Generation and functional characterization of anti-human and anti-mouse IL-36R antagonist monoclonal antibodies. Issue 7 (3rd October 2017)

• Record Type: Journal Article
• Authors: Ganesan, Rajkumar; Raymond, Ernest L.; Mennerich, Detlev; Woska, Joseph R.; Caviness, Gary; Grimaldi, Christine; Ahlberg, Jennifer; Perez, Rocio; Roberts, Simon; Yang, Danlin; Jerath, Kavita; Truncali, Kristopher; Frego, Lee; Sepulveda, Eliud; Gupta, Priyanka; Brown, Su-Ellen; Howell, Michael D.; Canada, Keith A.; Kroe-Barrett, Rachel; Fine, Jay S.; Singh, Sanjaya; Mbow, M. Lamine
• Is Part Of: MAbs. Volume 9:Issue 7(2017)
• Page Start: 1143
• Page End: 1154
• Publication Date: 2017-10-03
• Subjects: Generalized Pustular Psoriasis -- IL-36R -- IL1RL2 -- IL1R family -- antagonist antibody; Monoclonal antibodies -- Therapeutic use -- Periodicals; Monoclonal antibodies -- Periodicals; Antibodies, Monoclonal -- Periodicals; 616.0798
• DOI: 10.1080/19420862.2017.1353853
• Languages: English
• ISSNs: 1942-0862

Abstract

ABSTRACT: Deficiency of interleukin (IL)-36 receptor antagonist (DITRA) syndrome is a rare autosomal recessive disease caused by mutations in IL36RN . IL-36R is a cell surface receptor and a member of the IL1R family that is involved in inflammatory responses triggered in skin and other epithelial tissues. Accumulating evidence suggests that IL-36R signaling may play a role in the pathogenesis of psoriasis. Therapeutic intervention of IL-36R signaling offers an innovative treatment paradigm for targeting epithelial cell-mediated inflammatory diseases such as the life-threatening psoriasis variant called generalized pustular psoriasis (GPP). We report the discovery and characterization of MAB92, a potent, high affinity anti-human IL-36 receptor antagonistic antibody that blocks human IL-36 ligand (α, β and γ)-mediated signaling. In vitro treatment with MAB92 directly inhibits human IL-36R-mediated signaling and inflammatory cytokine production in primary human keratinocytes and dermal fibroblasts. MAB92 shows exquisite species specificity toward human IL-36R and does not cross react to murine IL-36R. To enable in vivo pharmacology studies, we developed a mouse cross-reactive antibody, MAB04, which exhibits overlapping binding and pharmacological activity as MAB92. Epitope mapping indicates that MAB92 and MAB04 bind primarily to domain-2 of the human and mouse IL-36R proteins, respectively. Treatment with MAB04 abrogates imiquimod and IL-36-mediated skin inflammation in the mouse, further supporting an important role for IL-36R signaling in epithelial cell-mediated inflammation.