Canine antibodies against canine IL-13

Abstract

The present invention provides canine antibodies that bind to canine interleukin-13 (canine IL-13), which have high binding affinity to canine IL-13 and can block the binding of canine IL-13 to the canine type II heterodimeric IL-4 receptor. The present invention also provides methods of using the antibodies of the present invention in the treatment of atopic dermatitis in dogs.

Description

[Technical Field]

[0001] The present invention relates to canine antibodies that bind to canine interleukin-13 (cIL-13), have high binding affinity to canine IL-13, and are capable of blocking the binding of canine IL-13 to the canine type II heterodimeric IL-4 receptor. The present invention also relates to the use of the antibodies of the present invention in the treatment of atopic dermatitis in dogs. [Background technology]

[0002] The immune system comprises a network of resident and recirculating specialized cells that function in concert to protect the host from infection and cancer. The ability of the immune system to perform this function depends largely on the biological activity of a group of signaling proteins secreted by white blood cells and collectively called interleukins. Two such interleukins are interleukin-4 (IL-4) and interleukin-13 (IL-13). IL-4 and IL-13 are expressed by CD4 + IL-4 and IL-13 are closely related proteins that can be secreted by many cell types, including Th2 cells, natural killer T cells (NKT), macrophages, mast cells, and basophils. IL-4 and IL-13 exhibit many overlapping functions and are important for the development of T cell-dependent humoral immune responses. IL-4 and IL-13 are also part of signaling pathways involved in atopic dermatitis.

[0003] IL-4 is known to bind with high affinity to two heterodimeric receptors, type I and type II. The type I heterodimeric IL-4 receptor consists of the IL-4 receptor alpha (IL-4Rα) chain and the common gamma C (γc) chain. The type II heterodimeric IL-4 receptor consists of the IL-4Rα chain and the IL-13 receptor alpha 1 (IL-13Rα1) chain. IL-13 binds to the IL-13Rα1 chain of the IL-4 type II receptor. IL-13 also binds to a unique receptor called IL-13 receptor alpha 2 (IL-13Rα2), which is secreted in a soluble form. IL-13 binding to IL-13Rα2 is not currently believed to transduce signals. Therefore, IL-13Rα2 has often been referred to as a decoy receptor.

[0004] Genes encoding IL-4 proteins from various species have been cloned and expressed in bacterial and mammalian cells. For example, a cDNA encoding human IL-4 (hIL-4) indicates that mature human IL-4 is a 129-amino acid secreted polypeptide with a predicted molecular weight of 15 Kd [Yokota et al., Proc Natl Acad Sci USA. 83(16):5894-5898 (1986)]. A cDNA encoding canine IL-4 (cIL-4) has also been identified and shown to encode a 132-amino acid polypeptide that shares 40% sequence identity with human IL-4 [van der Kaaij et al., Immunogenetics 49:142-143 (1999)].

[0005] The gene encoding human IL-13 (hIL-13) has been cloned and expressed in various host systems [Minty et al., Nature 362:248-50 (1993)]. The cDNA encoding hIL-13 indicates that mature hIL-13 is a secreted polypeptide with a molecular weight of 12.4 Kd. A cDNA encoding canine IL-13 (cIL-13) has also been identified [Yang et al., J. Interferon and Cytokine Research 20:779-785 (2000)]. The predicted mature cIL-13 polypeptide consists of 111 amino acids and shares 61.8% sequence identity with hIL-13. IL-4 and IL-13 are cytokines involved in generating immune responses necessary for protection against extracellular pathogens (e.g., parasites present in tissues or luminal spaces). These cytokines are also involved in the pathogenesis of allergic diseases in humans and animals, including atopic dermatitis (AD).

[0006] The therapeutic use of monoclonal antibodies to block signal transduction in specific pathways by binding to either a protein ligand or its protein receptor has proven widely successful. Indeed, such monoclonal antibodies have played a key role in the rapid growth of human biologics, accounting for over 25% of the human biologics market as of 2017. Of the 20 highest-selling drugs in 2014, six were monoclonal antibodies [Chung, Experimental & Molecular Medicine 49:e304;doi:10.1038 / emm.2017.46(2017)]. This trend continues to grow. Monoclonal antibodies raised against human IL-4Rα have been developed, and several of these antibodies have been extensively tested for their therapeutic efficacy in treating atopic dermatitis in humans [see, e.g., U.S. Patent Application Publication No. 2015 / 0017176]. One such antibody (dupilumab) was produced by immunization of transgenic mice in which mouse antibody genes had been replaced with human antibody genes; therefore, the resulting antibody is a human antibody, as opposed to, for example, a humanized mouse antibody.

[0007] While the high cost of monoclonal antibody therapeutics initially limited them to human biologics, canine monoclonal products have recently become available due to significant reductions in manufacturing costs. Early indications suggest that such monoclonal antibodies will likely become major therapeutic agents in the companion animal market. For example, antibodies against human interleukin-31 receptor alpha (hIL-31RA) have been tested and found to have significant effects on pruritus associated with atopic dermatitis in humans [Ruzicka, et al., New England Journal of Medicine, 376(9), 826-835(2017)]. Furthermore, antibodies against canine IL-31 (cIL-31) have been shown to have significant effects on pruritus associated with atopic dermatitis in dogs [U.S. Patent No. 8,790,651; U.S. Patent No. 10,093,731]. This caninized antibody blocks the binding of cIL-31 to the canine IL-31 receptor alpha (cIL-31RA), thereby blocking the cIL-31 / cIL-31RA signaling pathway. Therefore, preventing cIL-31 from binding to its receptor, cIL-31RA, reduces the pruritus associated with atopic dermatitis. However, simply blocking the cIL-31 / cIL-31R signaling pathway only improves the pruritus associated with atopic dermatitis, but does not stop the accompanying skin inflammation caused by the (cIL-4 or cIL-13) / canine type II IL-4 receptor signaling pathway.

[0008] More recently, caninized antibodies against canine IL-4Rα (the cIL-4Rα) that block the binding of cIL-4 to cIL-4Rα have also been disclosed (U.S. Patent Application Publication No. 2018 / 0346580, incorporated herein by reference in its entirety). These antibodies were produced by immunizing conventional, i.e., non-transgenic, mice with the cIL-4Rα extracellular domain (ECD). Because the type II cIL-4 receptor consists of the cIL-4Rα chain and the cIL-13R alpha1 chain, antibodies against canine IL-4Rα have been obtained that can block both cIL-4 and cIL-13 from binding to the type II cIL-4 receptor, thereby helping to block inflammation associated with atopic dermatitis. Recently, monoclonal antibody-based therapies targeting the hIL-4 and / or hIL-13 signaling pathways have been approved for the treatment of AD in humans.

[0009] However, despite recent successes in treating pruritus associated with atopic dermatitis and recent promising findings regarding the treatment of associated inflammation, many subjects suffering from this condition do not experience a rapid onset of antipruritic action accompanied by a significant effect on skin inflammation.Therefore, there is a need to design alternative therapies to address this unmet medical need.

[0010] Atopic dermatitis is also a common disease in companion animals, especially dogs, with an estimated prevalence of approximately 10-15% of the canine population. The pathogenesis of atopic dermatitis in dogs and cats (reviewed in Nuttall et al., Veterinary Records 172(8):201-207 (2013)) shares significant similarities with the pathogenesis of atopic dermatitis in humans, including skin infiltration by various immune cells and a CD4+ Th2-polarized cytokine environment, including a predominance of IL-4 and IL-13 cytokines. Therefore, there is an unmet medical need for safe and effective treatment options for atopic dermatitis in companion animals. Such treatments could potentially interfere with the underlying mechanisms of the disease, including correcting the apparent Th2 immune dysregulation resulting from aberrant expression of IL-4 and IL-13 cytokines in diseased animals. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] US Patent Application Publication No. 2015 / 0017176 [Patent Document 2] U.S. Patent No. 8,790,651 [Patent Document 3] U.S. Patent No. 10,093,731 [Patent Document 4] US Patent Application Publication No. 2018 / 0346580 [Non-patent literature]

[0012] [Non-Patent Document 1] Yokota et al., Proc Natl Acad Sci USA.83(16):5894-5898(1986) [Non-patent document 2] van der Kaaij et al., Immunogenetics 49:142-143(1999) [Non-patent document 3] Minty et al.,Nature 362:248-50(1993) [Non-patent document 4] Yang et al., J. Interferon and Cytokine Research 20:779-785(2000) [Non-Patent Document 5] Chung,Experimental&Molecular Medicine 49:e304;doi:10.1038 / emm.2017.46(2017) [Non-patent document 6] Ruzicka,et al.,New England Journal of Medicine,376(9),826-835(2017) [Non-Patent Document 7] Nuttall et al., Veterinary Records 172(8):201-207(2013) Summary of the Invention [Problem to be solved by the invention]

[0013] In one aspect, the present invention relates to canine antibodies and scFvs that bind to canine interleukin-13 (cIL-13). The present invention also relates to antigen-binding fragments of the canine antibodies that bind to cIL-13. The present invention further provides these canine antibodies and antigen-binding fragments thereof that bind to cIL-13 and block the binding of cIL-13 to the canine type II heterodimeric interleukin-4 receptor (type II cIL-4R). In certain embodiments, the canine antibodies or antigen-binding fragments thereof bind to cIL-13 and block the binding of cIL-13 to the canine type II cIL-4R, but do not block the binding of cIL-13 to cIL-13R alpha2.

[0014] Thus, the present invention provides canine antibodies, including isolated canine antibodies, that bind to cIL-13 and that have heavy and light chains that together comprise a set of six complementarity determining regions (CDRs), three of which are heavy chain CDRs: CDR heavy chain 1 (HCDR1), CDR heavy chain 2 (HCDR2), and CDR heavy chain 3 (HCDR3), and three of which are light chain CDRs: CDR light chain 1 (LCDR1), CDR light chain 2 (LCDR2), and CDR light chain 3 (LCDR3), a canine heavy chain variable region of the heavy chain of the canine antibody, a light chain variable region of the light chain of the canine antibody, an antigen-binding fragment of the heavy and light chains of the canine antibody, and an associated scFv.

[0015] The present invention further provides nucleic acids, including isolated nucleic acids, encoding any of a set of three heavy chain CDRs (HCDR1, HCDR2, and HCDR3), the heavy chain of a canine antibody and / or the canine heavy chain variable region of a heavy chain of a canine antibody or antigen-binding fragment thereof, any of a set of three light chain CDRs (LCDR1, LCDR2, and LCDR3), the light chain variable region of a canine antibody and / or the light chain of a canine antibody or antigen-binding fragment thereof of the present invention, and related scFvs.

[0016] A canine antibody that binds to cIL-13 comprises a heavy chain and a light chain that together comprise a set of six CDRs, three of which are heavy chain CDRs and three of which are light chain CDRs. In certain embodiments, the canine antibody or antigen-binding fragment thereof comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 114, HCDR2 comprising the amino acid sequence of SEQ ID NO: 115, HCDR3 comprising the amino acid sequence of SEQ ID NO: 116, LCDR1 comprising the amino acid sequence of SEQ ID NO: 117, LCDR2 comprising the amino acid sequence of SEQ ID NO: 118, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 119. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In certain embodiments, the antibody is a canine antibody.

[0017] In alternative embodiments of the canine antibody or antigen-binding fragment thereof, HCDR1 comprises the amino acid sequence of SEQ ID NO: 120, HCDR2 comprises the amino acid sequence of SEQ ID NO: 121, HCDR3 comprises the amino acid sequence of SEQ ID NO: 122, LCDR1 comprises the amino acid sequence of SEQ ID NO: 123, LCDR2 comprises the amino acid sequence of SEQ ID NO: 124, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 125. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0018] In other embodiments of the canine antibody or antigen-binding fragment thereof, HCDR1 comprises the amino acid sequence of SEQ ID NO: 126, HCDR2 comprises the amino acid sequence of SEQ ID NO: 127, HCDR3 comprises the amino acid sequence of SEQ ID NO: 128, LCDR1 comprises the amino acid sequence of SEQ ID NO: 129, LCDR2 comprises the amino acid sequence of SEQ ID NO: 130, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 131. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0019] In yet other embodiments of the canine antibody or antigen-binding fragment thereof, HCDR1 comprises the amino acid sequence of SEQ ID NO: 132, HCDR2 comprises the amino acid sequence of SEQ ID NO: 133, HCDR3 comprises the amino acid sequence of SEQ ID NO: 134, LCDR1 comprises the amino acid sequence of SEQ ID NO: 135, LCDR2 comprises the amino acid sequence of SEQ ID NO: 136, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 137. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0020] In yet other embodiments of the canine antibody or antigen-binding fragment thereof, HCDR1 comprises the amino acid sequence of SEQ ID NO: 138, HCDR2 comprises the amino acid sequence of SEQ ID NO: 139, HCDR3 comprises the amino acid sequence of SEQ ID NO: 140, LCDR1 comprises the amino acid sequence of SEQ ID NO: 141, LCDR2 comprises the amino acid sequence of SEQ ID NO: 142, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 143. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0021] In yet other embodiments of the canine antibody or antigen-binding fragment thereof, HCDR1 comprises the amino acid sequence of SEQ ID NO: 144, HCDR2 comprises the amino acid sequence of SEQ ID NO: 145, HCDR3 comprises the amino acid sequence of SEQ ID NO: 146, LCDR1 comprises the amino acid sequence of SEQ ID NO: 147, LCDR2 comprises the amino acid sequence of SEQ ID NO: 148, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 149. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0022] In yet other embodiments of the canine antibody or antigen-binding fragment thereof, HCDR1 comprises the amino acid sequence of SEQ ID NO: 150, HCDR2 comprises the amino acid sequence of SEQ ID NO: 151, HCDR3 comprises the amino acid sequence of SEQ ID NO: 152, LCDR1 comprises the amino acid sequence of SEQ ID NO: 153, LCDR2 comprises the amino acid sequence of SEQ ID NO: 154, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 155. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0023] In yet other embodiments of the canine antibody or antigen-binding fragment thereof, HCDR1 comprises the amino acid sequence of SEQ ID NO: 150, HCDR2 comprises the amino acid sequence of SEQ ID NO: 151, HCDR3 comprises the amino acid sequence of SEQ ID NO: 152, LCDR1 comprises the amino acid sequence of SEQ ID NO: 153, LCDR2 comprises the amino acid sequence of SEQ ID NO: 235, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 155. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0024] In yet other embodiments of the canine antibody or antigen-binding fragment thereof, HCDR1 comprises the amino acid sequence of SEQ ID NO: 248, HCDR2 comprises the amino acid sequence of SEQ ID NO: 249, HCDR3 comprises the amino acid sequence of SEQ ID NO: 250, LCDR1 comprises the amino acid sequence of SEQ ID NO: 251, LCDR2 comprises the amino acid sequence of SEQ ID NO: 252, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 253. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0025] In certain embodiments of a canine antibody or antigen-binding fragment thereof comprising the aforementioned set of six CDRs (including when the CDRs are in the presently disclosed heavy and light chain variable regions and heavy and light chains), when bound to cIL-13, the canine antibody or antigen-binding fragment thereof (i) binds to an epitope contained in the amino acid sequence of SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:239, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:98, or any combination thereof, or (ii) has an IC50 of less than 50 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells, or (iii) both bind to an epitope contained in the amino acid sequence of SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:239, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:98, or any combination thereof, and has an IC50 of less than 50 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells. In more specific embodiments, the canine antibody or antigen-binding fragment thereof, when bound to cIL-13, binds to an epitope contained in the amino acid sequence of SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 239, or any combination thereof. In even more specific embodiments, the canine antibody or antigen-binding fragment thereof binds to an epitope contained in the amino acid sequence of SEQ ID NO: 2 at the following amino acid residue position: 27 (S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 In a related embodiment, the antibody or antigen-binding fragment thereof binds to one or more serine residues of cIL-13 at the following amino acid residue position: 27 (S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 ) of cIL-13. In other embodiments, the antibody or antigen-binding fragment thereof binds to two or more serine residues of cIL-13 at the following amino acid residue position: 27 (S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S55 ), and 58(S 58 In yet other embodiments, the antibody or antigen-binding fragment thereof binds to three or more serine residues of cIL-13 at the following amino acid residue position: 27 (S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 In yet other embodiments, the antibody or antigen-binding fragment thereof binds to four or more serine residues of cIL-13 at the following amino acid residue position: 27 (S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 In yet another embodiment, the antibody binds to five or more serine residues of cIL-13 at the following amino acid residue position: 27 (S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 ) binds to all six serine residues of cIL-13.

[0026] In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to cIL-13 and has an IC50 of less than 25 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells. In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to cIL-13 and has an IC50 of 0.5 nM to 50 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells. In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to cIL-13 and has an IC50 of 2 nM to 25 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells. In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to cIL-13 and has an IC50 of 4 nM to 25 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells.

[0027] In an even more specific embodiment, the canine antibody or antigen-binding fragment thereof binds to an epitope of cIL-13 contained in the amino acid sequence of SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 239, or any combination thereof, and is located at the following amino acid residue position: 27(S) of the amino acid sequence of SEQ ID NO: 2. 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 ) binds to 1, 2, 3, 4, 5, or 6 serine residues of cIL-13 and has an IC50 of less than 50 nM, less than 25 nM, and / or 2 and / or 4 nM to 25 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells.

[0028] The present invention further provides a nucleic acid comprising a nucleotide sequence encoding a specific set of three heavy chain CDRs of the present invention, and a nucleic acid comprising a nucleotide sequence encoding a specific set of three light chain CDRs of the present invention. In a specific embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 114, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 115, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 116. In a related embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 117, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 118, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 119. The present invention further provides a pair of a nucleic acid encoding the set of three heavy chain CDRs and a nucleic acid encoding the set of three light chain CDRs. The present invention also provides a kit comprising these two nucleic acid pairs. In certain embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain variable region of a canine antibody, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain variable region of the canine antibody. In related embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0029] The chain CDRs encode the light chain of the canine antibody or antigen-binding fragment thereof.

[0030] In yet another embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 120, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 121, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 122. In a concomitant embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 123, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 124, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 125. The present invention further provides a pair of nucleic acids encoding the set of three heavy chain CDRs and a pair of nucleic acids encoding the set of three light chain CDRs. The present invention also provides a kit comprising these two pairs of nucleic acids. In certain embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain variable region of a canine antibody, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain variable region of the canine antibody. In a related embodiment, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0031] In yet another embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 126, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 127, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 128. In a concomitant embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 129, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 130, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 131. The present invention further provides a pair of nucleic acids encoding the set of three heavy chain CDRs and a pair of nucleic acids encoding the set of three light chain CDRs. The present invention also provides a kit comprising these two pairs of nucleic acids. In certain embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain variable region of a canine antibody, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain variable region of the canine antibody. In a related embodiment, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0032] In yet another embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 132, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 133, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 134. In a concomitant embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 135, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 136, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 137. The present invention further provides a pair of nucleic acids encoding the set of three heavy chain CDRs and a pair of nucleic acids encoding the set of three light chain CDRs. The present invention also provides a kit comprising these two pairs of nucleic acids. In certain embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain variable region of a canine antibody, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain variable region of the canine antibody. In a related embodiment, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0033] In yet another embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 138, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 139, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 140. In a concomitant embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 141, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 142, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 143. The present invention further provides a pair of nucleic acids encoding the set of three heavy chain CDRs and a pair of nucleic acids encoding the set of three light chain CDRs. The present invention also provides a kit comprising these two pairs of nucleic acids. In certain embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain variable region of a canine antibody, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain variable region of the canine antibody. In a related embodiment, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0034] In yet another embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 144, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 145, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 146. In a concomitant embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 147, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 148, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 149. The present invention further provides a pair of nucleic acids encoding the set of three heavy chain CDRs and a pair of nucleic acids encoding the set of three light chain CDRs. The present invention also provides a kit comprising these two pairs of nucleic acids. In certain embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain variable region of a canine antibody, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain variable region of the canine antibody. In a related embodiment, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0035] In yet another embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 152. In a concomitant embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 154, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 155. The present invention further provides a pair of nucleic acids encoding the set of three heavy chain CDRs and a pair of nucleic acids encoding the set of three light chain CDRs. The present invention also provides a kit comprising these two pairs of nucleic acids. In certain embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain variable region of a canine antibody, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain variable region of the canine antibody. In a related embodiment, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0036] In yet another embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 152. In a concomitant embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 235, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 155.

[0037] In yet another embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 248, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 249, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 250. In a concomitant embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 251, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 252, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 253.

[0038] The present invention further provides a pair of nucleic acids encoding a set of three heavy chain CDRs and a set of three light chain CDRs. The present invention also provides a kit comprising these two nucleic acid pairs. In certain embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain variable region of a canine antibody, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain variable region of the canine antibody. In related embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0039] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 62. Alternatively, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 65. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 68. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 71. In still other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 74. In still other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 77. In still other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 80. In still other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 244. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In certain embodiments, the antibody is a canine antibody.

[0040] The canine antibody or antigen-binding fragment thereof can also comprise a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 63. Alternatively, the canine antibody or antigen-binding fragment thereof can further comprise a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 66. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 69. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 72. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 75. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 78. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 81. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 234. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 245. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0041] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 62, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 114, HCDR2 comprising the amino acid sequence of SEQ ID NO: 115, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 116, and a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 63, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 117, LCDR2 comprising the amino acid sequence of SEQ ID NO: 118, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 119. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In yet other embodiments, the antibody is a canine antibody. In a specific embodiment, the canine antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:62 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:63.

[0042] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 65, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 120, HCDR2 comprising the amino acid sequence of SEQ ID NO: 121, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 122, and a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 66, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 123, LCDR2 comprising the amino acid sequence of SEQ ID NO: 124, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 125. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In yet other embodiments, the antibody is a canine antibody. In a specific embodiment, the canine antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:65 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:66.

[0043] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 68, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 126, HCDR2 comprising the amino acid sequence of SEQ ID NO: 127, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 128, and a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 69, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 129, LCDR2 comprising the amino acid sequence of SEQ ID NO: 130, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 131. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In yet other embodiments, the antibody is a canine antibody. In a specific embodiment, the canine antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:68 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:69.

[0044] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 71, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 132, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 133, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 134, and a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 72, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 135, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 136, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 137. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In yet other embodiments, the antibody is a canine antibody. In a specific embodiment, the canine antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:71 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:72.

[0045] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 74, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 138, HCDR2 comprising the amino acid sequence of SEQ ID NO: 139, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 140, and a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 75, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 141, LCDR2 comprising the amino acid sequence of SEQ ID NO: 142, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 143. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In yet other embodiments, the antibody is a canine antibody. In a specific embodiment, the canine antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:74 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:75.

[0046] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 77, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 144, HCDR2 comprising the amino acid sequence of SEQ ID NO: 145, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 146, and a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 78, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 147, LCDR2 comprising the amino acid sequence of SEQ ID NO: 148, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 149. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In yet other embodiments, the antibody is a canine antibody. In a specific embodiment, the canine antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:77 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:78.

[0047] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 80, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 152, and a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 81, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, LCDR2 comprising the amino acid sequence of SEQ ID NO: 154, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 155. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In yet other embodiments, the antibody is a canine antibody. In a specific embodiment, the canine antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:80 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:81.

[0048] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 80, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 152, and a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 234, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, LCDR2 comprising the amino acid sequence of SEQ ID NO: 235, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 155. In certain embodiments, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In yet other embodiments, the antibody is a canine antibody.

[0049] In certain embodiments of the canine antibody or antigen-binding fragment thereof comprising the aforementioned heavy chain variable region and light chain variable region, when bound to cIL-13, the canine antibody or antigen-binding fragment thereof (i) binds to an epitope contained in the amino acid sequence of SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:239, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:98, or any combination thereof, or (ii) has an IC50 of less than 50 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells, or (iii) both bind to an epitope contained in the amino acid sequence of SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:239, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:98, or any combination thereof and has an IC50 of less than 50 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells. In a more specific embodiment, the canine antibody or antigen-binding fragment thereof when bound to cIL-13 binds to an epitope contained in the amino acid sequence of SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:239, or any combination thereof. In an even more particular embodiment, the canine antibody or antigen-binding fragment thereof has an amino acid residue at the following amino acid residue position: 27(S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 In a related embodiment, the antibody or antigen-binding fragment thereof binds to one or more serine residues of cIL-13 at the following amino acid residue position: 27 (S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 ) of cIL-13. In other embodiments, the antibody or antigen-binding fragment thereof binds to two or more serine residues of cIL-13 at the following amino acid residue position: 27 (S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58In yet other embodiments, the antibody or antigen-binding fragment thereof binds to three or more serine residues of cIL-13 at the following amino acid residue position: 27 (S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 In yet other embodiments, the antibody or antigen-binding fragment thereof binds to four or more serine residues of cIL-13 at the following amino acid residue position: 27 (S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 In yet another embodiment, the antibody binds to five or more serine residues of cIL-13 at the following amino acid residue position: 27 (S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 ) binds to all six serine residues of cIL-13.

[0050] In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to cIL-13 and has an IC50 of less than 25 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells. In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to cIL-13 and has an IC50 of 0.5 nM to 50 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells. In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to cIL-13 and has an IC50 of 2 nM to 25 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells. In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to cIL-13 and has an IC50 of 4 nM to 25 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells.

[0051] In an even more specific embodiment, the canine antibody or antigen-binding fragment thereof binds to an epitope of cIL-13 contained in the amino acid sequence of SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 239, or any combination thereof, and is located at the following amino acid residue position: 27(S) of the amino acid sequence of SEQ ID NO: 2. 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 ) binds to 1, 2, 3, 4, 5, or 6 serine residues of cIL-13 and has an IC50 of less than 50 nM, less than 25 nM, and / or 2 and / or 4 nM to 25 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells.

[0052] The present invention further provides a nucleic acid that individually encodes one of the heavy chain variable regions of the present invention and a nucleic acid that individually encodes one of the corresponding light chain variable regions of the present invention. The present invention also provides a pair of nucleic acids: a nucleic acid that encodes a heavy chain variable region of a canine antibody or antigen-binding fragment thereof, and a nucleic acid that encodes the corresponding light chain variable region of the canine antibody or antigen-binding fragment thereof. The present invention also provides a kit comprising this pair of two nucleic acids. In certain embodiments, the nucleic acid encoding the heavy chain variable region encodes the heavy chain of the canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the light chain variable region encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0053] In a specific embodiment, one nucleic acid encodes a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:80, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO:150, an HCDR2 comprising the amino acid sequence of SEQ ID NO:151, and an HCDR3 comprising the amino acid sequence of SEQ ID NO:152, and another nucleic acid encodes a corresponding light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:234, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO:153, an LCDR2 comprising the amino acid sequence of SEQ ID NO:235, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:155. The present invention further provides a pair of nucleic acids encoding an antibody heavy chain variable region and a nucleic acid encoding the corresponding light chain variable region of that antibody. The present invention also provides a kit comprising this pair of nucleic acids. In certain embodiments, the nucleic acid encoding the heavy chain variable region encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the light chain variable region encodes the light chain of a canine antibody or antigen-binding fragment thereof.

[0054] In a more specific embodiment, the nucleic acid encodes a heavy chain variable region of a canine antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO: 80, and in a related embodiment, the nucleic acid encodes a corresponding light chain variable region comprising the amino acid sequence of SEQ ID NO: 234. The present invention further provides a pair of nucleic acids, one encoding a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 80 and the other encoding a light chain variable region comprising the amino acid sequence of SEQ ID NO: 234. The present invention also provides a kit comprising this pair of nucleic acids. In certain embodiments, the nucleic acid encoding the heavy chain variable region encodes the heavy chain of the canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the light chain variable region encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0055] The canine antibodies of the invention comprise a canine hinge region. In certain embodiments, the hinge region comprises an amino acid sequence that has at least 90%, 95%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 109. In other embodiments, the hinge region comprises an amino acid sequence that has at least 90%, 95%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 110. In yet other embodiments, the hinge region comprises an amino acid sequence that has at least 90%, 95%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 111. In yet other embodiments, the hinge region comprises an amino acid sequence that has at least 90%, 95%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 112. In yet other embodiments, the hinge region comprises an amino acid sequence that has at least 90%, 95%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 113. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In certain embodiments, the antibody is a canine antibody.

[0056] The canine antibodies of the present invention comprise a canine fragment crystallizable region (cFc). In certain embodiments, the cFc comprises an amino acid sequence that comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 99. In other embodiments, the cFc comprises an amino acid sequence that comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 100. In yet other embodiments, the cFc comprises an amino acid sequence that comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 101. In yet other embodiments, the cFc comprises an amino acid sequence that comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 102. In still other embodiments, the cFc comprises an amino acid sequence comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 103. In still other embodiments, the cFc comprises an amino acid sequence comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 104. In still other embodiments, the cFc comprises an amino acid sequence comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 105. In still other embodiments, the cFc comprises an amino acid sequence comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 106. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In specific embodiments, the antibody is a canine antibody.

[0057] In still other embodiments, the cFc comprises an amino acid sequence comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 255. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0058] In yet other preferred embodiments, the cFc comprises an amino acid sequence comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 256. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0059] In still other embodiments, the cFc comprises an amino acid sequence comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 257. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0060] In still other embodiments, the cFc comprises an amino acid sequence comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 258. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0061] In certain embodiments, the canine antibody comprises a heavy chain comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 82, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 144, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 145, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 146, and a light chain comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 83, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 147, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 148, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 149. In other embodiments, the canine antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 82 and a light chain comprising the amino acid sequence of SEQ ID NO: 83. The present invention further provides antigen-binding fragments of these canine antibodies.

[0062] In certain embodiments, the canine antibody comprises a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 82, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 144, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 145, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 146, wherein the amino acid sequence comprises at least a tyrosine residue at amino acid residue position 252 and an aspartic acid residue at amino acid residue position 256, numbered according to the EU index as in Kabat. The invention further provides antigen-binding fragments of these canine antibodies.

[0063] In certain embodiments, the canine antibody comprises a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 246, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 248, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 249, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 250, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 247, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 251, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 252, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 253. In other embodiments, the canine antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 246 and a light chain comprising the amino acid sequence of SEQ ID NO: 247. The present invention further provides antigen-binding fragments of these canine antibodies.

[0064] In certain embodiments, the canine antibody comprises a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 246, wherein the amino acid sequence comprises at least a tyrosine residue at amino acid residue position 252 and an aspartic acid residue at amino acid residue position 256, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 248, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 249, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 250, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 247, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 251, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 252, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 253, numbered according to the EU index as in Kabat. The invention further provides antigen-binding fragments of these canine antibodies.

[0065] In other embodiments, the canine antibody comprises a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 87, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 114, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 115, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 116, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 88, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 117, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 118, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 119. In more specific embodiments, the canine antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 87 and a light chain comprising the amino acid sequence of SEQ ID NO: 88. The present invention further provides antigen-binding fragments of these canine antibodies.

[0066] In certain embodiments, the canine antibody comprises a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 87, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 114, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 115, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 116, wherein the amino acid sequence comprises at least a tyrosine residue at amino acid residue position 252 and an aspartic acid residue at amino acid residue position 256, numbered according to the EU index as in Kabat. The invention further provides antigen-binding fragments of these canine antibodies.

[0067] In yet other embodiments, the canine antibody comprises a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 84, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 152, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 86, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 154, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 155. In more specific embodiments, the canine antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 84 and a light chain comprising the amino acid sequence of SEQ ID NO: 86. The present invention further provides antigen-binding fragments of these canine antibodies.

[0068] In yet other embodiments, the canine antibody comprises a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 84, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 152, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 85, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 235, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 155. In more particular embodiments of this type, the canine antibody or antigen-binding fragment thereof, when bound to cIL-13, binds to an epitope contained in the amino acid sequence of SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 239, or any combination thereof. In certain embodiments, the canine antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 84 and a light chain comprising the amino acid sequence of SEQ ID NO: 85. The present invention further provides antigen-binding fragments of these canine antibodies.

[0069] In some preferred embodiments, the canine antibody provided herein comprises a heavy chain comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 152; and a light chain comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 235, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 155, and comprises a cFc having an amino acid sequence comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to any one of the amino acid sequences selected from the group consisting of SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, and SEQ ID NO: 258. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In specific embodiments, the antibody is a canine antibody.

[0070] In yet other embodiments, the canine antibody comprises a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 240, while still retaining a tyrosine residue at amino acid residue position 252 and an aspartic acid residue at amino acid residue position 256, and while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 152, numbered according to the EU index as in Kabat; and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 86, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 154, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 155. In a more particular embodiment, the canine antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 240 and a light chain comprising the amino acid sequence of SEQ ID NO: 86. The present invention further provides antigen-binding fragments of these canine antibodies.

[0071] In yet other embodiments, the canine antibody comprises a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 240, while still retaining a tyrosine residue at amino acid residue position 252 and an aspartic acid residue at amino acid residue position 256, and while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 152, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 85, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 235, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 155. In more particular embodiments of this type, the canine antibody or antigen-binding fragment thereof, when bound to cIL-13, binds to an epitope contained in the amino acid sequence of SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 239, or any combination thereof. In particular embodiments, the canine antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 240 and a light chain comprising the amino acid sequence of SEQ ID NO: 85. The present invention further provides antigen-binding fragments of these canine antibodies.

[0072] A canine antibody comprising a heavy chain comprising at least 90%, 95%, 98%, 99% or 100%, preferably 100%, sequence identity to the amino acid sequence of SEQ ID NO: 240, while still retaining a tyrosine residue (Y) at amino acid residue position 252 and an aspartic acid (D) residue at amino acid residue position 256, numbered according to the EU index as in Kabat, and while also retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 152, and a light chain comprising at least 90%, 95%, 98%, 99% or 100%, preferably 100%, sequence identity to the amino acid sequence of SEQ ID NO: 85, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 235, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 155, has been found to have an improved half-life.

[0073] The cFc of the heavy chain of the canine antibody or antigen-binding fragment thereof of the present invention can further comprise one or more amino acid residue substitutions, where the amino acid residue positions are numbered according to the EU index as in Kabat. In certain embodiments, the single amino acid residue substitution is at amino acid residue position 252. In particular embodiments of this type, the substitution at amino acid residue position 252 is with a tyrosine residue. In other embodiments, the single amino acid residue substitution is at amino acid residue position 254. In particular embodiments of this type, the substitution at amino acid residue position 254 is with a threonine residue. In yet other embodiments, the single amino acid residue substitution is at amino acid residue position 256. In particular embodiments of this type, the substitution at amino acid residue position 256 is with an aspartic acid residue or a glutamic acid residue. In yet other embodiments, the single amino acid residue substitution is at amino acid residue position 308. In particular embodiments of this type, the substitution at amino acid residue position 308 is with a proline residue. In yet other embodiments, the amino acid residue substitution is at amino acid residue position 433. In particular embodiments of this type, the substitution at amino acid residue position 433 is with a lysine residue or a leucine residue. In yet other embodiments, the amino acid residue substitution is at amino acid residue position 434. In particular embodiments of this type, the substitution at amino acid residue position 434 is with a phenylalanine residue, a histidine residue, or a tyrosine residue. In more particular embodiments of this type, the substitution at amino acid residue position 434 is with a histidine residue. In yet other embodiments, the amino acid residue substitution is at amino acid residue position 436. In particular embodiments of this type, the substitution at amino acid residue position 436 is with a threonine residue.

[0074] In some embodiments, a canine IL13 antibody according to the invention is provided, the antibody comprising a modified Fc region having an amino acid sequence of at least 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 101 or SEQ ID NO: 102, wherein the amino acid sequence comprises at least one substitution at amino acid residue position 434 as numbered according to the EU index as in Kabat, wherein the substitution is with a histidine (H) residue.

[0075] In some embodiments, a canine IL13 antibody is provided, comprising a modified Fc region having an amino acid sequence with at least 95%, preferably 100%, sequence identity to SEQ ID NO: 257 or SEQ ID NO: 258, wherein a substitution with a histidine residue at amino acid residue position 434 as numbered according to the EU index as in Kabat is retained, and the canine IL13 antibody comprises a heavy chain comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 152, and a light chain comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 235, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 155.

[0076] In a related embodiment, canine IL13 antibodies comprising such modified Fc regions, preferably comprising said HCDRs and / or LCDRs, have been found to have an extended half-life compared to canine IL13 antibodies having an unmodified cFc.

[0077] The cFc of the heavy chain of the canine antibody or antigen-binding fragment thereof of the present invention can further comprise two or more amino acid residue substitutions, where the amino acid residue positions are numbered according to the EU index as in Kabat. In certain embodiments, one amino acid residue substitution is at amino acid residue position 252 and the second amino acid residue substitution is at amino acid residue position 256. In particular embodiments of this type, the substitution at amino acid residue position 252 is with a tyrosine residue and the substitution at amino acid residue position 256 is with an aspartic acid residue. As described and provided herein, substitution at amino acid residue position 252 with a tyrosine residue and substitution at amino acid residue position 256 with an aspartic acid residue have been found to preferably extend the antibody half-life of any one or more of the canine antibodies disclosed herein. For example, substitution at amino acid residue position 252 with a tyrosine residue and substitution at amino acid residue position 256 with an aspartic acid residue can extend the half-life of the canine IL13 antibody provided herein.

[0078] In a preferred embodiment, the substitution at amino acid residue position 252 with a tyrosine residue and the substitution at amino acid residue position 256 with an aspartic acid residue are in the amino acid sequence of a canine IL13 antibody having a modified Fc region represented by heavy chain SEQ ID NO: 240 and light chain SEQ ID NO: 85.

[0079] In one non-limiting example, a canine IL13 antibody having a modified Fc region had a prolonged antibody half-life in vivo compared to a canine IL13 antibody having an unmodified Fc region.

[0080] In a further non-limiting example (see Example 8), canine IL13 antibodies with modified Fc regions had extended antibody half-life in vivo compared to canine IL13 antibodies with unmodified Fc regions. In one non-limiting example, a canine IL13 antibody having a modified Fc region comprising a heavy chain having the amino acid sequence of SEQ ID NO: 255 or SEQ ID NO: 256, wherein the heavy chain comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 152, and a light chain comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 235, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 155, was found to exhibit extended antibody half-life in vivo compared to a canine IL13 antibody having an unmodified Fc region comprising a heavy chain having the amino acid sequence of SEQ ID NO: 101 or SEQ ID NO: 102, wherein the heavy chain comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 152, and a light chain comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 235, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 155.

[0081] Thus, in some embodiments, a canine IL13 antibody is provided, comprising a modified Fc region having an amino acid sequence comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to SEQ ID NO: 255 or SEQ ID NO: 256, wherein a substitution comprising a tyrosine residue at amino acid residue position 252 and an aspartic acid residue at amino acid residue position 256 is retained, and comprising a heavy chain comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 152, and a light chain comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 235, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 155.

[0082] In other embodiments, one amino acid residue substitution is at amino acid residue position 256 and a second amino acid residue substitution is at amino acid residue position 434. In particular embodiments of this type, the substitution at amino acid residue position 256 is with an aspartic acid residue and the substitution at amino acid residue position 434 is with a tyrosine residue. In alternative embodiments of this type, the substitution at amino acid residue position 256 is with an aspartic acid residue and the substitution at amino acid residue position 434 is with a histidine residue. In yet other embodiments, one amino acid residue substitution is at amino acid residue position 308 and a second amino acid residue substitution is at amino acid residue position 434. In particular embodiments of this type, the substitution at amino acid residue position 308 is with a proline residue and the substitution at amino acid residue position 434 is with a tyrosine residue. In alternative embodiments of this type, the substitution at amino acid residue position 308 is with a proline residue and the substitution at amino acid residue position 434 is with a histidine residue. In still other embodiments, one amino acid residue substitution is at amino acid residue position 433 and a second amino acid residue substitution is at amino acid residue position 434. In particular embodiments of this type, the substitution at amino acid residue position 433 is with a lysine residue and the substitution at amino acid residue position 434 is with a tyrosine residue. In alternative embodiments of this type, the substitution at amino acid residue position 433 is with a lysine residue and the substitution at amino acid residue position 434 is with a histidine residue. In yet other embodiments of this type, the substitution at amino acid residue position 433 is with a lysine residue and the substitution at amino acid residue position 434 is with a phenylalanine residue. In yet other embodiments of this type, the substitution at amino acid residue position 433 is with a leucine residue and the substitution at amino acid residue position 434 is with a phenylalanine residue. In yet other embodiments of this type, the substitution at amino acid residue position 433 is with a leucine residue and the substitution at amino acid residue position 434 is with a tyrosine residue.In yet another embodiment of this type, the substitution at amino acid residue position 433 is with a leucine residue and the substitution at amino acid residue position 434 is with a histidine residue. In yet other embodiments, one amino acid residue substitution is at amino acid residue position 434 and a second amino acid residue substitution is at amino acid residue position 436. In a particular embodiment of this type, the substitution is at amino acid residue position 434 with a tyrosine residue and the substitution at amino acid residue position 436 is with a threonine residue. In another embodiment of this type, the substitution at amino acid residue position 434 is with a phenylalanine residue and the substitution at amino acid residue position 436 is with a threonine residue. In an alternative embodiment of this type, the substitution at amino acid residue position 434 is with a histidine residue and the substitution at amino acid residue position 436 is with a threonine residue.

[0083] The cFc of the heavy chain of the canine antibody or antigen-binding fragment thereof of the present invention can further comprise three or more amino acid residue substitutions, where the amino acid residue positions are numbered according to the EU index as in Kabat. In certain embodiments, one amino acid residue substitution is at amino acid residue position 252, a second amino acid residue substitution is at amino acid residue position 254, and a third amino acid residue substitution is at amino acid residue position 256. In particular embodiments of this type, the substitution at amino acid residue position 252 is with a tyrosine residue, the substitution at amino acid residue position 254 is with a threonine residue, and the substitution at amino acid residue position 256 is with a glutamic acid residue. In other embodiments, one amino acid residue substitution is at amino acid residue position 256, the second amino acid residue substitution is at amino acid residue position 308, and the third amino acid residue substitution is at amino acid residue position 434. In particular embodiments of this type, the substitution at amino acid residue position 256 is with an aspartic acid residue, the substitution at amino acid residue position 308 is with a proline residue, and the substitution at amino acid residue position 434 is with a tyrosine residue. In yet other embodiments, one amino acid residue substitution is at amino acid residue position 433, a second amino acid residue substitution is at amino acid residue position 434, and a third amino acid residue substitution is at amino acid residue position 436. In particular embodiments of this type, the substitution at amino acid residue position 433 is with a lysine residue, the substitution at amino acid residue position 434 is with a phenylalanine residue, and the substitution at amino acid residue position 436 is with a threonine residue. In another embodiment of this type, the substitution at amino acid residue position 433 is with a lysine residue, the substitution at amino acid residue position 434 is with a tyrosine residue, and the substitution at amino acid residue position 436 is with a threonine residue. In yet another embodiment of this type, the substitution at amino acid residue position 433 is with a lysine residue, the substitution at amino acid residue position 434 is with a histidine residue, and the substitution at amino acid residue position 436 is with a threonine residue.In yet another embodiment of this type, the substitution at amino acid residue position 433 is with a leucine residue, the substitution at amino acid residue position 434 is with a phenylalanine residue, and the substitution at amino acid residue position 436 is with a threonine residue. In yet another embodiment of this type, the substitution at amino acid residue position 433 is with a leucine residue, the substitution at amino acid residue position 434 is with a tyrosine residue, and the substitution at amino acid residue position 436 is with a threonine residue. In yet another embodiment of this type, the substitution at amino acid residue position 433 is with a leucine residue, the substitution at amino acid residue position 434 is with a histidine residue, and the substitution at amino acid residue position 436 is with a threonine residue.

[0084] In certain embodiments of the canine antibody or antigen-binding fragment thereof comprising the aforementioned heavy and light chains, when bound to cIL-13, the canine antibody or antigen-binding fragment thereof (i) binds to an epitope contained in the amino acid sequence of SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:239, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:98, or any combination thereof, or (ii) has an IC50 of less than 50 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells, or (iii) both bind to an epitope contained in the amino acid sequence of SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:239, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:98, or any combination thereof and has an IC50 of less than 50 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells. In a more specific embodiment, the canine antibody or antigen-binding fragment thereof when bound to cIL-13 binds to an epitope contained in the amino acid sequence of SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:239, or any combination thereof. In an even more particular embodiment, the canine antibody or antigen-binding fragment thereof has an amino acid residue at the following amino acid residue position: 27(S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S58 In a related embodiment, the antibody or antigen-binding fragment thereof binds to one or more serine residues of cIL-13 at the following amino acid residue position: 27 (S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 ) of cIL-13. In other embodiments, the antibody or antigen-binding fragment thereof binds to two or more serine residues of cIL-13 at the following amino acid residue position: 27 (S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 In yet other embodiments, the antibody or antigen-binding fragment thereof binds to three or more serine residues of cIL-13 at the following amino acid residue position: 27 (S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 In yet other embodiments, the antibody or antigen-binding fragment thereof binds to four or more serine residues of cIL-13 at the following amino acid residue position: 27 (S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 In yet another embodiment, the antibody binds to five or more serine residues of cIL-13 at the following amino acid residue position: 27 (S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 ) binds to all six serine residues of cIL-13.

[0085] In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to cIL-13 and has an IC50 of less than 25 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells. In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to cIL-13 and has an IC50 of 0.5 nM to 50 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells. In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to cIL-13 and has an IC50 of 2 nM to 25 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells. In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to cIL-13 and has an IC50 of 4 nM to 25 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells.

[0086] In an even more specific embodiment, the canine antibody or antigen-binding fragment thereof binds to an epitope of cIL-13 contained in the amino acid sequence of SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 239, or any combination thereof, and is located at the following amino acid residue position: 27(S) of the amino acid sequence of SEQ ID NO: 2. 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 ) binds to 1, 2, 3, 4, 5, or 6 serine residues of cIL-13 and has an IC50 of less than 50 nM, less than 25 nM, and / or 2 and / or 4 nM to 25 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells.

[0087] The present invention further provides a nucleic acid that individually encodes one of the heavy chains of the antibody of the present invention, and a nucleic acid that individually encodes one of the corresponding light chains of the antibody of the present invention or an antigen-binding fragment thereof. The present invention further provides a pair of a nucleic acid that encodes the heavy chain or an antigen-binding fragment thereof of the antibody of the present invention, and a nucleic acid that encodes the corresponding light chain or an antigen-binding fragment thereof of the antibody of the present invention. The present invention also provides a kit comprising these two nucleic acid pairs.

[0088] In certain related embodiments, a nucleic acid encodes a heavy chain of a canine antibody or antigen-binding fragment thereof, wherein the heavy chain comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 87, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 114, HCDR2 comprising the amino acid sequence of SEQ ID NO: 115, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 116, and another nucleic acid encodes the corresponding light chain of that antibody, wherein the heavy chain comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 88, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 117, LCDR2 comprising the amino acid sequence of SEQ ID NO: 118, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 119. The present invention further provides a pair of nucleic acids, one encoding the heavy chain of the canine antibody and the other encoding the corresponding light chain of the canine antibody. The present invention also provides a kit comprising this pair of nucleic acids.

[0089] In another embodiment, a nucleic acid encodes the heavy chain of a canine antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO: 87, and another nucleic acid encodes the corresponding light chain of that antibody comprising the amino acid sequence of SEQ ID NO: 88. The invention further provides a pair of nucleic acids, one encoding a heavy chain comprising the amino acid sequence of SEQ ID NO: 87 and the other encoding the corresponding light chain comprising the amino acid sequence of SEQ ID NO: 88. The invention also provides a kit comprising this pair of nucleic acids.

[0090] In yet another embodiment, a nucleic acid encodes a heavy chain of a canine antibody or antigen-binding fragment thereof that comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 82, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 144, HCDR2 comprising the amino acid sequence of SEQ ID NO: 145, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 146, and another nucleic acid encodes the corresponding light chain of that antibody that comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 83, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 147, LCDR2 comprising the amino acid sequence of SEQ ID NO: 148, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 149. The present invention further provides a pair of nucleic acids, one encoding the heavy chain of the canine antibody and the other encoding the corresponding light chain of the canine antibody. The present invention also provides a kit comprising this pair of nucleic acids.

[0091] In yet another embodiment, the nucleic acid encodes a heavy chain or antigen-binding fragment thereof of a canine antibody comprising the amino acid sequence of SEQ ID NO: 82, and the corresponding light chain of that antibody comprising the amino acid sequence of SEQ ID NO: 83. The invention further provides a pair of nucleic acids, one encoding a heavy chain comprising the amino acid sequence of SEQ ID NO: 82 and the other encoding the corresponding light chain comprising the amino acid sequence of SEQ ID NO: 83. The invention also provides a kit comprising this pair of nucleic acids.

[0092] In a related specific embodiment, a nucleic acid encodes a heavy chain of a canine antibody or antigen-binding fragment thereof that comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 84, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 152, and another nucleic acid encodes the corresponding light chain of that antibody that comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 86, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 154, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 155. The present invention further provides a pair of nucleic acids, one encoding the heavy chain of the canine antibody and the other encoding the corresponding light chain of the canine antibody. The present invention also provides a kit comprising this pair of nucleic acids.

[0093] In a more specific embodiment, a nucleic acid encodes the heavy chain of a canine antibody comprising the amino acid sequence of SEQ ID NO: 84, and another nucleic acid encodes the corresponding light chain of that antibody comprising the amino acid sequence of SEQ ID NO: 86. The invention further provides a pair of nucleic acids, one encoding a heavy chain comprising the amino acid sequence of SEQ ID NO: 84 and the other encoding the corresponding light chain comprising the amino acid sequence of SEQ ID NO: 86. The invention also provides a kit comprising this pair of nucleic acids.

[0094] In yet another specific embodiment, a nucleic acid encodes a heavy chain of a canine antibody or antigen-binding fragment thereof that comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 84, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 152, and another nucleic acid encodes the corresponding light chain of that antibody that comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 85, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, LCDR2 comprising the amino acid sequence of SEQ ID NO: 235, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 155. The present invention further provides a pair of nucleic acids, one encoding the heavy chain of the canine antibody and the other encoding the corresponding light chain of the canine antibody. The present invention also provides a kit comprising this pair of nucleic acids.

[0095] In a more specific embodiment, a nucleic acid encodes the heavy chain of a canine antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO: 84, and another nucleic acid encodes the corresponding light chain of that antibody comprising the amino acid sequence of SEQ ID NO: 85. The present invention further provides a pair of nucleic acids, one encoding a heavy chain comprising the amino acid sequence of SEQ ID NO: 84 and the other encoding the corresponding light chain comprising the amino acid sequence of SEQ ID NO: 85. The present invention also provides a kit comprising this pair of nucleic acids.

[0096] In a related specific embodiment, a nucleic acid encodes a heavy chain of a canine antibody or antigen-binding fragment thereof comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 240, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 152, while still retaining a tyrosine residue at amino acid residue position 252 and an aspartic acid residue at amino acid residue position 256 according to the EU index as in Kabat; and another nucleic acid encodes the corresponding light chain of that antibody comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 86, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 154, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 155. The present invention further provides a pair of nucleic acids, one encoding a heavy chain of a canine antibody and the other encoding the corresponding light chain of the canine antibody. The present invention also provides a kit comprising the pair of these two nucleic acids.

[0097] In a more specific embodiment, a nucleic acid encodes the heavy chain of a canine antibody comprising the amino acid sequence of SEQ ID NO: 240, and another nucleic acid encodes the corresponding light chain of that antibody comprising the amino acid sequence of SEQ ID NO: 86. The invention further provides a pair of nucleic acids, one encoding a heavy chain comprising the amino acid sequence of SEQ ID NO: 240 and the other encoding the corresponding light chain comprising the amino acid sequence of SEQ ID NO: 86. The invention also provides a kit comprising this pair of two nucleic acids.

[0098] In certain embodiments, a nucleic acid encodes a heavy chain of a canine antibody or antigen-binding fragment thereof comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 240, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 152, while still retaining a tyrosine residue at amino acid residue position 252 and an aspartic acid residue at amino acid residue position 256 according to the EU index as in Kabat; and another nucleic acid encodes the corresponding light chain of that antibody comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 85, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 235, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 155. The present invention further provides a pair of nucleic acids, one encoding a heavy chain of a canine antibody and the other encoding the corresponding light chain of the canine antibody. The present invention also provides a kit comprising the pair of these two nucleic acids.

[0099] In a more specific embodiment, a nucleic acid encodes a heavy chain of a canine antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO: 240, and another nucleic acid encodes the corresponding light chain of that antibody comprising the amino acid sequence of SEQ ID NO: 85. The invention further provides a pair of nucleic acids, one encoding a heavy chain comprising the amino acid sequence of SEQ ID NO: 240 and the other encoding the corresponding light chain comprising the amino acid sequence of SEQ ID NO: 85. The invention also provides a kit comprising this pair of two nucleic acids.

[0100] In yet another specific embodiment, a nucleic acid encodes a heavy chain of a canine antibody or antigen-binding fragment thereof that comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 246, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 248, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 249, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 250, and another nucleic acid encodes the corresponding light chain of that antibody that comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 247, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 251, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 252, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 253. The present invention further provides a pair of nucleic acids, one encoding the heavy chain of the canine antibody and the other encoding the corresponding light chain of the canine antibody. The present invention also provides a kit comprising this pair of nucleic acids.

[0101] In yet another embodiment, the nucleic acid encodes a heavy chain or antigen-binding fragment thereof of a canine antibody comprising the amino acid sequence of SEQ ID NO: 246, and the corresponding light chain of that antibody comprising the amino acid sequence of SEQ ID NO: 247. The invention further provides a pair of nucleic acids, one encoding a heavy chain comprising the amino acid sequence of SEQ ID NO: 246 and the other encoding the corresponding light chain comprising the amino acid sequence of SEQ ID NO: 247. The invention also provides a kit comprising this pair of nucleic acids.

[0102] The present invention further provides that, when bound to cIL-13, the canine antibody or antigen-binding fragment thereof (i) binds to an epitope contained in the amino acid sequence of SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:239, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:98, or any combination thereof, or (ii) has an IC50 of less than 50 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells, or (iii) both bind to an epitope contained in the amino acid sequence of SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:239, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:98, or any combination thereof and has an IC50 of less than 50 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells. In a specific embodiment, the canine antibody or antigen-binding fragment thereof, when bound to cIL-13, binds to an epitope contained in the amino acid sequence of SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:239, or any combination thereof. In a more particular embodiment, the canine antibody or antigen-binding fragment thereof has an amino acid residue at the following amino acid residue position: 27 (S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 In a related embodiment, the antibody or antigen-binding fragment thereof binds to one or more serine residues of cIL-13 at the following amino acid residue position: 27 (S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 ) of cIL-13. In other embodiments, the antibody or antigen-binding fragment thereof binds to two or more serine residues of cIL-13 at the following amino acid residue position: 27 (S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58In yet other embodiments, the antibody or antigen-binding fragment thereof binds to three or more serine residues of cIL-13 at the following amino acid residue position: 27 (S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 In yet other embodiments, the antibody or antigen-binding fragment thereof binds to four or more serine residues of cIL-13 at the following amino acid residue position: 27 (S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 In yet another embodiment, the antibody binds to five or more serine residues of cIL-13 at the following amino acid residue position: 27 (S 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 ) binds to all six serine residues of cIL-13.

[0103] In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to cIL-13 and has an IC50 of less than 25 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells. In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to cIL-13 and has an IC50 of 0.5 nM to 50 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells. In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to cIL-13 and has an IC50 of 2 nM to 25 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells. In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to cIL-13 and has an IC50 of 4 nM to 25 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells.

[0104] In an even more specific embodiment, the canine antibody or antigen-binding fragment thereof binds to an epitope of cIL-13 contained in the amino acid sequence of SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 239, or any combination thereof, and is located at the following amino acid residue position: 27(S) of the amino acid sequence of SEQ ID NO: 2. 27 ), 32(S 32 ), 36(S 36 ), 50(S 50 ), 55(S 55 ), and 58(S 58 ) binds to 1, 2, 3, 4, 5, or 6 serine residues of cIL-13 and has an IC50 of less than 50 nM, less than 25 nM, and / or 2 and / or 4 nM to 25 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells.

[0105] The present invention further provides expression vectors that contain and express one or more of the nucleic acids of the invention. In specific embodiments, the expression vector contains and expresses a nucleic acid encoding the heavy chain of a canine antibody of the invention. In other embodiments, the expression vector contains and expresses a nucleic acid encoding the light chain of that canine antibody. In more specific embodiments, the expression vector contains a pair of nucleic acids, one of which contains a nucleotide sequence encoding the light chain of a specific canine antibody, and the other of which contains a nucleotide sequence encoding the heavy chain of that specific canine antibody. In related embodiments, the present invention provides a pair of expression vectors, one of which contains one of a pair of nucleic acids that contains a nucleotide sequence encoding the heavy chain of a specific canine antibody, and the other of which contains the other of the pair of nucleic acids that contains a nucleotide sequence encoding the light chain of that specific canine antibody. The present invention also provides host cells that contain one or more expression vectors or one or more pairs of expression vectors of the present invention. The present invention further provides a pair of host cells, one of which contains one of a pair of expression vectors comprising one of a pair of nucleic acids comprising a nucleotide sequence encoding the heavy chain of a specific canine antibody, and the other of which contains the other of the pair of expression vectors comprising the other of the pair of nucleic acids comprising a nucleotide sequence encoding the light chain of the specific canine antibody.

[0106] The present invention also provides pharmaceutical compositions and / or methods for treating atopic dermatitis using a pharmaceutical composition comprising a canine antibody and / or an antigen-binding fragment of the antibody and a pharmaceutically acceptable carrier or diluent. In certain embodiments, the pharmaceutical composition comprises a canine antibody comprising a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 80, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 152, and a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 81, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 154, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 155. In a more specific embodiment, the pharmaceutical composition comprises a canine antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 80 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 81. In yet other embodiments, the pharmaceutical composition comprises a canine antibody comprising a heavy chain variable region comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 80, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 152, and a light chain variable region comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 234, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 235, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 155. In certain embodiments, the pharmaceutical composition comprises a canine antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:80 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:234.

[0107] In a specific embodiment, the pharmaceutical composition comprises a canine antibody comprising a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 84, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 152, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 86, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 154, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 155. In a more specific embodiment, the pharmaceutical composition comprises a canine antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 84 and a light chain comprising the amino acid sequence of SEQ ID NO: 86. In yet another embodiment, the pharmaceutical composition comprises a canine antibody comprising a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 84, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 152, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 85, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 235, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 155. In a specific embodiment, the pharmaceutical composition comprises a canine antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 84 and a light chain comprising the amino acid sequence of SEQ ID NO: 85.

[0108] The invention further provides a pharmaceutical composition and / or method of treating atopic dermatitis with a pharmaceutical composition comprising a canine antibody comprising: a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 240, while still retaining a tyrosine residue at amino acid residue 252 and an aspartic acid residue at amino acid residue 256 according to the EU index as in Kabat, and also retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 152; and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 86, and still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 154, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 155. In a more specific embodiment, the pharmaceutical composition comprises a canine antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 240 and a light chain comprising the amino acid sequence of SEQ ID NO: 86. In yet other embodiments, the pharmaceutical composition comprises a canine antibody comprising a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 240, while still retaining a tyrosine residue at amino acid residue position 252 and an aspartic acid residue at amino acid residue position 256, and while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 152, numbered according to the EU index as in Kabat; and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 85, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 235, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 155. In certain embodiments, the pharmaceutical composition comprises a canine antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:240 and a light chain comprising the amino acid sequence of SEQ ID NO:85.

[0109] Further provided are pharmaceutical compositions comprising an expression vector containing both a nucleic acid encoding the heavy chain of a canine antibody of the invention and a nucleic acid encoding the light chain of the canine antibody, and a pharmaceutically acceptable carrier or diluent. In other embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable carrier or diluent and two expression vectors, one containing a nucleic acid encoding the heavy chain of a canine antibody of the invention and the other containing a nucleic acid encoding the light chain of the canine antibody. Such pharmaceutical compositions are capable of expressing canine antibodies and / or antigen-binding fragments of the antibodies of the invention in vivo. Any of the pharmaceutical compositions of the invention can further comprise a canine antibody or caninized antibody that binds to canine interleukin-4 (cIL-4), a canine antibody or caninized antibody that binds to canine interleukin-4 receptor alpha (cIL-4Rα), a canine antibody or caninized antibody that binds to canine interleukin-31 receptor alpha (cIL-31RA), or a canine antibody or caninized antibody that binds to canine interleukin-31 (cIL-31), or any combination thereof. In yet another embodiment, a pharmaceutical composition is provided for use in a method for reducing skin inflammation associated with atopic dermatitis in dogs, the method comprising administering to a dog in need thereof a therapeutically effective amount of a canine antibody that binds to cIL-13 or an antigen-binding fragment thereof of the present invention, or an expression vector of the present invention, or a pair of expression vectors of the present invention, or any combination thereof, together with a pharmaceutically acceptable carrier or diluent, wherein the method is used to treat atopic dermatitis. In yet a further embodiment, the present invention provides a pharmaceutical composition for use in the treatment of atopic dermatitis, preferably canine atopic dermatitis, the treatment comprising administering to a dog in need thereof a canine antibody that binds to cIL-13 or an antigen-binding fragment thereof of the present invention, or an expression vector of the present invention, or a pair of expression vectors of the present invention, or any combination thereof, together with a pharmaceutically acceptable carrier or diluent. The present invention further provides a pharmaceutical composition for use in the treatment of atopic dermatitis, the treatment comprising administering to an animal subject with atopic dermatitis one or more of the pharmaceutical compositions provided herein. Preferably, the animal subject is a dog.

[0110] The present invention further provides a method for treating atopic dermatitis, comprising administering one of the aforementioned pharmaceutical compositions to an animal subject with atopic dermatitis. In certain embodiments, the animal subject is a dog. The present invention also provides a method for helping to block skin inflammation associated with atopic dermatitis, comprising administering a therapeutically effective amount of a pharmaceutical composition of the present invention to an animal subject in need thereof. In certain embodiments, the animal subject is a dog.

[0111] In certain embodiments, a method for helping to block skin inflammation associated with atopic dermatitis is provided, comprising administering a therapeutically effective amount of a pharmaceutical composition of the present invention to a subject in need thereof. In certain embodiments, the animal subject is a dog. In other embodiments, a method for helping to block skin inflammation, pruritus, or both skin inflammation and pruritus associated with atopic dermatitis comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention comprising a canine antibody of the present invention that binds to cIL-13 and blocks the binding of cIL-13 to IL-13 receptor alpha 1 (cIL-13Ralpha1), together with a canine or caninized antibody that binds to canine interleukin-4 (cIL-4), a canine or caninized antibody that binds to canine interleukin-4 receptor alpha (cIL-4Rα), a canine or caninized antibody that binds to canine interleukin-31 receptor alpha (cIL-31RA), a canine or caninized antibody that binds to canine interleukin-31 (cIL-31), or any combination thereof. In certain embodiments, the animal subject is a dog.

[0112] In addition, the present invention provides a method for producing a canine antibody or antigen-binding fragment thereof that binds to canine IL-13. In certain embodiments, the method comprises culturing host cells comprising one or more expression vectors encoding and expressing the light chain of a canine antibody of the present invention or the heavy chain of that canine antibody, or both the light chain of a canine antibody of the present invention and the heavy chain of that canine antibody, in a culture medium (or culture media) under conditions for expression of the nucleic acid(s), thereby producing a polypeptide comprising the light chain of a canine antibody of the present invention, the heavy chain of that canine antibody, or both the light chain of a canine antibody of the present invention and the heavy chain of that canine antibody. The polypeptide is then recovered from the host cells or the culture medium (or culture media). In certain embodiments, a polypeptide comprising the light chain of a canine antibody of the present invention and a polypeptide comprising the heavy chain of that canine antibody are combined with each other under conditions favoring the formation of a canine antibody.

[0113] The present invention further provides single-chain Fv (scFv) antibodies that bind to cIL-13 and comprise a set of six complementarity determining regions, three of which are heavy chain CDRs (HCDR1, HCDR2, and HCDR3) and three of which are light chain CDRs (LCDR1, LCDR2, and LCDR3). In particular embodiments of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 114, HCDR2 comprises the amino acid sequence of SEQ ID NO: 115, HCDR3 comprises the amino acid sequence of SEQ ID NO: 116, LCDR1 comprises the amino acid sequence of SEQ ID NO: 117, LCDR2 comprises the amino acid sequence of SEQ ID NO: 118, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 119.

[0114] In an alternative embodiment of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 120, HCDR2 comprises the amino acid sequence of SEQ ID NO: 121, HCDR3 comprises the amino acid sequence of SEQ ID NO: 122, LCDR1 comprises the amino acid sequence of SEQ ID NO: 123, LCDR2 comprises the amino acid sequence of SEQ ID NO: 124, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 125.

[0115] In other embodiments of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 126, HCDR2 comprises the amino acid sequence of SEQ ID NO: 127, HCDR3 comprises the amino acid sequence of SEQ ID NO: 128, LCDR1 comprises the amino acid sequence of SEQ ID NO: 129, LCDR2 comprises the amino acid sequence of SEQ ID NO: 130, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 131.

[0116] In yet another embodiment of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 132, HCDR2 comprises the amino acid sequence of SEQ ID NO: 133, HCDR3 comprises the amino acid sequence of SEQ ID NO: 134, LCDR1 comprises the amino acid sequence of SEQ ID NO: 135, LCDR2 comprises the amino acid sequence of SEQ ID NO: 136, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 137.

[0117] In yet another embodiment of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 138, HCDR2 comprises the amino acid sequence of SEQ ID NO: 139, HCDR3 comprises the amino acid sequence of SEQ ID NO: 140, LCDR1 comprises the amino acid sequence of SEQ ID NO: 141, LCDR2 comprises the amino acid sequence of SEQ ID NO: 142, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 143.

[0118] In yet another embodiment of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 144, HCDR2 comprises the amino acid sequence of SEQ ID NO: 145, HCDR3 comprises the amino acid sequence of SEQ ID NO: 146, LCDR1 comprises the amino acid sequence of SEQ ID NO: 147, LCDR2 comprises the amino acid sequence of SEQ ID NO: 148, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 149.

[0119] In yet another embodiment of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 150, HCDR2 comprises the amino acid sequence of SEQ ID NO: 151, HCDR3 comprises the amino acid sequence of SEQ ID NO: 152, LCDR1 comprises the amino acid sequence of SEQ ID NO: 153, LCDR2 comprises the amino acid sequence of SEQ ID NO: 154, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 155.

[0120] In yet another embodiment of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 150, HCDR2 comprises the amino acid sequence of SEQ ID NO: 151, HCDR3 comprises the amino acid sequence of SEQ ID NO: 152, LCDR1 comprises the amino acid sequence of SEQ ID NO: 153, LCDR2 comprises the amino acid sequence of SEQ ID NO: 235, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 155.

[0121] In yet another embodiment of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 248, HCDR2 comprises the amino acid sequence of SEQ ID NO: 249, HCDR3 comprises the amino acid sequence of SEQ ID NO: 250, LCDR1 comprises the amino acid sequence of SEQ ID NO: 251, LCDR2 comprises the amino acid sequence of SEQ ID NO: 252, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 253.

[0122] The present invention further provides single chain Fv (scFv) antibodies that bind to cIL-13 and comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 62, and a light chain variable region comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 63. In other scFV embodiments, the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 65, and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 66. In yet other embodiments of the scFV, the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 68 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 69.

[0123] In yet other embodiments of the scFV, the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 71 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 72. In yet other embodiments of the scFV, the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 74 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 75. In yet other embodiments of the scFV, the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 77, and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 78.

[0124] In yet other embodiments of the scFV, the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 80, and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 81. In yet other embodiments of the scFV, the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 80, and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 234.

[0125] In yet other embodiments of the scFV, the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 244 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 245.

[0126] The present invention further provides a single-chain Fv (scFv) antibody that binds to cIL-13 and comprises the amino acid sequence of SEQ ID NO: 61. In yet other embodiments, the scFV comprises the amino acid sequence of SEQ ID NO: 64. In yet other embodiments, the scFV comprises the amino acid sequence of SEQ ID NO: 67. In yet other embodiments, the scFV comprises the amino acid sequence of SEQ ID NO: 70. In yet other embodiments, the scFV comprises the amino acid sequence of SEQ ID NO: 73. In yet other embodiments, the scFV comprises the amino acid sequence of SEQ ID NO: 76. In yet other embodiments, the scFV comprises the amino acid sequence of SEQ ID NO: 79. In yet other embodiments, the scFV comprises the amino acid sequence of SEQ ID NO: 243. In yet other embodiments, the scFV comprises the amino acid sequence of SEQ ID NO: 254.

[0127] The present invention further provides individual nucleic acids encoding each of the scFv of the invention that bind cIL-13.

[0128] In another aspect, the present invention further relates to canine antibodies and scFvs that bind to canine interleukin-4 (cIL-4). The present invention also relates to antigen-binding fragments of the canine antibodies that bind to cIL-4. The present invention further provides these canine antibodies and antigen-binding fragments thereof that bind to cIL-4 and block the binding of cIL-4 to the canine type II heterodimeric interleukin-4 receptor (type II cIL-4R), more specifically to the canine interleukin-4 receptor alpha (cIL-4Rα). In certain embodiments, the canine antibodies or antigen-binding fragments thereof bind to cIL-4 and block the binding of cIL-4 to type II cIL-4R, more specifically to the cIL-4Rα.

[0129] Thus, the present invention provides canine antibodies, including isolated canine antibodies, that bind to cIL-4 and have heavy and light chains that together comprise a set of six complementarity determining regions (CDRs), three of which are heavy chain CDRs: CDR heavy chain 1 (HCDR1), CDR heavy chain 2 (HCDR2), and CDR heavy chain 3 (HCDR3), and three of which are light chain CDRs: CDR light chain 1 (LCDR1), CDR light chain 2 (LCDR2), and CDR light chain 3 (LCDR3), canine heavy chain variable regions of the heavy chains of the canine antibodies, canine antibody light chain variable regions, antigen-binding fragments of the heavy and light chains of the canine antibodies, and related scFvs.

[0130] The present invention further provides nucleic acids, including isolated nucleic acids, encoding any of a set of three heavy chain CDRs (HCDR1, HCDR2, and HCDR3), the heavy chain of a canine antibody and / or the canine heavy chain variable region of a heavy chain of a canine antibody or antigen-binding fragment thereof, any of a set of three light chain CDRs (LCDR1, LCDR2, and LCDR3), the light chain variable region of a canine antibody and / or the light chain of a canine antibody or antigen-binding fragment thereof of the present invention, and related scFvs.

[0131] A canine antibody that binds to cIL-4 comprises a heavy chain and a light chain that together comprise a set of six CDRs, three of which are heavy chain CDRs and three of which are light chain CDRs. In certain embodiments, the canine antibody or antigen-binding fragment thereof comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 156, HCDR2 comprising the amino acid sequence of SEQ ID NO: 157, HCDR3 comprising the amino acid sequence of SEQ ID NO: 158, LCDR1 comprising the amino acid sequence of SEQ ID NO: 159, LCDR2 comprising the amino acid sequence of SEQ ID NO: 160, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 161. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In certain embodiments, the antibody is a canine antibody.

[0132] In alternative embodiments of the canine antibody or antigen-binding fragment thereof, HCDR1 comprises the amino acid sequence of SEQ ID NO: 162, HCDR2 comprises the amino acid sequence of SEQ ID NO: 163, HCDR3 comprises the amino acid sequence of SEQ ID NO: 164, LCDR1 comprises the amino acid sequence of SEQ ID NO: 165, LCDR2 comprises the amino acid sequence of SEQ ID NO: 166, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 167. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0133] In related embodiments of the canine antibody or antigen-binding fragment thereof, HCDR1 comprises the amino acid sequence of SEQ ID NO: 162, HCDR2 comprises the amino acid sequence of SEQ ID NO: 237, HCDR3 comprises the amino acid sequence of SEQ ID NO: 164, LCDR1 comprises the amino acid sequence of SEQ ID NO: 165, LCDR2 comprises the amino acid sequence of SEQ ID NO: 166, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 167. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0134] In other embodiments of the canine antibody or antigen-binding fragment thereof, HCDR1 comprises the amino acid sequence of SEQ ID NO: 168, HCDR2 comprises the amino acid sequence of SEQ ID NO: 169, HCDR3 comprises the amino acid sequence of SEQ ID NO: 170, LCDR1 comprises the amino acid sequence of SEQ ID NO: 171, LCDR2 comprises the amino acid sequence of SEQ ID NO: 172, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 173. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0135] In yet other embodiments of the canine antibody or antigen-binding fragment thereof, HCDR1 comprises the amino acid sequence of SEQ ID NO: 174, HCDR2 comprises the amino acid sequence of SEQ ID NO: 175, HCDR3 comprises the amino acid sequence of SEQ ID NO: 176, LCDR1 comprises the amino acid sequence of SEQ ID NO: 177, LCDR2 comprises the amino acid sequence of SEQ ID NO: 178, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 179. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0136] In yet other embodiments of the canine antibody or antigen-binding fragment thereof, HCDR1 comprises the amino acid sequence of SEQ ID NO: 180, HCDR2 comprises the amino acid sequence of SEQ ID NO: 181, HCDR3 comprises the amino acid sequence of SEQ ID NO: 182, LCDR1 comprises the amino acid sequence of SEQ ID NO: 183, LCDR2 comprises the amino acid sequence of SEQ ID NO: 184, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 185. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0137] In yet other embodiments of the canine antibody or antigen-binding fragment thereof, HCDR1 comprises the amino acid sequence of SEQ ID NO: 186, HCDR2 comprises the amino acid sequence of SEQ ID NO: 187, HCDR3 comprises the amino acid sequence of SEQ ID NO: 188, LCDR1 comprises the amino acid sequence of SEQ ID NO: 189, LCDR2 comprises the amino acid sequence of SEQ ID NO: 190, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 191. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0138] In yet other embodiments of the canine antibody or antigen-binding fragment thereof, HCDR1 comprises the amino acid sequence of SEQ ID NO: 192, HCDR2 comprises the amino acid sequence of SEQ ID NO: 193, HCDR3 comprises the amino acid sequence of SEQ ID NO: 194, LCDR1 comprises the amino acid sequence of SEQ ID NO: 195, LCDR2 comprises the amino acid sequence of SEQ ID NO: 196, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 197. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0139] In yet other embodiments of the canine antibody or antigen-binding fragment thereof, HCDR1 comprises the amino acid sequence of SEQ ID NO: 198, HCDR2 comprises the amino acid sequence of SEQ ID NO: 199, HCDR3 comprises the amino acid sequence of SEQ ID NO: 200, LCDR1 comprises the amino acid sequence of SEQ ID NO: 201, LCDR2 comprises the amino acid sequence of SEQ ID NO: 202, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 203. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0140] In yet other embodiments of the canine antibody or antigen-binding fragment thereof, HCDR1 comprises the amino acid sequence of SEQ ID NO: 204, HCDR2 comprises the amino acid sequence of SEQ ID NO: 205, HCDR3 comprises the amino acid sequence of SEQ ID NO: 206, LCDR1 comprises the amino acid sequence of SEQ ID NO: 207, LCDR2 comprises the amino acid sequence of SEQ ID NO: 208, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 209. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0141] In yet other embodiments of the canine antibody or antigen-binding fragment thereof, HCDR1 comprises the amino acid sequence of SEQ ID NO: 210, HCDR2 comprises the amino acid sequence of SEQ ID NO: 211, HCDR3 comprises the amino acid sequence of SEQ ID NO: 212, LCDR1 comprises the amino acid sequence of SEQ ID NO: 213, LCDR2 comprises the amino acid sequence of SEQ ID NO: 214, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 215. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0142] In yet other embodiments of the canine antibody or antigen-binding fragment thereof, HCDR1 comprises the amino acid sequence of SEQ ID NO: 216, HCDR2 comprises the amino acid sequence of SEQ ID NO: 217, HCDR3 comprises the amino acid sequence of SEQ ID NO: 218, LCDR1 comprises the amino acid sequence of SEQ ID NO: 219, LCDR2 comprises the amino acid sequence of SEQ ID NO: 220, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 221. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0143] In yet other embodiments of the canine antibody or antigen-binding fragment thereof, HCDR1 comprises the amino acid sequence of SEQ ID NO: 222, HCDR2 comprises the amino acid sequence of SEQ ID NO: 223, HCDR3 comprises the amino acid sequence of SEQ ID NO: 224, LCDR1 comprises the amino acid sequence of SEQ ID NO: 225, LCDR2 comprises the amino acid sequence of SEQ ID NO: 226, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 227. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0144] In yet other embodiments of the canine antibody or antigen-binding fragment thereof, HCDR1 comprises the amino acid sequence of SEQ ID NO: 228, HCDR2 comprises the amino acid sequence of SEQ ID NO: 229, HCDR3 comprises the amino acid sequence of SEQ ID NO: 230, LCDR1 comprises the amino acid sequence of SEQ ID NO: 231, LCDR2 comprises the amino acid sequence of SEQ ID NO: 232, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 233. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0145] In certain embodiments of a canine antibody or antigen-binding fragment thereof comprising the aforementioned set of six CDRs (including when the CDRs are in the presently disclosed heavy and light chain variable regions and heavy and light chains), when bound to cIL-4, the canine antibody or antigen-binding fragment thereof (i) binds to an epitope contained in the amino acid sequence of SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:238, or any combination thereof, or (ii) has an IC50 of less than 40 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells, or (iii) both bind to an epitope contained in the amino acid sequence of SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:238, or any combination thereof, and has an IC50 of less than 40 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. In more specific embodiments, the canine antibody or antigen-binding fragment thereof, when bound to cIL-4, binds to an epitope contained in the amino acid sequence of SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 238, or any combination thereof. In certain embodiments, the canine antibody or antigen-binding fragment thereof binds to an epitope contained in the amino acid sequence of SEQ ID NO: 1 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In other embodiments, the canine antibody or antigen-binding fragment thereof binds to one or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In yet other embodiments, the canine antibody or antigen-binding fragment thereof binds to two or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to three or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to four or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to five or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In certain embodiments, the canine antibody or antigen-binding fragment thereof binds to six or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 74(S 74 ), and 79(T79 In another specific embodiment, the canine antibody or antigen-binding fragment thereof binds to 3 to 5 amino acid residues of cIL-4 at the following amino acid residue position: 12 (K 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 ) binds to 3 to 5 or more amino acid residues of cIL-4.

[0146] The present invention further provides a canine antibody or antigen-binding fragment thereof that binds to cIL-4 and has an IC50 of less than 40 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. The present invention further provides a canine antibody or antigen-binding fragment thereof that binds to cIL-4 and has an IC50 of less than 20 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. In certain embodiments, the canine antibody or antigen-binding fragment thereof binds to cIL-4 and has an IC50 of less than 10 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. In yet other embodiments, the canine antibody or antigen-binding fragment thereof binds to cIL-4 and has an IC50 of 0.5 nM to 50 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. In yet other embodiments, the canine antibody or antigen-binding fragment thereof binds to cIL-4 and has an IC50 of 2 nM to 25 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. In yet other embodiments, the canine antibody, or antigen-binding fragment thereof, binds cIL-4 and has an IC50 of 4 nM to 20 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells.

[0147] In still further specific embodiments, the canine antibody or antigen-binding fragment thereof binds to an epitope of cIL-4 contained in the amino acid sequence of SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, and SEQ ID NO:238, or any combination thereof, and binds to an epitope of cIL-4 contained in the amino acid sequence of SEQ ID NO:1 at the following amino acid residue position: 12 (K 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 ) binds to one, two, three, four, five or more amino acid residues of cIL-4 and has an IC50 of less than 50 nM, less than 25 nM and / or 2 nM and / or 4 nM to 20 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells.

[0148] The present invention further provides a nucleic acid comprising a nucleotide sequence encoding a specific set of three heavy chain CDRs of the present invention, and a nucleic acid comprising a nucleotide sequence encoding a specific set of three light chain CDRs of the present invention. In a specific embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 156, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 157, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 158. In a related embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 159, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 160, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 161. The present invention also provides a pair of a nucleic acid encoding the set of three heavy chain CDRs and a nucleic acid encoding the set of three light chain CDRs. The present invention also provides a kit comprising these two nucleic acid pairs. In certain embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain variable region of a canine antibody, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain variable region of the canine antibody. In related embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0149] In another embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 162, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 163, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 164. In a concomitant embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 165, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 166, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 167. The present invention further provides a pair of nucleic acids encoding the set of three heavy chain CDRs and a pair of nucleic acids encoding the set of three light chain CDRs. The present invention also provides a kit comprising these two pairs of nucleic acids. In certain embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain variable region of a canine antibody, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain variable region of the canine antibody. In a related embodiment, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0150] In yet another embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 162, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 237, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 164. In a concomitant embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 165, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 166, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 167. The present invention further provides a pair of nucleic acids encoding the set of three heavy chain CDRs and a pair of nucleic acids encoding the set of three light chain CDRs. The present invention also provides a kit comprising these two pairs of nucleic acids. In certain embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain variable region of a canine antibody, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain variable region of the canine antibody. In a related embodiment, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0151] In yet another embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 168, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 169, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 170. In a concomitant embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 171, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 172, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 173. The present invention further provides a pair of nucleic acids encoding the set of three heavy chain CDRs and a pair of nucleic acids encoding the set of three light chain CDRs. The present invention also provides a kit comprising these two pairs of nucleic acids. In certain embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain variable region of a canine antibody, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain variable region of the canine antibody. In a related embodiment, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0152] In yet another embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 174, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 175, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 176. In a related embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 177, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 178, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 179. The present invention further provides a pair of nucleic acids encoding the set of three heavy chain CDRs and a pair of nucleic acids encoding the set of three light chain CDRs. The present invention also provides kits comprising these two pairs of nucleic acids. In certain embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0153] In yet another embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 180, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 181, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 182. In a concomitant embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 183, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 184, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 185. The present invention further provides a pair of nucleic acids encoding the set of three heavy chain CDRs and a pair of nucleic acids encoding the set of three light chain CDRs. The present invention also provides a kit comprising these two pairs of nucleic acids. In certain embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain variable region of a canine antibody, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain variable region of the canine antibody. In a related embodiment, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0154] In yet another embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 186, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 187, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 188. In a concomitant embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 189, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 190, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 191. The present invention further provides a pair of nucleic acids encoding the set of three heavy chain CDRs and a pair of nucleic acids encoding the set of three light chain CDRs. The present invention also provides a kit comprising these two pairs of nucleic acids. In certain embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain variable region of a canine antibody, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain variable region of the canine antibody. In a related embodiment, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0155] In yet another embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 192, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 193, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 194. In a concomitant embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 195, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 196, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 197. The present invention further provides a pair of nucleic acids encoding the set of three heavy chain CDRs and a pair of nucleic acids encoding the set of three light chain CDRs. The present invention also provides a kit comprising these two pairs of nucleic acids. In certain embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain variable region of a canine antibody, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain variable region of the canine antibody. In a related embodiment, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0156] In yet another embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 198, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 199, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 200. In a concomitant embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 201, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 202, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 203. The present invention further provides a pair of nucleic acids encoding the set of three heavy chain CDRs and a pair of nucleic acids encoding the set of three light chain CDRs. The present invention also provides a kit comprising these two pairs of nucleic acids. In certain embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain variable region of a canine antibody, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain variable region of the canine antibody. In a related embodiment, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0157] In yet another embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 204, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 205, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 206. In a related embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 207, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 208, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 209. The present invention further provides a pair of nucleic acids encoding the set of three heavy chain CDRs and a pair of nucleic acids encoding the set of three light chain CDRs. The present invention also provides a kit comprising these two pairs of nucleic acids. In certain embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain variable region of a canine antibody, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain variable region of the canine antibody. In a related embodiment, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0158] In yet another embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 210, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 211, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 212. In a concomitant embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 213, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 214, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 215. The present invention further provides a pair of nucleic acids encoding the set of three heavy chain CDRs and a pair of nucleic acids encoding the set of three light chain CDRs. The present invention also provides a kit comprising these two pairs of nucleic acids. In certain embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain variable region of a canine antibody, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain variable region of the canine antibody. In a related embodiment, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0159] In yet another embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 216, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 217, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 218. In a concomitant embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 219, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 220, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 221. The present invention further provides a pair of nucleic acids encoding the set of three heavy chain CDRs and a pair of nucleic acids encoding the set of three light chain CDRs. The present invention also provides a kit comprising these two pairs of nucleic acids. In certain embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain variable region of a canine antibody, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain variable region of the canine antibody. In a related embodiment, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0160] In yet another embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 222, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 223, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 224. In a concomitant embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 225, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 226, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 227. The present invention further provides a pair of nucleic acids encoding the set of three heavy chain CDRs and a pair of nucleic acids encoding the set of three light chain CDRs. The present invention also provides a kit comprising these two pairs of nucleic acids. In certain embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain variable region of a canine antibody, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain variable region of the canine antibody. In a related embodiment, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0161] In yet another embodiment, the nucleic acid encoding the set of three heavy chain CDRs comprises a nucleotide sequence encoding HCDR1 comprising the amino acid sequence of SEQ ID NO: 228, a nucleotide sequence encoding HCDR2 comprising the amino acid sequence of SEQ ID NO: 229, and a nucleotide sequence encoding HCDR3 comprising the amino acid sequence of SEQ ID NO: 230. In a concomitant embodiment, the nucleic acid encoding the set of three light chain CDRs comprises a nucleotide sequence encoding LCDR1 comprising the amino acid sequence of SEQ ID NO: 231, a nucleotide sequence encoding LCDR2 comprising the amino acid sequence of SEQ ID NO: 232, and a nucleotide sequence encoding LCDR3 comprising the amino acid sequence of SEQ ID NO: 233. The present invention further provides a pair of nucleic acids encoding the set of three heavy chain CDRs and a pair of nucleic acids encoding the set of three light chain CDRs. The present invention also provides a kit comprising these two pairs of nucleic acids. In certain embodiments, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain variable region of a canine antibody, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain variable region of the canine antibody. In a related embodiment, the nucleic acid encoding the set of three heavy chain CDRs encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the set of three light chain CDRs encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0162] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 4. Alternatively, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 7. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 10. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 236. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 13. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 16. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 19. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 22. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 25. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 28.

[0163] In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 31. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 34. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 37. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 40.

[0164] In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In particular embodiments, the antibody is a canine antibody.

[0165] The canine antibody or antigen-binding fragment thereof can also comprise a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 5. Alternatively, the canine antibody or antigen-binding fragment thereof can further comprise a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 8. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 11. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 14. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:17.

[0166] In still other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 20. In still other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 23. In still other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 26. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In specific embodiments, the antibody is a canine antibody.

[0167] In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 29. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 32. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 35. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 38. In yet other embodiments, the canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:41.

[0168] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:4, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO:156, HCDR2 comprising the amino acid sequence of SEQ ID NO:157, and HCDR3 comprising the amino acid sequence of SEQ ID NO:158, and a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:5, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO:159, LCDR2 comprising the amino acid sequence of SEQ ID NO:160, and LCDR3 comprising the amino acid sequence of SEQ ID NO:161. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In yet other embodiments, the antibody is a canine antibody. In a specific embodiment, the canine antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:5.

[0169] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:7, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO:162, HCDR2 comprising the amino acid sequence of SEQ ID NO:163, and HCDR3 comprising the amino acid sequence of SEQ ID NO:164, and a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:8, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO:165, LCDR2 comprising the amino acid sequence of SEQ ID NO:166, and LCDR3 comprising the amino acid sequence of SEQ ID NO:167. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In yet other embodiments, the antibody is a canine antibody. In a specific embodiment, the canine antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8.

[0170] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 236, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 162, HCDR2 comprising the amino acid sequence of SEQ ID NO: 237, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 164, and a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 8, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 165, LCDR2 comprising the amino acid sequence of SEQ ID NO: 166, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 167. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In yet other embodiments, the antibody is a canine antibody. In a specific embodiment, the canine antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:236 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8.

[0171] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 10, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 168, HCDR2 comprising the amino acid sequence of SEQ ID NO: 169, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 170, and a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 11, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 171, LCDR2 comprising the amino acid sequence of SEQ ID NO: 172, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 173. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In yet other embodiments, the antibody is a canine antibody. In a specific embodiment, the canine antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:10 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:11.

[0172] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 13, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 174, HCDR2 comprising the amino acid sequence of SEQ ID NO: 175, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 176, and a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 14, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 177, LCDR2 comprising the amino acid sequence of SEQ ID NO: 178, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 179. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In yet other embodiments, the antibody is a canine antibody. In a specific embodiment, the canine antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:13 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:14.

[0173] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 16, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 180, HCDR2 comprising the amino acid sequence of SEQ ID NO: 181, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 182, and a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 17, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 183, LCDR2 comprising the amino acid sequence of SEQ ID NO: 184, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 185. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In yet other embodiments, the antibody is a canine antibody. In a specific embodiment, the canine antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:16 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:17.

[0174] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 19, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 186, HCDR2 comprising the amino acid sequence of SEQ ID NO: 187, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 188, and a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 20, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 189, LCDR2 comprising the amino acid sequence of SEQ ID NO: 190, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 191. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In yet other embodiments, the antibody is a canine antibody. In a specific embodiment, the canine antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:19 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:20.

[0175] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 22, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 192, HCDR2 comprising the amino acid sequence of SEQ ID NO: 193, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 194, and a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 23, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 195, LCDR2 comprising the amino acid sequence of SEQ ID NO: 196, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 197. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In yet other embodiments, the antibody is a canine antibody. In a specific embodiment, the canine antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:22 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:23.

[0176] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 25, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 198, HCDR2 comprising the amino acid sequence of SEQ ID NO: 199, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 200, and a light chain variable region comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 26, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 201, LCDR2 comprising the amino acid sequence of SEQ ID NO: 202, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 203. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In yet other embodiments, the antibody is a canine antibody. In a specific embodiment, the canine antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:25 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:26.

[0177] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 28, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 204, HCDR2 comprising the amino acid sequence of SEQ ID NO: 205, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 206, and a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 29, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 207, LCDR2 comprising the amino acid sequence of SEQ ID NO: 208, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 209. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In yet other embodiments, the antibody is a canine antibody. In a specific embodiment, the canine antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:28 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:29.

[0178] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 31, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 210, HCDR2 comprising the amino acid sequence of SEQ ID NO: 211, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 212, and a light chain variable region comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 32, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 213, LCDR2 comprising the amino acid sequence of SEQ ID NO: 214, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 215. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In yet other embodiments, the antibody is a canine antibody. In a specific embodiment, the canine antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:31 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:32.

[0179] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 34, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 216, HCDR2 comprising the amino acid sequence of SEQ ID NO: 217, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 218, and a light chain variable region comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 35, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 219, LCDR2 comprising the amino acid sequence of SEQ ID NO: 220, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 221. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In yet other embodiments, the antibody is a canine antibody. In a specific embodiment, the canine antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:34 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:35.

[0180] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 37, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 222, HCDR2 comprising the amino acid sequence of SEQ ID NO: 223, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 224, and a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 38, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 225, LCDR2 comprising the amino acid sequence of SEQ ID NO: 226, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 227. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In yet other embodiments, the antibody is a canine antibody. In a specific embodiment, the canine antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:37 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:38.

[0181] The canine antibody or antigen-binding fragment thereof can further comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 40, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 228, HCDR2 comprising the amino acid sequence of SEQ ID NO: 229, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 230, and a light chain variable region comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 41, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 231, LCDR2 comprising the amino acid sequence of SEQ ID NO: 232, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 233. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In yet other embodiments, the antibody is a canine antibody. In a specific embodiment, the canine antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:40 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:41.

[0182] In certain embodiments of the canine antibody or antigen-binding fragment thereof comprising the aforementioned heavy chain variable region and light chain variable region, when bound to cIL-4, the canine antibody or antigen-binding fragment thereof (i) binds to an epitope contained in the amino acid sequence of SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:238, or any combination thereof, or (ii) has an IC50 of less than 40 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells, or (iii) both bind to an epitope contained in the amino acid sequence of SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:238, or any combination thereof and has an IC50 of less than 40 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. In more specific embodiments, the canine antibody or antigen-binding fragment thereof when bound to cIL-4 binds to an epitope contained in the amino acid sequence of SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:238, or any combination thereof. In certain embodiments, the canine antibody or antigen-binding fragment thereof has an amino acid sequence identical to that of the canine antibody or antigen-binding fragment thereof at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In other embodiments, the canine antibody or antigen-binding fragment thereof binds to one or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 74(S 74 ), 79(T79 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In yet other embodiments, the canine antibody or antigen-binding fragment thereof binds to two or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to three or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to four or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 20(R 20 ), 23(S 23 ), 28(T 28), 37(K 37 ), 39(T 39 ), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to five or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In certain embodiments, the canine antibody or antigen-binding fragment thereof binds to six or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 74(S 74 ), and 79(T 79 In another specific embodiment, the canine antibody or antigen-binding fragment thereof binds to 3 to 5 amino acid residues of cIL-4 at the following amino acid residue position: 12 (K 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96) binds to 3 to 5 or more amino acid residues of cIL-4.

[0183] The present invention further provides a canine antibody or antigen-binding fragment thereof that binds to cIL-4 and has an IC50 of less than 40 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. The present invention further provides a canine antibody or antigen-binding fragment thereof that binds to cIL-4 and has an IC50 of less than 20 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. In certain embodiments, the canine antibody or antigen-binding fragment thereof binds to cIL-4 and has an IC50 of less than 10 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. In yet other embodiments, the canine antibody or antigen-binding fragment thereof binds to cIL-4 and has an IC50 of 0.5 nM to 50 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. In yet other embodiments, the canine antibody or antigen-binding fragment thereof binds to cIL-4 and has an IC50 of 2 nM to 25 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. In yet other embodiments, the canine antibody, or antigen-binding fragment thereof, binds cIL-4 and has an IC50 of 4 nM to 20 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells.

[0184] In still further specific embodiments, the canine antibody or antigen-binding fragment thereof binds to an epitope of cIL-4 contained in the amino acid sequence of SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, and SEQ ID NO:238, or any combination thereof, and binds to an epitope of cIL-4 contained in the amino acid sequence of SEQ ID NO:1 at the following amino acid residue position: 12 (K 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96) binds to one, two, three, four, five or more amino acid residues of cIL-4 and has an IC50 of less than 50 nM, less than 25 nM and / or 2 nM and / or 4 nM to 20 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells.

[0185] The present invention further provides a nucleic acid that individually encodes one of the heavy chain variable regions of the present invention and a nucleic acid that individually encodes one of the corresponding light chain variable regions of the present invention. The present invention also provides a pair of nucleic acids: a nucleic acid that encodes a heavy chain variable region of a canine antibody or antigen-binding fragment thereof, and a nucleic acid that encodes the corresponding light chain variable region of the canine antibody or antigen-binding fragment thereof. The present invention also provides a kit comprising this pair of two nucleic acids. In certain embodiments, the nucleic acid encoding the heavy chain variable region encodes the heavy chain of the canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the light chain variable region encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0186] In a specific embodiment, one nucleic acid encodes a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 25, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 198, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 199, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 200, and another nucleic acid encodes a corresponding light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 26, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 201, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 202, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 203. The present invention further provides a pair of nucleic acids encoding an antibody heavy chain variable region and a nucleic acid encoding the corresponding light chain variable region of that antibody. The present invention also provides a kit comprising this pair of nucleic acids. In certain embodiments, the nucleic acid encoding the heavy chain variable region encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the light chain variable region encodes the light chain of a canine antibody or antigen-binding fragment thereof.

[0187] In a more specific embodiment, the nucleic acid encodes a heavy chain variable region of a canine antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO: 25, and in a related embodiment, the nucleic acid encodes a corresponding light chain variable region comprising the amino acid sequence of SEQ ID NO: 26. The present invention further provides a pair of nucleic acids, one encoding a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 25 and the other encoding a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26. The present invention also provides a kit comprising this pair of nucleic acids. In certain embodiments, the nucleic acid encoding the heavy chain variable region encodes the heavy chain of the canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the light chain variable region encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0188] In another specific embodiment, one nucleic acid encodes a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 28, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 204, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 205, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 206, and another nucleic acid encodes a corresponding light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 29, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 207, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 208, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 209. The present invention further provides a pair of nucleic acids encoding an antibody heavy chain variable region and a nucleic acid encoding the corresponding light chain variable region of that antibody. The present invention also provides a kit comprising this pair of nucleic acids. In certain embodiments, the nucleic acid encoding the heavy chain variable region encodes the heavy chain of a canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the light chain variable region encodes the light chain of a canine antibody or antigen-binding fragment thereof.

[0189] In a more specific embodiment, the nucleic acid encodes a heavy chain variable region of a canine antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO: 28, and in a related embodiment, the nucleic acid encodes a corresponding light chain variable region comprising the amino acid sequence of SEQ ID NO: 29. The present invention further provides a pair of nucleic acids, one encoding a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 28 and the other encoding a light chain variable region comprising the amino acid sequence of SEQ ID NO: 29. The present invention also provides a kit comprising this pair of nucleic acids. In certain embodiments, the nucleic acid encoding the heavy chain variable region encodes the heavy chain of the canine antibody or antigen-binding fragment thereof, and the corresponding nucleic acid encoding the light chain variable region encodes the light chain of the canine antibody or antigen-binding fragment thereof.

[0190] The canine antibodies of the invention comprise a canine hinge region. In certain embodiments, the hinge region comprises an amino acid sequence that has at least 90%, 95%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 109. In other embodiments, the hinge region comprises an amino acid sequence that has at least 90%, 95%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 110. In yet other embodiments, the hinge region comprises an amino acid sequence that has at least 90%, 95%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 111. In yet other embodiments, the hinge region comprises an amino acid sequence that has at least 90%, 95%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 112. In yet other embodiments, the hinge region comprises an amino acid sequence that has at least 90%, 95%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 113. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody. In certain embodiments, the antibody is a canine antibody.

[0191] The canine antibodies of the present invention comprise a canine fragment crystallizable region (cFc). In certain embodiments, the cFc comprises an amino acid sequence that comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 99. In other embodiments, the cFc comprises an amino acid sequence that comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 100. In yet other embodiments, the cFc comprises an amino acid sequence that comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 101. In yet other embodiments, the cFc comprises an amino acid sequence that comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 102. In yet other embodiments, the cFc comprises an amino acid sequence comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 103. In yet other embodiments, the cFc comprises an amino acid sequence comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 104. In yet other embodiments, the cFc comprises an amino acid sequence comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 105. In yet other embodiments, the cFc comprises an amino acid sequence comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 106. In yet other embodiments, the cFc comprises an amino acid sequence comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 255. In still other embodiments, the cFc comprises an amino acid sequence comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 256. In still other embodiments, the cFc comprises an amino acid sequence comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 257. In still other embodiments, the cFc comprises an amino acid sequence comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 258. In certain embodiments of this type, the antibody is a canine antibody or an antigen-binding fragment of a canine antibody.In certain embodiments, the antibody is a canine antibody.

[0192] In certain embodiments, the canine antibody comprises a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 42, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 204, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 205, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 206, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 43, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 207, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 208, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 209. In other embodiments, the canine antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 42 and a light chain comprising the amino acid sequence of SEQ ID NO: 43. The present invention further provides antigen-binding fragments of these canine antibodies.

[0193] In a specific embodiment, the canine antibody comprises a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 44, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 198, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 199, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 200, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 45, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 201, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 202, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 203. In a more specific embodiment, the canine antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 44 and a light chain comprising the amino acid sequence of SEQ ID NO: 45. The present invention further provides antigen-binding fragments of these canine antibodies.

[0194] In other specific embodiments, the canine antibody comprises a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 241, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 198, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 199, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 200, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 45, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 201, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 202, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 203. In more specific embodiments, the canine antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 241 and a light chain comprising the amino acid sequence of SEQ ID NO: 45. The present invention further provides antigen-binding fragments of these canine antibodies.

[0195] In yet other embodiments, the canine antibody comprises a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 241, while still retaining a tyrosine residue at amino acid residue position 252 and an aspartic acid residue at amino acid residue position 256, and while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 198, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 199, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 200, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 45, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 201, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 202, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 203. In a more particular embodiment, the canine antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 241 and a light chain comprising the amino acid sequence of SEQ ID NO: 45. The present invention further provides antigen-binding fragments of these canine antibodies.

[0196] In yet other embodiments, the canine antibody comprises a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 46, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 192, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 193, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 194, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 47, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 195, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 196, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 197. In more specific embodiments, the canine antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 46 and a light chain comprising the amino acid sequence of SEQ ID NO: 47. The present invention further provides antigen-binding fragments of these canine antibodies.

[0197] In yet other embodiments, the canine antibody comprises a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 48, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 186, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 187, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 188, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 49, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 189, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 190, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 191. In more specific embodiments, the canine antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 48 and a light chain comprising the amino acid sequence of SEQ ID NO: 49. The present invention further provides antigen-binding fragments of these canine antibodies.

[0198] In yet other embodiments, the canine antibody comprises a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 50, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 180, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 181, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 182, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 51, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 183, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 184, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 185. In more specific embodiments, the canine antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 50 and a light chain comprising the amino acid sequence of SEQ ID NO: 51. The present invention further provides antigen-binding fragments of these canine antibodies.

[0199] In yet other embodiments, the canine antibody comprises a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 52, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 156, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 157, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 158, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 53, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 159, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 160, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 161. In more specific embodiments, the canine antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 53. The present invention further provides antigen-binding fragments of these canine antibodies.

[0200] In yet other embodiments, the canine antibody comprises a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 54, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 162, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 163, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 164, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 55, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 165, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 167. In more specific embodiments, the canine antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 54 and a light chain comprising the amino acid sequence of SEQ ID NO: 55. The present invention further provides antigen-binding fragments of these canine antibodies.

[0201] In yet other embodiments, the canine antibody comprises a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 56, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 162, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 237, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 164, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 55, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 165, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 166, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 167. In more specific embodiments, the canine antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 56 and a light chain comprising the amino acid sequence of SEQ ID NO: 55. The present invention further provides antigen-binding fragments of these canine antibodies.

[0202] In yet other embodiments, the canine antibody comprises a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 57, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 168, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 169, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 170, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 58, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 171, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 172, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 173. In more specific embodiments, the canine antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 57 and a light chain comprising the amino acid sequence of SEQ ID NO: 58. The present invention further provides antigen-binding fragments of these canine antibodies.

[0203] In yet other embodiments, the canine antibody comprises a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 59, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 174, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 175, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 176, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 60, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 177, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 178, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 179. In more specific embodiments, the canine antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 59 and a light chain comprising the amino acid sequence of SEQ ID NO: 60. The present invention further provides antigen-binding fragments of these canine antibodies.

[0204] The cFc of the heavy chain of the canine antibody or antigen-binding fragment thereof of the present invention can further comprise one or more amino acid residue substitutions, where the amino acid residue positions are numbered according to the EU index as in Kabat. In certain embodiments, the single amino acid residue substitution is at amino acid residue position 252. In particular embodiments of this type, the substitution at amino acid residue position 252 is with a tyrosine residue. In other embodiments, the single amino acid residue substitution is at amino acid residue position 254. In particular embodiments of this type, the substitution at amino acid residue position 254 is with a threonine residue. In yet other embodiments, the single amino acid residue substitution is at amino acid residue position 256. In particular embodiments of this type, the substitution at amino acid residue position 256 is with an aspartic acid residue or a glutamic acid residue. In yet other embodiments, the single amino acid residue substitution is at amino acid residue position 308. In particular embodiments of this type, the substitution at amino acid residue position 308 is with a proline residue. In yet other embodiments, the amino acid residue substitution is at amino acid residue position 433. In particular embodiments of this type, the substitution at amino acid residue position 433 is with a lysine residue or a leucine residue. In yet other embodiments, the amino acid residue substitution is at amino acid residue position 434. In particular embodiments of this type, the substitution at amino acid residue position 434 is with a phenylalanine residue, a histidine residue, or a tyrosine residue. In yet other embodiments, the amino acid residue substitution is at amino acid residue position 436.

[0205] In particular embodiments of this type, the substitution at amino acid residue position 436 is with a threonine residue.

[0206] The cFc of the heavy chain of the canine antibody or antigen-binding fragment thereof of the invention can further comprise two or more amino acid residue substitutions, where the amino acid residue positions are numbered according to the EU index as in Kabat. In certain embodiments, one amino acid residue substitution is at amino acid residue position 252 and a second amino acid residue substitution is at amino acid residue position 256. In particular embodiments of this type, the substitution at amino acid residue position 252 is with a tyrosine residue and the substitution at amino acid residue position 256 is with an aspartic acid residue. In other embodiments, one amino acid residue substitution is at amino acid residue position 256 and a second amino acid residue substitution is at amino acid residue position 434. In particular embodiments of this type, the substitution at amino acid residue position 256 is with an aspartic acid residue and the substitution at amino acid residue position 434 is with a tyrosine residue. In an alternative embodiment of this type, the substitution at amino acid residue position 256 is with an aspartic acid residue and the substitution at amino acid residue position 434 is with a histidine residue. In still other embodiments, one amino acid residue substitution is at amino acid residue position 308 and a second amino acid residue substitution is at amino acid residue position 434. In particular embodiments of this type, the substitution at amino acid residue position 308 is with a proline residue and the substitution at amino acid residue position 434 is with a tyrosine residue. In alternative embodiments of this type, the substitution at amino acid residue position 308 is with a proline residue and the substitution at amino acid residue position 434 is with a histidine residue. In still other embodiments, one amino acid residue substitution is at amino acid residue position 433 and a second amino acid residue substitution is at amino acid residue position 434. In particular embodiments of this type, the substitution at amino acid residue position 433 is with a lysine residue and the substitution at amino acid residue position 434 is with a tyrosine residue. In alternative embodiments of this type, the substitution at amino acid residue position 433 is with a lysine residue and the substitution at amino acid residue position 434 is with a histidine residue.In yet another embodiment of this type, the substitution at amino acid residue position 433 is with a lysine residue and the substitution at amino acid residue position 434 is with a phenylalanine residue. In yet another embodiment of this type, the substitution at amino acid residue position 433 is with a leucine residue and the substitution at amino acid residue position 434 is with a phenylalanine residue. In yet another embodiment of this type, the substitution at amino acid residue position 433 is with a leucine residue and the substitution at amino acid residue position 434 is with a tyrosine residue. In yet another embodiment of this type, the substitution at amino acid residue position 433 is with a leucine residue and the substitution at amino acid residue position 434 is with a histidine residue. In yet other embodiments, one amino acid residue substitution is at amino acid residue position 434 and a second amino acid residue substitution is at amino acid residue position 436. In a particular embodiment of this type, the substitution is at amino acid residue 434 with a tyrosine residue and the substitution at amino acid residue position 436 is a threonine residue. In another embodiment of this type, the substitution at amino acid residue position 434 is with a phenylalanine residue and the substitution at amino acid residue position 436 is with a threonine residue. In an alternative embodiment of this type, the substitution at amino acid residue position 434 is with a histidine residue and the substitution at amino acid residue position 436 is with a threonine residue.

[0207] The cFc of the heavy chain of the canine antibody or antigen-binding fragment thereof of the present invention can further comprise three or more amino acid residue substitutions, where the amino acid residue positions are numbered according to the EU index as in Kabat. In certain embodiments, one amino acid residue substitution is at amino acid residue position 252, a second amino acid residue substitution is at amino acid residue position 254, and a third amino acid residue substitution is at amino acid residue position 256. In particular embodiments of this type, the substitution at amino acid residue position 252 is with a tyrosine residue, the substitution at amino acid residue position 254 is with a threonine residue, and the substitution at amino acid residue position 256 is with a glutamic acid residue. In other embodiments, one amino acid residue substitution is at amino acid residue position 256, the second amino acid residue substitution is at amino acid residue position 308, and the third amino acid residue substitution is at amino acid residue position 434. In particular embodiments of this type, the substitution at amino acid residue position 256 is with an aspartic acid residue, the substitution at amino acid residue position 308 is with a proline residue, and the substitution at amino acid residue position 434 is with a tyrosine residue. In yet other embodiments, one amino acid residue substitution is at amino acid residue position 433, a second amino acid residue substitution is at amino acid residue position 434, and a third amino acid residue substitution is at amino acid residue position 436. In particular embodiments of this type, the substitution at amino acid residue position 433 is with a lysine residue, the substitution at amino acid residue position 434 is with a phenylalanine residue, and the substitution at amino acid residue position 436 is with a threonine residue. In another embodiment of this type, the substitution at amino acid residue position 433 is with a lysine residue, the substitution at amino acid residue position 434 is with a tyrosine residue, and the substitution at amino acid residue position 436 is with a threonine residue. In yet another embodiment of this type, the substitution at amino acid residue position 433 is with a lysine residue, the substitution at amino acid residue position 434 is with a histidine residue, and the substitution at amino acid residue position 436 is with a threonine residue.In yet another embodiment of this type, the substitution at amino acid residue position 433 is with a leucine residue, the substitution at amino acid residue position 434 is with a phenylalanine residue, and the substitution at amino acid residue position 436 is with a threonine residue. In yet another embodiment of this type, the substitution at amino acid residue position 433 is with a leucine residue, the substitution at amino acid residue position 434 is with a tyrosine residue, and the substitution at amino acid residue position 436 is with a threonine residue. In yet another embodiment of this type, the substitution at amino acid residue position 433 is with a leucine residue, the substitution at amino acid residue position 434 is with a histidine residue, and the substitution at amino acid residue position 436 is with a threonine residue.

[0208] In certain embodiments of the canine antibody or antigen-binding fragment thereof comprising the above-described heavy and light chains, when bound to cIL-4, the canine antibody or antigen-binding fragment thereof (i) binds to an epitope contained in the amino acid sequence of SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:238, or any combination thereof, or (ii) has an IC50 of less than 40 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells, or (iii) both bind to an epitope contained in the amino acid sequence of SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:238, or any combination thereof and has an IC50 of less than 40 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. In a more specific embodiment, the canine antibody or antigen-binding fragment thereof when bound to cIL-4 binds to an epitope contained in the amino acid sequence of SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:238, or any combination thereof. In certain embodiments, the canine antibody or antigen-binding fragment thereof has an amino acid sequence identical to that of the canine antibody or antigen-binding fragment thereof at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T39 ), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In other embodiments, the canine antibody or antigen-binding fragment thereof binds to one or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In yet other embodiments, the canine antibody or antigen-binding fragment thereof binds to two or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to three or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 20(R 20), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to four or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to five or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96In certain embodiments, the canine antibody or antigen-binding fragment thereof binds to six or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 74(S 74 ), and 79(T 79 In another specific embodiment, the canine antibody or antigen-binding fragment thereof binds to 3 to 5 amino acid residues of cIL-4 at the following amino acid residue position: 12 (K 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 ) binds to 3 to 5 or more amino acid residues of cIL-4.

[0209] The present invention further provides a canine antibody or antigen-binding fragment thereof that binds to cIL-4 and has an IC50 of less than 40 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. The present invention further provides a canine antibody or antigen-binding fragment thereof that binds to cIL-4 and has an IC50 of less than 20 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. In certain embodiments, the canine antibody or antigen-binding fragment thereof binds to cIL-4 and has an IC50 of less than 10 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. In yet other embodiments, the canine antibody or antigen-binding fragment thereof binds to cIL-4 and has an IC50 of 0.5 nM to 50 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. In yet other embodiments, the canine antibody or antigen-binding fragment thereof binds to cIL-4 and has an IC50 of 2 nM to 25 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. In yet other embodiments, the canine antibody, or antigen-binding fragment thereof, binds cIL-4 and has an IC50 of 4 nM to 20 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells.

[0210] In still further specific embodiments, the canine antibody or antigen-binding fragment thereof binds to an epitope of cIL-4 contained in the amino acid sequence of SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, and SEQ ID NO:238, or any combination thereof, and binds to an epitope of cIL-4 contained in the amino acid sequence of SEQ ID NO:1 at the following amino acid residue position: 12 (K 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96) binds to one, two, three, four, five or more amino acid residues of cIL-4 and has an IC50 of less than 50 nM, less than 25 nM and / or 2 nM and / or 4 nM to 20 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells.

[0211] The present invention further provides a nucleic acid that individually encodes one of the heavy chains of the antibody of the present invention, and a nucleic acid that individually encodes one of the corresponding light chains of the antibody of the present invention or an antigen-binding fragment thereof. The present invention further provides a pair of a nucleic acid that encodes the heavy chain or an antigen-binding fragment thereof of the antibody of the present invention, and a nucleic acid that encodes the corresponding light chain or an antigen-binding fragment thereof of the antibody of the present invention. The present invention also provides a kit comprising these two nucleic acid pairs.

[0212] In a specific embodiment, one nucleic acid encodes a heavy chain comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 42, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 204, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 205, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 206, and another nucleic acid encodes a corresponding light chain comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 43, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 207, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 208, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 209. The present invention further provides a pair of nucleic acids encoding a heavy chain of a canine antibody and a nucleic acid encoding the corresponding light chain of the canine antibody. The present invention also provides a kit comprising this pair of nucleic acids.

[0213] In a more specific embodiment, a nucleic acid encodes the heavy chain of a canine antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO: 42, and another nucleic acid encodes the corresponding light chain of that antibody comprising the amino acid sequence of SEQ ID NO: 43. The invention further provides a pair of nucleic acids, one encoding a heavy chain comprising the amino acid sequence of SEQ ID NO: 42 and the other encoding the corresponding light chain comprising the amino acid sequence of SEQ ID NO: 43. The invention also provides a kit comprising this pair of two nucleic acids.

[0214] In a specific embodiment, one nucleic acid encodes a heavy chain comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 44, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 198, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 199, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 200, and another nucleic acid encodes a corresponding light chain comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 45, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 201, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 202, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 203. The present invention further provides a pair of nucleic acids encoding a heavy chain of a canine antibody and a nucleic acid encoding the corresponding light chain of the canine antibody. The present invention also provides a kit comprising this pair of nucleic acids.

[0215] In a more specific embodiment, the nucleic acid encodes a heavy chain or antigen-binding fragment thereof of a canine antibody comprising the amino acid sequence of SEQ ID NO: 44, and the corresponding light chain of that antibody comprising the amino acid sequence of SEQ ID NO: 45. The invention further provides a pair of nucleic acids, one encoding a heavy chain comprising the amino acid sequence of SEQ ID NO: 44 and the other encoding the corresponding light chain comprising the amino acid sequence of SEQ ID NO: 45. The invention also provides a kit comprising this pair of nucleic acids.

[0216] In another specific embodiment, one nucleic acid encodes a heavy chain comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:241, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO:198, an HCDR2 comprising the amino acid sequence of SEQ ID NO:199, and an HCDR3 comprising the amino acid sequence of SEQ ID NO:200, and another nucleic acid encodes a corresponding light chain comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:45, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO:201, an LCDR2 comprising the amino acid sequence of SEQ ID NO:202, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:203. The present invention further provides a pair of nucleic acids encoding a heavy chain of a canine antibody and a nucleic acid encoding the corresponding light chain of the canine antibody. The present invention also provides a kit comprising this pair of nucleic acids.

[0217] In yet another embodiment, the nucleic acid encodes a heavy chain comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:241, while still retaining a tyrosine residue at amino acid residue position 252 and an aspartic acid residue at amino acid residue position 256, numbered according to the EU index as in Kabat, and while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO:198, an HCDR2 comprising the amino acid sequence of SEQ ID NO:199, and an HCDR3 comprising the amino acid sequence of SEQ ID NO:200; and a light chain comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:45, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO:201, an LCDR2 comprising the amino acid sequence of SEQ ID NO:202, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:203. The present invention further provides a pair of nucleic acids encoding a heavy chain of a canine antibody and a nucleic acid encoding the corresponding light chain of the canine antibody. The present invention also provides a kit comprising this pair of nucleic acids.

[0218] In a more specific embodiment, the nucleic acid encodes a heavy chain or antigen-binding fragment thereof of a canine antibody comprising the amino acid sequence of SEQ ID NO: 241, and the corresponding light chain of that antibody comprising the amino acid sequence of SEQ ID NO: 45. The invention further provides a pair of nucleic acids, one encoding a heavy chain comprising the amino acid sequence of SEQ ID NO: 241 and the other encoding the corresponding light chain comprising the amino acid sequence of SEQ ID NO: 45. The invention also provides a kit comprising this pair of nucleic acids.

[0219] In a related specific embodiment, a nucleic acid encodes a heavy chain of a canine antibody or antigen-binding fragment thereof that comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 46, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 192, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 193, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 194, and another nucleic acid encodes the corresponding light chain of that antibody that comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 47, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 195, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 196, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 197. The present invention further provides a pair of nucleic acids, one encoding the heavy chain of the canine antibody and the other encoding the corresponding light chain of the canine antibody. The present invention also provides a kit comprising this pair of nucleic acids.

[0220] In a more specific embodiment, a nucleic acid encodes the heavy chain of a canine antibody comprising the amino acid sequence of SEQ ID NO: 46, and another nucleic acid encodes the corresponding light chain of that antibody comprising the amino acid sequence of SEQ ID NO: 47. The invention further provides a pair of nucleic acids, one encoding a heavy chain comprising the amino acid sequence of SEQ ID NO: 46 and the other encoding the corresponding light chain comprising the amino acid sequence of SEQ ID NO: 47. The invention also provides a kit comprising this pair of two nucleic acids.

[0221] In another specific embodiment, a nucleic acid encodes a heavy chain of a canine antibody or antigen-binding fragment thereof that comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 48, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 186, HCDR2 comprising the amino acid sequence of SEQ ID NO: 187, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 188, and another nucleic acid encodes the corresponding light chain of that antibody that comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 49, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 189, LCDR2 comprising the amino acid sequence of SEQ ID NO: 190, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 191. The present invention further provides a pair of nucleic acids, one encoding the heavy chain of the canine antibody and the other encoding the corresponding light chain of the canine antibody. The present invention also provides a kit comprising this pair of nucleic acids.

[0222] In an even more specific embodiment, a nucleic acid encodes the heavy chain of a canine antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO: 48, and another nucleic acid encodes the corresponding light chain of that antibody comprising the amino acid sequence of SEQ ID NO: 49. The invention further provides a pair of nucleic acids, one encoding a heavy chain comprising the amino acid sequence of SEQ ID NO: 48 and the other encoding the corresponding light chain comprising the amino acid sequence of SEQ ID NO: 49. The invention also provides a kit comprising this pair of nucleic acids.

[0223] In yet another related specific embodiment, a nucleic acid encodes a heavy chain of a canine antibody or antigen-binding fragment thereof that comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 52, while still retaining HCDR1 comprising the amino acid sequence of SEQ ID NO: 156, HCDR2 comprising the amino acid sequence of SEQ ID NO: 157, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 158, and another nucleic acid encodes the corresponding light chain of that antibody that comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 53, while still retaining LCDR1 comprising the amino acid sequence of SEQ ID NO: 159, LCDR2 comprising the amino acid sequence of SEQ ID NO: 160, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 161. The present invention further provides a pair of nucleic acids, one encoding the heavy chain of the canine antibody and the other encoding the corresponding light chain of the canine antibody. The present invention also provides a kit comprising this pair of nucleic acids.

[0224] In an even more specific embodiment, a nucleic acid encodes the heavy chain of a canine antibody or antigen-binding fragment thereof comprising the amino acid sequence of SEQ ID NO: 52, and another nucleic acid encodes the corresponding light chain of that antibody comprising the amino acid sequence of SEQ ID NO: 53. The invention further provides a pair of nucleic acids, one encoding a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and the other encoding the corresponding light chain comprising the amino acid sequence of SEQ ID NO: 53. The invention also provides a kit comprising this pair of nucleic acids.

[0225] The present invention further provides that, when bound to cIL-4, the canine antibody or antigen-binding fragment thereof (i) binds to an epitope contained in the amino acid sequence of SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:238, or any combination thereof, or (ii) has an IC50 of less than 40 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells, or (iii) both bind to an epitope contained in the amino acid sequence of SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:238, or any combination thereof and has an IC50 of less than 40 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. In a more specific embodiment, the canine antibody or antigen-binding fragment thereof, when bound to cIL-4, binds to an epitope contained in the amino acid sequence of SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:238, or any combination thereof. In certain embodiments, the canine antibody or antigen-binding fragment thereof has an amino acid sequence identical to that of the canine antibody or antigen-binding fragment thereof at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In other embodiments, the canine antibody or antigen-binding fragment thereof binds to one or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In yet other embodiments, the canine antibody or antigen-binding fragment thereof binds to two or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to three or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to four or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In yet another embodiment, the canine antibody or antigen-binding fragment thereof binds to five or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 74(S 74 ), 79(T 79 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 In certain embodiments, the canine antibody or antigen-binding fragment thereof binds to six or more amino acid residues of cIL-4 at the following amino acid residue positions: 6 (T6), 8 (K8), 12 (K) of the amino acid sequence of SEQ ID NO: 1. 12 ), 74(S 74 ), and 79(T 79 In another specific embodiment, the canine antibody or antigen-binding fragment thereof binds to 3 to 5 amino acid residues of cIL-4 at the following amino acid residue position: 12 (K 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96 ) binds to 3 to 5 or more amino acid residues of cIL-4.

[0226] The present invention further provides a canine antibody or antigen-binding fragment thereof that binds to cIL-4 and has an IC50 of less than 40 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. The present invention further provides a canine antibody or antigen-binding fragment thereof that binds to cIL-4 and has an IC50 of less than 20 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. In certain embodiments, the canine antibody or antigen-binding fragment thereof binds to cIL-4 and has an IC50 of less than 10 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. In yet other embodiments, the canine antibody or antigen-binding fragment thereof binds to cIL-4 and has an IC50 of 0.5 nM to 50 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. In yet other embodiments, the canine antibody or antigen-binding fragment thereof binds to cIL-4 and has an IC50 of 2 nM to 25 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. In yet other embodiments, the canine antibody, or antigen-binding fragment thereof, binds cIL-4 and has an IC50 of 4 nM to 20 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells.

[0227] In still further specific embodiments, the canine antibody or antigen-binding fragment thereof binds to an epitope of cIL-4 contained in the amino acid sequence of SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, and SEQ ID NO:238, or any combination thereof, and binds to an epitope of cIL-4 contained in the amino acid sequence of SEQ ID NO:1 at the following amino acid residue position: 12 (K 12 ), 20(R 20 ), 23(S 23 ), 28(T 28 ), 37(K 37 ), 39(T 39 ), 86(K 86 ), 87(K 87 ), 88(S 88 ), 89(T 89 ), 91(K 91 ), and 96(R 96) binds to one, two, three, four, five or more amino acid residues of cIL-4 and has an IC50 of less than 50 nM, less than 25 nM and / or 2 nM and / or 4 nM to 20 nM for canine IL-4-mediated STAT-6 phosphorylation in DH82 cells.

[0228] The present invention further provides expression vectors that contain and express one or more of the nucleic acids of the invention. In specific embodiments, the expression vector contains and expresses a nucleic acid encoding the heavy chain of a canine antibody of the invention. In other embodiments, the expression vector contains and expresses a nucleic acid encoding the light chain of that canine antibody. In more specific embodiments, the expression vector contains a pair of nucleic acids, one of which contains a nucleotide sequence encoding the light chain of a specific canine antibody, and the other of which contains a nucleotide sequence encoding the heavy chain of that specific canine antibody. In related embodiments, the present invention provides a pair of expression vectors, one of which contains one of a pair of nucleic acids that contains a nucleotide sequence encoding the heavy chain of a specific canine antibody, and the other of which contains the other of the pair of nucleic acids that contains a nucleotide sequence encoding the light chain of that specific canine antibody. The present invention also provides host cells that contain one or more expression vectors or one or more pairs of expression vectors of the present invention. The present invention further provides a pair of host cells, one of which contains one of a pair of expression vectors comprising one of a pair of nucleic acids comprising a nucleotide sequence encoding the heavy chain of a specific canine antibody, and the other of which contains the other of the pair of expression vectors comprising the other of the pair of nucleic acids comprising a nucleotide sequence encoding the light chain of the specific canine antibody.

[0229] The present invention also provides pharmaceutical compositions and / or methods for treating atopic dermatitis using a pharmaceutical composition comprising a canine antibody and / or an antigen-binding fragment of the antibody and a pharmaceutically acceptable carrier or diluent. In certain embodiments, the pharmaceutical composition comprises a canine antibody comprising a heavy chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 25, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 198, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 199, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 200, and a light chain variable region comprising at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 26, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 201, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 202, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 203. In certain embodiments, the pharmaceutical composition comprises a canine antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 25 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26. In yet other embodiments, the pharmaceutical composition comprises a canine antibody comprising a heavy chain variable region comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 28, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 204, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 205, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 206, and a light chain variable region comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 29, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 207, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 208, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 209. In certain embodiments, the pharmaceutical composition comprises a canine antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:28 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:29.

[0230] In a specific embodiment, the pharmaceutical composition comprises a canine antibody comprising a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 44, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 198, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 199, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 200, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 45, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 201, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 202, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 203. In a more specific embodiment, the pharmaceutical composition comprises a canine antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 44 and a light chain comprising the amino acid sequence of SEQ ID NO: 45.

[0231] In other embodiments, the pharmaceutical composition comprises a canine antibody comprising a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 241, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 198, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 199, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 200, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 45, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 201, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 202, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 203. In a more specific embodiment, the pharmaceutical composition comprises a canine antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 241 and a light chain comprising the amino acid sequence of SEQ ID NO: 45.

[0232] In a related embodiment, the pharmaceutical composition comprises a canine antibody comprising a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 241, while still retaining a tyrosine residue at amino acid residue position 252 and an aspartic acid residue at amino acid residue position 256, and while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 198, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 199, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 200, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 45, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 201, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 202, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 203.

[0233] In yet another embodiment, the pharmaceutical composition comprises a canine antibody comprising a heavy chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 42, while still retaining an HCDR1 comprising the amino acid sequence of SEQ ID NO: 204, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 205, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 206, and a light chain comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 43, while still retaining an LCDR1 comprising the amino acid sequence of SEQ ID NO: 207, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 208, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 209. In yet another embodiment, the pharmaceutical composition comprises a canine antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 42 and a light chain comprising the amino acid sequence of SEQ ID NO: 43.

[0234] Further provided are pharmaceutical compositions comprising an expression vector containing both a nucleic acid encoding the heavy chain of a canine antibody of the invention and a nucleic acid encoding the light chain of the canine antibody, and a pharmaceutically acceptable carrier or diluent. In other embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable carrier or diluent and two expression vectors, one containing a nucleic acid encoding the heavy chain of a canine antibody of the invention and the other containing a nucleic acid encoding the light chain of the canine antibody. Such pharmaceutical compositions are capable of expressing canine antibodies and / or antigen-binding fragments of the antibodies of the invention in vivo. Any of the pharmaceutical compositions of the invention can further comprise a canine antibody or caninized antibody that binds to canine interleukin-13 (cIL-13), a canine antibody or caninized antibody that binds to canine interleukin-13 receptor alpha 1 (cIL-13Ralpha1), a canine antibody or caninized antibody that binds to canine interleukin-31 receptor alpha (cIL-31RA), or a canine antibody or caninized antibody that binds to canine interleukin-31 (cIL-31), or any combination thereof. In yet another embodiment, there is provided a pharmaceutical composition for use in a method for reducing skin inflammation associated with atopic dermatitis in a dog, the method comprising administering to a dog in need thereof a therapeutically effective amount of a canine antibody or antigen-binding fragment thereof that binds to cIL-4 of the present invention, an expression vector of the present invention, or a pair of expression vectors of the present invention, or any combination thereof, and a pharmaceutically acceptable carrier or diluent, wherein the method is used to treat atopic dermatitis.

[0235] In yet another embodiment, the present invention provides a pharmaceutical composition for use in treating canine atopic dermatitis, preferably atopic dermatitis, wherein the treatment comprises administering to a dog in need thereof a canine antibody or antigen-binding fragment thereof that binds to cIL-13 of the present invention, an expression vector of the present invention, or a pair of expression vectors of the present invention, or any combination thereof, together with a pharmaceutically acceptable carrier or diluent. Preferably, the treatment has the effect of reducing skin inflammation and / or pruritus associated with canine atopic dermatitis.

[0236] The present invention further provides a method for treating atopic dermatitis, comprising administering one of the aforementioned pharmaceutical compositions to an animal subject with atopic dermatitis. In certain embodiments, the animal subject is a dog. The present invention also provides a method for helping to block skin inflammation associated with atopic dermatitis, comprising administering a therapeutically effective amount of a pharmaceutical composition of the present invention to an animal subject in need thereof. In certain embodiments, the animal subject is a dog.

[0237] The present invention further provides pharmaceutical compositions for use in treating atopic dermatitis, the treatment comprising administering one of the pharmaceutical compositions to an animal subject having atopic dermatitis. Preferably, the animal subject is a dog. Preferably, the treatment has the effect of reducing skin inflammation and / or pruritus associated with atopic dermatitis in the dog. In certain embodiments, a method is provided for helping to block skin inflammation associated with atopic dermatitis, the method comprising administering a therapeutically effective amount of a pharmaceutical composition of the present invention to a subject in need thereof. In certain embodiments, the animal subject is a dog. In certain embodiments, a method for helping to block skin inflammation, pruritus, or both skin inflammation and pruritus associated with atopic dermatitis comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention comprising a canine antibody of the invention that binds to cIL-4 and blocks the binding of cIL-4 to interleukin-4 receptor alpha (cIL-4Rα), together with a canine or caninized antibody that binds to canine interleukin-13 (cIL-13), a canine or caninized antibody that binds to canine IL-13 receptor alpha 1 (cIL-13Ralpha1), a canine or caninized antibody that binds to canine interleukin-31 receptor alpha (cIL-31RA), a canine or caninized antibody that binds to canine interleukin-31 (cIL-31), or any combination thereof. In a specific embodiment, the animal subject is a canine.

[0238] Additionally, the present invention provides a method for producing a canine antibody or antigen-binding fragment thereof that binds to canine IL-4. In certain embodiments, the method comprises culturing host cells comprising one or more expression vectors encoding and expressing the light chain of a canine antibody of the present invention or the heavy chain of that canine antibody, or both the light chain of a canine antibody of the present invention and the heavy chain of that canine antibody, in a culture medium (or culture media) under conditions for expression of the nucleic acid(s), thereby producing a polypeptide comprising the light chain of a canine antibody of the present invention, the heavy chain of that canine antibody, or both the light chain of a canine antibody of the present invention and the heavy chain of that canine antibody. The polypeptide is then recovered from the host cells or the culture medium (or culture media). In certain embodiments, a polypeptide comprising the light chain of a canine antibody of the present invention and a polypeptide comprising the heavy chain of that canine antibody are combined with each other under conditions favoring the formation of a canine antibody.

[0239] The present invention further provides a single-chain Fv (scFv) antibody that binds to cIL-4 and comprises a set of six complementarity-determining regions, three of which are heavy chain CDRs (HCDR1, HCDR2, and HCDR3) and three of which are light chain CDRs (LCDR1, LCDR2, and LCDR3).

[0240] In certain embodiments of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 156, HCDR2 comprises the amino acid sequence of SEQ ID NO: 157, HCDR3 comprises the amino acid sequence of SEQ ID NO: 158, LCDR1 comprises the amino acid sequence of SEQ ID NO: 159, LCDR2 comprises the amino acid sequence of SEQ ID NO: 160, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 161.

[0241] In an alternative embodiment of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 162, HCDR2 comprises the amino acid sequence of SEQ ID NO: 163, HCDR3 comprises the amino acid sequence of SEQ ID NO: 164, LCDR1 comprises the amino acid sequence of SEQ ID NO: 165, LCDR2 comprises the amino acid sequence of SEQ ID NO: 166, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 167.

[0242] In related embodiments of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 162, HCDR2 comprises the amino acid sequence of SEQ ID NO: 237, HCDR3 comprises the amino acid sequence of SEQ ID NO: 164, LCDR1 comprises the amino acid sequence of SEQ ID NO: 165, LCDR2 comprises the amino acid sequence of SEQ ID NO: 166, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 167.

[0243] In other embodiments of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 168, HCDR2 comprises the amino acid sequence of SEQ ID NO: 169, HCDR3 comprises the amino acid sequence of SEQ ID NO: 170, LCDR1 comprises the amino acid sequence of SEQ ID NO: 171, LCDR2 comprises the amino acid sequence of SEQ ID NO: 172, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 173.

[0244] In yet another embodiment of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 174, HCDR2 comprises the amino acid sequence of SEQ ID NO: 175, HCDR3 comprises the amino acid sequence of SEQ ID NO: 176, LCDR1 comprises the amino acid sequence of SEQ ID NO: 177, LCDR2 comprises the amino acid sequence of SEQ ID NO: 178, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 179.

[0245] In yet another embodiment of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 180, HCDR2 comprises the amino acid sequence of SEQ ID NO: 181, HCDR3 comprises the amino acid sequence of SEQ ID NO: 182, LCDR1 comprises the amino acid sequence of SEQ ID NO: 183, LCDR2 comprises the amino acid sequence of SEQ ID NO: 184, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 185.

[0246] In yet another embodiment of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 186, HCDR2 comprises the amino acid sequence of SEQ ID NO: 187, HCDR3 comprises the amino acid sequence of SEQ ID NO: 188, LCDR1 comprises the amino acid sequence of SEQ ID NO: 189, LCDR2 comprises the amino acid sequence of SEQ ID NO: 190, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 191.

[0247] In yet another embodiment of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 192, HCDR2 comprises the amino acid sequence of SEQ ID NO: 193, HCDR3 comprises the amino acid sequence of SEQ ID NO: 194, LCDR1 comprises the amino acid sequence of SEQ ID NO: 195, LCDR2 comprises the amino acid sequence of SEQ ID NO: 196, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 197.

[0248] In yet another embodiment of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 198, HCDR2 comprises the amino acid sequence of SEQ ID NO: 199, HCDR3 comprises the amino acid sequence of SEQ ID NO: 200, LCDR1 comprises the amino acid sequence of SEQ ID NO: 201, LCDR2 comprises the amino acid sequence of SEQ ID NO: 202, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 203.

[0249] In yet another embodiment of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 204, HCDR2 comprises the amino acid sequence of SEQ ID NO: 205, HCDR3 comprises the amino acid sequence of SEQ ID NO: 206, LCDR1 comprises the amino acid sequence of SEQ ID NO: 207, LCDR2 comprises the amino acid sequence of SEQ ID NO: 208, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 209.

[0250] In yet another embodiment of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 210, HCDR2 comprises the amino acid sequence of SEQ ID NO: 211, HCDR3 comprises the amino acid sequence of SEQ ID NO: 212, LCDR1 comprises the amino acid sequence of SEQ ID NO: 213, LCDR2 comprises the amino acid sequence of SEQ ID NO: 214, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 215.

[0251] In yet another embodiment of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 216, HCDR2 comprises the amino acid sequence of SEQ ID NO: 217, HCDR3 comprises the amino acid sequence of SEQ ID NO: 218, LCDR1 comprises the amino acid sequence of SEQ ID NO: 219, LCDR2 comprises the amino acid sequence of SEQ ID NO: 220, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 221.

[0252] In yet another embodiment of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 222, HCDR2 comprises the amino acid sequence of SEQ ID NO: 223, HCDR3 comprises the amino acid sequence of SEQ ID NO: 224, LCDR1 comprises the amino acid sequence of SEQ ID NO: 225, LCDR2 comprises the amino acid sequence of SEQ ID NO: 226, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 227.

[0253] In yet another embodiment of the scFv, HCDR1 comprises the amino acid sequence of SEQ ID NO: 228, HCDR2 comprises the amino acid sequence of SEQ ID NO: 229, HCDR3 comprises the amino acid sequence of SEQ ID NO: 230, LCDR1 comprises the amino acid sequence of SEQ ID NO: 231, LCDR2 comprises the amino acid sequence of SEQ ID NO: 232, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 233.

[0254] The present invention further provides single chain Fv (scFv) antibodies that bind to cIL-4 and comprise a heavy chain variable region comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 4 and a light chain variable region comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 5. In other scFV embodiments, the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 7 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 8. In yet other embodiments of the scFV, the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 236 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 8.

[0255] In yet other embodiments of the scFV, the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 10, and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 11. In yet other embodiments of the scFV, the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 13, and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 14. In yet other embodiments of the scFV, the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 16, and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 17.

[0256] In yet other embodiments of the scFV, the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 19, and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 20. In yet other embodiments of the scFV, the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 22, and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 23.

[0257] In yet other embodiments of the scFV, the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 25 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 26. In yet other embodiments of the scFV, the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 28 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 29.

[0258] In yet other embodiments of the scFV, the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 31 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 32. In yet other embodiments of the scFV, the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 34 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 35.

[0259] In yet other embodiments of the scFV, the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 37, and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 38. In yet other embodiments of the scFV, the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 40, and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 41.

[0260] The present invention further provides a single-chain Fv (scFv) antibody that binds to cIL-4 and comprises the amino acid sequence of SEQ ID NO: 3. In yet another embodiment, the scFV comprises the amino acid sequence of SEQ ID NO: 6. In yet another embodiment, the scFV comprises the amino acid sequence of SEQ ID NO: 9. In yet another embodiment, the scFV comprises the amino acid sequence of SEQ ID NO: 12. In yet another embodiment, the scFV comprises the amino acid sequence of SEQ ID NO: 15. In yet another embodiment, the scFV comprises the amino acid sequence of SEQ ID NO: 18. In yet another embodiment, the scFV comprises the amino acid sequence of SEQ ID NO: 21. In yet another embodiment, the scFV comprises the amino acid sequence of SEQ ID NO: 24. In yet another embodiment, the scFV comprises the amino acid sequence of SEQ ID NO: 27. In yet another embodiment, the scFV comprises the amino acid sequence of SEQ ID NO: 30. In yet another embodiment, the scFV comprises the amino acid sequence of SEQ ID NO: 33. In yet another embodiment, the scFV comprises the amino acid sequence of SEQ ID NO: 36. In yet another embodiment, the scFV comprises the amino acid sequence of SEQ ID NO: 39.

[0261] The present invention further provides individual nucleic acids encoding each of the scFv of the invention that bind cIL-4.

[0262] These and other aspects of the present invention will be better understood by reference to the following brief description and detailed description of the drawings. [Brief explanation of the drawings]

[0263] [Figure 1]

[0033] Figure 1 shows a dose-response curve for the inhibition of canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. Cells were treated with canine IL-4 alone or with canine IL-4 mixed with various concentrations of anti-canine IL-4 antibody. The results show that the addition of anti-canine IL-4 antibody results in a dose-dependent inhibition of STAT-6 phosphorylation. The IL-4 control is indicated by a single large dot (●) in the upper right corner of the plot.

[0264] IL4-P3-1B9VH-cIgGB / IL4-P3-1B9VL-cCL(●) IL4-P3-1B10VH-cIgGB / IL4-P3-1B10VL-cCL( TIFF2026508149000001.tif554) IL4-P3-1B10VHm-cIgGB / IL4-P3-1B10VL-cCL(▲) IL4-P3-1D7VH-cIgGB / IL4-P3-D7VL-cCL(▼) IL4-P4-1G3VH-cIgGB / IL4-P4-1G3VL-cCl(◆) [Figure 2] 1 shows a dose-response curve for the inhibition of canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. Cells were treated with canine IL-4 alone or with canine IL-4 mixed with various concentrations of anti-canine IL-4 antibody. The results show that the addition of anti-canine IL-4 antibody results in a dose-dependent inhibition of STAT-6 phosphorylation.

[0265] Figure 2 shows the single larger square ( IL-4 control (TIFF2026508149000002.tif554) is shown.

[0266] IL4-P4A-2D11VH-cIgGB / IL4-P4A-2D11VL-cCL(●) IL4-P4A-1F10VH-cIgGB / IL4-P4A-1F10VL-cCL( TIFF2026508149000003.tif554) IL4-P4A-1A10VH-cIgGB / IL4-P4-1A10VL-cCL(▲) IL4-P3-1A6VH-cIgGB / IL4-P3-1A6VL-cCL(▼) IL4-P3-1C4VH-cIgGB / IL4-P3-1C4VL-cCl(◆) [Figure 3]

[0033] Figure 1 shows a dose-response curve for the inhibition of canine IL-13-mediated STAT-6 phosphorylation in DH82 cells. Cells were treated with canine IL-13 alone or mixed with various concentrations of anti-canine IL-13 antibody. The results show that the addition of anti-canine IL-13 antibody results in a dose-dependent inhibition of STAT-6 phosphorylation. The canine IL-13 control is indicated by a single inverted triangle (▼) in the upper right corner of the plot.

[0267] IL13-P3-1G5VH-cIgGB / IL13-P3-1G5VL-cCL(●) IL13-P3-05VH-cIgGB / IL13-P3-05VL-cCL( TIFF2026508149000004.tif554) IL13-P3-05VH-cIgGB / IL13-P3-05VLm-cCL(▲) [Figure 4] 1 shows a dose-response curve for the inhibition of canine IL-4-mediated STAT-6 phosphorylation in DH82 cells. Cells were treated with canine IL-4 alone or with canine IL-4 mixed with various concentrations of anti-canine IL-4 antibody. The results show that the addition of anti-canine IL-4 antibody results in a dose-dependent inhibition of STAT-6 phosphorylation.

[0268] The canine IL-4 control is represented by the single larger square in the upper right corner of the plot ( TIFF2026508149000005.tif554). IL4-P4A-1A4VH-cIgGB / IL4-P4A-1A4VL-cCL(▼) IL4-P4A-1D9VH-cIgGB / IL4-P4A-1D9VL-cCl(◆) [Figure 5]An alignment of the amino acid sequences of the Fc regions from human IgG1 Fc [SEQ ID NO: 107], canine IgG-A [SEQ ID NO: 99], canine IgG-B [SEQ ID NO: 101], canine IgG-C [SEQ ID NO: 103], and canine IgG-D [SEQ ID NO: 105] is shown, along with the consensus sequence [SEQ ID NO: 242]. Solid arrows indicate specific amino acid residue positions, reflecting the EU numbering scheme according to Sequences of Proteins of Immunological Interest, 5th ed., Kabat et al., National Institutes of Health, Bethesda, Md. (1991). An "X" reflects the lack of uniformity at positions 252 and 254 in the consensus sequences for the five amino acid sequences being compared. [Figure 6] 1 shows characterization of the interface between canine IL-4 and two antibodies designated IL4-2D11 (i.e., IL4-P4A-2D11VH-cIgGB / IL4-P4A-2D11VL-cCL) and IL4-1F10 (i.e., IL4-P4A-1F10VH-cIgGB / IL4-P4A-1F10VL-cCL). The amino acid residue positions indicated are relative to the numbering of the amino acid sequence in SEQ ID NO: 1. Determination was performed by chemical cross-linking, high-mass MALDI mass spectrometry, and nLC-Orbitrap mass spectrometry. (See Example 7 below.)

[0269] Figure A shows the characterization of the interface between canine IL-4 and canine antibody IL4-P4A-2D11VH-cIgGB / IL4-P4A-2D11VL-cCL, which identified an epitope with two adjacent interaction sites (labeled as two separate epitopes in the figure) contained in the amino acid sequence of SEQ ID NO: 89 and another epitope (see Table 7 below) contained in the amino acid sequence of SEQ ID NO: 90. The specific amino acid residues identified for binding of the two interaction sites of the first epitope to the IL-4 antigen are the lysine residue at position 12 of the first interaction site (K 12 ), the arginine residue at position 20 (R 20 ) and the serine residue at position 23 (S23 ) and the threonine residue at position 28 (T 28 ), the lysine residue at position 37 (K 37 ) and the threonine residue at position 39 (T 39 The specific amino acid residues identified as the sole interaction site of the second epitope binding to the IL-4 antigen are the pair of lysine residues at positions 86 and 87 (K 86 and K. 87 ), serine residue at position 88 (S 88 ), a threonine residue at position 89 (T 89 ), the lysine residue at position 91 (K 91 ), and an arginine residue at position 96 (R 96 )

[0270] Figure B shows the characterization of the interface between canine IL-4 and the identified canine antibody IL4-P4A-1F10VH-cIgGB / IL4-P4A-1F10VL-cCL, which has two epitopes, the former contained in the amino acid sequence of SEQ ID NO: 91 and the latter contained in the amino acid sequence of SEQ ID NO: 92 (see Table 7 below). The specific amino acid residues identified as binding to the first epitope to the IL-4 antigen are the threonine residue at position 6 (T6), the lysine residue at position 8 (K8), and the lysine residue at position 12 (K 12 ) is K 12 The second epitope is identified as binding to the IL-4 antigen by both the IL4-2D11 antibody and the IL4-1F10 antibody. The specific amino acid residue identified as binding to the IL-4 antigen of the second epitope is the serine residue at position 74 (S 74 ) and a threonine residue at position 79 (T 79 ) [Figure 7]1 shows the characterization of the interface between canine IL-13 and canine antibody IL13-P3-05VH-cIgGB / IL13-P3-05VLm-cCL. The amino acid residue positions indicated are relative to the numbering of the amino acid sequence in SEQ ID NO: 2. Determination was performed by chemical cross-linking, high-mass MALDI mass spectrometry, and nLC-Orbitrap mass spectrometry (see Example 7 below). Specific amino acid residues identified as binding to the first epitope to the IL-13 antigen are the three serine residues at positions 27 (S27), 32 (S32), and 36 (S36), respectively. Specific amino acid residues identified as binding to the second epitope to the IL-13 antigen are the serine residues at positions 50 (S50), 55 (S55), and 58 (S58), respectively. DETAILED DESCRIPTION OF THE INVENTION

[0271] It is contemplated that any product, method, use, or composition described herein can be implemented with respect to any other product, method, use, or composition described herein. Embodiments disclosed in the context of a product, method, use, or composition of the invention can be used with respect to any other product, method, use, or composition described herein. Thus, embodiments with respect to one product, method, use, or composition can also be applied to other products, methods, uses, or compositions of the invention.

[0272] The present invention provides antibodies that bind to either canine IL-4 or canine IL-13. These antibodies include canine and scFv antibodies. In certain embodiments, the antibodies are canine antibodies, as specifically exemplified below.

[0273] IL-4 is known to bind with high affinity to two heterodimeric receptors, namely, type I and type II IL-4 receptors. Type I heterodimeric IL-4 receptor consists of the IL-4 receptor alpha chain and the common gamma C (γc) chain. Type II heterodimeric IL-4 receptor consists of the IL-4 receptor alpha chain and the IL-13 receptor alpha 1 (IL-13R alpha 1) chain. IL-13 is known to bind to a unique receptor called the IL-13R alpha 1 chain and IL-13 receptor alpha 2 of the IL-4 type II receptor.

[0274] The canine antibodies of the present invention comprise a canine IgG-A, IgG-B, IgG-C, or IgG-D heavy chain together with a canine kappa or lambda light chain of the present invention. In a specific embodiment, the canine antibody comprises a canine IgG-B Fc, as specifically exemplified below. Specific CDR sets for canine IL-4 antibodies or canine IL-13 antibodies are provided, as are the corresponding variable heavy and light chain regions.

[0275] Thus, the present invention provides canine antibodies that bind to either canine IL-13 or canine IL-4, respectively, wherein the canine antibody or antigen-binding fragment thereof comprises a specific set of six CDRSs, three in the heavy chain variable region of the heavy chain and three in the light chain variable region of the light chain. The canine antibody or antigen-binding fragment thereof can also comprise a specific heavy chain variable region of the heavy chain and a specific light chain variable region of the light chain. The canine antibody or antigen-binding fragment thereof can further comprise the specific heavy chain and light chain of the canine antibody.

[0276] The present invention further provides nucleic acids encoding any one of the canine antibodies of the present invention and any one of the antigen-binding fragments of the antibodies of the present invention. The present invention further provides nucleic acids encoding the heavy chain variable region of the canine antibody or antigen-binding fragment thereof; the heavy chain of the canine antibody or antigen-binding fragment thereof; the light chain variable region of the canine antibody or antigen-binding fragment thereof; and / or the light chain of the canine antibody or antigen-binding fragment thereof.

[0277] Thus, the present invention provides nucleic acids encoding the heavy chain variable region of a canine antibody or antigen-binding fragment thereof of the present invention. The present invention further provides nucleic acids encoding the heavy chain of a canine antibody or antigen-binding fragment thereof of the present invention. The present invention also provides nucleic acids encoding the light chain variable region of a canine antibody or antigen-binding fragment thereof of the present invention. The present invention also provides nucleic acids encoding the light chain of a canine antibody or antigen-binding fragment thereof of the present invention. In certain embodiments, the nucleic acid encoding the heavy chain variable region encodes the heavy chain of the canine antibody, and the corresponding nucleic acid encoding the light chain variable region encodes the light chain of the canine antibody.

[0278] The present invention also provides pairs of nucleic acids, one of which contains a nucleotide sequence encoding the light chain of any one of the specific canine antibodies of the present invention, and the other of which contains a nucleotide sequence encoding the heavy chain of that specific canine antibody. The present invention also provides expression vectors comprising such pairs of nucleic acids, or individual nucleic acids of the present invention. Furthermore, the present invention provides pairs of expression vectors, one of which contains a nucleic acid containing a nucleotide sequence encoding the light chain of any one of the specific canine antibodies of the present invention, and the other of which contains a nucleic acid containing a nucleotide sequence encoding the heavy chain of that specific canine antibody.

[0279] Abbreviation The following abbreviations are used throughout the detailed description and examples of the present invention:

[0280] ADCC antibody-dependent cytotoxicity CDC Complement-dependent cytotoxicity CDR Complementarity determining region in an immunoglobulin variable region, defined using the Kabat numbering system EC50 Concentration that produces 50% efficacy or binding ELISA Enzyme-linked immunosorbent assay FR Antibody framework region: immunoglobulin variable region excluding the CDR regions.

[0281] IC50: Concentration that produces 50% inhibition IgG immunoglobulin G The immunoglobulin alignment and numbering system pioneered by Elvin A. Kabat [Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)].

[0282] KD is the dissociation constant, which is the concentration of a ligand (e.g., a specific antibody) at which half of the ligand binding sites on a protein (e.g., a protein antigen such as cIL-4 or cIL-13) for that particular ligand are occupied at system equilibrium. This is expressed as the koff value (k -1 ) by the k on value (k1), e.g., KD=k -1 / k1.

[0283] mAb Monoclonal antibody (also Mab or MAb) V region The segment of an IgG chain that is variable in sequence among different antibodies.

[0284] VH immunoglobulin heavy chain variable region VL immunoglobulin light chain variable region Vk immunoglobulin kappa light chain variable region Vl immunoglobulin lambda light chain variable region definition So that the present invention may be more readily understood, certain technical and scientific terms are specifically defined below. Unless specifically defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0285] As used in this specification, including the appended claims, the singular forms of words such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0286] The "activity" of a molecule may describe or refer to the molecule's binding to a ligand or receptor, catalytic activity; the ability to stimulate gene expression or cell signaling, differentiation, or maturation; antigenic activity, modulation of the activity of other molecules, etc. The "activity" of a molecule may also refer to activity that modulates or maintains cell-cell interactions, e.g., adhesion, or activity that maintains the structure of a cell, e.g., a cell membrane or cytoskeleton. "Activity" may also refer to specific activity, e.g., [catalytic activity] / [mg protein], or [immune activity] / [mg protein], concentration in a biological compartment, etc. "Activity" may refer to modulation of a component of the in...

Claims

1. 1. A canine antibody or antigen-binding fragment thereof that binds to canine interleukin-13 (cIL-13), the antibody comprising a heavy chain and a light chain that together comprise a set of six complementarity determining regions (CDRs), three of which are heavy chain CDRs: CDR heavy chain 1 (HCDR1), CDR heavy chain 2 (HCDR2), and CDR heavy chain 3 (HCDR3), and three of which are light chain CDRs: CDR light chain 1 (LCDR1), CDR light chain 2 (LCDR2), and CDR light chain 3 (LCDR3), each CDR comprising the amino acid sequence: the set of six CDRs is selected from the group consisting of: (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), and (ix); For set (i), HCDR1 comprises the amino acid sequence of SEQ ID NO: 150; HCDR2 comprises the amino acid sequence of SEQ ID NO: 151; HCDR3 comprises the amino acid sequence of SEQ ID NO: 152; LCDR1 comprises the amino acid sequence of SEQ ID NO: 153; LCDR2 comprises the amino acid sequence of SEQ ID NO: 235; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 155; For set (ii), HCDR1 comprises the amino acid sequence of SEQ ID NO: 150; HCDR2 comprises the amino acid sequence of SEQ ID NO: 151; HCDR3 comprises the amino acid sequence of SEQ ID NO: 152; LCDR1 comprises the amino acid sequence of SEQ ID NO: 153; LCDR2 comprises the amino acid sequence of SEQ ID NO: 154; LCDR3 comprises the amino acid sequence of SEQ ID NO: 155; For set (iii), HCDR1 comprises the amino acid sequence of SEQ ID NO: 126; HCDR2 comprises the amino acid sequence of SEQ ID NO: 127; HCDR3 comprises the amino acid sequence of SEQ ID NO: 128; LCDR1 comprises the amino acid sequence of SEQ ID NO: 129; LCDR2 comprises the amino acid sequence of SEQ ID NO: 130, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 131; Regarding set (iv), HCDR1 comprises the amino acid sequence of SEQ ID NO: 132; HCDR2 comprises the amino acid sequence of SEQ ID NO: 133; HCDR3 comprises the amino acid sequence of SEQ ID NO: 134; LCDR1 comprises the amino acid sequence of SEQ ID NO: 135; LCDR2 comprises the amino acid sequence of SEQ ID NO: 136; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 137; For set (v), HCDR1 comprises the amino acid sequence of SEQ ID NO: 138; HCDR2 comprises the amino acid sequence of SEQ ID NO: 139; HCDR3 comprises the amino acid sequence of SEQ ID NO: 140; LCDR1 comprises the amino acid sequence of SEQ ID NO: 141; LCDR2 comprises the amino acid sequence of SEQ ID NO: 142, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 143; For set (vi), HCDR1 comprises the amino acid sequence of SEQ ID NO: 144; HCDR2 comprises the amino acid sequence of SEQ ID NO: 145; HCDR3 comprises the amino acid sequence of SEQ ID NO: 146; LCDR1 comprises the amino acid sequence of SEQ ID NO: 147; LCDR2 comprises the amino acid sequence of SEQ ID NO: 148; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 149; Regarding set (vii) HCDR1 comprises the amino acid sequence of SEQ ID NO: 120; HCDR2 comprises the amino acid sequence of SEQ ID NO: 121; HCDR3 comprises the amino acid sequence of SEQ ID NO: 122; LCDR1 comprises the amino acid sequence of SEQ ID NO: 123; LCDR2 comprises the amino acid sequence of SEQ ID NO: 124, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 125; For set (viii), HCDR1 comprises the amino acid sequence of SEQ ID NO: 114; HCDR2 comprises the amino acid sequence of SEQ ID NO: 115; HCDR3 comprises the amino acid sequence of SEQ ID NO: 116; LCDR1 comprises the amino acid sequence of SEQ ID NO: 117; LCDR2 comprises the amino acid sequence of SEQ ID NO: 118, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 119; For set (ix), HCDR1 comprises the amino acid sequence of SEQ ID NO: 248; HCDR2 comprises the amino acid sequence of SEQ ID NO: 249; HCDR3 comprises the amino acid sequence of SEQ ID NO: 250; LCDR1 comprises the amino acid sequence of SEQ ID NO: 251; LCDR2 comprises the amino acid sequence of SEQ ID NO: 252, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 253; the canine antibody or antigen-binding fragment thereof binds to cIL-13; A canine antibody or antigen-binding fragment thereof that binds to canine interleukin-13 (cIL-13).

2. The canine antibody or antigen-binding fragment thereof of claim 1, wherein the antibody comprises a heavy chain variable region comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO:80, SEQ ID NO:62, SEQ ID NO:65, SEQ ID NO:68, SEQ ID NO:71, SEQ ID NO:74, SEQ ID NO:77 and SEQ ID NO:

244.

3. The canine antibody or antigen-binding fragment thereof of claim 1 or 2, wherein the antibody comprises a light chain variable region comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO:234, SEQ ID NO:81, SEQ ID NO:63, SEQ ID NO:66, SEQ ID NO:69, SEQ ID NO:72, SEQ ID NO:75, SEQ ID NO:78 and SEQ ID NO:

245.

4. the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 62 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 63; or the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO:65 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO:66; or the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO:68 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO:69; or the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 71, and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 72; the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 74 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 75; or the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 77 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 78; or the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 80 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 81; or the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 80 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 234; or the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO:244, and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO:245; A canine antibody, or an antigen-binding fragment thereof, according to any one of claims 1 to 3.

5. The canine antibody or antigen-binding fragment thereof of claim 2 or 4, comprising a heavy chain variable region that has at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO:

80.

6. The canine antibody, or antigen-binding fragment thereof, of any one of claims 3 to 5, comprising a light chain variable region that has at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO:

234.

7. the HCDR1 comprises the amino acid sequence of SEQ ID NO: 150; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 151; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 152; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 153; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 235; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 155; 7. The canine antibody, or antigen-binding fragment thereof, of claim 1, 5, or 6.

8. The canine antibody, or antigen-binding fragment thereof, of any one of claims 1 to 7, comprising a canine hinge region comprising an amino acid sequence comprising at least 90%, 95%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111, SEQ ID NO: 112, and SEQ ID NO:

113.

9. 9. The canine antibody or antigen-binding fragment thereof of any one of claims 1 to 8, comprising a canine fragment crystallizable region (cFc), wherein the cFc comprises an amino acid sequence comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105 and SEQ ID NO:

106.

10. The canine antibody, or antigen-binding fragment thereof, of claim 9, wherein the cFc comprises an amino acid sequence that has at least 90%, 95%, 98%, 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 101 or SEQ ID NO:

102.

11. the heavy chain comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 82 and the light chain comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 83; or the heavy chain comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 84 and the light chain comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 85; or the heavy chain comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 84 and the light chain comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 86; or the heavy chain comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 87, and the light chain comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 88; A canine antibody, or an antigen-binding fragment thereof, according to any one of claims 1 to 10.

12. The canine antibody or antigen-binding fragment thereof of claim 11, wherein the heavy chain comprises at least 90%, 95%, 98%, 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 84 and the light chain comprises at least 90%, 95%, 98%, 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO:

85.

13. the cFc comprises one or more amino acid substitutions, wherein the one or more amino acid residue substitutions are at amino acid residue positions selected from the group consisting of 252, 254, 256, 308, 433, 434, 436, or any combination thereof, wherein said amino acid residue positions are numbered according to the EU index as in Kabat; if the substitution is at amino acid residue position 252, the substitution is with a tyrosine residue; if the substitution is at amino acid residue position 254, the substitution is with a threonine residue; If the substitution is at amino acid residue position 256, the substitution is with an aspartic acid residue or a glutamic acid residue. if the substitution is at amino acid residue position 308, the substitution is with a proline residue; if the substitution is at amino acid residue position 433, the substitution is with a lysine residue or a leucine residue; if the substitution is at amino acid residue position 434, the substitution is with a phenylalanine residue, a histidine residue, or a tyrosine residue; and if the substitution is at amino acid residue position 436, the substitution is with a threonine residue; A canine antibody, or an antigen-binding fragment thereof, according to any one of claims 9 to 12.

14. The cFc is (i) a substitution at amino acid residue position 252 with a tyrosine residue and at amino acid residue position 256 with an aspartic acid residue; (ii) a substitution at amino acid residue position 256 with an aspartic acid residue and at amino acid residue position 434 with a tyrosine residue; (iii) a substitution at amino acid residue position 308 with a proline residue and at amino acid residue position 434 with a tyrosine residue; (iv) a substitution at amino acid residue position 433 with a lysine residue and at amino acid residue position 434 with a phenylalanine residue; (v) a substitution at amino acid residue position 433 with a lysine residue and at amino acid residue position 434 with a tyrosine residue; (vi) a substitution at amino acid residue position 433 with a leucine residue and at amino acid residue position 434 with a phenylalanine residue; (vii) a substitution at amino acid residue position 433 with a leucine residue and at 434 with a tyrosine residue; (viii) a substitution at amino acid residue position 434 with a tyrosine residue and at amino acid residue position 436 with a threonine residue; (ix) a substitution at amino acid residue position 252 with a tyrosine residue, a substitution at amino acid residue position 254 with a threonine residue, and a substitution at amino acid residue position 256 with a glutamic acid residue; (x) a substitution at amino acid residue position 256 with an aspartic acid residue, a substitution at amino acid residue position 308 with a proline residue, and a substitution at amino acid residue position 434 with a tyrosine residue; (xi) a substitution at amino acid residue position 433 with a lysine residue, a substitution at amino acid residue position 434 with a phenylalanine residue, and a substitution at amino acid residue position 436 with a threonine residue; (xii) a substitution at amino acid residue position 433 with a lysine residue, a substitution at amino acid residue position 434 with a tyrosine residue, and a substitution at amino acid residue position 436 with a threonine residue; (xiii) a substitution at amino acid residue position 433 with a leucine residue, a substitution at amino acid residue position 434 with a phenylalanine residue, and a substitution at amino acid residue position 436 with a threonine residue; and (xiv) a substitution at amino acid residue position 433 with a leucine residue, a substitution at amino acid residue position 434 with a tyrosine residue, and a substitution at amino acid residue position 436 with a threonine residue; (xv) substitution at amino acid residue position 434 with a histidine residue and wherein the cFc comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 257 or SEQ ID NO:

258.

15. 15. The canine antibody or antigen-binding fragment thereof of claim 14, wherein the cFc comprises a substitution at amino acid residue position 252 with a tyrosine residue and a substitution at amino acid residue position 256 with an aspartic acid residue, and preferably the cFc comprises an amino acid sequence comprising at least 90%, 95%, 98%, 99% or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 255 or SEQ ID NO:

256.

16. The canine antibody or antigen-binding fragment thereof of claim 15, wherein the heavy chain comprises at least 90%, 95%, 98%, 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO: 240 and the light chain comprises at least 90%, 95%, 98%, 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO:

85.

17. The canine antibody or antigen-binding fragment thereof of any one of claims 1 to 16, which binds to canine interleukin-13 (cIL-13) and has an IC50 of less than 50 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells.

18. A canine antibody or antigen-binding fragment thereof that binds to canine interleukin-13 (cIL-13) and has an IC50 of less than 50 nM for canine IL-13-mediated STAT-6 phosphorylation in DH82 cells.

19. 19. The canine antibody or antigen-binding fragment thereof of any one of claims 1 to 18, wherein the antibody binds to an epitope contained in an amino acid sequence selected from the group consisting of SEQ ID NO:239, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, and any combination thereof when bound to cIL-13.

20. When the antibody binds to cIL-13, it binds to the amino acid residue at position 27 (SEQ ID NO: 2) of the amino acid sequence of SEQ ID NO:

2. ２７ ), 32 (S ３２ ), 36 (S ３６ ), 50 (S ５０ ), 55 (S ５５ ), and 58 (S ５８ The canine antibody or antigen-binding fragment thereof of claim 19, which binds to 1, 2, 3, 4, 5, or 6 serine residues on cIL-13 in the sequence (III) of the canine antibody or antigen-binding fragment thereof.

21. A nucleic acid comprising a nucleotide sequence encoding the heavy chain of the canine antibody or antigen-binding fragment thereof of any one of claims 1 to 20.

22. A nucleic acid comprising a nucleotide sequence encoding the light chain or antigen-binding fragment thereof of the canine antibody of any one of claims 1 to 20.

23. A pair of nucleic acids, wherein one of the pair of nucleic acids comprises a nucleotide sequence encoding the light chain of a specific canine antibody of the antibody of any one of claims 1 to 20, and the other of the pair of nucleic acids comprises a nucleotide sequence encoding the heavy chain of the specific canine antibody.

24. 24. An expression vector comprising a pair of nucleic acids according to claim 23 or a nucleic acid according to claim 21 or 22.

25. A pair of expression vectors, one of which comprises the pair of nucleic acids described in claim 23, which comprises a nucleotide sequence encoding the heavy chain of the specific dog antibody, and the other of which comprises the other of the pair of nucleic acids, which comprises a nucleotide sequence encoding the light chain of the specific dog antibody.

26. A host cell comprising an expression vector according to claim 24 or a pair of expression vectors according to claim 25.

27. A pharmaceutical composition comprising a canine antibody or antigen-binding fragment thereof described in any one of claims 1 to 20, or an expression vector described in claim 24, or a pair of expression vectors described in claim 25, or any combination thereof, and a pharmaceutically acceptable carrier or diluent.

28. 28. The pharmaceutical composition of claim 27, further comprising a canine or caninized antibody that binds to canine interleukin-4 (cIL-4), a canine or caninized antibody that binds to canine interleukin-4 receptor alpha (cIL-4Rα), or a combination thereof.

29. 29. The pharmaceutical composition of claim 27 or 28, further comprising a canine or caninized antibody that binds to canine interleukin-31 receptor alpha (cIL-31RA), a canine or caninized antibody that binds to canine interleukin-31 (cIL-31), or any combination thereof.

30. 30. A method for assisting in blocking skin inflammation associated with atopic dermatitis, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of any one of claims 27, 28, or 29.

31. 30. A method for helping to block skin inflammation and pruritus associated with atopic dermatitis, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of any one of claims 27, 28, or 29.

32. A pharmaceutical composition for use in a method for reducing skin inflammation associated with atopic dermatitis in a dog, the method comprising administering to the dog in need thereof a therapeutically effective amount of a canine antibody or antigen-binding fragment thereof described in any one of claims 1 to 20, or an expression vector described in claim 24, or a pair of expression vectors described in claim 25, or any combination thereof, and a pharmaceutically acceptable carrier or diluent, wherein the method is used to treat atopic dermatitis.

33. 1. A single chain Fv (scFv) antibody comprising a set of six complementarity determining regions (CDRs), three of which are heavy chain CDRs: CDR heavy chain 1 (HCDR1), CDR heavy chain 2 (HCDR2), and CDR heavy chain 3 (HCDR3), and three of which are light chain CDRs: CDR light chain 1 (LCDR1), CDR light chain 2 (LCDR2), and CDR light chain 3 (LCDR3), each CDR comprising the amino acid sequence: For set (i), HCDR1 comprises the amino acid sequence of SEQ ID NO: 114; HCDR2 comprises the amino acid sequence of SEQ ID NO: 115; HCDR3 comprises the amino acid sequence of SEQ ID NO: 116; LCDR1 comprises the amino acid sequence of SEQ ID NO: 117; LCDR2 comprises the amino acid sequence of SEQ ID NO: 118, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 119; For set (ii), HCDR1 comprises the amino acid sequence of SEQ ID NO: 120; HCDR2 comprises the amino acid sequence of SEQ ID NO: 121; HCDR3 comprises the amino acid sequence of SEQ ID NO: 122; LCDR1 comprises the amino acid sequence of SEQ ID NO: 123; LCDR2 comprises the amino acid sequence of SEQ ID NO: 124, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 125; For set (iii), HCDR1 comprises the amino acid sequence of SEQ ID NO: 126; HCDR2 comprises the amino acid sequence of SEQ ID NO: 127; HCDR3 comprises the amino acid sequence of SEQ ID NO: 128; LCDR1 comprises the amino acid sequence of SEQ ID NO: 129; LCDR2 comprises the amino acid sequence of SEQ ID NO: 130; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 131; Regarding set (iv), HCDR1 comprises the amino acid sequence of SEQ ID NO: 132; HCDR2 comprises the amino acid sequence of SEQ ID NO: 133; HCDR3 comprises the amino acid sequence of SEQ ID NO: 134; LCDR1 comprises the amino acid sequence of SEQ ID NO: 135; LCDR2 comprises the amino acid sequence of SEQ ID NO: 136; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 137; For set (v), HCDR1 comprises the amino acid sequence of SEQ ID NO: 138; HCDR2 comprises the amino acid sequence of SEQ ID NO: 139; HCDR3 comprises the amino acid sequence of SEQ ID NO: 140; LCDR1 comprises the amino acid sequence of SEQ ID NO: 141; LCDR2 comprises the amino acid sequence of SEQ ID NO: 142; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 143; For set (vi), HCDR1 comprises the amino acid sequence of SEQ ID NO: 144; HCDR2 comprises the amino acid sequence of SEQ ID NO: 145; HCDR3 comprises the amino acid sequence of SEQ ID NO: 146; LCDR1 comprises the amino acid sequence of SEQ ID NO: 147; LCDR2 comprises the amino acid sequence of SEQ ID NO: 148; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 149; For set (vii), HCDR1 comprises the amino acid sequence of SEQ ID NO: 150; HCDR2 comprises the amino acid sequence of SEQ ID NO: 151; HCDR3 comprises the amino acid sequence of SEQ ID NO: 152; LCDR1 comprises the amino acid sequence of SEQ ID NO: 153; LCDR2 comprises the amino acid sequence of SEQ ID NO: 235; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 155; For set (viii), HCDR1 comprises the amino acid sequence of SEQ ID NO: 150; HCDR2 comprises the amino acid sequence of SEQ ID NO: 151; HCDR3 comprises the amino acid sequence of SEQ ID NO: 152; LCDR1 comprises the amino acid sequence of SEQ ID NO: 153; LCDR2 comprises the amino acid sequence of SEQ ID NO: 154; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 155; For set (ix), HCDR1 comprises the amino acid sequence of SEQ ID NO: 248; HCDR2 comprises the amino acid sequence of SEQ ID NO: 249; HCDR3 comprises the amino acid sequence of SEQ ID NO: 250; LCDR1 comprises the amino acid sequence of SEQ ID NO: 251; LCDR2 comprises the amino acid sequence of SEQ ID NO: 252; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 253; the scFv antibody binds to cIL-13; A single-chain Fv (scFv) antibody containing a set of six complementarity-determining regions (CDRs).

34. the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 62 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 63; or the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO:65 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO:66; or the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO:68 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO:69; or the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 71 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 72; or the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 74 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 75; or the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 77 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 78; or the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 80 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 81; or the heavy chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 80 and the light chain variable region comprises at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 234; or the heavy chain variable region comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:244, and the light chain variable region comprises at least 90%, 95%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:245; 34. The scFv antibody of claim 33.

35. The scFv antibody of claim 33 or 34, wherein the scFv has an amino acid sequence selected from the group consisting of SEQ ID NO: 61, SEQ ID NO: 64, SEQ ID NO: 67, SEQ ID NO: 70, SEQ ID NO: 73, SEQ ID NO: 76, SEQ ID NO: 79, SEQ ID NO: 243 and SEQ ID NO: 254.

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