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A7759 - ABM125 Anti-IL-25 Antibody Pre-Clinical Development for Viral Asthma Exacerbations Identifies IL-25 Mediated Regulation of Type-2- and Anti-Viral Immunity
Author Block: N. Bartlett1, J. Girkin1, T. Williams1, T. Vincent2, C. Jackson2, K. Alton2, R. Shimkets2; 1University of Newcastle, Newcastle, Australia, 2Abeome Corporation, Athens, GA, United States.
Background IL-25 is a type-2 immune activating cytokine that is highly expressed in asthma. We have reported that undifferentiated asthmatic bronchial epithelial cells (BECs) infected ex vivo and human asthmatic subjects infected in vivo with rhinovirus exhibit up-regulated expression of IL-25, identifying this molecule as a target for mAb-based therapy for viral asthma exacerbations. Despite this an effective therapeutic anti-IL-25 mAb has yet to progress through pre-clinical development, potentially due to issues with generating potent, highly expressed neutralizing anti-IL-25 mAbs in mice. We hypothesized that the AbeoMouse™ platform would enable production of high affinity mAbs against IL-25 that block both human and mouse IL-25 in pre-clinical models of rhinovirus induced asthma exacerbations. Methods AbeoMouse™ enables generation of therapeutic mAbs against ‘difficult’ targets that are highly conserved between human and mouse and using this we have generated a highly potent mAb (ABM125) with low picomolar binding affinity for both human and mouse IL-25. To block IL-25 with ABM125 in vitro we used fully differentiated asthmatic BECs from mild, moderate and severe eosinophilic asthmatics (>3% airway eosinophils). BECs were obtained by brushing at bronchoscopy and cultured on transwell inserts at the air-liquid interface for 24 days before treatment with ABM125. At day 25 ALI epithelial cultures were infected with minor group RV1B or major group RV43 MOI 0.1. Cells and apical media were collected to assess impact of IL-25 blockade on RV-induced inflammatory and anti-viral immune gene and protein expression. To test efficacy of candidate anti-IL-25 mAbs in vivo we employed a mouse model of RV infection induced exacerbation of OVA-induced allergic airways disease. Results From a panel of monoclonal antibodies, we identified one mAb (ABM125) that exhibited potent neutralizing activity in vitro against mammalian cell expressed human and mouse IL-25 with sub-micromolar IC50. Differentiate asthmatic BECs expressed IL-6, CCL5, CXCL10, CCL22 and IL-25 in response to RV infection. IL-25 blockade in RV-infected ALI-BEC cultures with ABM125 modified viral induction of inflammatory cytokines whilst increasing expression of anti-viral interferons. In vivo ABM125 suppressed a range of type-2 associated inflammatory markers including eosinophilic airway inflammation and lung type-2 cytokine expression whilst limiting viral replication. Conclusions ABM125 is a potent anti-IL-25 therapeutic mAb that neutralizes human and mouse IL-25. Using ABM125 we demonstrated the key role of IL-25 in driving virus induced allergic airways disease. We have also identified a novel immunopathogenic mechanism: blocking IL-25 in RV-infected asthmatic epithelium also improved anti-viral interferon production.