title: Dual Inhibition of Interleukin-23 and Interleukin-17 Offers Superior Efficacy in Mouse Models of Autoimmunity.
abstract: Therapies targeting either interleukin (IL)-23 or IL-17 have shown promise in treating T helper 17 (Th17)-driven autoimmune diseases. Although IL-23 is a critical driver of IL-17, recognition of nonredundant and independent functions of IL-23 and IL-17 has prompted the notion that dual inhibition of both IL-23 and IL-17 could offer even greater efficacy for treating autoimmune diseases relative to targeting either cytokine alone. To test this hypothesis, we generated selective inhibitors of IL-23 and IL-17 and tested the effect of either treatment alone compared with their combination in vitro and in vivo. In vitro, using a novel culture system of murine Th17 cells and NIH/3T3 fibroblasts, we showed that inhibition of both IL-23 and IL-17 completely suppressed IL-23-dependent IL-22 production from Th17 cells and cooperatively blocked IL-17-dependent IL-6 secretion from the NIH/3T3 cells to levels below either inhibitor alone. In vivo, in the imiquimod induced skin inflammation model, and in the myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis model, we demonstrated that dual inhibition of IL-17 and IL-23 was more efficacious in reducing disease than targeting either cytokine alone. Together, these data support the hypothesis that neutralization of both IL-23 and IL-17 may provide enhanced benefit against Th17 mediated autoimmunity and provide a basis for a therapeutic strategy aimed at dual targeting IL-23 and IL-17.
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.) paul.mangan@bms.com.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Mangan
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
authors.forename: Linhui Julie
authors.initials: LJ
authors.lastname: Su
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
authors.forename: Victoria
authors.initials: V
authors.lastname: Jenny
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Tatum
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
authors.forename: Caryn
authors.initials: C
authors.lastname: Picarillo
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
authors.forename: Stacey
authors.initials: S
authors.lastname: Skala
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
authors.forename: Noah
authors.initials: N
authors.lastname: Ditto
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
authors.forename: Zheng
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
authors.forename: XiaoXia
authors.initials: X
authors.lastname: Yang
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
authors.forename: Pete Z
authors.initials: PZ
authors.lastname: Cotter
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
authors.forename: David J
authors.initials: DJ
authors.lastname: Shuster
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
authors.forename: Yunling
authors.initials: Y
authors.lastname: Song
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
authors.forename: Virna
authors.initials: V
authors.lastname: Borowski
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
authors.forename: Rochelle L
authors.initials: RL
authors.lastname: Thomas
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Heimrich
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
authors.forename: Brigitte
authors.initials: B
authors.lastname: Devaux
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
authors.forename: Ruchira
authors.initials: R
authors.lastname: Das Gupta
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
authors.forename: Irvith
authors.initials: I
authors.lastname: Carvajal
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
authors.forename: Kim W
authors.initials: KW
authors.lastname: McIntyre
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
authors.forename: Jenny
authors.initials: J
authors.lastname: Xie
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
authors.forename: Qihong
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
authors.forename: Mary
authors.initials: M
authors.lastname: Struthers
authors.affiliation: Discovery Biology, Immunoscience (P.R.M., S.S., X.Y., D.J.S., Y.S., V.B., R.L.T., E.M.H., K.W.M., J.X., Q.Z., M.S., L.M.S.-C.) Selection Technologies (L.J.S., V.J.), Immunogenicity Prediction (C.P.), Pharmacology (P.Z.C., I.C.), Discovery Assays (R.D.G.), Bristol-Myers Squibb Research and Development, Waltham, Massachusetts; Protein Science and Structure, Bristol-Myers Squibb Research and Development, Princeton, New Jersey (Z.L.); Hybridoma Research, Bristol-Myers Squibb Research and Development, Redwood City, California (A.L.T., B.D.); and Wasatch Microfluidics, Salt Lake City, Utah (N.D.).
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Salter-Cid
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D015551:Autoimmunity / Q000187:drug effects / Q000276:immunology*; D018920:Coculture Techniques; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D053759:Interleukin-23 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D011897:Random Allocation
chemical_list: D000911:Antibodies, Monoclonal; D020381:Interleukin-17; D053759:Interleukin-23