.g., Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989), which is incorporated herein in its entirety and for all purposes. Any methods, devices and materials similar or equivalent to those described herein can be used in the practice of this invention. The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure.

[0030] As used herein, the term "about" means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, the term "about" means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to + / - 10% of the specified value. In embodiments, about means the specified value.

[0031] As used herein, the terms "includes" or “including” are used to indicate that the list of elements or steps that follow is not exhaustive. This means that additional elements or steps may be present in the invention, even if they are not explicitly mentioned. The terms "includes" or “including” are synonymous with "comprising" and are considered open-ended, allowing for the inclusion of other unrecited elements or steps.PATENT Attorney Docket No.: 062698-505001WO

[0032] As used herein, the terms “consists” or "consisting of" are used as closed-ended terms that exclude any element, step, or ingredient not specifically mentioned after the term. Use of the terms “consists” or "consisting of" means that the recited feature is limited to only those components and does not allow for the inclusion of any additional elements.

[0033] "Nucleic acid" refers to nucleotides (e.g., deoxyribonucleotides or ribonucleotides) and polymers thereof in either single-, double- or multiple-stranded form, or complements thereof; or nucleosides (e.g., deoxyribonucleosides or ribonucleosides). In embodiments, “nucleic acid” does not include nucleosides. The terms “polynucleotide,” “oligonucleotide,” “oligo” or the like refer, in the usual and customary sense, to a linear sequence of nucleotides. The term “nucleoside” refers, in the usual and customary sense, to a glycosylamine including a nucleobase and a five-carbon sugar (ribose or deoxyribose). Non limiting examples, of nucleosides include, cytidine, uridine, adenosine, guanosine, thymidine and inosine. The term “nucleotide” refers, in the usual and customary sense, to a single unit of a polynucleotide, i.e., a monomer. Nucleotides can be ribonucleotides, deoxyribonucleotides, or modified versions thereof. Examples of polynucleotides contemplated herein include single and double stranded DNA, single and double stranded RNA, and hybrid molecules having mixtures of single and double stranded DNA and RNA. Examples of nucleic acid, e.g. polynucleotides contemplated herein include any types of RNA, e.g. mRNA, siRNA, miRNA, and guide RNA and any types of DNA, genomic DNA, plasmid DNA, and minicircle DNA, and any fragments thereof. The term “duplex” in the context of polynucleotides refers, in the usual and customary sense, to double strandedness. Nucleic acids can be linear or branched. For example, nucleic acids can be a linear chain of nucleotides or the nucleic acids can be branched, e.g., such that the nucleic acids comprise one or more arms or branches of nucleotides. Optionally, the branched nucleic acids are repetitively branched to form higher ordered structures such as dendrimers and the like.

[0034] Nucleic acids, including e.g., nucleic acids with a phosphothioate backbone, can include one or more reactive moieties. As used herein, the term reactive moiety includes any group capable of reacting with another molecule, e.g., a nucleic acid or polypeptide through covalent, non-covalent or other interactions. By way of example, the nucleic acid can include an amino acid reactive moiety that reacts with an amio acid on a protein or polypeptide through a covalent, non-covalent or other interaction.PATENT Attorney Docket No.: 062698-505001WO

[0035] The terms also encompass nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphodiester derivatives including, e.g., phosphoramidate, phosphorodiamidate, phosphorothioate (also known as phosphothioate having double bonded sulfur replacing oxygen in the phosphate), phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boron phosphonate, or O-methylphosphoroamidite linkages (see Eckstein, OLIGONUCLEOTIDES AND ANALOGUES: A PRACTICAL APPROACH, Oxford University Press, which is incorporated herein in its entirety and for all purposes) as well as modifications to the nucleotide bases such as in 5-methyl cytidine or pseudouridine.; and peptide nucleic acid backbones and linkages. Other analog nucleic acids include those with positive backbones; non-ionic backbones, modified sugars, and non-ribose backbones (e.g. phosphorodiamidate morpholino oligos or locked nucleic acids (LNA) as known in the art), including those described in U.S. Patent Nos.5,235,033 and 5,034,506, and Chapters 6 and 7, ASC Symposium Series 580, CARBOHYDRATE MODIFICATIONS IN ANTISENSE RESEARCH, Sanghui & Cook, eds, which are incorporated herein in their entirety and for all purposes. Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids. Modifications of the ribose-phosphate backbone may be done for a variety of reasons, e.g., to increase the stability and half-life of such molecules in physiological environments or as probes on a biochip. Mixtures of naturally occurring nucleic acids and analogs can be made; alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made. In embodiments, the internucleotide linkages in DNA are phosphodiester, phosphodiester derivatives, or a combination of both.

[0036] Nucleic acids can include nonspecific sequences. As used herein, the term "nonspecific sequence" refers to a nucleic acid sequence that contains a series of residues that are not designed to be complementary to or are only partially complementary to any other nucleic acid sequence. By way of example, a nonspecific nucleic acid sequence is a sequence of nucleic acid residues that does not function as an inhibitory nucleic acid when contacted with a cell or organism.PATENT Attorney Docket No.: 062698-505001WO

[0037] A polynucleotide is typically composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); and thymine (T) (uracil (U) for thymine (T) when the polynucleotide is RNA). Thus, the term “polynucleotide sequence” is the alphabetical representation of a polynucleotide molecule; alternatively, the term may be applied to the polynucleotide molecule itself. This alphabetical representation can be input into databases in a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology searching. Polynucleotides may optionally include one or more non-standard nucleotide(s), nucleotide analog(s) and / or modified nucleotides.

[0038] The term “complement,” as used herein, refers to a nucleotide (e.g., RNA or DNA) or a sequence of nucleotides capable of base pairing with a complementary nucleotide or sequence of nucleotides. As described herein and commonly known in the art the complementary (matching) nucleotide of adenosine is thymidine and the complementary (matching) nucleotide of guanosine is cytosine. Thus, a complement may include a sequence of nucleotides that base pair with corresponding complementary nucleotides of a second nucleic acid sequence. The nucleotides of a complement may partially or completely match the nucleotides of the second nucleic acid sequence. Where the nucleotides of the complement completely match each nucleotide of the second nucleic acid sequence, the complement forms base pairs with each nucleotide of the second nucleic acid sequence. Where the nucleotides of the complement partially match the nucleotides of the second nucleic acid sequence only some of the nucleotides of the complement form base pairs with nucleotides of the second nucleic acid sequence. Examples of complementary sequences include coding and a non-coding sequences, wherein the non-coding sequence contains complementary nucleotides to the coding sequence and thus forms the complement of the coding sequence. A further example of complementary sequences are sense and antisense sequences, wherein the sense sequence contains complementary nucleotides to the antisense sequence and thus forms the complement of the antisense sequence.

[0039] As described herein the complementarity of sequences may be partial, in which only some of the nucleic acids match according to base pairing, or complete, where all the nucleic acids match according to base pairing. Thus, two sequences that are complementary to each other, may have a specified percentage of nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%,PATENT Attorney Docket No.: 062698-505001WO 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region).

[0040] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ-carboxyglutamate, and O- phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an α carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. The terms “non-naturally occurring amino acid” and “unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.

[0041] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[0042] The terms "polypeptide," "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may In embodiments be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. A "fusion protein" refers to a chimeric protein encoding two or more separate protein sequences that are recombinantly expressed as a single moiety.

[0043] An amino acid or nucleotide base "position" is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its positionPATENT Attorney Docket No.: 062698-505001WO relative to the N-terminus (or 5'-end). Due to deletions, insertions, truncations, fusions, and the like that must be taken into account when determining an optimal alignment, in general the amino acid residue number in a test sequence determined by simply counting from the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence. For example, in a case where a variant has a deletion relative to an aligned reference sequence, there will be no amino acid in the variant that corresponds to a position in the reference sequence at the site of deletion. Where there is an insertion in an aligned reference sequence, that insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of truncations or fusions there can be stretches of amino acids in either the reference or aligned sequence that do not correspond to any amino acid in the corresponding sequence.

[0044] The terms "numbered with reference to" or "corresponding to," when used in the context of the numbering of a given amino acid or polynucleotide sequence, refers to the numbering of the residues of a specified reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence. An amino acid residue in a protein "corresponds" to a given residue when it occupies the same essential structural position within the protein as the given residue. One skilled in the art will immediately recognize the identity and location of residues corresponding to a specific position in a protein (e.g., WISP1) in other proteins with different numbering systems. For example, by performing a simple sequence alignment with a protein (e.g., WISP1) the identity and location of residues corresponding to specific positions of the protein are identified in other protein sequences aligning to the protein. For example, a selected residue in a selected protein corresponds to glutamic acid at position 138 when the selected residue occupies the same essential spatial or other structural relationship as a glutamic acid at position 138. In some embodiments, where a selected protein is aligned for maximum homology with a protein, the position in the aligned selected protein aligning with glutamic acid 138 is the to correspond to glutamic acid 138. Instead of a primary sequence alignment, a three dimensional structural alignment can also be used, e.g., where the structure of the selected protein is aligned for maximum correspondence with the glutamic acid at position 138, and the overall structures compared. In this case, an amino acid that occupies the same essential position as glutamic acid 138 in the structural model is the to correspond to the glutamic acid 138 residue.PATENT Attorney Docket No.: 062698-505001WO

[0045] "Conservatively modified variants" applies to both amino acid and nucleic acid sequences.With respect to particular nucleic acid sequences, "conservatively modified variants" refers to those nucleic acids that encode identical or essentially identical amino acid sequences. Because of the degeneracy of the genetic code, a number of nucleic acid sequences will encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine. Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are "silent variations," which are one species of conservatively modified variations. Every nucleic acid sequence herein which encodes a polypeptide also describes every possible silent variation of the nucleic acid. One of skill will recognize that each codon in a nucleic acid (except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan) can be modified to yield a functionally identical molecule. Accordingly, each silent variation of a nucleic acid which encodes a polypeptide is implicit in each described sequence.

[0046] As to amino acid sequences, one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a "conservatively modified variant" where the alteration results in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles of the disclosure.

[0047] The following eight groups each contain amino acids that are conservative substitutions for one another: 1) Alanine (A), Glycine (G); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V);PATENT Attorney Docket No.: 062698-505001WO 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine (C), Methionine (M) (see, e.g., Creighton, Proteins (1984)).

[0048] In embodiments, amino acid sequence variants (e.g., antibody variants of the anti-WISP1 antibodies and antigen-binding fragments thereof including one or more amino acid residue alterations) of the antibodies provided herein are contemplated. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody. Amino acid sequence variants of an antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and / or insertions into and / or substitutions of residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, for example, antigen binding.

[0049] In embodiments, antibody variants having one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include the CDRs and FRs. Such variants may be “conservatively modified variants” wherein the substitution comprises exchanging one or more amino acids with another from the same group as set out above. Such variants may be “non- conservatively modified variants” wherein the substitution comprises exchanging one or more amino acids with another from a different group as set out above.

[0050] Furthermore, any native residue in the polypeptide may also be substituted with alanine, as has been previously described for alanine scanning mutagenesis (MacLennan et al. (1998) Acta Physiol Sc and Suppl 643: 55-67; Sasaki et al. (1998) Adv Biophys 35: 1-24). Amino acid substitutions to the antibodies of the invention may be made by known methods for example by PCR mutagenesis (U.S. Pat. No.4,683,195). Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, for example, retained / improved antigen binding, decreased immunogenicity, or improved ADCC or CDC.PATENT Attorney Docket No.: 062698-505001WO

[0051] In embodiments, an antibody provided herein is altered to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of glycosylation sites to an antibody may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.

[0052] Where the antibody comprises an Fc region, the carbohydrate attached thereto may be altered. Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH2 domain of the Fc region. See, e.g., Wright et al., TIBTECH 15:26-32 (1997). The oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the “stem” of the biantennary oligosaccharide structure. In some embodiments, modifications of the oligosaccharide in an antibody of the invention may be made in order to create antibody variants with improved properties.

[0053] In one embodiment, antibody variants are provided having a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region. For example, the amount of fucose in such antibody may be from 1% to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn297 (e.g. complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008 / 077546, for example. Asn297 refers to the asparagine residue located at about position 297 in the Fc region (Eu numbering of Fc region residues); however, Asn297 may also be located about ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, for example, US Patent Publication Nos. US 2003 / 0157108; US 2004 / 0093621. Examples of publications related to “defucosylated” or “fucose-deficient” antibody variants include: US 2003 / 0157108; WO 2000 / 61739; WO 2001 / 29246; US 2003 / 0115614; US 2002 / 0164328; US 2004 / 0093621; US 2004 / 0132140; US 2004 / 0110704; US 2004 / 0110282; US 2004 / 0109865; WO 2003 / 085119; WO 2003 / 084570; WO 2005 / 035586; WO 2005 / 035778; WO2005 / 053742; WO2002 / 031140; Okazaki et al., J. Mol. Biol.336:1239-1249 (2004); Yamane-Ohnuki et al., Biotech. Bioeng.87: 614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells deficient in protein fucosylation (Ripka et al., Arch. Biochem.PATENT Attorney Docket No.: 062698-505001WO Biophys.249:533-545 (1986); US Pat Appl No US 2003 / 0157108 A1, Presta, L; and WO 2004 / 056312 A1, Adams et al., especially at Example 11), and knockout cell lines, such as alpha- 1,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al., Biotech. Bioeng.87: 614 (2004); Kanda et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and WO2003 / 085107).

[0054] Antibody variants are further provided with bisected oligosaccharides, e.g., in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibody variants may have reduced fucosylation and / or improved ADCC function. Examples of such antibody variants are described, e.g., in WO 2003 / 011878; U.S. Pat. No.6,602,684; and US 2005 / 0123546 (Umana et al.). Antibody variants with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, for example, in WO 1997 / 30087; WO 1998 / 58964; and WO 1999 / 22764 (Raju, S.).

[0055] In embodiments, one or more amino acid modifications may be introduced into the Fc region of an antibody provided herein, thereby generating an Fc region variant. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3 or IgG4 Fc region) comprising an amino acid residue alteration (e.g., a substitution) at one or more amino acid positions.

[0056] In embodiments, the invention contemplates an antibody variant that possesses some but not all effector functions, which make it a desirable candidate for applications in which the half life of the antibody in vivo is important yet effector functions (such as complement and ADCC) are unnecessary or deleterious. In vitro and / or in vivo cytotoxicity assays can be conducted to confirm the reduction / depletion of CDC and / or ADCC activities. For example, Fc receptor (FcR) binding assays can be conducted to ensure that the antibody lacks FcγR binding (hence likely lacking ADCC activity), but retains FcRn binding ability. The primary cells for mediating ADCC, NK cells, express Fc(RIII only, whereas monocytes express Fc(RI, Fc(RII and Fc(RIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol.9:457-492 (1991).PATENT Attorney Docket No.: 062698-505001WO

[0057] Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest are described in U.S. Pat. No.5,500,362 (see, e.g. Hellstrom et al., Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986) and Hellstrom, I et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985); U.S. Pat. No.5,821,337; and Bruggemann et al., J. Exp. Med.166:1351-1361 (1987)). Alternatively, non-radioactive assays methods may be employed (see, for example, ACTI™ non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA; and CYTOTOX 96® non-radioactive cytotoxicity assay (Promega, Madison, WI). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, for example, in a animal model such as that disclosed in Clynes et al., Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). C1q binding assays may also be carried out to confirm that the antibody is unable to bind C1q and hence lacks CDC activity. See, for example, C1q and C3c binding ELISA in WO 2006 / 029879 and WO 2005 / 100402. To assess complement activation, a CDC assay may be performed (see, e.g., Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg et al., Blood 101:1045-1052 (2003); and Cragg et al., Blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance / half life determinations can also be performed using methods known in the art (see, e.g., Petkova et al., Int'l. Immunol.18(12):1759-1769 (2006)).

[0058] Antibodies with reduced effector function include those with substitution of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (U.S. Pat. No.6,737,056). Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called “DANA” Fc mutant with substitution of residues 265 and 297 to alanine (U.S. Pat. No.7,332,581).

[0059] Antibody variants with improved or diminished binding to FcRs are described. (See, e.g., U.S. Pat. No.6,737,056; WO 2004 / 056312, and Shields et al., J. Biol. Chem.9(2): 6591-6604 (2001)).

[0060] The terms “identical” or percent “identity,” in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,PATENT Attorney Docket No.: 062698-505001WO 99%, or higher identity over a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection (see, e.g., NCBI web site http: / / www.ncbi.nlm.nih.gov / BLAST / or the like). Such sequences are then said to be “substantially identical.” This definition also refers to, or may be applied to, the compliment of a test sequence. The definition also includes sequences that have deletions and / or additions, as well as those that have substitutions. As described below, the preferred algorithms can account for gaps and the like. Preferably, identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50- 100 amino acids or nucleotides in length.

[0061] “Percentage of sequence identity” is determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity.

[0062] A “comparison window”, as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of, e.g., a full length sequence or from 20 to 600, about 50 to about 200, or about 100 to about 150 amino acids or nucleotides in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. Methods of alignment of sequences for comparison are well-known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith and Waterman (1970) Adv. Appl. Math. 2:482c, which is incorporated herein in its entirety and for all purposes, by the homology alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol.48:443, which is incorporated herein in its entirety and for all purposes, by the search for similarity method of Pearson and Lipman (1988) Proc. Nat’l. Acad. Sci. USA 85:2444, which is incorporated herein in its entirety and for allPATENT Attorney Docket No.: 062698-505001WO purposes, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by manual alignment and visual inspection (see, e.g., Ausubel et al., Current Protocols in Molecular Biology (1995 supplement)), which is incorporated herein in its entirety and for all purposes.

[0063] An example of an algorithm that is suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1977) Nuc. Acids Res.25:3389-3402, and Altschul et al. (1990) J. Mol. Biol.215:403-410, respectively, which are incorporated herein in their entirety and for all purposes. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (http: / / www.ncbi.nlm.nih.gov / ). This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues; always < 0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative- scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a word length (W) of 11, an expectation (E) or 10, M=5, N=-4 and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a word length of 3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89:10915, which is incorporated herein in its entirety and for all purposes) alignments (B) of 50, expectation (E) of 10, M=5, N=-4, and a comparison of both strands.PATENT Attorney Docket No.: 062698-505001WO

[0064] The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5787, which is incorporated herein in its entirety and for all purposes). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001.

[0065] An indication that two nucleic acid sequences or polypeptides are substantially identical is that the polypeptide encoded by the first nucleic acid is immunologically cross reactive with the antibodies raised against the polypeptide encoded by the second nucleic acid, as described below. Thus, a polypeptide is typically substantially identical to a second polypeptide, for example, where the two peptides differ only by conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that the two molecules or their complements hybridize to each other under stringent conditions, as described below. Yet another indication that two nucleic acid sequences are substantially identical is that the same primers can be used to amplify the sequence.

[0066] Antibodies are large, complex molecules (molecular weight of ~150,000 or about 1320 amino acids) with intricate internal structure. A natural antibody molecule contains two identical pairs of polypeptide chains, each pair having one light chain and one heavy chain. Each light chainand heavy chain in turn consists of two regions: a variable (“V”) region, involved in binding thetarget antigen, and a constant (“C”) region that interacts with other components of the immune system. The light and heavy chain variable regions (also referred to herein as light chain variable (VL) domain and heavy chain variable (VH) domain, respectively) come together in 3-dimensional space to form a variable region that binds the antigen (for example, a receptor on the surface of a cell). Within each light or heavy chain variable region, there are three short segments (averaging about 3 to about 16 amino acids in length) called the complementarity determining regions (“CDRs”). The six CDRs in an antibody variable domain (three from the light chain and three from the heavy chain) fold up together in 3-dimensional space to form the actual antibody binding site which docks onto the target antigen. The position and length of the can be defined in accordancePATENT Attorney Docket No.: 062698-505001WO with the Kabat numbering system; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)., or the IMGT numbering system; Lefranc, M.P. et al. Nucl. Acids Res.27:209-212 (1999), Ruiz, M. e al. Nucl. Acids Res.28:219-221 (2000). In embodiments, the CDRs are around about residues 24-34 (L1), 50-56 (L2) and 89-97 (L3) in the VL, and around about 31-35 (H1), 50-66 (H2) and 99-111 (H3) in the VH when numbered in accordance with the Kabat numbering system. In embodiments, the CDRs are around about residues 27-32 (L1), 50-52 (L2) and 89-97 (L3) in the VL, and 26-33 (H1), 51-58 (H2) and 97-111 (H3) in the VH when numbered in accordance with the IMGT numbering system. The part of a variable region not contained in the CDRs is called the framework ("FR"), which forms the environment for the CDRs.

[0067] An “antibody fragment” as provided herein refers to a polypeptide capable of binding to an antigen and including one or more structural domains (e.g., light chain variable domain, heavy chain variable domain) of an antibody. Non-limiting examples of antibody fragments include single- domain antibodies or nanobodies, monospecific Fab2, bispecific Fab2, trispecific Fab3, monovalent IgGs, scFv, bispecific antibodies, bispecific diabodies, trispecific triabodies, scFv-Fc, minibodies, IgNAR, V-NAR, hcIgG, VhH, or peptibodies. A “peptibody” as provided herein refers to a peptide moiety attached (through a covalent or non-covalent linker) to the Fc domain of an antibody. Further non-limiting examples of antibodies known in the art include antibodies produced by cartilaginous fish or camelids. A general description of antibodies from camelids and the variable regions thereof and methods for their production, isolation, and use may be found in references WO97 / 49805 and WO 97 / 49805 which are incorporated by reference herein in their entirety and for all purposes. Likewise, antibodies from cartilaginous fish and the variable regions thereof and methods for their production, isolation, and use may be found in WO2005 / 118629, which is incorporated by reference herein in its entirety and for all purposes.

[0068] The terms “CDR L1”, “CDR L2” and “CDR L3” as provided herein refer to the complementarity determining regions (CDR) 1, 2, and 3 of the variable light (L) chain of an antibody. In embodiments, the variable light chain provided herein includes in N-terminal to C- terminal direction a CDR L1, a CDR L2 and a CDR L3. Likewise, the terms “CDR H1”, “CDR H2” and “CDR H3” as provided herein refer to the complementarity determining regions (CDR) 1, 2, and 3 of the variable heavy (H) chain of an antibody. In embodiments, the variable heavy chainPATENT Attorney Docket No.: 062698-505001WO provided herein includes in N-terminal to C-terminal direction a CDR H1, a CDR H2 and a CDR H3.

[0069] The terms “FR L1”, “FR L2”, “FR L3” and “FR L4” as provided herein are used according to their common meaning in the art and refer to the framework regions (FR) 1, 2, 3 and 4 of the variable light (L) chain of an antibody. In embodiments, the variable light chain provided herein includes in N-terminal to C-terminal direction a FR L1, a FR L2, a FR L3 and a FR L4. Likewise, the terms "FR H1", "FR H2", "FR H3" and "FR H4" as provided herein are used according to their common meaning in the art and refer to the framework regions (FR) 1, 2, 3 and 4 of the variable heavy (H) chain of an antibody. In embodiments, the variable heavy chain provided herein includes in N-terminal to C-terminal direction a FR H1, a FR H2, a FR H3 and a FR H4.

[0070] An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kD) and one “heavy” chain (about 50-70 kD). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (VL), variable light chain (VL) domain or light chain variable region and variable heavy chain (VH), variable heavy chain (VH) domain or heavy chain variable region refer to these light and heavy chain regions, respectively. The terms variable light chain (VL), variable light chain (VL) domain and light chain variable region as referred to herein may be used interchangeably. The terms variable heavy chain (VH), variable heavy chain (VH) domain and heavy chain variable region as referred to herein may be used interchangeably. The Fc (i.e. fragment crystallizable region) is the "base" or "tail" of an immunoglobulin and is typically composed of two heavy chains that contribute two or three constant domains depending on the class of the antibody. By binding to specific proteins, the Fc region ensures that each antibody generates an appropriate immune response for a given antigen. The Fc region also binds to various cell receptors, such as Fc receptors, and other immune molecules, such as complement proteins.

[0071] The term “antibody” is used according to its commonly known meaning in the art. Antibodies exist, e.g., as intact immunoglobulins or as a number of well-characterized fragments produced by digestion with various peptidases. Thus, for example, pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)'2, a dimer of Fab which itself is a lightPATENT Attorney Docket No.: 062698-505001WO chain joined to VH-CH1by a disulfide bond. The F(ab)'2may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)'2 dimer into an Fab' monomer. The Fab' monomer is essentially Fab with part of the hinge region (see Fundamental Immunology (Paul ed., 3d ed.1993), which is incorporated herein in its entirety and for all purposes. While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by using recombinant DNA methodology. Thus, the term antibody, as used herein, also includes antibody fragments either produced by the modification of whole antibodies, or those synthesized de novo using recombinant DNA methodologies (e.g., single chain Fv) or those identified using phage display libraries (see, e.g., McCafferty et al., Nature 348:552-554 (1990), which is incorporated herein in its entirety and for all purposes). The term “antibody” as referred to herein further includes antibody fragments such as single domain antibodies. Thus, in embodiments an antibody includes a single monomeric variable antibody domain. Thus, in embodiments, the antibody, includes a variable light chain (VL) domain or a variable heavy chain (VH) domain. In embodiments, the antibody is a variable light chain (VL) domain or a variable heavy chain (VH) domain.

[0072] For preparation of monoclonal or polyclonal antibodies, any technique known in the art can be used (see, e.g., Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al., Immunology Today 4:72 (1983); Cole et al., pp.77-96 in Monoclonal Antibodies and Cancer Therapy (1985), which are incorporated herein in their entirety and for all purposes). “Monoclonal” antibodies (mAb) refer to antibodies derived from a single clone. Techniques for the production of single chain antibodies (U.S. Pat. No.4,946,778, which is incorporated herein in its entirety and for all purposes) can be adapted to produce antibodies to polypeptides of this invention. Also, transgenic mice, or other organisms such as other mammals, may be used to express humanized antibodies. Alternatively, phage display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens (see, e.g., McCafferty et al., Nature 348:552- 554 (1990); Marks et al., Biotechnology 10:779-783 (1992), which is incorporated herein in its entirety and for all purposes).

[0073] A single-chain variable fragment (scFv) is typically a fusion protein of the variable regions of the heavy (VH) and light chains (VL) of immunoglobulins, connected with a short linker peptide of 10 to about 25 amino acids. The linker may usually be rich in glycine for flexibility, as well asPATENT Attorney Docket No.: 062698-505001WO serine or threonine for solubility. The linker can either connect the N-terminus of the VH with the C-terminus of the VL, or vice versa.

[0074] Another example of antibody fragments according to the disclosure are Fab’ fragments. Fab' fragments differ from Fab fragments by the presence of additional residues including one or more cysteines from the antibody hinge region at the C-terminus of the CH1 domain. F(ab')2 antibody fragments are pairs of Fab' fragments linked by cysteine residues in the hinge region. Other chemical couplings of antibody fragments are also known.

[0075] A "Fv" fragment contains a complete antigen-recognition and binding site consisting of a dimer of one heavy and one light chain variable domain in tight, non-covalent association. In this configuration, the three CDRs of each variable domain interact to define an antigen-biding site on the surface of the VH-VL dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody.

[0076] Antibody fragments may also form tandem Fd segments, which comprise a pair of tandem Fd segments (VH-CH1-VH-CH1) to form a pair of antigen binding regions. These “linear antibodies” can be bispecific or monospecific as described in, for example, Zapata et al.1995, Protein Eng.8(10):1057-1062.

[0077] The epitope of a mAb is the region of its antigen to which the mAb binds. Two antibodies bind to the same or overlapping epitope if each competitively inhibits (blocks) binding of the other to the antigen. That is, a 1x, 5x, 10x, 20x or 100x excess of one antibody inhibits binding of the other by at least 30% but preferably 50%, 75%, 90% or even 99% as measured in a competitive binding assay (see, e.g., Junghans et al., Cancer Res.50:1495, 1990, which is incorporated herein in its entirety and for all purposes). Alternatively, two antibodies have the same epitope if essentially all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other. Two antibodies have overlapping epitopes if some amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other.

[0078] For preparation of suitable antibodies of the invention and for use according to the invention, e.g., recombinant, monoclonal, or polyclonal antibodies, many techniques known in the art can be used (see, e.g., Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al.,PATENT Attorney Docket No.: 062698-505001WO Immunology Today 4: 72 (1983); Cole et al., pp.77-96 in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985); Coligan, Current Protocols in Immunology (1991); Harlow & Lane, Antibodies, A Laboratory Manual (1988); and Goding, Monoclonal Antibodies: Principles and Practice (2d ed.1986), which are incorporated herein in their entirety and for all purposes). The genes encoding the heavy and light chains of an antibody of interest can be cloned from a cell, e.g., the genes encoding a monoclonal antibody can be cloned from a hybridoma and used to produce a recombinant monoclonal antibody. Gene libraries encoding heavy and light chains of monoclonal antibodies can also be made from hybridoma or plasma cells. Random combinations of the heavy and light chain gene products generate a large pool of antibodies with different antigenic specificity (see, e.g., Kuby, Immunology (3rd ed.1997), which is incorporated herein in its entirety and for all purposes). Techniques for the production of single chain antibodies or recombinant antibodies (U.S. Patent 4,946,778, U.S. Patent No.4,816,567, which are incorporated herein in their entirety and for all purposes) can be adapted to produce antibodies to polypeptides of this invention. Also, transgenic mice, or other organisms such as other mammals, may be used to express humanized or human antibodies (see, e.g., U.S. Patent Nos.5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, Marks et al., Bio / Technology 10:779-783 (1992); Lonberg et al., Nature 368:856-859 (1994); Morrison, Nature 368:812-13 (1994); Fishwild et al., Nature Biotechnology 14:845-51 (1996); Neuberger, Nature Biotechnology 14:826 (1996); and Lonberg & Huszar, Intern. Rev. Immunol.13:65-93 (1995), which are incorporated herein in their entirety and for all purposes). Alternatively, phage display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens (see, e.g., McCafferty et al., Nature 348:552-554 (1990); Marks et al., Biotechnology 10:779-783 (1992), which are incorporated herein in their entirety and for all purposes). Antibodies can also be made bispecific, i.e., able to recognize two different antigens (see, e.g., WO 93 / 08829, Traunecker et al., EMBO J.10:3655-3659 (1991); and Suresh et al., Methods in Enzymology 121:210 (1986), which are incorporated herein in their entirety and for all purposes). Antibodies can also be heteroconjugates, e.g., two covalently joined antibodies, or immunotoxins (see, e.g., U.S. Patent No.4,676,980 , WO 91 / 00360; WO 92 / 200373; and EP 03089, which are incorporated herein in their entirety and for all purposes).

[0079] Methods for humanizing or primatizing non-human antibodies are well known in the art (e.g., U.S. Patent Nos.4,816,567; 5,530,101; 5,859,205; 5,585,089; 5,693,761; 5,693,762;PATENT Attorney Docket No.: 062698-505001WO 5,777,085; 6,180,370; 6,210,671; and 6,329,511; WO 87 / 02671; EP Patent Application 0173494; Jones et al. (1986) Nature 321:522; and Verhoyen et al. (1988) Science 239:1534, which are incorporated herein in their entirety and for all purposes). Humanized antibodies are further described in, e.g., Winter and Milstein (1991) Nature 349:293, which is incorporated herein in its entirety and for all purposes. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as import residues, which are typically taken from an import variable domain. Humanization can be essentially performed following the method of Winter and co-workers (see, e.g., Morrison et al., PNAS USA, 81:6851-6855 (1984), Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Morrison and Oi, Adv. Immunol., 44:65-92 (1988), Verhoeyen et al., Science 239:1534-1536 (1988) and Presta, Curr. Op. Struct. Biol.2:593-596 (1992), Padlan, Molec. Immun., 28:489-498 (1991); Padlan, Molec. Immun., 31(3):169-217 (1994), which are incorporated herein in their entirety and for all purposes), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such humanized antibodies are chimeric antibodies (U.S. Patent No.4,816,567, which is incorporated herein in its entirety and for all purposes), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies. For example, polynucleotides comprising a first sequence coding for humanized immunoglobulin framework regions and a second sequence set coding for the desired immunoglobulin complementarity determining regions can be produced synthetically or by combining appropriate cDNA and genomic DNA segments. Human constant region DNA sequences can be isolated in accordance with well known procedures from a variety of human cells.

[0080] A “chimeric antibody” is an antibody molecule in which (a) the constant region, or a portion thereof, is altered, replaced or exchanged so that the antigen binding site (variable region) is linked to a constant region of a different or altered class, effector function and / or species, or an entirely different molecule which confers new properties to the chimeric antibody, e.g., an enzyme, toxin, hormone, growth factor, drug, etc.; or (b) the variable region, or a portion thereof, is altered, replaced or exchanged with a variable region having a different or altered antigen specificity. ThePATENT Attorney Docket No.: 062698-505001WO preferred antibodies of, and for use according to the invention include humanized and / or chimeric monoclonal antibodies.

[0081] The phrase “specifically (or selectively) binds” to an antibody or “specifically (or selectively) immunoreactive with”, when referring to a protein or peptide, refers to a binding reaction that is determinative of the presence of the protein, often in a heterogeneous population of proteins and other biologics. Thus, under designated immunoassay conditions, the specified antibodies bind to a particular protein at least two times the background and more typically more than 10 to 100 times background. Specific binding to an antibody under such conditions requires an antibody that is selected for its specificity for a particular protein. For example, polyclonal antibodies can be selected to obtain only a subset of antibodies that are specifically immunoreactive with the selected antigen and not with other proteins. This selection may be achieved by subtracting out antibodies that cross-react with other molecules. A variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein. For example, solid- phase ELISA immunoassays are routinely used to select antibodies specifically immunoreactive with a protein (see, e.g., Harlow & Lane, Using Antibodies, A Laboratory Manual (1998), which is incorporated herein in its entirety and for all purposes, for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity).

[0082] A “ligand” refers to an agent, e.g., a polypeptide or other molecule, capable of binding to a receptor or antibody, antibody variant, antibody region or fragment thereof.

[0083] Techniques for conjugating therapeutic agents to antibodies are well known (see, e.g., Arnon et al., “Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy”, in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp.243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery” in Controlled Drug Delivery (2ndEd.), Robinson et al. (eds.), pp.623-53 (Marcel Dekker, Inc.1987); Thorpe, “Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review” in Monoclonal Antibodies ‘84: Biological And Clinical Applications, Pinchera et al. (eds.), pp.475-506 (1985); and Thorpe et al., “The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates”, Immunol. Rev., 62:119-58 (1982), which are incorporated herein in their entirety and for all purposes). As used herein, the termPATENT Attorney Docket No.: 062698-505001WO “antibody-drug conjugate” or “ADC” refers to a therapeutic agent conjugated or otherwise covalently bound to to an antibody.

[0084] The term “WISP1 protein” or “WISP1”" as used herein includes any of the recombinant or naturally-occurring forms of WNT1-inducible-signaling pathway protein 1 (WISP1), also known asCellular Communication Network Factor 4, CCN family member 4, Wnt-1-induced secreted protein,CCN4, or variants or homologs thereof that maintain WISP1 activity (e.g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to WISP1). In some aspects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring WISP1 protein. In embodiments, the WISP1 protein is a mammalian WISP1 protein. In embodiments, the WISP1 protein is a human WISP1 protein. In embodiments, the WISP1 protein is substantially identical to the protein identified by SEQ ID NO:15. In embodiments, the WISP1 protein is substantially identical to the protein identified by SEQ ID NO:16. In embodiments, the WISP1 protein is substantially identical to the protein identified by SEQ ID NO:17. In embodiments, the WISP1 protein is substantially identical to the protein identified by SEQ ID NO:19. In embodiments, the WISP1 protein is substantially identical to the protein identified by SEQ ID NO:20. In embodiments, the WISP1 protein is substantially identical to the protein identified by the UniProt reference number O95388 or a variant or homolog having substantial identity thereto. In embodiments, the WISP1 protein includes any one of domains 1-4 or a combination thereof. Thus, in embodiments, the WISP1 protein includes domain 1, domain 2, domain 3, or domain 4 of WISP1 protein. In embodiments, domain 1 includes the sequence of SEQ ID NO:25. In embodiments, the WISP1 protein includes the sequence of SEQ ID NO:25. In embodiments, domain 2 includes the sequence of SEQ ID NO:26. In embodiments, the WISP1 protein includes the sequence of SEQ ID NO:26. In embodiments, domain 3 includes the sequence of SEQ ID NO:27. In embodiments, the WISP1 protein includes the sequence of SEQ ID NO:27. In embodiments, domain 4 includes the sequence of SEQ ID NO:28. In embodiments, the WISP1 protein includes the sequence of SEQ ID NO:28.

[0085] For specific proteins described herein, the named protein includes any of the protein’s naturally occurring forms, variants or homologs that maintain the protein activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to the native protein).PATENT Attorney Docket No.: 062698-505001WO In some embodiments, variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring form. In other embodiments, the protein is the protein as identified by its NCBI sequence reference. In other embodiments, the protein is the protein as identified by its NCBI sequence reference, homolog or functional fragment thereof.

[0086] The term “gene” means the segment of DNA involved in producing a protein; it includes regions preceding and following the coding region (leader and trailer) as well as intervening sequences (introns) between individual coding segments (exons). The leader, the trailer as well as the introns include regulatory elements that are necessary during the transcription and the translation of a gene. Further, a "protein gene product" is a protein expressed from a particular gene.

[0087] The terms “plasmid”, “vector” or “expression vector” refer to a nucleic acid molecule that encodes for genes and / or regulatory elements necessary for the expression of genes. Expression of a gene from a plasmid can occur in cis or in trans. If a gene is expressed in cis, the gene and the regulatory elements are encoded by the same plasmid. Expression in trans refers to the instance where the gene and the regulatory elements are encoded by separate plasmids.

[0088] The terms “transfection”, “transduction”, “transfecting” or “transducing” can be used interchangeably and are defined as a process of introducing a nucleic acid molecule or a protein to a cell. Nucleic acids are introduced to a cell using non-viral or viral-based methods. The nucleic acid molecules may be gene sequences encoding complete proteins or functional portions thereof. Non- viral methods of transfection include any appropriate transfection method that does not use viral DNA or viral particles as a delivery system to introduce the nucleic acid molecule into the cell. Exemplary non-viral transfection methods include calcium phosphate transfection, liposomal transfection, nucleofection, sonoporation, transfection through heat shock, magnetifection and electroporation. In some embodiments, the nucleic acid molecules are introduced into a cell using electroporation following standard procedures well known in the art. For viral-based methods of transfection any useful viral vector may be used in the methods described herein. Examples for viral vectors include, but are not limited to retroviral, adenoviral, lentiviral and adeno-associated viral vectors. In some embodiments, the nucleic acid molecules are introduced into a cell using aPATENT Attorney Docket No.: 062698-505001WO retroviral vector following standard procedures well known in the art. The terms ″transfection″ or ″transduction″ also refer to introducing proteins into a cell from the external environment. Typically, transduction or transfection of a protein relies on attachment of a peptide or protein capable of crossing the cell membrane to the protein of interest. See, e.g., Ford et al. (2001) Gene Therapy 8:1-4 and Prochiantz (2007) Nat. Methods 4:119-20., which is incorporated herein in its entirety and for all purposes.

[0089] A “label” or a “detectable moiety” is a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means. For example, useful labels include 32P, fluorescent dyes, electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide. Any appropriate method known in the art for conjugating an antibody to the label may be employed, e.g., using methods described in Hermanson, Bioconjugate Techniques 1996, Academic Press, Inc., San Diego., which is incorporated herein in its entirety and for all purposes.

[0090] “Contacting” is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. antibodies and antigens) to become sufficiently proximal to react, interact, or physically touch. It should be appreciated; however, that the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.

[0091] The term “contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be, for example, a pharmaceutical composition as provided herein and a cell. In embodiments contacting includes, for example, allowing an antibody as described herein to interact with a cell. In embodiments contacting includes, for example, allowing an antibody as described herein to physically interact with a WISP1 protein or a fragment thereof.

[0092] A “cell” as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaryotic cells. Prokaryotic cells include butPATENT Attorney Docket No.: 062698-505001WO are not limited to bacteria. Eukaryotic cells include, but are not limited to, yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells.

[0093] The term “recombinant” when used with reference, e.g., to a cell, nucleic acid, protein, or vector, indicates that the cell, nucleic acid, protein or vector, has been modified by the introduction of a heterologous nucleic acid or protein or the alteration of a native nucleic acid or protein, or that the cell is derived from a cell so modified. Thus, for example, recombinant cells express genes that are not found within the native (non-recombinant) form of the cell or express native genes that are otherwise abnormally expressed, under expressed or not expressed at all. Transgenic cells and plants are those that express a heterologous gene or coding sequence, typically as a result of recombinant methods.

[0094] The term “isolated”, when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified.

[0095] The term “heterologous” when used with reference to portions of a nucleic acid indicates that the nucleic acid comprises two or more subsequences that are not found in the same relationship to each other in nature. For instance, the nucleic acid is typically recombinantly produced, having two or more sequences from unrelated genes arranged to make a new functional nucleic acid, e.g., a promoter from one source and a coding region from another source. Similarly, a heterologous protein indicates that the protein comprises two or more subsequences that are not found in the same relationship to each other in nature (e.g., a fusion protein).

[0096] The term “exogenous” refers to a molecule or substance (e.g., a compound, nucleic acid or protein) that originates from outside a given cell or organism. For example, an "exogenous promoter" as referred to herein is a promoter that does not originate from the cell or organism it is expressed by. Conversely, the term “endogenous” or “endogenous promoter” refers to a molecule or substance that is native to, or originates within, a given cell or organism.PATENT Attorney Docket No.: 062698-505001WO

[0097] As defined herein, the term “inhibition”, “inhibit”, “inhibiting” and the like in reference to protein activity means negatively affecting (e.g., decreasing) the function of the protein. In some embodiments, inhibition refers to reduction of a disease or symptoms of disease (e.g., fibrosis (e.g. liver fibrosis, lung fibrosis, etc.)). Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein (e.g. WISP1 protein). Similarly an “inhibitor” is a compound or protein that inhibits a receptor or another protein, e.g., by binding, partially or totally blocking, decreasing, preventing, delaying, inactivating, desensitizing, or down-regulating activity (e.g., a receptor activity or a protein activity).

[0098] As defined herein, the term “inhibition”, “inhibit”, “inhibiting” and the like in reference to a protein-inhibitor interaction means negatively affecting (e.g. decreasing) the activity or function of the protein (e.g. WISP1 protein) relative to the activity or function of the protein in the absence of the inhibitor. In embodiments inhibition means negatively affecting (e.g. decreasing) the concentration or levels of WISP1 relative to the concentration or level of the protein in the absence of the inhibitor. In embodiments inhibition refers to reduction of a disease or symptoms of disease (e.g. fibrosis). In embodiments, inhibition refers to a reduction in the activity of WISP1. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of WISP1. In embodiments, inhibition refers to a reduction of activity of WISP1 resulting from a direct interaction (e.g. an inhibitor binds to WISP1). In embodiments, inhibition refers to a reduction of activity of WISP1 from an indirect interaction (e.g. an inhibitor binds to a protein that activates WISP1, thereby preventing target protein activation).

[0099] Thus, the terms “inhibitor,” “repressor” or “antagonist” or “downregulator” interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein (e.g. WISP1 protein). The antagonist can decrease WISP1 expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the antagonist. In certain instances, WISP1 expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist.PATENT Attorney Docket No.: 062698-505001WO

[0100] The term “expression” includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post- translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0101] “Biological sample” or “sample” refer to materials obtained from or derived from a subject or patient. A biological sample includes sections of tissues such as biopsy and autopsy samples, and frozen sections taken for histological purposes. Such samples include bodily fluids such as blood and blood fractions or products (e.g., serum, plasma, platelets, red blood cells, and the like), sputum, tissue, cultured cells (e.g., primary cultures, explants, and transformed cells) stool, urine, immune cells, hematopoietic cells, fibroblasts, macrophages, T cells, etc. A biological sample is typically obtained from a eukaryotic organism, such as a mammal such as a primate e.g., chimpanzee or human; cow; dog; cat; a rodent, e.g., guinea pig, rat, mouse; rabbit; or a bird; reptile; or fish. In embodiments the biological sample is bronchoalveolar lavage fluid (BALF). In embodiments, the biological sample is plasma. In embodiments, the biological sample is tissue, for example, tissue derived from the lungs, liver, or heart of a subject.

[0102] A “control” or “standard control” refers to a sample, measurement, or value that serves as a reference, usually a known reference, for comparison to a test sample, measurement, or value. For example, a test sample can be taken from a patient suspected of having a given disease (e.g. fibrosis) and compared to a known normal (non-diseased) individual (e.g. a standard control subject). In embodiments, the control is a biological sample taken from a subject who does not have fibrosis. A standard control can also represent an average measurement or value gathered from a population of similar individuals (e.g. standard control subjects) that do not have a given disease (i.e. standard control population), e.g., healthy individuals with a similar medical background, same age, weight, etc. A standard control value can also be obtained from the same individual, e.g. from an earlier- obtained sample from the patient prior to disease onset. For example, a control can be devised to compare therapeutic benefit based on pharmacological data (e.g., half-life) or therapeutic measures (e.g., comparison of side effects). Controls are also valuable for determining the significance of data. For example, in embodiments, a control may be a test sample that does not include an anti- WISP1 antibody as provided herein. For example, if values for a given parameter are widely variantPATENT Attorney Docket No.: 062698-505001WO in controls, variation in test samples will not be considered as significant. One of skill will recognize that standard controls can be designed for assessment of any number of parameters (e.g. RNA levels, protein levels, specific cell types, specific bodily fluids, specific tissues, etc).

[0103] One of skill in the art will understand which standard controls are most appropriate in a given situation and be able to analyze data based on comparisons to standard control values. Standard controls are also valuable for determining the significance (e.g. statistical significance) of data. For example, if values for a given parameter are widely variant in standard controls, variation in test samples will not be considered as significant.

[0104] “Patient” or “subject in need thereof” refers to a living organism suffering from or prone to a disease (e.g. fibrosis) or condition that can be treated by administration of a composition or pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human.

[0105] The terms “disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. The disease may be fibrosis. Fibrosis is a condition which may be characterized by an abnormal accumulation of a collagen matrix following injury or inflammation which alters the structure and function of various tissues. In embodiments, the fibrosis is in the kidney, liver, lung, heart, bone or bone marrow, or skin.

[0106] The term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease (e.g. a protein associated disease (e.g., fibrosis associated with WISP1 activity)) means that the disease (e.g. fibrosis) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function. As used herein, what is described as being associated with a disease, if a causative agent, could be a target for treatment of the disease. For example, fibrosis associated with WISP1 activity or function or a WISP1 associated disease (e.g. fibrosis (e.g. liver fibrosis, lung fibrosis, etc.)), may be treated with a WISP1 modulator or WISP1 inhibitor, in the instance where increased WISP1 activity or function (e.g. signaling pathway activity) causes the disease (e.g., fibrosis). For example, a fibrotic disorder associated with WISP1 activity may be treated with anPATENT Attorney Docket No.: 062698-505001WO WISP1 modulator or WISP1 inhibitor, in the instance where increased WISP1 activity or function (e.g. signaling pathway activity) causes the disease.

[0107] The term “signaling pathway” as used herein refers to a series of interactions between cellular and optionally extra-cellular components (e.g. proteins, nucleic acids, small molecules, ions, lipids) that conveys a change in one component to one or more other components, which in turn may convey a change to additional components, which is optionally propagated to other signaling pathway components.

[0108] The term “aberrant” as used herein refers to different from normal. When used to describe enzymatic activity, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease- associated amount (e.g. by using a method as described herein), results in reduction of the disease or one or more disease symptoms.

[0109] A “therapeutic agent” as referred to herein, is a composition useful in treating or preventing fibrosis (e.g. liver fibrosis, lung fibrosis, etc.). In embodiments, the therapeutic agent is an anti-fibrotic agent. For example, an anti-fibrotic agent may refer to a composition (e.g. compound, drug, antagonist, inhibitor, modulator) having the ability to inhibit or slow the rate of fibrosis or scarring. In embodiments, an anti-fibrotic agent is an agent approved by the FDA or similar regulatory agency of a country other than the USA, for treating fibrosis.

[0110] As used herein, “treating” or “treatment of” a condition, disease or disorder or symptoms associated with a condition, disease or disorder refers to an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of condition, disorder or disease, stabilization of the state of condition, disorder or disease, prevention of development of condition, disorder or disease, prevention of spread of condition, disorder or disease, delay or slowing of condition, disorder or disease progression, delay or slowing of condition, disorder or disease onset, amelioration or palliation of the condition, disorder or disease state, and remission, whether partial or total. “Treating” can also mean prolonging survival of a subject beyond that expected in the absence of treatment. “Treating” can also mean inhibitingPATENT Attorney Docket No.: 062698-505001WO the progression of the condition, disorder or disease, slowing the progression of the condition, disorder or disease temporarily, although in some instances, it involves halting the progression of the condition, disorder or disease permanently. As used herein the terms treatment, treat, or treating refers to a method of reducing the effects of one or more symptoms of a disease or condition characterized by expression of the protease or symptom of the disease or condition characterized by expression of the protease. Thus, in the disclosed method, treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of an established disease, condition, or symptom of the disease or condition. For example, a method for treating a disease is considered to be a treatment if there is a 10% reduction in one or more symptoms of the disease in a subject as compared to a control. Thus, the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percent reduction in between 10% and 100% as compared to native or control levels. It is understood that treatment does not necessarily refer to a cure or complete ablation of the disease, condition, or symptoms of the disease or condition. Further, as used herein, references to decreasing, reducing, or inhibiting include a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater as compared to a control level and such terms can include but do not necessarily include complete elimination.

[0111] The terms “dose” and “dosage” are used interchangeably herein. A dose refers to the amount of active ingredient given to an individual at each administration. The dose will vary depending on a number of factors, including the range of normal doses for a given therapy, frequency of administration; size and tolerance of the individual; severity of the condition; risk of side effects; and the route of administration. One of skill will recognize that the dose can be modified depending on the above factors or based on therapeutic progress. The term “dosage form” refers to the particular format of the pharmaceutical or pharmaceutical composition, and depends on the route of administration. For example, a dosage form can be in a liquid form for nebulization, e.g., for inhalants, in a tablet or liquid, e.g., for oral delivery, or a saline solution, e.g., for injection.

[0112] By “therapeutically effective amount” as used herein is meant any amount that produces effects for which it is administered (e.g. treating or preventing a disease). By “therapeutically effective dose” as used herein is meant a specific amount of a substance (such as an antibody disclosed herein) administered to a subject at one time or over a specified period. A “therapeutically effective amount” may comprise one or more “therapeutically effective dose(s)” required to achievePATENT Attorney Docket No.: 062698-505001WO the desired therapeutic effect. The exact dose and formulation will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Remington: The Science and Practice of Pharmacy, 20th Edition, Gennaro, Editor (2003), and Pickar, Dosage Calculations (1999), which are incorporated herein in their entirety and for all purposes). For example, for the given parameter, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy can also be expressed as “-fold” increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a standard control. A therapeutically effective dose or amount may ameliorate one or more symptoms of a disease. A therapeutically effective dose or amount may prevent or delay the onset of a disease or one or more symptoms of a disease when the effect for which it is being administered is to treat a person who is at risk of developing the disease.

[0113] As used herein, the term “administering” means oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini- osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal. Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By “co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies, for example, an anti-fibrotic agent. The compounds of the invention can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation). The compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.PATENT Attorney Docket No.: 062698-505001WO

[0114] As used herein, the term “pharmaceutically acceptable” is used synonymously with “physiologically acceptable” and “pharmacologically acceptable”. A pharmaceutical composition will generally comprise agents for buffering and preservation in storage, and can include buffers and carriers for appropriate delivery, depending on the route of administration.

[0115] “Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0116] The term "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

[0117] The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0118] The pharmaceutical preparation is optionally in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component.PATENT Attorney Docket No.: 062698-505001WO The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. The unit dosage form can be of a frozen dispersion.

[0119] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. ANTI-WISP1 ANTIBODIES

[0120] Provided herein are, inter alia, antibodies (e.g., humanized antibodies, monoclonal antibodies) and antibody fragments (e.g., scFvs), which bind WNT1-inducible-signaling pathway protein 1 (WISP1) with high efficiency and specificity. The antibodies and antibody compositions provided herein include novel light and heavy chain domain CDRs and have been identified to bind domain 2 of WISP1 protein. Antibodies described herein including embodiments thereof, are useful for binding WISP1 with high effectivity and affinity and inhibit WISP1 activity in cells expressing WISP1. The antibodies provided herein including embodiments thereof, may be used for diagnostic and therapeutic purposes in WISP1-related fibrotic disorders. The antibodies provided herein including embodiments thereof, have an ability to suppress collagen formation and therefore are capable of inhibiting or slowing fibrosis (e.g. liver fibrosis, lung fibrosis, etc.).

[0121] An exemplary anti-WISP1 antibody provided herein is referred to by name (e.g. K4, K4 antibody).

[0122] In an aspect is provided an anti-WNT1-inducible-signaling pathway protein 1 (WISP1) antibody, including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes: a CDR H1 as set forth in SEQ ID NO:1, a CDR H2 as set forth in SEQ ID NO:2 and a CDR H3 as set forth in SEQ ID NO:3; and wherein the light chain variable domain includes: a CDR L1 as set forth in SEQ ID NO:4, a CDR L2 including AAS, and a CDR L3 as set forth in SEQ ID NO:6.PATENT Attorney Docket No.: 062698-505001WO

[0123] As described above, a "light chain variable (VL) domain" as provided herein refers to the variable region of the light chain of an antibody, an antibody variant or fragment thereof. Likewise, the "heavy chain variable (VH) domain" as provided herein refers to the variable region of the heavy chain of an antibody, an antibody variant or fragment thereof. The light chain variable domain and the heavy chain variable domain together form the paratope, which binds an antigen (epitope). The paratope or antigen-binding site is formed at the N-terminus of an antibody, an antibody variant or fragment thereof. In embodiments, the light chain variable (VL) domain includes CDR L1, CDR L2, CDR L3 and FR L1, FR L2, FR L3 and FR L4 (framework regions) of an antibody light chain. In embodiments, the heavy chain variable (VH) domain includes CDR H1, CDR H2, CDR H3 and FR H1, FR H2, FR H3 and FR H4 (framework regions) of an antibody heavy chain. In embodiments, the light chain variable (VL) domain and a light chain constant (CL) domain form part of an antibody light chain. In embodiments, the heavy chain variable (VH) domain and a heavy chain constant (CH1) domain form part of an antibody heavy chain. In embodiments, the heavy chain variable (VH) domain and one or more heavy chain constant (CH1, CH2, or CH3) domains form part of an antibody heavy chain. Thus, in embodiments, the light chain variable (VL) domain forms part of an antibody. In embodiments, the heavy chain variable (VH) domain forms part of an antibody. In embodiments, the light chain variable (VL) domain forms part of a therapeutic antibody. In embodiments, the heavy chain variable (VH) domain forms part of a therapeutic antibody. In embodiments, the light chain variable (VL) domain forms part of a human antibody. In embodiments, the heavy chain variable (VH) domain forms part of a human antibody. In embodiments, the light chain variable (VL) domain forms part of a humanized antibody. In embodiments, the heavy chain variable (VH) domain forms part of a humanized antibody. In embodiments, the light chain variable (VL) domain forms part of a chimeric antibody. In embodiments, the heavy chain variable (VH) domain forms part of a chimeric antibody. In embodiments, the light chain variable (VL) domain forms part of an antibody fragment. In embodiments, the heavy chain variable (VH) domain forms part of an antibody fragment. In embodiments, the light chain variable (VL) domain forms part of an antibody variant. In embodiments, the heavy chain variable (VH) domain forms part of an antibody variant. In embodiments, the light chain variable (VL) domain forms part of a Fab. In embodiments, the heavy chain variable (VH) domain forms part of a Fab. In embodiments, the light chain variable (VL)PATENT Attorney Docket No.: 062698-505001WO domain forms part of a scFv. In embodiments, the heavy chain variable (VH) domain forms part of a scFv.

[0124] In embodiments, the heavy chain variable domain includes a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:13. In embodiments, the heavy chain variable domain includes a sequence having at least 90% identity to SEQ ID NO:13. In embodiments, the heavy chain variable domain includes a sequence having at least 91% identity to SEQ ID NO:13. In embodiments, the heavy chain variable domain includes a sequence having at least 92% identity to SEQ ID NO:13. In embodiments, the heavy chain variable domain includes a sequence having at least 93% identity to SEQ ID NO:13. In embodiments, the heavy chain variable domain includes a sequence having at least 94% identity to SEQ ID NO:13. In embodiments, the heavy chain variable domain includes a sequence having at least 95% identity to SEQ ID NO:13. In embodiments, the heavy chain variable domain includes a sequence having at least 96% identity to SEQ ID NO:13. In embodiments, the heavy chain variable domain includes a sequence having at least 97% identity to SEQ ID NO:13. In embodiments, the heavy chain variable domain includes a sequence having at least 98% identity to SEQ ID NO:13. In embodiments, the heavy chain variable domain includes a sequence having at least 99% identity to SEQ ID NO:13. In embodiments, said heavy chain variable domain includes SEQ ID NO:13. In embodiments, said heavy chain variable domain is SEQ ID NO:13.

[0125] In embodiments, the light chain variable domain includes a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:14. In embodiments, the light chain variable domain includes a sequence having at least 90% identity to SEQ ID NO:14. In embodiments, the light chain variable domain includes a sequence having at least 91% identity to SEQ ID NO:14. In embodiments, the light chain variable domain includes a sequence having at least 92% identity to SEQ ID NO:14. In embodiments, the light chain variable domain includes a sequence having at least 93% identity to SEQ ID NO:14. In embodiments, the light chain variable domain includes a sequence having at least 94% identity to SEQ ID NO:14. In embodiments, the light chain variable domain includes a sequence having at least 95% identity to SEQ ID NO:14. In embodiments, the light chain variable domain includes a sequence having at least 96% identity to SEQ ID NO:14. In embodiments, the light chain variable domain includes a sequence having at least 97% identity to SEQ ID NO:14. In embodiments, the light chain variable domain includes aPATENT Attorney Docket No.: 062698-505001WO sequence having at least 98% identity to SEQ ID NO:14. In embodiments, the light chain variable domain includes a sequence having at least 99% identity to SEQ ID NO:14. In embodiments, said light chain variable domain includes SEQ ID NO:14. In embodiments, said light chain variable domain is SEQ ID NO:14.

[0126] In embodiments, the heavy chain variable domain includes a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:13 and the light chain variable domain includes a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:14. In embodiments, the heavy chain variable domain includes a sequence having at least 90% identity to SEQ ID NO:13 and the light chain variable domain includes a sequence having at least 90% identity to SEQ ID NO:14. In embodiments, the heavy chain variable domain includes a sequence having at least 91% identity to SEQ ID NO:13 and the light chain variable domain includes a sequence having at least 91% identity to SEQ ID NO:14. In embodiments, the heavy chain variable domain includes a sequence having at least 92% identity to SEQ ID NO:13 and the light chain variable domain includes a sequence having at least 92% identity to SEQ ID NO:14. In embodiments, the heavy chain variable domain includes a sequence having at least 93% identity to SEQ ID NO:13 and the light chain variable domain includes a sequence having at least 93% identity to SEQ ID NO:14. In embodiments, the heavy chain variable domain includes a sequence having at least 94% identity to SEQ ID NO:13 and the light chain variable domain includes a sequence having at least 94% identity to SEQ ID NO:14. In embodiments, the heavy chain variable domain includes a sequence having at least 95% identity to SEQ ID NO:13 and the light chain variable domain includes a sequence having at least 95% identity to SEQ ID NO:14. In embodiments, the heavy chain variable domain includes a sequence having at least 96% identity to SEQ ID NO:13 and the light chain variable domain includes a sequence having at least 96% identity to SEQ ID NO:14. In embodiments, the heavy chain variable domain includes a sequence having at least 97% identity to SEQ ID NO:13 and the light chain variable domain includes a sequence having at least 97% identity to SEQ ID NO:14. In embodiments, the heavy chain variable domain includes a sequence having at least 98% identity to SEQ ID NO:13 and the light chain variable domain includes a sequence having at least 98% identity to SEQ ID NO:14. In embodiments, the heavy chain variable domain includes a sequence having at least 99% identity to SEQ ID NO:13 and the light chain variable domain includes a sequence having at least 99% identity to SEQ ID NO:14. InPATENT Attorney Docket No.: 062698-505001WO embodiments, said heavy chain variable domain includes SEQ ID NO:13 and the light chain variable domain includes SEQ ID NO:14. In embodiments, said heavy chain variable domain is SEQ ID NO:13 and the light chain variable domain is SEQ ID NO:14.

[0127] In embodiments, the heavy chain includes a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:29. In embodiments, the heavy chain includes a sequence having at least 90% identity to SEQ ID NO:29. In embodiments, the heavy chain includes a sequence having at least 91% identity to SEQ ID NO:29. In embodiments, the heavy chain includes a sequence having at least 92% identity to SEQ ID NO:29. In embodiments, the heavy chain includes a sequence having at least 93% identity to SEQ ID NO:29. In embodiments, the heavy chain includes a sequence having at least 94% identity to SEQ ID NO:29. In embodiments, the heavy chain includes a sequence having at least 95% identity to SEQ ID NO:29. In embodiments, the heavy chain includes a sequence having at least 96% identity to SEQ ID NO:29. In embodiments, the heavy chain includes a sequence having at least 97% identity to SEQ ID NO:29. In embodiments, the heavy chain includes a sequence having at least 98% identity to SEQ ID NO:29. In embodiments, the heavy chain includes a sequence having at least 99% identity to SEQ ID NO:29. In embodiments, said heavy chain includes SEQ ID NO:29. In embodiments, said heavy chain is SEQ ID NO:29.

[0128] In embodiments, the light chain includes a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:30. In embodiments, the light chain includes a sequence having at least 90% identity to SEQ ID NO:30. In embodiments, the light chain includes a sequence having at least 91% identity to SEQ ID NO:30. In embodiments, the light chain includes a sequence having at least 92% identity to SEQ ID NO:30. In embodiments, the light chain includes a sequence having at least 93% identity to SEQ ID NO:30. In embodiments, the light chain includes a sequence having at least 94% identity to SEQ ID NO:30. In embodiments, the light chain includes a sequence having at least 95% identity to SEQ ID NO:30. In embodiments, the light chain includes a sequence having at least 96% identity to SEQ ID NO:30. In embodiments, the light chain includes a sequence having at least 97% identity to SEQ ID NO:30. In embodiments, the light chain includes a sequence having at least 98% identity to SEQ ID NO:30. In embodiments, the light chain includes a sequence having at least 99% identity to SEQ ID NO:30. In embodiments, said light chain includes SEQ ID NO:30. In embodiments, said light chain is SEQ ID NO:30.PATENT Attorney Docket No.: 062698-505001WO

[0129] In embodiments, the heavy chain includes a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:29 and the light chain includes a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:30. In embodiments, the heavy chain includes a sequence having at least 90% identity to SEQ ID NO:29 and the light chain includes a sequence having at least 90% identity to SEQ ID NO:30. In embodiments, the heavy chain includes a sequence having at least 91% identity to SEQ ID NO:29 and the light chain includes a sequence having at least 91% identity to SEQ ID NO:30. In embodiments, the heavy chain includes a sequence having at least 92% identity to SEQ ID NO:29 and the light chain includes a sequence having at least 92% identity to SEQ ID NO:30. In embodiments, the heavy chain includes a sequence having at least 93% identity to SEQ ID NO:29 and the light chain includes a sequence having at least 93% identity to SEQ ID NO:30. In embodiments, the heavy chain includes a sequence having at least 94% identity to SEQ ID NO:29 and the light chain includes a sequence having at least 94% identity to SEQ ID NO:30. In embodiments, the heavy chain includes a sequence having at least 95% identity to SEQ ID NO:29 and the light chain includes a sequence having at least 95% identity to SEQ ID NO:30. In embodiments, the heavy chain includes a sequence having at least 96% identity to SEQ ID NO:29 and the light chain includes a sequence having at least 96% identity to SEQ ID NO:30. In embodiments, the heavy chain includes a sequence having at least 97% identity to SEQ ID NO:29 and the light chain includes a sequence having at least 97% identity to SEQ ID NO:30. In embodiments, the heavy chain includes a sequence having at least 98% identity to SEQ ID NO:29 and the light chain includes a sequence having at least 98% identity to SEQ ID NO:30. In embodiments, the heavy chain includes a sequence having at least 99% identity to SEQ ID NO:29 and the light chain includes a sequence having at least 99% identity to SEQ ID NO:30. In embodiments, the heavy chain includes SEQ ID NO:29 and the light chain includes SEQ ID NO:30. In embodiments, the heavy chain is SEQ ID NO:29 and the light chain is SEQ ID NO:30.

[0130] In embodiments, the antibody is an IgG. In embodiments, the antibody is an IgG1 or an IgG2. In embodiments, the antibody is an IgG1. In embodiments, the antibody is an IgG2. In embodiments, the antibody is a humanized IgG1. In embodiments, the antibody is a humanized IgG2.PATENT Attorney Docket No.: 062698-505001WO

[0131] In embodiments, the antibody is a humanized antibody or a chimeric antibody. In embodiments, the antibody is a humanized antibody. In embodiments, the antibody is a chimeric antibody.

[0132] As described above, in embodiments, the antibody may be a fragment of an antibody. In embodiments, the antibody includes a Fab fragment. In embodiments, the antibody is a single chain antibody (scFv). In embodiments, the light chain variable domain and the heavy chain variable domain form part of an scFv. In embodiments, the antibody includes a fragment crystallizable (Fc) domain. In embodiments, the antibody is a single domain antibody. In embodiments, the single domain antibody includes a light chain variable domain. In embodiments, the single domain antibody includes a heavy chain variable domain.

[0133] The antibodies provided herein may include one or more glycosylation sites within the IgG heavy chain. For example, the glycosylation site may be within the variable heavy domain of the antibody. In embodiments, the Fc domain of the antibody includes one or more glycosylation sites. In embodiments, the antibodies provided herein include one or more modifications that remove a potential glycosylation site. In embodiments, the Fc domain may include one or more modifications wherein one or more one or more carbohydrate moiety is added, substituted, deleted or modified. For example, substitution of a residue with asparagine-X-serine or asparagine-X-threonine motif may create a potential site for enzymatic attachment of carbohydrate moieties and may, therefore, be used to regulate glycosylation of an antibody. In embodiments, the one or more glycosylation sites may be involved in or enhance binding of the antibody to an Fc receptor (e.g. FcγRI, FcγRII, FcγRII). Thus, in embodiments, the presence of one or more glycosylation sites in the antibody may enhance, for example, antibody dependent cellular cytotoxicity (ADCC) and / or complement- dependent cytotoxicity (CDC). In embodiments, the Fc domain includes one or more modifications to decrease binding to an Fc receptor. In embodiments, the Fc domain may include one or more modifications wherein one or more one glycosylation site is modified or deleted. In embodiments, the one or more modifications includes removal of a glycosylation site.

[0134] In embodiments, the antibodies provided herein including embodiments thereof may include a modified Fc domain that does not elicit an antibody dependent cellular cytotoxicity (ADCC). In embodiments, the antibodies provided herein including embodiments thereof include FcPATENT Attorney Docket No.: 062698-505001WO portions that do not trigger ADCC in the presence of an effector cell (e.g. (e.g., cytotoxic T cells). In embodiments, the antibodies provided herein including embodiments thereof may include a modified Fc domain that does not elicit complement dependent cytotoxicity (CDC). In embodiments, the Fc domain includes an effector cell inhibiting substitution. In the presence of an effector cell inhibiting substitution the binding of the Fc domain to the effector cell ligand decreases activation of an effector cell relative to the absence of said substitution. In embodiments, the binding of the Fc domain to the effector cell ligand results in substantially no activation of an effector cell relative to the absence of said substitution.

[0135] In embodiments, the antibody is capable of binding a WISP1 protein. In embodiments, the WISP1 protein is a mammalian WISP1 protein. In embodiments, the WISP1 protein is a human WISP1 protein. In embodiments, the WISP1 protein includes the sequence of SEQ ID NO:15, 16, or 17. In embodiments, the WISP1 protein includes the sequence of SEQ ID NO:19. In embodiments, the WISP1 protein includes the sequence of SEQ ID NO:20. In embodiments, the WISP1 protein is the sequence of SEQ ID NO:19. In embodiments, the WISP1 protein is the sequence of SEQ ID NO:20. In embodiments, the antibody is capable of binding domain 2 of WISP1. In embodiments, the WISP1 protein includes domain 2 of WISP1. In embodiments, domain 2 includes the sequence of SEQ ID NO:26. Thus, in embodiments, the WISP1 protein includes the sequence of SEQ ID NO:26. In embodiments, the WISP1 protein is the sequence of SEQ ID NO:26.

[0136] In embodiments, the antibody is capable of binding domain 2 of the WISP1 protein. In embodiments, domain 2 of said WISP1 protein includes residues corresponding to positions 121 to 203 of SEQ ID NO:19. In embodiments, the antibody is capable of binding residues within a region corresponding to 121 to 203 of SEQ ID NO:19.

[0137] The anti-WISP1 antibodies provided herein including embodiments thereof exhibit high affinity binding and specificity. In embodiments, the anti-WISP1 antibodies have the benefit of being cross-reactive towards human and non-human primate WISP1 (e.g, cynomolgus WISP1), thereby facilitating production and pre-clinical testing. Thus, in embodiments, the antibody binds to human WISP1 or cynomolgus WISP1.

[0138] The ability of an antibody to bind a specific epitope (e.g., a WISP1 protein, domain 2 of WISP1 protein) can be described by the equilibrium dissociation constant (KD). The equilibriumPATENT Attorney Docket No.: 062698-505001WO dissociation constant (KD) as defined herein is the ratio of the dissociation rate (K-off) and the association rate (K-on) of an antibody to a WISP1 protein. It is described by the following formula: KD = K-off / K-on.

[0139] In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.5 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 1 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 1.5 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 2 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 2.5 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 3 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 3.5 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 4 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 4.5 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 5 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 5.5 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 6 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 6.5 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 7 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 7.5 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 8 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 8.5 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 9 nM to about 20 nM. In embodiments,PATENT Attorney Docket No.: 062698-505001WO the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 9.5 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 10 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 10.5 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 11 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 11.5 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 12 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 12.5 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 13 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 13.5 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 14 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 14.5 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 15 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 15.5 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 16 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 16.5 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 17 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 17.5 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 18 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 18.5 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 19 nM to about 20 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 19.5 nM to about 20 nM.PATENT Attorney Docket No.: 062698-505001WO

[0140] In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 19.5 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 19 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 18.5 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 18 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 17.5 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 17 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 16.5 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 16 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 15.5 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 15 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 14.5 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 14 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 13.5 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 13 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 12.5 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 12 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 11.5 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 11 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 10.5 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with an equilibriumPATENT Attorney Docket No.: 062698-505001WO dissociation constant (KD) from about 0.01 nM to about 9.5 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 9 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 8.5 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 8 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 7.5 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 7 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 6.5 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 6 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 5.5 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 5 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 4.5 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 4 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 3.5 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 3 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 2.5 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 2 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 1.5 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 1 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about .5 nM.

[0141] In embodiments, the antibody binds the WISP1 protein with a KD of about 0.01, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12,5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, or 20 nM.PATENT Attorney Docket No.: 062698-505001WO

[0142] In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.1 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.2 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.3 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.4 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.5 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.6 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.7 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.8 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.9 nM to 1 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 1 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 1.1 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 1.2 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 1.3 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 1.4 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 1.5 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 1.6 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 1.7 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 1.8 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 1.9 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 2 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 2.1 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 2.2 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 2.3 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 2.4 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 2.5 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 2.6 nM to about 10 nM. In embodiments,PATENT Attorney Docket No.: 062698-505001WO the antibody binds the WISP1 protein with a KDfrom about 2.7 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 2.8 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 2.9 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 3 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 4.1 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 4.2 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 4.3 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 4.4 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 4.5 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 4.6 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 4.7 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 4.8 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 4.9 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 5 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 5.1 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 5.2 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 5.3 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 5.4 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 5.5 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 5.6 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 5.7 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 5.8 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 5.9 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 6 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 6.1 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 6.2 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 6.3 nM to about 10 nM. In embodiments, the antibody bindsPATENT Attorney Docket No.: 062698-505001WO the WISP1 protein with a KDfrom about 6.4 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 6.5 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 6.6 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 6.7 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 6.8 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 6.9 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 7 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 7.1 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 7.2 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 7.3 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 7.4 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 7.5 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 7.6 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 7.7 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 7.8 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 7.9 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 8 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociation constant (KD) from about 8.1 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 8.2 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 8.3 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 8.4 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 8.5 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 8.6 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 8.7 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 8.8 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 8.9 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 9 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with an equilibrium dissociationPATENT Attorney Docket No.: 062698-505001WO constant (KD) from about 9.1 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 9.2 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 9.3 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 9.4 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 9.5 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 9.6 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 9.7 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 9.8 nM to about 10 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 9.9 nM to about 10 nM.

[0143] In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about about 9.9 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 9.8 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 9.7 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 9.6 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 9.5 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 9.4 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 9.3 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 9.2 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 9.1 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 9 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 8.9 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 8.8 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 8.7 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 8.6 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 8.5 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 8.4 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 8.3 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 8.2 nM. In embodiments, the antibody binds the WISP1 protein with a KDfromPATENT Attorney Docket No.: 062698-505001WO about 0.01 nM to about 8.1 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 8 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 7.9 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 7.8 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 7.7 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 7.6 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 7.5 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 7.4 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 7.3 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 7.2 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 7.1 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 7 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 6.9 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 6.8 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 6.7 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 6.6 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 6.5 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 6.4 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 6.3 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 6.2 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 6.1 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 6 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 5.9 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 5.8 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 5.7 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 5.6 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 5.5 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 5.4 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to aboutPATENT Attorney Docket No.: 062698-505001WO 5.3 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 5.2 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 5.1 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 5 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 4.9 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 4.8 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 4.7 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 4.6 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 4.5 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 4.4 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 4.3 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 4.2 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 4.1 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 4 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 3.9 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 3.8 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 3.7 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 3.6 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 3.5 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 3.4 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 3.3 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 3.2 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 3.1 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 3 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 2.9 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 2.8 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 2.7 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 2.6 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 2.5 nM. In embodiments,PATENT Attorney Docket No.: 062698-505001WO the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 2.4 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 2.3 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 2.2 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 2.1 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 2 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 1.9 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 1.8 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 1.7 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 1.6 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 1.5 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 1.4 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 1.3 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 1.2 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 1.1 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 0.9 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 0.8 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 0.7 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 0.6 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 0.5 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 0.4 nM. In embodiments, the antibody binds the WISP1 protein with a KD from about 0.01 nM to about 0.3 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 0.2 nM. In embodiments, the antibody binds the WISP1 protein with a KDfrom about 0.01 nM to about 0.1 nM.

[0144] In embodiments, the antibody binds the WISP1 protein with a KD of about 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4,PATENT Attorney Docket No.: 062698-505001WO 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10 nM.

[0145] In embodiments, the antibody binds the WISP1 protein with a KDof about 5.55 nM. In embodiments, the antibody is antibody K4 and binds a WISP1 protein with a KDof 0.01 nM to about 20 nM. In embodiments, the antibody K4 binds a WISP1 protein with a KD of about 0.01, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12,5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, or 20 nM. In embodiments, the antibody is antibody K4 and binds a WISP1 protein with a KDof 0.01 nM to about 10 nM. In embodiments, the antibody K4 binds a WISP1 protein with a KD of 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 nM. In embodiments, the antibody is antibody K4 and binds a WISP1 protein with a KDof 5.55 nM.

[0146] In one embodiment, the antibody includes a heavy chain variable domain including a CDR H1 as set forth in SEQ ID NO:1, a CDR H2 as set forth in SEQ ID NO:2; a CDR H3 as set forth in SEQ ID NO:3; and a light chain variable domain including a CDR L1 as set forth in SEQ ID NO:4, a CDR L2 including AAS, a CDR L3 as set forth in SEQ ID NO:6. In one embodiment, the antibody includes a heavy chain variable domain of SEQ ID NO:13 and a light chain variable domain of SEQ ID NO:14. In one further embodiment, the antibody is antibody K4.

[0147] In embodiments, the antibody is attached to a therapeutic agent. In embodiments, the antibody is attached to a diagnostic agent. In embodiments, the diagnostic agent is a detectable moiety.

[0148] In an aspect is provided an anti-WISP1 antibody. The anti-WISP1 antibody binds the same epitope as an anti-WISP1 antibody including a heavy chain variable domain including: a CDR H1 as set forth in SEQ ID NO:1, a CDR H2 as set forth in SEQ ID NO:2 and a CDR H3 as set forth in SEQ ID NO:3; and a light chain variable domain including: a CDR L1 as set forth in SEQ ID NO:4, a CDR L2 including AAS, and a CDR L3 as set forth in SEQ ID NO:6. In embodiments, the antibody includes a heavy chain variable domain including SEQ ID NO:13 and a light chain variable domain including SEQ ID NO:14.PATENT Attorney Docket No.: 062698-505001WO

[0149] In an aspect is provided an anti-WISP1 antibody. The antibody competes with an anti- WISP1 antibody for binding to a WISP1 protein, wherein the anti-WISP1 antibody includes a heavy chain variable domain including: a CDR H1 as set forth in SEQ ID NO:1, a CDR H2 as set forth in SEQ ID NO:2 and a CDR H3 as set forth in SEQ ID NO:3; and a light chain variable domain including: a CDR L1 as set forth in SEQ ID NO:4, a CDR L2 including AAS, and a CDR L3 as set forth in SEQ ID NO:6. In embodiments, the antibody includes a heavy chain variable domain including SEQ ID NO:13 and a light chain variable domain including SEQ ID NO:14.

[0150] In embodiments, the antibody is capable of binding a WISP1 protein. In embodiments, the WISP1 protein is a mammalian WISP1 protein. In embodiments, the WISP1 protein is a human WISP1 protein. In embodiments, the antibody binds a WISP1 protein. In embodiments, the WISP1 protein includes the amino acid sequence of SEQ ID NO:19. In embodiments, the WISP1 protein includes the amino acid sequence of SEQ ID NO:20. In embodiments, the WISP1 protein is the amino acid sequence of SEQ ID NO:19. In embodiments, the WISP1 protein is the amino acid sequence of SEQ ID NO:20. In embodiments, the antibody is capable of binding domain 2 of the WISP1 protein.

[0151] In embodiments, the anti-WISP1 antibody provided herein including embodiments thereof inhibits WISP1 signaling or activity relative to WISP1 signaling or activity in the absence of the anti-WISP1 antibody. In embodiments, WISP1 signaling or activity can be assessed by expression of pro-fibrotic or inflammatory genes (e.g. IL-6, pSMAD2, pSMAD3, Col1a1, Col3a1, Fn1, Tgfb1, and Ccn2, etc.). In embodiments, WISP1 signaling or activity can be assessed by collagen content or hydroxyproline production. In embodiments, WISP1 signaling or activity can be assessed by fibroblast chemotaxis or migration. In embodiments, the anti-WISP1 antibody inhibits WISP1 signaling or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to WISP1 signaling or activity in the absence of the anti-WISP1 antibody. In embodiments, the anti- WISP1 antibody can decrease WISP1 signaling or activity 10% in comparison to WISP1 signaling or activity in the absence of the anti-WISP1 antibody. In embodiments, the anti-WISP1 antibody can decrease WISP1 signaling or activity 20% in comparison to WISP1 signaling or activity in the absence of the anti-WISP1 antibody. In embodiments, the anti-WISP1 antibody can decrease WISP1 signaling or activity 30% in comparison to WISP1 signaling or activity in the absence of the anti-WISP1 antibody. In embodiments, the anti-WISP1 antibody can decrease WISP1 signaling orPATENT Attorney Docket No.: 062698-505001WO activity 40% in comparison to WISP1 signaling or activity in the absence of the anti-WISP1 antibody. In embodiments, the anti-WISP1 antibody can decrease WISP1 signaling or activity 50% in comparison to WISP1 signaling or activity in the absence of the anti-WISP1 antibody. In embodiments, the anti-WISP1 antibody can decrease WISP1 signaling or activity 60% in comparison to WISP1 signaling or activity in the absence of the anti-WISP1 antibody. In embodiments, the anti-WISP1 antibody can decrease WISP1 signaling or activity 70% in comparison to WISP1 signaling or activity in the absence of the anti-WISP1 antibody. In embodiments, the anti-WISP1 antibody can decrease WISP1 signaling or activity 80% in comparison to WISP1 signaling or activity in the absence of the anti-WISP1 antibody. In embodiments, the anti-WISP1 antibody can decrease WISP1 signaling or activity 90% in comparison to WISP1 signaling or activity in the absence of the anti-WISP1 antibody. In embodiments, the anti-WISP1 antibody can decrease WISP1 signaling or activity 95% in comparison to WISP1 signaling or activity in the absence of the anti-WISP1 antibody. In embodiments, the anti-WISP1 antibody can decrease WISP1 signaling or activity 95% or more in comparison to WISP1 signaling or activity in the absence of the anti-WISP1 antibody.

[0152] In embodiments, the anti-WISP1 antibody provided herein including embodiments thereof can decrease WISP1 signaling or activity 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower in comparison to WISP1 signaling or activity in the absence of the anti-WISP1 antibody. In embodiments, the anti-WISP1 antibody provided herein including embodiments thereof can decrease WISP1 signaling or activity 1.5-fold or lower in comparison to WISP1 signaling or activity in the absence of the anti-WISP1 antibody. In embodiments, the anti-WISP1 antibody provided herein including embodiments thereof can decrease WISP1 signaling or activity 2-fold or lower in comparison to WISP1 signaling or activity in the absence of the anti-WISP1 antibody. In embodiments, the anti-WISP1 antibody provided herein including embodiments thereof can decrease WISP1 signaling or activity 3-fold or lower in comparison to WISP1 signaling or activity in the absence of the anti-WISP1 antibody. In embodiments, the anti-WISP1 antibody provided herein including embodiments thereof can decrease WISP1 signaling or activity 4-fold or lower in comparison to WISP1 signaling or activity in the absence of the anti-WISP1 antibody. In embodiments, the anti-WISP1 antibody provided herein including embodiments thereof can decrease WISP1 signaling or activity 5-fold or lower in comparison to WISP1 signaling or activityPATENT Attorney Docket No.: 062698-505001WO in the absence of the anti-WISP1 antibody. In embodiments, the anti-WISP1 antibody provided herein including embodiments thereof can decrease WISP1 signaling or activity 10-fold or lower in comparison to WISP1 signaling or activity in the absence of the anti-WISP1 antibody. NUCLEIC ACID COMPOSITIONS

[0153] The compositions provided herein include nucleic acid molecules encoding the anti-WISP1 antibodies or fragments thereof provided herein including embodiments thereof. The antibodies encoded by the isolated nucleic acid are described in detail throughout this application (including the description above and in the examples section). Thus, in an aspect, an isolated nucleic acid encoding an antibody as provided herein including embodiments thereof is provided.

[0154] In embodiments, the isolated nucleic acid encodes a variable heavy chain domain or a variable light chain domain provided herein. In embodiments, the isolated nucleic acid encodes a variable heavy chain domain. In embodiments, the isolated nucleic acid encodes a variable light chain domain.

[0155] In embodiments, the isolated nucleic acid may be provided in a vector, such as an expression vector. Thus, in another aspect a vector including the isolated nucleic acid provided herein including embodiments thereof is provided. In embodiments, the vector is an expression vector capable of directing the expression of nucleic acids to which they are operatively linked. The term “operably linked” means that the nucleotide sequence of interest is linked to regulatory sequence(s) in a manner that allows for expression of the nucleotide sequence. The regulatory sequence may include, for example, promoters, enhancers, and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are well known in the art and are described, for example, in Goeddel; Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, CA (1990)., which is incorporated herein in its entirety and for all purposes. METHODS

[0156] The compositions (e.g., the anti-WISP1 antibodies) provided herein, including embodiments thereof, are contemplated as providing effective treatments for diseases such as fibrosis (e.g., liver fibrosis, lung fibrosis, cardiac fibrosis etc.). Thus, in an aspect is provided aPATENT Attorney Docket No.: 062698-505001WO method of treating fibrosis in a subject in need thereof, the method including administering to the subject a therapeutically effective amount of an antibody.

[0157] In embodiments, the fibrosis is kidney fibrosis, fibrotic liver disease, lung fibrosis, cardiac fibrosis, bone or bone marrow fibrosis, or skin fibrosis. In embodiments, the fibrosis is fibrotic liver disease, lung fibrosis, or heart fibrosis. In embodiments, the fibrosis is fibrotic liver disease. In embodiments, fibrotic liver disease may be referred to as “liver fibrosis”. In embodiments, the fibrosis is lung fibrosis. In embodiments, lung fibrosis may be referred to as “pulmonary fibrosis”. In embodiments, the fibrosis is cardiac fibrosis. In embodiments, cardiac fibrosis may be referred to as “heart fibrosis”. In embodiments, the lung fibrosis is idiopathic pulmonary fibrosis (IPF). In embodiments, the fibrosis is skin fibrosis. In embodiments, the fibrosis is kidney fibrosis. In embodiments, the fibrosis is bone fibrosis. In embodiments, the fibrosis is bone marrow fibrosis.

[0158] In embodiments, subject has interstitial lung disease. In embodiments, the interstitial lung disease causes pulmonary fibrosis in the subject. For example, when the interstitial lung disease causes scarring of lung tissue, the subject has pulmonary lung fibrosis. The interstitial lung disease and / or pulmonary fibrosis may, in embodiments, be idiopathic, autoimmune-associated, connective- tissue disease-associated, environmental, occupational, radiation-induced, or drug-induced. In embodiments, the interstitial lung disease and / or pulmonary fibrosis may be associated with a viral infection or lymphangioleiomyomatosis. In embodiments, the interstitial lung disease and / or pulmonary fibrosis may be genetic.

[0159] In embodiments, the interstitial lung disease is non-specific interstitial pneumonia, rheumatoid arthritis interstitial lung disease, hypersensitivity pneumonitis, berylliosis, respiratory bronchiolitis interstitial lung disease, desquamative interstitial pneumonitis, sarcoidosis, acute interstitial pneumonitis, cryptogenic-organizing pneumonitis, lymphocytic interstitial pneumonitis, or pleuroparenchymal fibroelastosis. In embodiments, the interstitial lung disease is non-specific interstitial pneumonia. In embodiments, the interstitial lung disease is rheumatoid arthritis interstitial lung disease. In embodiments, the interstitial lung disease is hypersensitivity pneumonitis. In embodiments, the interstitial lung disease is berylliosis. In embodiments, the interstitial lung disease is respiratory bronchiolitis interstitial lung disease. In embodiments, the interstitial lung disease is desquamative interstitial pneumonitis. In embodiments, the interstitial lung disease is sarcoidosis. InPATENT Attorney Docket No.: 062698-505001WO embodiments, the interstitial lung disease is acute interstitial pneumonitis. In embodiments, the interstitial lung disease is cryptogenic-organizing pneumonitis. In embodiments, the interstitial lung disease is lymphocytic interstitial pneumonitis. In embodiments, the interstitial lung disease is pleuroparenchymal fibroelastosis.

[0160] In embodiments, the lung fibrosis is idiopathic pulmonary fibrosis, systemic sclerosis associated pulmonary fibrosis, progressive pulmonary fibrosis, pulmonary fibrosis associated with Sjogrens Syndrome., pneumoconiosis, asbestosis, silicosis, radiation-induced pulmonary fibrosis, drug-induced pulmonary fibrosis, COVID-19-related pulmonary fibrosis, pulmonary fibrosis following acute respiratory distress syndrome, pulmonary fibrosis associated with lymphangioleiomyomatosis, familial pulmonary fibrosis, pulmonary fibrosis associated with Hermansky Pudlak syndrome, or pulmonary fibrosis associated with dyskeratosis congenita. In embodiments, the lung fibrosis is idiopathic pulmonary fibrosis, systemic sclerosis associated pulmonary fibrosis, or progressive pulmonary fibrosis.

[0161] In embodiments, the lung fibrosis is idiopathic pulmonary fibrosis. In embodiments, the lung fibrosis is systemic sclerosis associated pulmonary fibrosis. In embodiments, the lung fibrosis is progressive pulmonary fibrosis. In embodiments, the lung fibrosis is pulmonary fibrosis associated with Sjogrens Syndrome. In embodiments, the lung fibrosis is pneumoconiosis. In embodiments, the lung fibrosis is asbestosis. In embodiments, the lung fibrosis is silicosis. In embodiments, the lung fibrosis is radiation-induced pulmonary fibrosis. In embodiments, the lung fibrosis is drug-induced pulmonary fibrosis. In embodiments, the lung fibrosis is COVID-19-related pulmonary fibrosis. In embodiments, the lung fibrosis is pulmonary fibrosis following acute respiratory distress syndrome. In embodiments, the lung fibrosis is pulmonary fibrosis associated with lymphangioleiomyomatosis. In embodiments, the lung fibrosis is familial pulmonary fibrosis. In embodiments, the lung fibrosis is pulmonary fibrosis associated with Hermansky Pudlak syndrome. In embodiments, the lung fibrosis is pulmonary fibrosis associated with dyskeratosis congenita.

[0162] In embodiments, the fibrosis is autoimmune-associated. For example, in embodiments, the subject has an auto-immune disorder that causes over-production of collagen, leading to fibrosis. In embodiments, the subject has scleroderma.PATENT Attorney Docket No.: 062698-505001WO

[0163] In embodiments, the method further includes identifying in a biological sample obtained from the subject an elevated level of WISP1 relative to a standard control, an elevated level of α- Smooth Muscle Actin (α-SMA) relative to a standard control, an elevated level of collagen type I alpha 1 chain (Col1a1) relative to a standard control, an elevated level of tissue inhibitor of metalloproteinase 1 (Timp1) relative to a standard control, an elevated level of fibronectin (Fn1) relative to a standard control, an elevated level of interleukin 6 (IL-6) relative to a standard control, an elevated level of phosphorylated Small Mother Against Decapentaplegic 2 (pSMAD2) relative to a standard control, an elevated level of phosphorylated Small Mother Against Decapentaplegic 3 (pSMAD3) relative to a standard control, or a combination thereof.

[0164] In another aspect is provided a method of treating fibrosis in a subject in need thereof, the method including: a) identifying in a biological sample obtained from the subject an elevated level of WISP1 relative to a standard control, an elevated level of α-Smooth Muscle Actin (α-SMA) relative to the standard control, an elevated level of collagen type I alpha 1 chain (Col1a1) relative to the standard control, an elevated level of tissue inhibitor of metalloproteinase 1 (Timp1) relative to the standard control, an elevated level of fibronectin (Fn1) relative to the standard control, an elevated level of interleukin 6 (IL-6) relative to the standard control, an elevated level of phosphorylated Small Mother Against Decapentaplegic 2 (pSMAD2) relative to the standard control, an elevated level of phosphorylated Small Mother Against Decapentaplegic 3 (pSMAD3) relative to the standard control, or a combination thereof; and b) administering to the subject a therapeutically effective amount of an anti-WISP1 antibody provided herein including embodiments thereof.

[0165] In embodiments, the method includes identifying in a biological sample obtained from the subject an elevated level of WISP1 relative to a standard control. In embodiments, the method includes identifying in a biological sample obtained from the subject an elevated level of α-Smooth Muscle Actin (α-SMA) relative to the standard control In embodiments, the method includes identifying in a biological sample obtained from the subject an elevated level of collagen type I alpha 1 chain (Col1a1) relative to the standard control. In embodiments, the method includes identifying in a biological sample obtained from the subject an elevated level of tissue inhibitor of metalloproteinase 1 (Timp1) relative to the standard control. In embodiments, the method includes identifying in a biological sample obtained from the subject an elevated level of fibronectin (Fn1)PATENT Attorney Docket No.: 062698-505001WO relative to the standard control. In embodiments, the method includes identifying in a biological sample obtained from the subject an elevated level of interleukin 6 (IL-6) relative to the standard control. In embodiments, the method includes identifying in a biological sample obtained from the subject an elevated level of phosphorylated Small Mother Against Decapentaplegic 2 (pSMAD2) relative to the standard control. In embodiments, the method includes identifying in a biological sample obtained from the subject an elevated level of phosphorylated Small Mother Against Decapentaplegic 3 (pSMAD3) relative to the standard control. In embodiments, the standard control is a biological sample obtained from a subject who does not have fibrosis. In embodiments, the standard control includes cells derived from the liver tissue of a subject who does not have fibrosis. In embodiments, the standard control includes cells derived from the lung tissue of a subject who does not have fibrosis.

[0166] In embodiments, the fibrosis is fibrotic liver disease, lung fibrosis, or cardiac fibrosis. In embodiments, the fibrosis is fibrotic liver disease. In embodiments, the fibrosis is lung fibrosis. In embodiments, the fibrosis is cardiac fibrosis.

[0167] In embodiments, the subject has interstitial lung disease. In embodiments, the interstitial lung disease is non-specific interstitial pneumonia, rheumatoid arthritis interstitial lung disease, hypersensitivity pneumonitis, berylliosis, respiratory bronchiolitis interstitial lung disease, desquamative interstitial pneumonitis, sarcoidosis, acute interstitial pneumonitis, cryptogenic- organizing pneumonitis, lymphocytic interstitial pneumonitis, or pleuroparenchymal fibroelastosis.

[0168] In embodiments, the lung fibrosis is idiopathic pulmonary fibrosis, systemic sclerosis associated pulmonary fibrosis, progressive pulmonary fibrosis, pulmonary fibrosis associated with Sjogrens Syndrome., pneumoconiosis, asbestosis, silicosis, radiation-induced pulmonary fibrosis, drug-induced pulmonary fibrosis, COVID-19-related pulmonary fibrosis, pulmonary fibrosis following acute respiratory distress syndrome, pulmonary fibrosis associated with lymphangioleiomyomatosis, familial pulmonary fibrosis, pulmonary fibrosis associated with Hermansky Pudlak syndrome, or pulmonary fibrosis associated with dyskeratosis congenita.

[0169] For the methods provided herein, in embodiments, the lung fibrosis is idiopathic pulmonary fibrosis, systemic sclerosis associated pulmonary fibrosis, progressive pulmonary fibrosis, pulmonary fibrosis associated with Sjogrens Syndrome., pneumoconiosis, asbestosis,PATENT Attorney Docket No.: 062698-505001WO silicosis, radiation-induced pulmonary fibrosis, drug-induced pulmonary fibrosis, COVID-19- related pulmonary fibrosis, pulmonary fibrosis following acute respiratory distress syndrome, pulmonary fibrosis associated with lymphangioleiomyomatosis, familial pulmonary fibrosis, pulmonary fibrosis associated with Hermansky Pudlak syndrome, or pulmonary fibrosis associated with dyskeratosis congenita. In embodiments, in embodiments, the lung fibrosis is idiopathic pulmonary fibrosis, systemic sclerosis associated pulmonary fibrosis, progressive pulmonary fibrosis. In embodiments, the lung fibrosis is idiopathic pulmonary fibrosis.

[0170] In another aspect is provided a method of inhibiting release of interleukin 6 (IL-6), phosphorylated Small Mother Against Decapentaplegic 2 (pSMAD2), phosphorylated Small Mother Against Decapentaplegic 3 (pSMAD3), or a combination thereof from a cell, the method including contacting the cell with an anti-WISP1 antibody provided herein including embodiments thereof. In embodiments, the method includes inhibiting release of IL-6 from a cell. In embodiments, the method includes inhibiting release of pSMAD2 from a cell. In embodiments, the method includes inhibiting release of pSMAD3 from a cell.

[0171] In embodiments, the cell is an immune cell. In embodiments, the cell is a fibroblast.

[0172] In another aspect is provided a method of inhibiting migration of a WISP-1 receptor expressing cell, the method including contacting the cell with an anti-WISP1 antibody provided herein including embodiments thereof. As used herein, “WISP-1 receptor” refers to a protein that binds a WISP-1 protein. In embodiments, the WISP-1 receptor is an integrin.

[0173] In embodiments, the cell is a fibroblast or a stellate cell. In embodiments, the cell is a fibroblast. In embodiments, the cell is a stellate cell. In embodiments, the stellate cell is a hepatic stellate cell.

[0174] In an aspect is provided a method of detecting a WISP1 expressing cell, the method including (i) contacting a WISP1-expressing cell with an antibody provided herein including embodiments thereof; (ii) and detecting binding of the antibody to a WISP1 protein expressed by the cell. In embodiments, the antibody is attached to a detectable moiety.

[0175] In an aspect is a method of delivering a therapeutic agent to a WISP1 expressing cell, the method including contacting a WISP1 expressing cell with an antibody provided herein includingPATENT Attorney Docket No.: 062698-505001WO embodiments thereof, wherein the antibody is attached to a therapeutic agent. In embodiments, the therapeutic agent is an anti-fibrotic agent.

[0176] For the methods provided herein, in embodiments, the contacting occurs in vitro. In embodiments, the WISP1-expressing cell is in a subject. In embodiments, the subject is a healthy subject. In embodiments, the subject is a subject having fibrosis. In embodiments, the fibrosis is lung fibrosis or liver fibrosis. In embodiments, the fibrosis is lung fibrosis. In embodiments, the fibrosis is liver fibrosis.

[0177] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. P EMBODIMENTS

[0178] Embodiment P1. An anti-WNT1-inducible-signaling pathway protein 1 (WISP1) antibody, comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy chain variable domain comprises: a CDR H1 as set forth in SEQ ID NO:1, a CDR H2 as set forth in SEQ ID NO:2 and a CDR H3 as set forth in SEQ ID NO:3; and wherein said light chain variable domain comprises: a CDR L1 as set forth in SEQ ID NO:4, a CDR L2 as set forth in SEQ ID NO:5, and a CDR L3 as set forth in SEQ ID NO:6.

[0179] Embodiment P2. The antibody of Embodiment P1, wherein said heavy chain variable domain comprises a sequence having at least 90% identity to SEQ ID NO:13.

[0180] Embodiment P3. The antibody of Embodiment P1 or P2, wherein said heavy chain variable domain comprises a sequence having at least 95% identity to SEQ ID NO:13

[0181] Embodiment P4. The antibody of any one of Embodiments P1 to P3, wherein said heavy chain variable domain comprises a sequence having at least 98% identity to SEQ ID NO:13.

[0182] Embodiment P5. The antibody of any one of Embodiments P1 to P4, wherein said heavy chain variable domain comprises SEQ ID NO:13.PATENT Attorney Docket No.: 062698-505001WO

[0183] Embodiment P6. The antibody of any one of Embodiments P1 to P5, wherein said light chain variable domain comprises a sequence having at least 90% identity to SEQ ID NO:14.

[0184] Embodiment P7. The antibody of any one of Embodiments P1 to P6, wherein said light chain variable domain comprises a sequence having at least 95% identity to SEQ ID NO:14.

[0185] Embodiment P8. The antibody of any one of Embodiments P1 to P7, wherein said light chain variable domain comprises a sequence having at least 98% identity to SEQ ID NO:14.

[0186] Embodiment P9. The antibody of any one of Embodiments P1 to P8, wherein said light chain variable domain comprises SEQ ID NO:14.

[0187] Embodiment P10. The antibody of any one of Embodiments P1 to P9, wherein said antibody is an IgG.

[0188] Embodiment P11. The antibody of any one of Embodiments P1 to P10, wherein said antibody is a humanized antibody or a chimeric antibody.

[0189] Embodiment P12. The antibody of any one of Embodiments P1 to P11, wherein said antibody comprises a Fab fragment.

[0190] Embodiment P13. The antibody of any one of Embodiments P1 to P11, wherein said antibody is a single chain antibody (scFv).

[0191] Embodiment P14. The antibody of any one of Embodiments P1 to P13, wherein said antibody is capable of binding a WISP1 protein.

[0192] Embodiment P15. The antibody of Embodiment P14, wherein said WISP1 protein is a human WISP1 protein.

[0193] Embodiment P16. The antibody of Embodiment P14 or P15, wherein said WISP1 protein comprises the sequence of SEQ ID NO:19 or 20.

[0194] Embodiment P17. The antibody of any one of Embodiments P14 to P16, wherein said antibody is capable of binding domain 2 of said WISP1 protein.

[0195] Embodiment P18. The antibody of any one of Embodiments P14 to P17, wherein domain 2 of said WISP1 protein comprises residues corresponding to 121 to 203 of SEQ ID NO:19.PATENT Attorney Docket No.: 062698-505001WO

[0196] Embodiment P19. The antibody of any one of Embodiments P14 to P18, wherein said antibody is capable of binding said WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 20 nM.

[0197] Embodiment P20. The antibody of Embodiment P19, wherein said antibody is capable of binding said WISP1 protein with a KD of about 5.55 nM.

[0198] Embodiment P21. An anti-WNT1-inducible-signaling pathway protein 1 (WISP1) antibody, wherein said anti-WISP1 antibody binds the same epitope as an anti-WISP1 antibody comprising a heavy chain variable domain comprising: a CDR H1 as set forth in SEQ ID NO:1, a CDR H2 as set forth in SEQ ID NO:2 and a CDR H3 as set forth in SEQ ID NO:3; and a light chain variable domain comprising: a CDR L1 as set forth in SEQ ID NO:4, a CDR L2 as set forth in SEQ ID NO:5, and a CDR L3 as set forth in SEQ ID NO:6.

[0199] Embodiment P22. An antibody that competes with an anti-WNT1-inducible-signaling pathway protein 1 (WISP1) antibody for binding to a WISP1 protein, wherein the anti-WISP1 antibody comprises: a heavy chain variable domain comprising: a CDR H1 as set forth in SEQ ID NO:1, a CDR H2 as set forth in SEQ ID NO:2 and a CDR H3 as set forth in SEQ ID NO:3; and a light chain variable domain comprising: a CDR L1 as set forth in SEQ ID NO:4, a CDR L2 as set forth in SEQ ID NO:5, and a CDR L3 as set forth in SEQ ID NO:6.

[0200] Embodiment P23. The antibody of any one of Embodiments P1 to P22, wherein said antibody is attached to a therapeutic agent.

[0201] Embodiment P24. The antibody of any one of Embodiments P1 to P22, wherein said antibody is attached to a diagnostic agent.

[0202] Embodiment P25. A method of treating fibrosis in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of an antibody of any one of Embodiments P1 to P24

[0203] Embodiment P26. The method of Embodiment P25, wherein said fibrosis is fibrotic liver disease

[0204] Embodiment P27. The method of Embodiment P25, wherein said fibrosis is lung fibrosis.PATENT Attorney Docket No.: 062698-505001WO

[0205] Embodiment P28. A method of treating fibrosis in a subject in need thereof, the method comprising: a) identifying in a biological sample obtained from the subject an elevated level of WISP1 relative to a standard control, an elevated level of α-Smooth Muscle Actin (α-SMA) relative to the standard control, an elevated level of collagen type I alpha 1 chain (Col1a1) relative to the standard control, an elevated level of tissue inhibitor of metalloproteinase 1 (Timp1) relative to the standard control, an elevated level of fibronectin (Fn1) relative to the standard control, an elevated level of interleukin 6 (IL-6) relative to the standard control, an elevated level of phosphorylated Small Mother Against Decapentaplegic 2 (pSMAD2) relative to the standard control, an elevated level of phosphorylated Small Mother Against Decapentaplegic 3 (pSMAD3) relative to the standard control, or a combination thereof; and b) administering to the subject a therapeutically effective amount of the anti-WISP1 antibody of any one of Embodiments P1 to P24.

[0206] Embodiment P29. The method of Embodiment P28, wherein said fibrosis is fibrotic liver disease.

[0207] Embodiment P30. The method of Embodiment P28, wherein said fibrosis is lung fibrosis.

[0208] Embodiment P31. A method of inhibiting release of interleukin 6 (IL-6), phosphorylated Small Mother Against Decapentaplegic 2 (pSMAD2), phosphorylated Small Mother Against Decapentaplegic 3 (pSMAD3), or a combination thereof from a cell, the method comprising contacting the cell with the anti-WISP1 antibody of any one of Embodiments P1 to P24.

[0209] Embodiment P32. The method of Embodiment P31, wherein the cell is an immune cell.

[0210] Embodiment P33. The method of Embodiment P31, wherein the cell is a fibroblast.

[0211] Embodiment P34. A method of inhibiting migration of a WISP-1 receptor expressing cell, the method comprising contacting said cell with the anti-WISP1 antibody of any one of Embodiments P1 to P24.

[0212] Embodiment P35. The method of Embodiment P34, wherein said WISP-1 receptor is an integrin.

[0213] Embodiment P36. The method of Embodiment P34 or P35, wherein the cell is a fibroblast or a stellate cell.PATENT Attorney Docket No.: 062698-505001WO

[0214] Embodiment P37. A method of detecting a WISP1-expressing cell, said method comprising. (i) contacting a WISP1-expressing cell with the antibody of any one of Embodiments P1 to P24; and (ii) detecting binding of said antibody to a WISP1 protein expressed by said cell

[0215] Embodiment P38. The method of Embodiment P37, wherein the antibody is attached to a detectable moiety. EMBODIMENTS

[0216] Embodiment 1. An anti-WNT1-inducible-signaling pathway protein 1 (WISP1) antibody, comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy chain variable domain comprises: a CDR H1 as set forth in SEQ ID NO:1, a CDR H2 as set forth in SEQ ID NO:2 and a CDR H3 as set forth in SEQ ID NO:3; and wherein said light chain variable domain comprises: a CDR L1 as set forth in SEQ ID NO:4, a CDR L2 comprising AAS, and a CDR L3 as set forth in SEQ ID NO:6.

[0217] Embodiment 2. The antibody of Embodiment 1, wherein said heavy chain variable domain comprises a sequence having at least 90% identity to SEQ ID NO:13.

[0218] Embodiment 3. The antibody of Embodiment 1 or 2, wherein said heavy chain variable domain comprises a sequence having at least 95% identity to SEQ ID NO:13

[0219] Embodiment 4. The antibody of any one of Embodiments 1 to 3, wherein said heavy chain variable domain comprises a sequence having at least 98% identity to SEQ ID NO:13.

[0220] Embodiment 5. The antibody of any one of Embodiments 1 to 4, wherein said heavy chain variable domain comprises SEQ ID NO:13.

[0221] Embodiment 6. The antibody of any one of Embodiments 1 to 5, wherein said light chain variable domain comprises a sequence having at least 90% identity to SEQ ID NO:14.

[0222] Embodiment 7. The antibody of any one of Embodiments 1 to 6, wherein said light chain variable domain comprises a sequence having at least 95% identity to SEQ ID NO:14.

[0223] Embodiment 8. The antibody of any one of Embodiments 1 to 7, wherein said light chain variable domain comprises a sequence having at least 98% identity to SEQ ID NO:14.PATENT Attorney Docket No.: 062698-505001WO

[0224] Embodiment 9. The antibody of any one of Embodiments 1 to 8, wherein said light chain variable domain comprises SEQ ID NO:14.

[0225] Embodiment 10. The antibody of any one of Embodiments 1 to 9, wherein said antibody is an IgG.

[0226] Embodiment 11. The antibody of any one of Embodiments 1 to 10, wherein said antibody is a humanized antibody or a chimeric antibody.

[0227] Embodiment 12. The antibody of any one of Embodiments 1 to 11, wherein said antibody comprises a Fab fragment.

[0228] Embodiment 13. The antibody of any one of Embodiments 1 to 11, wherein said antibody is a single chain antibody (scFv).

[0229] Embodiment 14. The antibody of any one of Embodiments 1 to 13, wherein said antibody is capable of binding a WISP1 protein.

[0230] Embodiment 15. The antibody of Embodiment 14, wherein said WISP1 protein is a human WISP1 protein.

[0231] Embodiment 16. The antibody of Embodiment 14 or 15, wherein said WISP1 protein comprises the sequence of SEQ ID NO:19 or 20.

[0232] Embodiment 17. The antibody of any one of Embodiments 14 to 16, wherein said antibody is capable of binding domain 2 of said WISP1 protein.

[0233] Embodiment 18. The antibody of any one of Embodiments 14 to 17, wherein domain 2 of said WISP1 protein comprises residues corresponding to 121 to 203 of SEQ ID NO:19.

[0234] Embodiment 19. The antibody of any one of Embodiments 14 to 18, wherein said antibody is capable of binding said WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 20 nM.

[0235] Embodiment 20. The antibody of Embodiment 19, wherein said antibody is capable of binding said WISP1 protein with a KD of about 5.55 nM.PATENT Attorney Docket No.: 062698-505001WO

[0236] Embodiment 21. An anti-WNT1-inducible-signaling pathway protein 1 (WISP1) antibody, wherein said anti-WISP1 antibody binds the same epitope as an anti-WISP1 antibody comprising a heavy chain variable domain comprising: a CDR H1 as set forth in SEQ ID NO:1, a CDR H2 as set forth in SEQ ID NO:2 and a CDR H3 as set forth in SEQ ID NO:3; and a light chain variable domain comprising: a CDR L1 as set forth in SEQ ID NO:4, a CDR L2 comprising AAS, and a CDR L3 as set forth in SEQ ID NO:6.

[0237] Embodiment 22. An antibody that competes with an anti-WNT1-inducible-signaling pathway protein 1 (WISP1) antibody for binding to a WISP1 protein, wherein the anti-WISP1 antibody comprises: a heavy chain variable domain comprising: a CDR H1 as set forth in SEQ ID NO:1, a CDR H2 as set forth in SEQ ID NO:2 and a CDR H3 as set forth in SEQ ID NO:3; and a light chain variable domain comprising: a CDR L1 as set forth in SEQ ID NO:4, a CDR L2 comprising AAS, and a CDR L3 as set forth in SEQ ID NO:6.

[0238] Embodiment 23. The antibody of any one of Embodiments 1 to 22, wherein said antibody is attached to a therapeutic agent.

[0239] Embodiment 24. The antibody of any one of Embodiments 1 to 22, wherein said antibody is attached to a diagnostic agent.

[0240] Embodiment 25. A method of treating fibrosis in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of an antibody of any one of Embodiments 1 to 24.

[0241] Embodiment 26. The method of Embodiment 25, wherein said fibrosis is fibrotic liverdisease, lung fibrosis, or cardiac fibrosis.

[0242] Embodiment 27. The method of Embodiment 26, wherein said fibrosis is fibrotic liver disease.

[0243] Embodiment 28. The method of Embodiment 26, wherein said fibrosis is lung fibrosis.

[0244] Embodiment 29. The method of Embodiment 28, wherein the subject has interstitial lung disease.PATENT Attorney Docket No.: 062698-505001WO

[0245] Embodiment 30. The method of Embodiment 29, wherein the interstitial lung disease is non-specific interstitial pneumonia, rheumatoid arthritis interstitial lung disease, hypersensitivity pneumonitis, berylliosis, respiratory bronchiolitis interstitial lung disease, desquamative interstitial pneumonitis, sarcoidosis, acute interstitial pneumonitis, cryptogenic-organizing pneumonitis, lymphocytic interstitial pneumonitis, or pleuroparenchymal fibroelastosis.

[0246] Embodiment 31. The method of any one of Embodiments 28 to 30, wherein the lung fibrosis is idiopathic pulmonary fibrosis, systemic sclerosis associated pulmonary fibrosis, progressive pulmonary fibrosis, pulmonary fibrosis associated with Sjogrens Syndrome., pneumoconiosis, asbestosis, silicosis, radiation-induced pulmonary fibrosis, drug-induced pulmonary fibrosis, COVID-19-related pulmonary fibrosis, pulmonary fibrosis following acute respiratory distress syndrome, pulmonary fibrosis associated with lymphangioleiomyomatosis, familial pulmonary fibrosis, pulmonary fibrosis associated with Hermansky Pudlak syndrome, or pulmonary fibrosis associated with dyskeratosis congenita.

[0247] Embodiment 32. The method of Embodiment 31, wherein the lung fibrosis is idiopathic pulmonary fibrosis, systemic sclerosis associated pulmonary fibrosis, or progressive pulmonary fibrosis.

[0248] Embodiment 33. The method of Embodiment 32, wherein the lung fibrosis is idiopathic pulmonary fibrosis.

[0249] Embodiment 34. The method of Embodiment 26, wherein said fibrosis is cardiac fibrosis.

[0250] Embodiment 35. The method of any one of Embodiments 25-34, wherein the subject has scleroderma.

[0251] Embodiment 36. A method of treating fibrosis in a subject in need thereof, the method comprising: a) identifying in a biological sample obtained from the subject an elevated level of WISP1 relative to a standard control, an elevated level of α-Smooth Muscle Actin (α-SMA) relative to the standard control, an elevated level of collagen type I alpha 1 chain (Col1a1) relative to the standard control, an elevated level of tissue inhibitor of metalloproteinase 1 (Timp1) relative to the standard control, an elevated level of fibronectin (Fn1) relative to the standard control, an elevated level of interleukin 6 (IL-6) relative to the standard control, an elevated level of phosphorylatedPATENT Attorney Docket No.: 062698-505001WO Small Mother Against Decapentaplegic 2 (pSMAD2) relative to the standard control, an elevated level of phosphorylated Small Mother Against Decapentaplegic 3 (pSMAD3) relative to the standard control, or a combination thereof; and b) administering to the subject a therapeutically effective amount of the anti-WISP1 antibody of any one of Embodiments 1 to 24.

[0252] Embodiment 37. The method of Embodiment 36, wherein said fibrosis is fibrotic liver disease, lung fibrosis, or cardiac fibrosis.

[0253] Embodiment 38. The method of Embodiment 36, wherein said fibrosis is fibrotic liver disease.

[0254] Embodiment 39. The method of Embodiment 36, wherein said fibrosis is lung fibrosis.

[0255] Embodiment 40. The method of Embodiment 39, wherein the subject has interstitial lung disease.

[0256] Embodiment 41. The method of Embodiment 40, wherein the interstitial lung disease is non-specific interstitial pneumonia, rheumatoid arthritis interstitial lung disease, hypersensitivity pneumonitis, berylliosis, respiratory bronchiolitis interstitial lung disease, desquamative interstitial pneumonitis, sarcoidosis, acute interstitial pneumonitis, cryptogenic-organizing pneumonitis, lymphocytic interstitial pneumonitis, or pleuroparenchymal fibroelastosis.

[0257] Embodiment 42. The method of any one of Embodiments 39 to 41, wherein the lung fibrosis is idiopathic pulmonary fibrosis, systemic sclerosis associated pulmonary fibrosis, progressive pulmonary fibrosis, pulmonary fibrosis associated with Sjogrens Syndrome., pneumoconiosis, asbestosis, silicosis, radiation-induced pulmonary fibrosis, drug-induced pulmonary fibrosis, COVID-19-related pulmonary fibrosis, pulmonary fibrosis following acute respiratory distress syndrome, pulmonary fibrosis associated with lymphangioleiomyomatosis, familial pulmonary fibrosis, pulmonary fibrosis associated with Hermansky Pudlak syndrome, or pulmonary fibrosis associated with dyskeratosis congenita.

[0258] Embodiment 43. The method of Embodiment 42, wherein the lung fibrosis is idiopathic pulmonary fibrosis, systemic sclerosis associated pulmonary fibrosis, or progressive pulmonary fibrosis.PATENT Attorney Docket No.: 062698-505001WO

[0259] Embodiment 44. The method of Embodiment 43, wherein the lung fibrosis is idiopathic pulmonary fibrosis.

[0260] Embodiment 45. The method of Embodiment 37, wherein said fibrosis is cardiac fibrosis.

[0261] Embodiment 46. The method of any one of Embodiments 36 to 45, wherein the subject has scleroderma.

[0262] Embodiment 47. A method of inhibiting release of interleukin 6 (IL-6), phosphorylated Small Mother Against Decapentaplegic 2 (pSMAD2), phosphorylated Small Mother Against Decapentaplegic 3 (pSMAD3), or a combination thereof from a cell, the method comprising contacting the cell with the anti-WISP1 antibody of any one of Embodiments 1 to 24.

[0263] Embodiment 48. The method of Embodiment 47, wherein the cell is an immune cell.

[0264] Embodiment 49. The method of Embodiment 47, wherein the cell is a fibroblast.

[0265] Embodiment 50. A method of inhibiting migration of a WISP-1 receptor expressing cell, the method comprising contacting said cell with the anti-WISP1 antibody of any one of Embodiments 1 to 24.

[0266] Embodiment 51. The method of Embodiment 50, wherein said WISP-1 receptor is an integrin.

[0267] Embodiment 52. The method of Embodiment 50 or 51, wherein the cell is a fibroblast or a stellate cell.

[0268] Embodiment 53. A method of detecting a WISP1-expressing cell, said method comprising. (i) contacting a WISP1-expressing cell with the antibody of any one of Embodiments 1 to 24; and (ii) detecting binding of said antibody to a WISP1 protein expressed by said cell

[0269] Embodiment 54. The method of Embodiment 53, wherein the antibody is attached to a detectable moiety.

[0270] Embodiment 55. An antibody according to any one of Embodiments 1 to 24 for use in a method of treating fibrosis in a subject in need thereof.PATENT Attorney Docket No.: 062698-505001WO

[0271] Embodiment 56. The antibody for use according to Embodiment 55, wherein said fibrosisis fibrotic liver disease, lung fibrosis, or cardiac fibrosis.

[0272] Embodiment 57. The antibody for use according to Embodiment 56, wherein said fibrosis is fibrotic liver disease.

[0273] Embodiment 58. The antibody for use according to Embodiment 56, wherein said fibrosis is lung fibrosis.

[0274] Embodiment 59. The antibody for use according to Embodiment 58, wherein the subject has interstitial lung disease.

[0275] Embodiment 60. The antibody for use according to Embodiment 59, wherein the interstitial lung disease is non-specific interstitial pneumonia, rheumatoid arthritis interstitial lung disease, hypersensitivity pneumonitis, berylliosis, respiratory bronchiolitis interstitial lung disease, desquamative interstitial pneumonitis, sarcoidosis, acute interstitial pneumonitis, cryptogenic- organizing pneumonitis, lymphocytic interstitial pneumonitis, or pleuroparenchymal fibroelastosis.

[0276] Embodiment 61. The antibody for use according to any one of Embodiments 58 to 60, wherein the lung fibrosis is idiopathic pulmonary fibrosis, systemic sclerosis associated pulmonary fibrosis, progressive pulmonary fibrosis, pulmonary fibrosis associated with Sjogrens Syndrome., pneumoconiosis, asbestosis, silicosis, radiation-induced pulmonary fibrosis, drug-induced pulmonary fibrosis, COVID-19-related pulmonary fibrosis, pulmonary fibrosis following acute respiratory distress syndrome, pulmonary fibrosis associated with lymphangioleiomyomatosis, familial pulmonary fibrosis, pulmonary fibrosis associated with Hermansky Pudlak syndrome, or pulmonary fibrosis associated with dyskeratosis congenita.

[0277] Embodiment 62. The antibody for use according to Embodiment 61, wherein the lung fibrosis is idiopathic pulmonary fibrosis, systemic sclerosis associated pulmonary fibrosis, or progressive pulmonary fibrosis.

[0278] Embodiment 63. The antibody for use according to Embodiment 62, wherein the lung fibrosis is idiopathic pulmonary fibrosis.PATENT Attorney Docket No.: 062698-505001WO

[0279] Embodiment 64. The antibody for use according to Embodiment 56, wherein said fibrosis is cardiac fibrosis.

[0280] Embodiment 65. The antibody for use according to any one of Embodiments 55-64, wherein the subject has scleroderma.

[0281] Embodiment 66. An antibody according to any one of Embodiments 1 to 24 for use in a method of treating fibrosis in a subject in need thereof, the method comprising: a) identifying in a biological sample obtained from the subject an elevated level of WISP1 relative to a standard control, an elevated level of α-Smooth Muscle Actin (α-SMA) relative to the standard control, an elevated level of collagen type I alpha 1 chain (Col1a1) relative to the standard control, an elevated level of tissue inhibitor of metalloproteinase 1 (Timp1) relative to the standard control, an elevated level of fibronectin (Fn1) relative to the standard control, an elevated level of interleukin 6 (IL-6) relative to the standard control, an elevated level of phosphorylated Small Mother Against Decapentaplegic 2 (pSMAD2) relative to the standard control, an elevated level of phosphorylated Small Mother Against Decapentaplegic 3 (pSMAD3) relative to the standard control, or a combination thereof; and b) administering to the subject a therapeutically effective amount of the anti-WISP1 antibody of any one of embodiments 1 to 24.

[0282] Embodiment 67. The antibody for use according to Embodiment 66, wherein said fibrosis is fibrotic liver disease, lung fibrosis, or cardiac fibrosis.

[0283] Embodiment 68. The antibody for use according to Embodiment 66, wherein said fibrosis is fibrotic liver disease.

[0284] Embodiment 69. The antibody for use according to Embodiment 66, wherein said fibrosis is lung fibrosis.

[0285] Embodiment 70. The antibody for use according to Embodiment 69, wherein the subject has interstitial lung disease.

[0286] Embodiment 71. The antibody for use according to Embodiment 70, wherein the interstitial lung disease is non-specific interstitial pneumonia, rheumatoid arthritis interstitial lung disease, hypersensitivity pneumonitis, berylliosis, respiratory bronchiolitis interstitial lung disease,PATENT Attorney Docket No.: 062698-505001WO desquamative interstitial pneumonitis, sarcoidosis, acute interstitial pneumonitis, cryptogenic- organizing pneumonitis, lymphocytic interstitial pneumonitis, or pleuroparenchymal fibroelastosis.

[0287] Embodiment 72. The antibody for use according to any one of Embodiments 69 to 71, wherein the lung fibrosis is idiopathic pulmonary fibrosis, systemic sclerosis associated pulmonary fibrosis, progressive pulmonary fibrosis, pulmonary fibrosis associated with Sjogrens Syndrome., pneumoconiosis, asbestosis, silicosis, radiation-induced pulmonary fibrosis, drug-induced pulmonary fibrosis, COVID-19-related pulmonary fibrosis, pulmonary fibrosis following acute respiratory distress syndrome, pulmonary fibrosis associated with lymphangioleiomyomatosis, familial pulmonary fibrosis, pulmonary fibrosis associated with Hermansky Pudlak syndrome, or pulmonary fibrosis associated with dyskeratosis congenita.

[0288] Embodiment 73. The antibody for use according to Embodiment 72, wherein the lung fibrosis is idiopathic pulmonary fibrosis, systemic sclerosis associated pulmonary fibrosis, or progressive pulmonary fibrosis.

[0289] Embodiment 74. The antibody for use according to Embodiment 73, wherein the lung fibrosis is idiopathic pulmonary fibrosis.

[0290] Embodiment 75. The antibody for use according to Embodiment 67, wherein said fibrosis is cardiac fibrosis.

[0291] Embodiment 76. The antibody for use according to Embodiment 66 to 75, wherein the subject has scleroderma.

[0292] Embodiment 77. An antibody according to any one of Embodiments 1 to 24 for use in a method of inhibiting release of interleukin 6 (IL-6), phosphorylated Small Mother Against Decapentaplegic 2 (pSMAD2), phosphorylated Small Mother Against Decapentaplegic 3 (pSMAD3), or a combination thereof from a cell, the method comprising contacting the cell with the anti-WISP1 antibody of any one of Embodiments 1 to 24.

[0293] Embodiment 78. The antibody for use according to Embodiment 77, wherein the cell is an immune cell.PATENT Attorney Docket No.: 062698-505001WO

[0294] Embodiment 79. The antibody for use according to Embodiment 78, wherein the cell is a fibroblast.

[0295] Embodiment 80. An antibody according to any one of Embodiments 1 to 24 for use in a method of inhibiting migration of a WISP-1 receptor expressing cell, the method comprising contacting said cell with the anti-WISP1 antibody of any one of Embodiments 1 to 24.

[0296] Embodiment 81. The antibody for use according to Embodiment 80, wherein said WISP-1 receptor is an integrin.

[0297] Embodiment 82. The antibody for use according to Embodiment 80 or 81, wherein the cell is a fibroblast or a stellate cell.

[0298] Embodiment 83. An antibody according to any one of Embodiments 1 to 24 for use in a method of detecting a WISP1-expressing cell, said method comprising. (i) contacting a WISP1- expressing cell with the antibody of any one of Embodiments 1 to 24; and (ii) detecting binding of said antibody to a WISP1 protein expressed by said cell

[0299] Embodiment 84. The antibody for use according to Embodiment 83, wherein the antibody is attached to a detectable moiety.

[0300] Embodiment 85. An in vitro method of inhibiting release of interleukin 6 (IL-6), phosphorylated Small Mother Against Decapentaplegic 2 (pSMAD2), phosphorylated Small Mother Against Decapentaplegic 3 (pSMAD3), or a combination thereof from a cell, the method comprising contacting the cell with the anti-WISP1 antibody of any one of Embodiments 1 to 24.

[0301] Embodiment 86. The in vitro method of Embodiment 85, wherein the cell is an immune cell.

[0302] Embodiment 87. The in vitro method of Embodiment 85, wherein the cell is a fibroblast.

[0303] Embodiment 88. An in vitro method of inhibiting migration of a WISP-1 receptor expressing cell, the method comprising contacting said cell with the anti-WISP1 antibody of any one of Embodiments 1 to 24.PATENT Attorney Docket No.: 062698-505001WO

[0304] Embodiment 89. The in vitro method of Embodiment 88, wherein said WISP-1 receptor is an integrin.

[0305] Embodiment 90. The in vitro method of Embodiment 88 or 89, wherein the cell is a fibroblast or a stellate cell.

[0306] Embodiment 91. An in vitro method of detecting a WISP1-expressing cell, said method comprising. (i) contacting a WISP1-expressing cell with the antibody of any one of Embodiments 1 to 24; and (ii) detecting binding of said antibody to a WISP1 protein expressed by said cell

[0307] Embodiment 92. The in vitro method of Embodiment 91, wherein the antibody is attached to a detectable moiety.

[0308] Embodiment 93. Use of an antibody according to any one of Embodiments 1 to 24 in the manufacture of a medicament for the treatment of fibrosis in a subject in need thereof.

[0309] Embodiment 94. The use according to Embodiment 93, wherein said fibrosis is fibroticliver disease, lung fibrosis, or cardiac fibrosis.

[0310] Embodiment 95. The use according to Embodiment 94, wherein said fibrosis is fibrotic liver disease.

[0311] Embodiment 96. The use according to Embodiment 94, wherein said fibrosis is lung fibrosis.

[0312] Embodiment 97. The use according to Embodiment 96, wherein the subject has interstitial lung disease.

[0313] Embodiment 98. The use according to Embodiment 97, wherein the interstitial lung disease is non-specific interstitial pneumonia, rheumatoid arthritis interstitial lung disease, hypersensitivity pneumonitis, berylliosis, respiratory bronchiolitis interstitial lung disease, desquamative interstitial pneumonitis, sarcoidosis, acute interstitial pneumonitis, cryptogenic-organizing pneumonitis, lymphocytic interstitial pneumonitis, or pleuroparenchymal fibroelastosis.

[0314] Embodiment 99. The use according to any one of Embodiments 96 to 98, wherein the lung fibrosis is idiopathic pulmonary fibrosis, systemic sclerosis associated pulmonary fibrosis,PATENT Attorney Docket No.: 062698-505001WO progressive pulmonary fibrosis, pulmonary fibrosis associated with Sjogrens Syndrome., pneumoconiosis, asbestosis, silicosis, radiation-induced pulmonary fibrosis, drug-induced pulmonary fibrosis, COVID-19-related pulmonary fibrosis, pulmonary fibrosis following acute respiratory distress syndrome, pulmonary fibrosis associated with lymphangioleiomyomatosis, familial pulmonary fibrosis, pulmonary fibrosis associated with Hermansky Pudlak syndrome, or pulmonary fibrosis associated with dyskeratosis congenita.

[0315] Embodiment 100. The use according to Embodiment 99, wherein the lung fibrosis is idiopathic pulmonary fibrosis, systemic sclerosis associated pulmonary fibrosis, or progressive pulmonary fibrosis.

[0316] Embodiment 101. The use according to Embodiment 100, wherein the lung fibrosis is idiopathic pulmonary fibrosis.

[0317] Embodiment 102. The use according to Embodiment 94, wherein said fibrosis is cardiac fibrosis.

[0318] Embodiment 103. The use according to any one of Embodiments 93-102, wherein the subject has scleroderma.

[0319] Embodiment 104. Use of an antibody according to any one of Embodiments 1 to 24 in the manufacture of a medicament for the treatment of fibrosis in a subject in need thereof, the use comprising: a) identifying in a biological sample obtained from the subject an elevated level of WISP1 relative to a standard control, an elevated level of α-Smooth Muscle Actin (α-SMA) relative to the standard control, an elevated level of collagen type I alpha 1 chain (Col1a1) relative to the standard control, an elevated level of tissue inhibitor of metalloproteinase 1 (Timp1) relative to the standard control, an elevated level of fibronectin (Fn1) relative to the standard control, an elevated level of interleukin 6 (IL-6) relative to the standard control, an elevated level of phosphorylated Small Mother Against Decapentaplegic 2 (pSMAD2) relative to the standard control, an elevated level of phosphorylated Small Mother Against Decapentaplegic 3 (pSMAD3) relative to the standard control, or a combination thereof; and b) administering to the subject a therapeutically effective amount of the anti-WISP1 antibody of any one of Embodiments 1 to 24.PATENT Attorney Docket No.: 062698-505001WO

[0320] Embodiment 105. The use according to Embodiment 104, wherein said fibrosis is fibrotic liver disease, lung fibrosis, or cardiac fibrosis.

[0321] Embodiment 106. The use according to Embodiment 104, wherein said fibrosis is fibrotic liver disease.

[0322] Embodiment 107. The use according to Embodiment 104, wherein said fibrosis is lung fibrosis.

[0323] Embodiment 108. The use according to Embodiment 107, wherein the subject has interstitial lung disease.

[0324] Embodiment 109. The use according to Embodiment 108, wherein the interstitial lung disease is non-specific interstitial pneumonia, rheumatoid arthritis interstitial lung disease, hypersensitivity pneumonitis, berylliosis, respiratory bronchiolitis interstitial lung disease, desquamative interstitial pneumonitis, sarcoidosis, acute interstitial pneumonitis, cryptogenic- organizing pneumonitis, lymphocytic interstitial pneumonitis, or pleuroparenchymal fibroelastosis.

[0325] Embodiment 110. The use according to any one of Embodiments 107 to 109, wherein the lung fibrosis is idiopathic pulmonary fibrosis, systemic sclerosis associated pulmonary fibrosis, progressive pulmonary fibrosis, pulmonary fibrosis associated with Sjogrens Syndrome., pneumoconiosis, asbestosis, silicosis, radiation-induced pulmonary fibrosis, drug-induced pulmonary fibrosis, COVID-19-related pulmonary fibrosis, pulmonary fibrosis following acute respiratory distress syndrome, pulmonary fibrosis associated with lymphangioleiomyomatosis, familial pulmonary fibrosis, pulmonary fibrosis associated with Hermansky Pudlak syndrome, or pulmonary fibrosis associated with dyskeratosis congenita.

[0326] Embodiment 111. The use according to Embodiment 110, wherein the lung fibrosis is idiopathic pulmonary fibrosis, systemic sclerosis associated pulmonary fibrosis, or progressive pulmonary fibrosis.

[0327] Embodiment 112. The use according to Embodiment 111, wherein the lung fibrosis is idiopathic pulmonary fibrosis.PATENT Attorney Docket No.: 062698-505001WO

[0328] Embodiment 113. The use according to Embodiment 105, wherein said fibrosis is cardiac fibrosis.

[0329] Embodiment 114. The use according to Embodiment 104 to 113, wherein the subject has scleroderma.

[0330] Embodiment 115. Use of an antibody according to any one of Embodiments 1 to 24 in the manufacture of a medicament for inhibiting release of interleukin 6 (IL-6), phosphorylated Small Mother Against Decapentaplegic 2 (pSMAD2), phosphorylated Small Mother Against Decapentaplegic 3 (pSMAD3), or a combination thereof from a cell, the use comprising contacting the cell with the anti-WISP1 antibody of any one of Embodiments 1 to 24.

[0331] Embodiment 116. The use according to Embodiment 115, wherein the cell is an immune cell.

[0332] Embodiment 117. The use according to Embodiment 115, wherein the cell is a fibroblast.

[0333] Embodiment 118. Use of an antibody according to any one of Embodiments 1 to 24 in the manufacture of a medicament for inhibiting migration of a WISP-1 receptor expressing cell, the use comprising contacting said cell with the anti-WISP1 antibody of any one of Embodiments 1 to 24.

[0334] Embodiment 119. The use according to Embodiment 118, wherein said WISP-1 receptor is an integrin.

[0335] Embodiment 120. The use according to Embodiment 118 or 119, wherein the cell is a fibroblast or a stellate cell.

[0336] Embodiment 121. Use of an antibody according to any one of Embodiments 1 to 24 in the manufacture of a medicament for detecting a WISP1-expressing cell, said use comprising (i) contacting a WISP1-expressing cell with the antibody of any one of Embodiments 1 to 24; and (ii) detecting binding of said antibody to a WISP1 protein expressed by said cell.

[0337] Embodiment 122. The use according to Embodiment 121, wherein the antibody is attached to a detectable moiety.PATENT Attorney Docket No.: 062698-505001WO

[0338] Embodiment 123. The method according to any one of Embodiments 25 to 54, wherein the subject is human.

[0339] Embodiment 124. The antibody for use according to any one of Embodiments 55 to 76, wherein the antibody is for use in a human.

[0340] Embodiment 125. The use according to any one of Embodiments 93 to 114, wherein the subject is human. EXAMPLES Example 1: Generation of anti-WISP1 antibody clones

[0341] Anti-Human WISP1 antibodies were generated utilizing the Alloy Therapeutics transgenic mouse platform, engineered to express antibodies with fully human variable regions. Alloy mice, strains ATX-GK and ATX-GK+, were immunized with recombinant human WISP1 (SEQ ID NO:15) following rapid immunization methods to achieve robust titers in 3 to 5 weeks. The mouse anti-WISP1 titers were followed by ELISA on recombinant human WISP1 (SEQ ID NO:15), mouse WISP1 (SEQ ID NO:17), and for an off-target control, human CCN2 / CTGF (R&D cat#1680 - SEQ ID NO:18). Mice displaying strong anti-WISP1 antibody titers were sacrificed, and the harvested spleens and lymph nodes were processed by standard hybridoma fusion procedures.

[0342] After the selection and recovery steps, anti-WISP1 antibody titers were confirmed in the hybridoma pool supernatants before single cell plating individual hybridoma clones by FACS sorting methods. The monoclonal hybridomas were expanded and then supernatants were screened by ELISA for binding to recombinant human, cynomolgus, and mouse WISP1 (SEQ ID NO:15, 16, and 17) and counter screened for binding to recombinant human CCN2 / CTGF (FIG.1). Hybridoma expressed antibodies which displayed specific binding to the WISP1 proteins, but not CCN2 / CTGF were selected for sequencing.

[0343] Selected monoclonal anti-WISP1 hybridomas were sequenced by RT-PCR methods utilizing primer sets provided for the Alloy mice. Heavy and light chain variable regions were aligned to remove duplicate clones and to group clones with related variable regions into sequence bin groupings. The unique antibody variable region sequences, such as M6-NYS, K4, A1, and A2 (expressed by hybridomas 1D03, 2F09, 3C09, and 9H06, respectively) were subsequentlyPATENT Attorney Docket No.: 062698-505001WO synthesized by recombinant expression methods to generate full length anti-WISP1 antibodies for further characterization and testing. Example 2: Analysis of anti-WISP1 antibody binding activity

[0344] The evaluation of the binding specificity of anti-WISP1 antibodies to human WISP1 was carried out using a direct coat ELISA assay (FIG.2). Full length human WISP1 protein (Human_FL_CCN4) was diluted to a concentration of 5 μg / mL in 100 μl of 1x coat buffer per well (Biolegend cat #421701) and immobilized on to Immulon-2HB plate (ThermoFischer Scientific cat #3445) for 1 hour at room temperature. The antigen solution was aspirated and washed three times with approximately 300 μl of 1 x TBST (VWR cat #K873), and then 200 μl of blocking solution was allowed to incubate at room temperature for 1 hour. The plate was then washed three times with 1 x TBST, and appropriate serial dilutions of the antigens were prepared and added to the plate to incubate for 1 hour. Following incubation with the primary antibody, the plate was washed as previously described, and 100 μl of an anti-human IgG Fc gamma-HRP (Jackson Immunoresearch cat #109-035-170) was added at a 5000 fold dilution and incubated at room temperature for 1 hour. The plate was washed, and 100 ul of TMB developing reagent was added and allowed to develop for 1 minute. Following development, 100 ul of the TMB stop solution was added and absorbance was measured at 450 nm.

[0345] Binding kinetics were established by Surface Plasmon Resonance (SPR) performed by Genscript USA (FIG.3). Human full length WISP1 was immobilized on a Series S sensor ChipCM5 (GE Healthcare cat # BR-1005-30) by activating the sensor chip with 50 mM N-Hydroxysuccinamide (NHS) and 200 mM 1-ethyl-3-93-dimethylaminopropyl) carbodiimide hydrochloride (EDC). The WISP1 antigen was diluted to 30 mM in sodium acetate buffer, pH 4.5 and flowed over the sensor chip to facilitate the amine coupling reaction. Following WISP1 dilution to appropriate concentrations, affinity measurement was performed at 25 °C in HBS-EP+ buffer at pH 7.4. Data was processed via the Biacore 8K evaluation software version 1.1 and the flow cell and blank injection buffer were used as double references. Example 3: Analysis of WISP1 domain binding

[0346] Binding of anti-WISP1 antibodies to different domains of WISP1 protein was evaluated by ELISA (FIG.4). Human full length WISP1 (Hu_FL_CCN4), domain 1 WISP1 (human CCN4-PATENT Attorney Docket No.: 062698-505001WO Domain 1), domains 1 and 2 of WISP1 (Human CCN4-Domain 12), domains 3 and 4 of WISP1 (Human CCN4-Domain 34) and domain 4 WISP1 (Human CCN4-Domain 4) constructs were directly coated on plates (Immulon-2HB plate; Thermo Scientific cat# 3455) for 1 hour at room temperature at a concentration of 5 μg / mL. The antigen solution was aspirated and washed two times with approximately 300 μl of 1 x TBST (VWR cat #K873), and then 200 μl of blocking solution was allowed to incubate at room temperature for 1 hour. The block solution was aspirated and 100 μl of M6-NYS antibody expressed with the mouse IgG2 constant region and Ab162 were added to the wells at concentration of 0.1 μg / mL. Following incubation with the primary antibody, the plate was washed as described before, and 100 μl of an anti-human IgG Fc gamma-HRP (Jackson Immunoresearch cat #109-035-170) was added at a 5000 fold dilution and incubated at room temperature for 1 hour. The plate was washed, and 100 ul of TMB developing reagent was added and allowed to develop for 1 minute. Following the development, 100 ul of the TMB stop solution was added and absorbance was measured at 450 nm. K4 anti-WISP1 antibody was shown to bind to domain 2 of WISP1 protein (FIG.4). Example 4: In vivo studies showing therapeutic effects of Anti-WISP1 antibody in carbon tetrachloride (CCL4) mouse model of liver fibrosis

[0347] To induce liver fibrosis, male BALB / c mice were administered with Carbon Tetrachloride (CCl4) in mineral oil at 1:1 ratio (1 ml / kg) twice a week via intraperitoneal route for 6 weeks. Therapeutic treatment regimen was initiated on Day 21 post first CCl4 administration and continued until study termination at day 41. Animals were treated intraperitoneally three times a week with vehicle or test antibodies.

[0348] At the end of the study, mice were euthanized, and liver tissue harvested. Fibrosis was measured by quantifying collagen content in the liver by hydroxyproline.

[0349] CCL4induced an increase in collagen content in the liver, as shown by increased hydroxyproline production, when compared to the control group. Anti-WISP1 antibodies suppressed liver fibrosis. M6-QYS antibody at 3 mg / kg resulted in 79.7% reduction in hydroxyproline compared to vehicle group (+PBS). Anti-WISP1 antibody K4 at 10 mg / kg resulted in 76.4% reduction in hydroxyproline compared to vehicle group (+PBS) (FIG.s 5A-5B). The anti-WISP1 antibodies used in this study were expressed with mouse IgG constant regions.PATENT Attorney Docket No.: 062698-505001WO

[0350] The results demonstrate that the anti-WISP1 antibody is effective for suppressing liver fibrosis. Example 5: In vivo studies showing therapeutic effects of anti-WISP1 antibody in bile duct ligation (BDL) mouse model of liver fibrosis

[0351] Male Sprague-Dawley rats underwent either sham or bile duct ligation (BDL) surgery at day 0 to induce liver injury and fibrosis. Rats received 10 mg / kg of M6-QYS antibody or K4 antibody every three days (Q3D) from day 3 through day 18. The anti-WISP1 antibodies were expressed with mouse IgG2 constant regions. All dosing was given i.p. in volumes equal to 2 mL / kg. Rats were humanely euthanized and tissues harvested at day 21. Impact on myofibroblast was measured by alpha-smooth actin (a-SMA) staining in liver.

[0352] One section (5 µm) of paraffin-embedded liver tissue was obtained and mounted. Sections were stained against α-smooth muscle actin (α-SMA) using standard immunohistochemistry (IHC) methods. Images (n = 10 / section) of liver tissue stained against α-SMA were obtained using a Zeiss AxioImager.A2 microscope at 100x magnification (enough to obtain a representation of ~60 – 70% of the area) and subjected to quantitative image analysis. Quantitative histological image analysis of anti-α-SMA-stained tissue sections was performed using color spectral segmentation methods. α- SMA (percent total tissue area imaged) was expressed as the average positive diaminobenzidine (DAB) stain across sampled images (FIG.6A).

[0353] Representative photomicrographs of liver tissue stained against α-SMA are illustrated in FIG.6B.

[0354] BDL increased α-SMA staining in the liver relative to sham-operated controls (7.96 ± 0.35 vs 0.01 ± 0.00%). M6-QYS antibody and K4 antibody attenuated BDL-induced increases in α-SMA (M6-QYS: 5.33 ± 0.47; and K4: 4.84 ± 0.47 vs Vehicle: 7.96 ± 0.35%).

[0355] The results demonstrate that the anti-WISP1 antibody is effective for attenuating BDL- induced increases in liver alpha-SMA. Example 6: Anti-WISP1 antibody K4 inhibits pSMAD2

[0356] The canonical TGF^1 signaling pathway includes activation of Small Mother Against Decapentaplegic (SMAD) proteins, with phosphorylation of SMAD2 and SMAD3 among thePATENT Attorney Docket No.: 062698-505001WO primary mediators of downstream TGF^1-mediated fibrosis (Schmierer and Hall 2007; Frangogiannis 2020). Various reports have shown that WISP1 can act in concert with TGF^ signaling thus demonstrating a potential mechanism by which WISP1 may enhance or exacerbate fibrosis (Wang et al., 2020; Zhang et al.2020; Inkson et al 2008).

[0357] Thus, Applicant evaluated the ability of anti-WISP1 antibodies to modulate pSMAD2 and pSMAD3 signaling. Normal Rat Kidney Fibroblasts (NRKF) were treated with recombinant human WISP1 (10 ^g / mL) for 30 min in the absence or presence of anti-WISP1 antibodies and pSMAD2 evaluated in cell lysates by Luminex assay. The ability of various antibodies to inhibit pSMAD2 signal was determined relative to treatment with an isotype control antibody (% inhibition). Percent inhibition of pSMAD2 ranged from 0% to 71% (FIG.7). Monoclonal antibody E8 reduced pSMAD2 by 44% while antibody K4 reduced signal by 63%, which was comparable to inhibition by polyclonal anti-WISP1 antibody AF1627 (65%; positive control). Similar results were observed with pSMAD3 (data not shown). Example 7: Anti-WISP1 antibody K4 inhibits primary Human Hepatic Stellate Cell chemotaxis / mobility

[0358] Wound healing requires localization of required cells and factors to the site of injury in order to initiate repair. When this process persists or becomes unregulated due to continued insult, fibrosis can occur resulting in stiffening of the tissue and ultimately organ failure (Knoedler et al. 2023). In the case of the liver, hepatic stellate cell differentiation into myofibroblasts has been shown to be a driving factor in liver fibrosis (Tsuchida and Friedman, 2017). Biochemically, WISP1 has been shown to be able to linearize collagen I, a key component of the ECM. This activity has been shown to impact cell motility in vitro as well as cancer metastasis in vivo (Jia et al EMBO 2019; Janajanam et al 2021). Further, Xi et al. (2022) demonstrates that WISP1 is increased in the plasma of NASH patients and that WISP1 increases motility of HHSCs via integrin interactions.

[0359] To evaluate the ability of monoclonal antibody K4 to modulate this phenotype, the upper chambers of a 96-well transwell plate were coated with recombinant human WISP1 and 10% FBS was provided in the lower chambers as a chemoattractant. Primary HHSCs were added to the upper chamber at 1 or 2K per well. Antibodies were added to each well at indicated concentrations andPATENT Attorney Docket No.: 062698-505001WO migration of cells to the lower chamber were measured (48h shown). Without antibody (0 ^g / mL), significant chemotaxis occurred with an increase of cells on the lower side of the transwell (FIG.8, first column). IgG antibody treatment did not alter chemotaxis rates compared to wells receiving no antibody even at the highest concentration evaluated (FIG.8, top row). Treatment with a polyclonal anti-WISP1 antibody (R&D AF1627) substantially reduced WISP1-driven chemotaxis starting at 2 ^g / mL (FIG.8, middle row). Monoclonal anti-WISP1 antibody K4 also began to inhibit chemotaxis at 2 µg / mL with increasing inhibition at higher doses (FIG.8, lower row).

[0360] Quantitation of HHSC chemotaxis / migration was calculated at 48h. The “Phase Area Bottom Normalized to Initial Top Value” metric was used for calculating chemotaxis. This method takes the total masked cell area on the basal side of the membrane (bottom) and normalizes it to the masked area on the apical side of the membrane (top) from the first scan (4h), representing the number of cells that have migrated from the apical to the basal side of the transwell. Utilizing the 4h timepoint as a starting point was found to result in slightly lower chemotaxis rates but more uniform values across plates, likely due to the large morphological changes that occur shortly after seeding and through the first couple of hours as the cells adhere to the plate.

[0361] Significant HHSC chemotaxis occured with a combination of WISP1 and 10% FBS, but not without fetal bovine serum (FBS) (FIG.9). Non-specific IgG antibody did not inhibit chemotaxis / cell migration even at the highest concentration (100 ^g / mL). The polyclonal anti- WISP1 antibody AF1627 inhibited chemotaxis starting at 2 ^g / mL and inhibition increased with higher antibody concentrations. Monoclonal anti-WISP1 antibody K4 significantly inhibited chemotaxis starting at 2 ^g / mL and inhibition increased with antibody concentration. Significance is indicated relative to IgG at 100 ^g / mL with 10% FBS (* p < 0.05).

[0362] IC50 and IC80 values were determined using a python-based nonlinear regression curve-fit for dose response data from final timepoint (48h; FIG.10). Monoclonal anti-WISP1 antibody K4 generated an IC50 of 1.8788 ^g / mL and IC80 of 4.7959 ^g / mL; polyclonal anti-WISP1 antibody AF1627 has an IC50of 1.6629 µg / mL and IC80of 5.152 µg / mL. TABLES

[0363] Table 1. Antibody K4 SequencesPATENT Attorney Docket No.: 062698-505001WO Name Sequence SEQ ID NO CDR H1 1

[0364] Table 2. WISP1 Protein SequencesPATENT Attorney Docket No.: 062698-505001WO SEQ ID Name SequenceNOPATENT Attorney Docket No.: 062698-505001WO SEQ ID Name SequenceNOPATENT Attorney Docket No.: 062698-505001WO SEQ ID Name SequenceNO

[0365] Table 3. Exemplary heavy chain and light chain antibody sequences SEQ ID NSNPATENT Attorney Docket No.: 062698-505001WO REFERENCES

[0366] 1. Schmierer and Hill (Nat Rev Mol Cell Biol 2007) PMID: 18000526

[0367] 2. Frangogiannis N. (JEM 2020) PMID: 32997468

[0368] 3. Wang et al. (FASEB 2020) PMID: 32896021

[0369] 4. Zhang et al. (MCB 2020) PMID: 32458119

[0370] 5. Inkson et al. (JCB 2008) PMID: 18404666

[0371] 6. Knoedler et al. (Front in Immunol 2023) PMID 37646029

[0372] 7. D’Urso and Kurniawan (Front BioEng and Biotech 2020) PMID 37646029

[0373] 8. Jia et al. (EMBO 2019) PMID 31294477

[0374] 9. Janjanam et al. (Cancer Research 2021) PMID 34385183

[0375] 10. Xi et al. (Cell Metabolism 2022) PMID 35987202

Claims

PATENT Attorney Docket No.: 062698-505001WO WHAT IS CLAIMED IS:

1. An anti-WNT1-inducible-signaling pathway protein 1 (WISP1) antibody, comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy chain variable domain comprises: a CDR H1 as set forth in SEQ ID NO:1, a CDR H2 as set forth in SEQ ID NO:2 and a CDR H3 as set forth in SEQ ID NO:3; and wherein said light chain variable domain comprises: a CDR L1 as set forth in SEQ ID NO:4, a CDR L2 comprising AAS, and a CDR L3 as set forth in SEQ ID NO:

6.

2. The antibody of claim 1, wherein said heavy chain variable domain comprises a sequence having at least 90% identity to SEQ ID NO:

13.

3. The antibody of claim 1, wherein said heavy chain variable domain comprises a sequence having at least 95% identity to SEQ ID NO:

13.

4. The antibody of claim 1, wherein said heavy chain variable domain comprises a sequence having at least 98% identity to SEQ ID NO:

13.

5. The antibody of claim 1, wherein said heavy chain variable domain comprises SEQ ID NO:

13.

6. The antibody of claim 1, wherein said light chain variable domain comprises a sequence having at least 90% identity to SEQ ID NO:

14.

7. The antibody of claim 1, wherein said light chain variable domain comprises a sequence having at least 95% identity to SEQ ID NO:

14.

8. The antibody of claim 1, wherein said light chain variable domain comprises a sequence having at least 98% identity to SEQ ID NO:14.PATENT Attorney Docket No.: 062698-505001WO 9. The antibody of claim 1, wherein said light chain variable domain comprises SEQ ID NO:

14.

10. The antibody of claim 1, wherein said antibody is an IgG.

11. The antibody of claim 1, wherein said antibody is a humanized antibody or a chimeric antibody.

12. The antibody of claim 1, wherein said antibody comprises a Fab fragment.

13. The antibody of claim 1, wherein said antibody is a single chain antibody (scFv).

14. The antibody of claim 1, wherein said antibody is capable of binding a WISP1 protein.

15. The antibody of claim 14, wherein said WISP1 protein is a human WISP1 protein.

16. The antibody of claim 14, wherein said WISP1 protein comprises the sequence of SEQ ID NO:19 or 20.

17. The antibody of claim 14, wherein said antibody is capable of binding domain 2 of said WISP1 protein.

18. The antibody of claim 14, wherein domain 2 of said WISP1 protein comprises residues corresponding to 121 to 203 of SEQ ID NO:

19.

19. The antibody of claim 14, wherein said antibody is capable of binding said WISP1 protein with an equilibrium dissociation constant (KD) from about 0.01 nM to about 20 nM.

20. The antibody of claim 19, wherein said antibody is capable of binding said WISP1 protein with a KD of about 5.55 nM.PATENT Attorney Docket No.: 062698-505001WO 21. An anti-WNT1-inducible-signaling pathway protein 1 (WISP1) antibody, wherein said anti-WISP1 antibody binds the same epitope as an anti-WISP1 antibody comprising a heavy chain variable domain comprising: a CDR H1 as set forth in SEQ ID NO:1, a CDR H2 as set forth in SEQ ID NO:2 and a CDR H3 as set forth in SEQ ID NO:3; and a light chain variable domain comprising: a CDR L1 as set forth in SEQ ID NO:4, a CDR L2 comprising AAS, and a CDR L3 as set forth in SEQ ID NO:

6.

22. An antibody that competes with an anti-WNT1-inducible-signaling pathway protein 1 (WISP1) antibody for binding to a WISP1 protein, wherein the anti-WISP1 antibody comprises: a heavy chain variable domain comprising: a CDR H1 as set forth in SEQ ID NO:1, a CDR H2 as set forth in SEQ ID NO:2 and a CDR H3 as set forth in SEQ ID NO:3; and a light chain variable domain comprising: a CDR L1 as set forth in SEQ ID NO:4, a CDR L2 comprising AAS, and a CDR L3 as set forth in SEQ ID NO:

6.

23. The antibody of claim 1, wherein said antibody is attached to a therapeutic agent.

24. The antibody of claim 1, wherein said antibody is attached to a diagnostic agent.

25. A method of treating fibrosis in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of an antibody of claim 1.

26. The method of claim 25, wherein said fibrosis is fibrotic liver disease, lung fibrosis, or cardiac fibrosis.

27. The method of claim 26, wherein said fibrosis is fibrotic liver disease.PATENT Attorney Docket No.: 062698-505001WO 28. The method of claim 26, wherein said fibrosis is lung fibrosis.

29. The method of claim 28, wherein the subject has interstitial lung disease.

30. The method of claim 29, wherein the interstitial lung disease is non- specific interstitial pneumonia, rheumatoid arthritis interstitial lung disease, hypersensitivity pneumonitis, berylliosis, respiratory bronchiolitis interstitial lung disease, desquamative interstitial pneumonitis, sarcoidosis, acute interstitial pneumonitis, cryptogenic-organizing pneumonitis, lymphocytic interstitial pneumonitis, or pleuroparenchymal fibroelastosis.

31. The method of claim 28, wherein the lung fibrosis is idiopathic pulmonary fibrosis, systemic sclerosis associated pulmonary fibrosis, progressive pulmonary fibrosis, pulmonary fibrosis associated with Sjogrens Syndrome., pneumoconiosis, asbestosis, silicosis, radiation-induced pulmonary fibrosis, drug-induced pulmonary fibrosis, COVID-19-related pulmonary fibrosis, pulmonary fibrosis following acute respiratory distress syndrome, pulmonary fibrosis associated with lymphangioleiomyomatosis, familial pulmonary fibrosis, pulmonary fibrosis associated with Hermansky Pudlak syndrome, or pulmonary fibrosis associated with dyskeratosis congenita.

32. The method of claim 31, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis, systemic sclerosis associated pulmonary fibrosis, or progressive pulmonary fibrosis.

33. The method of claim 32, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

34. The method of claim 26, wherein said fibrosis is cardiac fibrosis.

35. The method of claim 25, wherein the subject has scleroderma.

36. A method of treating fibrosis in a subject in need thereof, the method comprising: a) identifying in a biological sample obtained from the subject an elevatedlevel of WISP1 relative to a standard control, an elevated level of α-Smooth Muscle Actin (α-PATENT Attorney Docket No.: 062698-505001WO SMA) relative to the standard control, an elevated level of collagen type I alpha 1 chain (Col1a1) relative to the standard control, an elevated level of tissue inhibitor of metalloproteinase 1 (Timp1) relative to the standard control, an elevated level of fibronectin (Fn1) relative to the standard control, an elevated level of interleukin 6 (IL-6) relative to the standard control, an elevated level of phosphorylated Small Mother Against Decapentaplegic 2 (pSMAD2) relative to the standard control, an elevated level of phosphorylated Small Mother Against Decapentaplegic 3 (pSMAD3) relative to the standard control, or a combination thereof; and b). administering to the subject a therapeutically effective amount of the anti- WISP1 antibody of claim 1.

37. The method of claim 36, wherein said fibrosis is fibrotic liver disease, lung fibrosis, or cardiac fibrosis.

38. The method of claim 36, wherein said fibrosis is fibrotic liver disease.

39. The method of claim 36, wherein said fibrosis is lung fibrosis.

40. The method of claim 39, wherein the subject has interstitial lung disease.

41. The method of claim 40, wherein the interstitial lung disease is non- specific interstitial pneumonia, rheumatoid arthritis interstitial lung disease, hypersensitivity pneumonitis, berylliosis, respiratory bronchiolitis interstitial lung disease, desquamative interstitial pneumonitis, sarcoidosis, acute interstitial pneumonitis, cryptogenic-organizing pneumonitis, lymphocytic interstitial pneumonitis, or pleuroparenchymal fibroelastosis.

42. The method of claim 39, wherein the lung fibrosis is idiopathic pulmonary fibrosis, systemic sclerosis associated pulmonary fibrosis, progressive pulmonary fibrosis, pulmonary fibrosis associated with Sjogrens Syndrome., pneumoconiosis, asbestosis, silicosis, radiation-induced pulmonary fibrosis, drug-induced pulmonary fibrosis, COVID-19-related pulmonary fibrosis, pulmonary fibrosis following acute respiratory distress syndrome, pulmonary fibrosis associated with lymphangioleiomyomatosis, familial pulmonary fibrosis, pulmonary fibrosis associated with Hermansky Pudlak syndrome, or pulmonary fibrosis associated with dyskeratosis congenita.PATENT Attorney Docket No.: 062698-505001WO 43. The method of claim 42, wherein the lung fibrosis is idiopathic pulmonary fibrosis, systemic sclerosis associated pulmonary fibrosis, or progressive pulmonary fibrosis.

44. The method of claim 43, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

45. The method of claim 37, wherein said fibrosis is cardiac fibrosis.

46. The method of claim 36, wherein the subject has scleroderma.

47. A method of inhibiting release of interleukin 6 (IL-6), phosphorylated Small Mother Against Decapentaplegic 2 (pSMAD2), phosphorylated Small Mother Against Decapentaplegic 3 (pSMAD3), or a combination thereof from a cell, the method comprising contacting the cell with the anti-WISP1 antibody of claim 1.

48. The method of claim 47, wherein the cell is an immune cell.

49. The method of claim 47, wherein the cell is a fibroblast.

50. A method of inhibiting migration of a WISP-1 receptor expressing cell, the method comprising contacting said cell with the anti-WISP1 antibody of claim 1.

51. The method of claim 50, wherein said WISP-1 receptor is an integrin.

52. The method of claim 50, wherein the cell is a fibroblast or a stellate cell.

53. A method of detecting a WISP1-expressing cell, said method comprising. (i) contacting a WISP1-expressing cell with the antibody of claim 1; and(ii) detecting binding of said antibody to a WISP1 protein expressed by saidcell.

54. The method of claim 53, wherein the antibody is attached to a detectable moiety.

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