Targeting IL-22 activity to the gut epithelium confers disease benefit without provoking skin inflammation

Introduction/Rationale: IL-22 is a cytokine acting on surface-lining epithelial cells to induce antimicrobial defense and barrier regeneration. It has gained clinical interest for the treatment of inflammatory bowel disease due to its non-immunosuppressive mechanism. Prior clinical efforts have delivered IL-22 systemically, but development was constrained by dose-limiting skin toxicity. This presents an opportunity to widen the therapeutic index by targeting IL-22 to gut epithelium while avoiding keratinocytes and other IL-22-responsive cells.

Methods: A cell-surface protein specifically expressed on gut epithelium was identified using Ampersand’s proprietary Address Map. Candidate AND-Body molecules were engineered by pairing an Address binder with a modified IL-22 which signals only when the Address binder is engaged. Activity was evaluated in vitro and in vivo in rodents and in non-human primates (NHPs) for potency on gut vs. skin tissue.

Results: Studies on human cell lines showed that the AND-Body AMP-220 has >500-fold increased potency on enterocytes compared to a non-targeted IL-22 control, with no activity on keratinocytes. Mouse studies showed enrichment of AMP-220 in small intestine and colon relative to non-targeted tissues. This was accompanied by highly selective activity in small intestine and colon when compared to a non-targeted IL-22 Fc control. Moreover, AMP-220 delivered significant benefit in both therapeutic and prophylactic models of DSS-induced colitis. In NHPs the AND-Body demonstrated robust induction of IL-22 target genes in colon with minimal evidence of skin activity or systemic inflammation.

Conclusion: By identifying a gut-specific address and tuning of gut-targeting and cytokine effector moieties, our IL-22 AND-Body shows potent and specific activity on human enterocytes, gut-specific PK/PD and efficacy in rodents, and localized activity in NHPs. These results support continued advancement of AMP-220 through IND-enabling studies and highlight the potential of precision-targeted cytokines.