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JP-7857291-B2 - Antibodies against canid and feline oncostatin M receptor beta, and their use

JP7857291B2JP 7857291 B2JP7857291 B2JP 7857291B2JP-7857291-B2

Inventors

  • バマート，ギャリー・フランシス
  • ゴンザレス，アンドレア・ジョイ

Assignees

  • ゾエティス・サービシーズ・エルエルシー

Dates

Publication Date
20260512
Application Date
20211018
Priority Date
20201019

Claims (20)

  1. 1) 02D09: Variable heavy chain (VH)-CDR1 (DYGMH) of SEQ ID NO: 1, VH-CDR2 (YISSGSRAVFFADTVKG) of SEQ ID NO: 2, VH-CDR3 (DRYDGRGFAY) of SEQ ID NO: 3, Variable light chain (VL)-CDR1 (RASQSISNNLH) of SEQ ID NO: 4, VL-CDR2 (YASQSIS) of SEQ ID NO: 5, and VL-CDR3 (QQSNSWPLT) of SEQ ID NO: 6 2) 09E09: Sequence ID 7 VH-CDR1 (SYAMS), Sequence ID 8 VH-CDR2 (YISSGGDYIYYADTVKG), Sequence ID 9 VH-CDR3 (DPITGTFAY), Sequence ID 10 VL-CDR1 (RASQDINNYLN), Sequence ID 11 VL-CDR2 (YTSTLHS), and Sequence ID 12 VL-CDR3 (QQGNTLPWT), 3) 10F07: Sequence ID 13 VH-CDR1 (SYAMS), Sequence ID 14 VH-CDR2 (YISSGGDYFYYADTVKG), Sequence ID 15 VH-CDR3 (DPITGTFAY), Sequence ID 16 VL-CDR1 (RASQDITNYLN), Sequence ID 17 VL-CDR2 (YTSTLHS), and Sequence ID 18 VL-CDR3 (QQGHMLPWT), 4) 14C04: VH-CDR1 (NYWMN) of SEQ ID NO: 19, VH-CDR2 (QIYPGHVNTNYNGNFKD) of SEQ ID NO: 20, VH-CDR3 (SADNSGFVLFAY) of SEQ ID NO: 21, VL-CDR1 (RASKSVSTSGYSYLH) of SEQ ID NO: 22, VL-CDR2 (LASNLES) of SEQ ID NO: 23, and VL-CDR3 (QHSRELPLT) of SEQ ID NO: 24, or 5) 19F07: Sequence ID 25 VH-CDR1 (DYYMA), Sequence ID 26 VH-CDR2 (NINYDGSSTYYLDSLKS), Sequence ID 27 VH-CDR3 (GLTWDFDV), Sequence ID 28 VL-CDR1 (KASQDVDTAVA), Sequence ID 29 VL-CDR2 (LASTRHT), and Sequence ID 30 VL-CDR3 (QQYSRFPLT) An isolated antibody, or its antigen-binding moiety, comprising a combination of complementarity-determining region (CDR) sequences selected from the group consisting of the following, wherein the antibody binds to at least one of canid or feline oncostatin M receptor beta (OSMR-β), and the antibody antagonistizes IL-31-mediated signaling, OSM-mediated signaling, or both, in canid and/or feline cells.
  2. (a) Variable heavy chains including the following: SEQ ID NO: 31 (MU_02D09_VH)EVQLVESGGGLLVKPGGSLTLSCAASGFTFFSDYGMHWLRQAPEKGLEWVAYISSGSRAVFFADTVKGRFTISRDNAKNTLFLQMTSLRSDDTAMYYYCARDRYDGRGFAYWGQGTLVTVSA, and a variable light chain including the following: Sequence ID 33 (MU_02D09_VL) DIVLTQSPATLSVTPGDSVSLSCLASQSISNNNLHWYQQTSHESPRLITYASQSISGIPSRFSGSGSGTDFFTLSINSVETEDDFGMYFCQQSNSWPLTFGAGTKLELK, (b) Variable heavy chains including the following: Sequence ID 35 (MU_09E09_VH)DVKLVESGEGLVKPGGSLKLSCAASGFTFSSYAMSWVRQTPEKRLEWVAYISSGGDYIYYADTVKGRFTISRDNARNTLYLQMSSLKSEDTAMYYYCTRDPITGTFAYWGQGTLVTVSA, and variable light chains including the following: Sequence ID 37 (MU_09E09_VL)DLQMTQTTSSLSASLGDRVTISCRASQDINNYLNWYQQKPDGTVKLLIYYTSTLHSGVPSRFSGSGSGTDYSLTISNLEEQEDIAATYFCQQGNTLLPWTFGGGTKLEIK, (c) Variable heavy chains including the following: SEQ ID NO: 39 (MU_10F07_VH)DVKLVESGEGLVKPGGSLKLSCAASGFTFSSSYAMSWVRQTPEKRLEWVTYISSGGDYFYYADTVKGRFTISRDNARNTLYLQMSSLKSEDTAMYYYCTRDPITGTFAYWGQGTLVTVSA, and variable light chains including the following: Sequence ID 41 (MU_10F07_VL)DIQMTQTTSSLSASLGDRVTISCRASQDITNYLNWYQQKPDGTVKLLIYYTSTLHSGVPSRFSGSGSGTDFSLTISNLEEQEDIATYFCQQGHMLPWTFGGGTKLEIK, (d) Variable heavy chains including the following: Sequence ID 43 (MU_14C04_VH) EVQLQESGAELVKPGASVKISCKASGYAFSNYWMNWMKQRPGKGLEWIGQIYPGHVNTNYNGNFKDKATLTADK SSSTAYMQLSSLTSEDSAVYFCARSADNSGFVLFAYWGQGTLVTVS, and variable light chains including the following: Sequence ID 45 (MU_14C04_VL) DIVLTQSPASLAVSLGQRATISCRASKSVSTSGYSYLHWYQQKPGQPPKLLIFLASNLESGVPPARFSGSGSGTDFTLNIHPVEEEDAATYYCQHSRELPLTFGAGTKLELK, (e) Variable heavy chains including the following: Sequence ID 47 (MU_19F07_VH) EVKLVESEGGLVQPGSSMKLSCTASGFTFSDYYMAWVRQVPEKGLEWVANINYDGSSTYYLDSLKSRFIISRDNAKNILY LQMSSLKSEDTATYYCARGLTWWDFDVWGTGTTVTVSS, and variable light chains including the following: Sequence ID 49 (MU_19F07_VL) DIVMTQSHKFMSPSVGGDRVSITCKASQDVDTAVAWYQQKPGQSPKLLIYLASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSRFPLTFGAGTKLELK, (f) Variable heavy chains including the following: SEQ ID NO: 51 (FEL_02D09_VH1)DVQLVESGGDLVKPGGSLRLTCVASGFTYSDYGMHWVRQAPGKGLQWVAYISSGSRAVFFADTVKGRFTISRDNAKNTLYLQMNSLKTEDTATYYCVRDRYDGRGFAYWGQGTLVTVSS, and variable light chains including the following: Sequence ID 55 (FEL_02D09_VL1)EIQMTQSPSSLSASPGDRVTITCRASQSISNNLHWYQQKPGKVPKLLLIYYASQSISGVPSRFSGSGSGTDFTLTISSLEPEDAATYYCQQSNSWPLTFGQGT, Variable heavy chains containing (g) or less: SEQ ID NO: 53 (FEL_02D09_VH2)DVQLVESGGDLVKPGGSLRLTCVASGFTFSDYGMHWVRQAPGKGLQWVAYISSGSRAVFFADTVKGRFTISRDNAKNTLYLQMNGLRTEDTATYYCARDRYDGRGFAYWGQGTLVTVSS, and variable light chains including the following: Sequence ID 57 (FEL_02D09_VL2) DIVMTQTPPLSLSVTPPGESASISCRASQSISNNLHWYLQKSGQSPRRLIYYASQSISGVPDRFSGSGSGTDFTTLRISRVEADDVGVYYCQQSNSWPLTFGQGT, Variable heavy chains including (h) below: SEQ ID NO: 59 (CAN_09E09_VH1)EVQLVESGGDLVKPGGSLRLSCVASGFTFSSSYAMSWVRQAPGKGLQWVAYISSGGDYIYYADTVKGRFTISRDNAKNTLYLQMNSLRAEDTAMYYYCVRDPITGTFAYWGQGTLVTVSS, and variable light chains including the following: Sequence ID 63 (CAN_09E09_VL1) EIVMTQSPASLSLSQEEKVTITCRASQDINNYLNWYQQKPGQAPKLLLIYYTSTLHSGVPSRFSGSGSGTDFSFTISSLEPEDVAVYYCQQGNTLLPWTFGQGT, (i) Variable heavy chains including the following: SEQ ID NO: 61 (CAN_09E09_VH2)EVQLVESGGDLLVKPAGSLTLSCLASGFTFSSSYAMSWVRQTPEKGLQWVAYISSGGDYIYYADTVKGRFTISRDNAKNTLYLQMNSLRDEDTAVYYCARDPITGTFAYWGQGTLVTVSS, and a variable light chain including the following: Sequence ID 65 (CAN_09E09_VL2) DIVLTQPTSVSGSLGQRVTISCRASQDINNYLNWYQQLPGKAAPKLLLVYYTSTLHSGVPDRFSGSNSGSATLTITGLQAEDEADYYCQQGNTLLPWTFGQGT, Variable heavy chains including (j) below: Sequence ID 67 (FEL_09E09_VH1)DVQLVESGGDLVKPGGSLRLTCVVASGFTYSSYAMSWVRQAPGKGLQWVAYISSGGDYIYYADTVKGRFTISRDNAKNTLYLQMNSLKTEDTATYYCVRD PITGTFAYWGQGTLVTVSS, and variable light chains including the following: Sequence ID 71 (FEL_09E09_VL1)EIQMTQSPSSLSASPGDRVTITCRASQDINNYLNWYQQKPGKVPKLLLIYYTSTLHSGVPSRFSGSGSGTDFTLTISSLEPEDAATYYCQQGNTLLPWTFGQGT, Variable heavy chains including (k) and below: SEQ ID NO: 69 (FEL_09E09_VH2)DVQLVESGGGNLVKPGGSLRLTCVASGFTFSSYAMSWVRQAPGKGLQWVAYISSGGDYIYYADTVKGRFTISKDNAKNTLYLQMNSLKTEDTATYYCARDPITGTFAYWGQGTLVTVSS, and variable light chains including the following: Sequence ID 73 (FEL_09E09_VL2) DITMTQSPGSLAGSPGQQVTMNCRASQDINNYLNWYQQKPGQHPKLLLIYYTSTLHSGVPDRFSGSGSGTDFTLTISNLQAEDVASYYCQQGNTLLPWTFGQGT, (l) Variable heavy chains including the following: SEQ ID NO: 75 (CAN_10F07_VH1)EVQLVESGGDLVKPGGSLRLSCVASGFTFSSSYAMSWVRQAPGKGLQWVAYISSGGDYFYYADTVKGRFTISRDNAKNTLYLQMNSLRAEDTAMYYCVRDPITGTFAYWGQGTLVTVSS, and variable light chains including the following: Sequence ID 77 (CAN_10F07_VL1) EIVMTQSPASLSLSQEEKVTITCRASQDITNYLNWYQQKPGQAPKLLLIYYTSTLHSGVPSRFSGSGSGTDFSFTISSLEPEDVAVYYCQQGHMLLPWTFGQGT, Variable heavy chains including (m) or less: SEQ ID NO: 79 (CAN_10F07_VH2)EVQLVESGGDLLVKPAGSLTLSCLASGFTFSSSYAMSWVRQTPEKGLQWVAYISSGGDYFYYADTVKGRFTISRDNAKNTLYLQMNSLRDEDTAVYYCARDPITGTFAYWGQGTLVTVSS, and variable light chain including the following: Sequence ID 81 (CAN_10F07_VL2) DIVLTQPTSVSGSLGQRVTISCRASQDITNYLNWYQQLPGKAAPKLLLVYYTSTLHSGVPDRFSGSNSGSATLTITITGLQAEDEADYYCQQGHMLLPWTFGQGT, Variable heavy chains including (n) below: SEQ ID NO: 83 (FEL_10F07_VH1)DVQLVESGGDLVKPGGSLRLTCVVASGFTYSSYAMSWVRQAPGKGLQWVAYISSGGDYFYYADTVKGRFTISRDNAKNTLYLQMNSLKTEDTATYYCVRDPITGTFAYWGQGTLVTVSS, and variable light chains including the following: Sequence ID 85 (FEL_10F07_VL1)EIQMTQSPSSLSASPGDRVTITCRASQDITNYLNWYQQKPGKVPKLLLIYYTSTLHSGVPSRFSGSGSGTDFTLTISSLEPEDAATYYCQQGHMLLPWTFGQGT, (o) Variable heavy chains including the following: Sequence ID 87 (FEL_10F07_VH2)DVQLVESGGDLVKPGGSLRLTCVVASGFTFSSYAMSWVRQAPGKGLQWVAYISSGGDYFYYADTVKGRFTISRDDAKNTLYLQMSSLKTEDTATYYCTGD PITGTFAYWGQGTLVTVSS, and variable light chains including the following: Sequence ID 89 (FEL_10F07_VL2) DITMTQSPGSLAGSPGQQVTMNCRASQDITNYLNWYQQKPGQHPKLLLIYYTSTLHSGVPDRFSGSGSGTDFTLTISNLQAEDVASYYCQQGHMLPWTFGQGT, Variable heavy chains including (p) and below: SEQ ID NO: 91 (CAN_19F07_VH1)EVQLVESGGDLVKPGGSLRLSCVASGFTFFSDYYMAWVRQAPGKGLQWVANINYDGSSTYYLDSLKSRFTISRDNAKNTLYLQMNSLRAEDTAMYYCVRGLLTWDFDDVWGQGTLVTVSS, and variable light chains including the following: Sequence ID 93 (CAN_19F07_VL1) EIVMTQSPASLSLSQEEKVTITCKASQDVDTAVAWYQQKPGQAPKLLLIYLASTRHTGVPSRFSGSGSGTDFSFTISSLEPEDVAVYYCQQYSRFPLTFGQGT, Variable heavy chains including (q) and below: SEQ ID NO: 95 (CAN_19F07_VH2)EVQLVESGGDLVKPAGSLTLSCLASGFTFFSDYYMAWVRQTPEKGLQWVANINYDGSSTYYLDSLKSRFTISRDNAKNTLYLQMNSLRDEDTAVYYCARGLTWWDFDVWGQGTLVTVSS, and a variable light chain including the following: Sequence ID 97 (CAN_19F07_VL2) DIVMTQTPPLSLSVSPGETASISCKASQDVDTAVAWFRQKPGQSPQRLIYLASTRHTGVPDRFSGSGSGTDFTTLRISRVEADDTGVYYCQQYSRFPLTFGQGT, Variable heavy chains including (r) below: SEQ ID NO: 99 (FEL_19F07_VH1)DVQLVESGGDLVKPGGSLRLTCVASGFTYSDYYMAWVRQAPGKGLQWVANINYDGSSTYYLDSLKSRFTISRDNAKNTLYLQMNSLKTEDTATYYCVRGLLTWDDFDVWGQGTLVTVSS, and variable light chains including the following: Sequence ID 101 (FEL_19F07_VL1)EIQMTQSPSSLSASPGDRVTITCKASQDVDTAVAWYQQKPGKVPKLLLIYLASTRHTGVPSRFSGSGSGTDFTLTISSLEPEDAATYYCQQYSRFPLTFGQGT, Variable heavy chains including (s) and below: SEQ ID NO: 103 (FEL_19F07_VH2)DVQLVESGGGNLVKPGGSLRLTCVVASGFTFSDYYMAWVRQAPGKGLQWVANINYDGSSTYYLDSLKSRFTISRDNAKNTLYLQMNSLKTEDTATYYCARGLTWWDFDVWGQGTLVTVSS, and a variable light chain including the following: Sequence ID 105 (FEL_19F07_VL2) DITMTQSPGSLAGSPGQQVTMNCKASQDVDTAVAWYQQKPGQHPKLLLIYLASTRHTGVPDRFSGSGSGTDFTLTISNLQAEDVASYYCQQYSRFPLTFGQGT, Variable heavy chains including (t) or less: Sequence ID 127. (CAN_14C04_VH1) EVQLVESGGDLVKPGGSLRLSCVASGFTFSNYWMNWVRQAPGKGLQWVAQIYPGHVNTNYNGNFKDRFTISRDNARNTVY LQMNSLRAEDTAVYYCARSADNNSGFVLFAYWGQGTLVTVSS, and variable light chains including the following: Sequence ID 131. (CAN_14C04_VL1) EIVMTQSPASLSLSQEEKVTITCRASKSVSSTSGYSYLHWYQQKPGQAPKLLLIYLASNLESGVPPSRFSGSGSGTDFSFTISSLEPEDVAVYYCQHSRELPLTFGQGT, or a variable heavy chain including (u) below: Sequence ID 129. (CAN_14C04_VH2) EVQLVESGGDLVKPGGSLRLSCVASGFTFSNYWMNWVRQSPGKGLQWVAQIYPGHVNTNYNGNFKDRFTISRDNAKNTLYLQMNSLRAEDTAVYFCARSADNSGFVLFAYWGQGTLVTVSS; and variable light chains including the following: Sequence ID 133. (CAN_14C04_VL2) DIVMTQTPLSLSVSPGETASISCRASKSVSTSGYSYLHWYLQKPGQSPQLLIYLASNLESGVSKRFSGSGSGTDFTLRISRVEADDDTGIYYCQHSRELPLTFGQGT The antibody according to claim 1, comprising at least one from the group consisting of the following.
  3. The antibody according to claim 1 or 2, wherein the antibody is a chimeric antibody.
  4. The antibody according to claim 1 or 2, wherein the antibody is canine-like or feline-like.
  5. The antibody according to claim 1 or 2, wherein the antibody inhibits or neutralizes IL-31-mediated or OSM-mediated pruritic or allergic conditions in dogs or cats.
  6. The antibody according to claim 5, wherein the IL-31-mediated or OSM-mediated pruritic condition is selected from the group consisting of atopic dermatitis, eczema, psoriasis, scleroderma, and pruritus.
  7. The antibody according to claim 5, wherein the IL-31-mediated or OSM-mediated allergic condition is selected from the group consisting of allergic dermatitis, summer eczema, urticaria, respiratory fatigue, inflammatory airway disease, recurrent airway obstruction, airway hypersensitivity, chronic obstructive pulmonary disease, and inflammatory processes arising from autoimmunity.
  8. The antibody according to claim 1 or 2, wherein the antibody inhibits IL-31-mediated or OSM-mediated fibrous or inflammatory disorders.
  9. The antibody according to claim 8, wherein the IL-31-mediated or OSM-mediated fibrotic disorder is selected from the group consisting of renal fibrosis, pulmonary fibrosis, and cutaneous fibrosis.
  10. The antibody according to claim 8, wherein the IL-31-mediated or OSM-mediated inflammatory disorder is selected from the group consisting of autoimmune inflammatory processes, inflammation of the skin or joints in animals suffering from osteoarthritis, immune-mediated polyarthritis, chronic bronchitis, allergic asthma, atopic dermatitis, allergic dermatitis, suppurative traumatic dermatitis, atherosclerosis, and cardiovascular disease.
  11. The antibody according to claim 1 or 2, wherein the antibody reduces IL-31-mediated or OSM-mediated inflammatory pain.
  12. The antibody according to claim 11, wherein the IL-31-mediated or OSM-mediated inflammatory pain is osteoarthritis pain.
  13. A veterinary composition comprising a therapeutically effective amount of the antibody described in claim 1 or 2.
  14. A veterinary composition for use in a method for treating IL-31-mediated or OSM-mediated disorders in a subject, the veterinary composition according to claim 13.
  15. The veterinary composition according to claim 14, wherein the IL-31-mediated or OSM-mediated disorder is selected from the group consisting of pruritic state, allergic state, fibrotic disorder, inflammatory disorder, and inflammatory pain.
  16. The veterinary composition according to claim 15, wherein the IL-31-mediated or OSM-mediated pruritic condition is selected from the group consisting of atopic dermatitis, eczema, psoriasis, scleroderma, and pruritus.
  17. The veterinary composition according to claim 15, wherein the IL-31-mediated or OSM-mediated allergic condition is selected from the group consisting of allergic dermatitis, summer eczema, urticaria, respiratory distress, inflammatory airway disease, recurrent airway obstruction, airway hypersensitivity, chronic obstructive pulmonary disease, and inflammatory processes arising from autoimmunity.
  18. The veterinary composition according to claim 15, wherein the IL-31-mediated or OSM-mediated fibrotic disorder is selected from the group consisting of renal fibrosis, pulmonary fibrosis, and cutaneous fibrosis.
  19. The veterinary composition according to claim 15, wherein the IL-31-mediated or OSM-mediated inflammatory disorder is selected from the group consisting of autoimmune inflammatory processes, inflammation of the skin or joints of animals suffering from osteoarthritis, immune-mediated polyarthritis, chronic bronchitis, allergic asthma, atopic dermatitis, allergic dermatitis, suppurative traumatic dermatitis, atherosclerosis, and cardiovascular disease.
  20. The veterinary composition according to claim 15, wherein the IL-31-mediated or OSM-mediated inflammatory pain is osteoarthritis pain.

Description

This invention belongs to the field of immunotherapy. More specifically, this invention relates to the oncostatin M (OSM) receptor, and its modifiers, such as monoclonal antibodies that bind to the canine and/or feline oncostatin M receptor beta subunit (OSMR-β). This invention also relates to the diagnosis and/or treatment of diseases in canines and felines associated with OSM and IL-31 using anti-OSMR-β antibodies. Cytokines comprise a large population of small proteins that play crucial roles in the development and regulation of immune responses. Certain cytokines are associated with the initiation and persistence of pathological pain behavior, including nerve and skin injury. Interleukin-31 (IL-31), a more recently discovered cytokine, is associated with the induction of chronic skin inflammation (Dillon et al. (2004) Nat. Immunol. 5, 752-760). Human and mouse data show high expression of IL-31 associated with pruritus, alopecia, skin lesions, and severe inflammatory skin disorders including atopic dermatitis (AD), as well as other controlled allergic diseases such as asthma (Dillon et al. (2004) (above), Neis et al. (2006) J. Allergy Clin. Immunol. 118, 930-937, Rabenhorst et al. (2014) Curr. Allergy Asthma Rep. 14, 423, Cornelissen et al. (2012) Eur. J. Cell Biol. 91, 552-566, Takaoka et al. al. (2006) Exp. Dermatol. 15, 161-167, Sonkoly et al. (2006) J. Allergy Clin. Immunol. 117, 411-417, Lewis et al. (2017) J. Eur. Acad. Dermatology Venereol. 31, 142-150). Experimental animal models of human Alzheimer's disease (AD) have reported a strong correlation between itchiness-related scratching behavior and IL-31 mRNA expression in NC/Nga mice (Takaoka et al. (see above)). Compared to healthy controls, elevated IL-31 serum levels were found in adult patients with AD (Raap et al. (2008) J. Allergy Clin. Immunol. 122, 421-423) and in pediatric patients experiencing AD flares and remission (Ezzat et al. (2011) J. Eur. Acad. Dermatology Venereol. 25, 334-339). Furthermore, these data suggest that IL-31 represents an important target for the development of treatments for such inflammatory skin diseases in humans. Antagonist anti-IL-31 monoclonal antibodies (mAbs) are currently under development for human health (Pantazi et al. (2017) Nat. Rev. Drug Discov. 17, 237-238, Nemoto et al. (2016) Br. J. Dermatol. 174, 296-304). In addition, ant-IL-31 mAbs have already been developed for animal health (U.S. Patent No. 8,790,651B2 against Bammert et al., Michels et al. (2016) Vet. Dermatol. 27, 478-e129). For example, the anti-hIL-31RA mAb CIM331 binds to IL-31RA, inhibits IL-31 signaling, and reduces severe pruritus (Nemoto et al. (2016) (see above)). In veterinary medicine, lokivetomab, a "canine-derived" anti-IL-31 mAb, has shown efficacy in clinical trials for pruritus in canines and is currently approved as a treatment for AD in dogs (Michels et al. (2016) (see above)). IL-31 is a member of the IL-6 cytokine superfamily, preferentially produced by T helper type 2 cells (Dillon et al. (2004) (see above)). Mature human IL-31 (hIL-31) has a predicted topology of four antiparallel helices (Le Saux et al. (2010) J. Biol. Chem. 285, 3470-3477) and is composed of 141 amino acids (Dillon et al. (2004) (see above)). The IL-31 signaling pathway is thought to be mediated via the gp130-like type 1 cytokine receptor (IL-31RA, also known as GPL) and the oncostatin M receptor (OSMR) (Dillon et al. (see above), Le Saux et al. (2010) (see above), Diveu et al. (2004) Eur. Cytokine Netw. 15, 291-302, Zhang et al. (2008) Cytokine Growth Factor Rev. 19, 347-356). Both receptors belong to the type I cytokine receptor family, sharing a common cytokine-binding domain (CBD) formed by two fibronectin type III-like domains (Diveu et al. (2003) J. Biol. Chem. 278, 49850-49859). Previous studies provided immunoprecipitation evidence that human IL-31RA (hIL-31RA) directly binds to hIL-31. These same studies failed to detect direct binding of human OSMR (hOSMR) to hIL-31 through immunoprecipitation (Le Saux et al. (2010) Molecular discrimination of human interleukin-31-mediated signal transmission through site-directed mutagenesis. J. Biol. Chem. 285, 3470-3477; Diveu et al. (2004) (see above)). However, when hIL-31RA and hOSMR are combined, there is a significant increase in binding, suggesting that hIL-31 first binds to hIL-31RA, at which point hOSMR is recruited to form a ternary complex (Le Saux et al. (2010) (above), Diveu et al. (2004) (above)). In this model, the ternary complex activates numerous downstream signaling pathways (Dillon et al. (2004) (see above), Le Saux et al. (2010) (see above), Diveu et al. (2004) (see above), Dambacher et al. (2007) Gut 56, 1257-1265, Dreuw et al. (2004) J. Biol. Chem. 279, 36112-36120). Based on the structure of the IL-6/IL-6α-receptor/gp130 complex (Boulanger et al. (2003) Science. 300, 2101-2104), the IL-6 cytokine superfamily is thought to interact with its receptor via three distinct contact bindi