Use of a Tissue-Targeting Recombinant Human Interleukin-22 Fusion Molecule (F-652) for the Treatment of Advanced Refractory Lower GI Acute Gvhd

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Steroid-refractory (SR) gastrointestinal acute graft vs. host disease (GI aGVHD) remains a major complication of allogeneic hematopoietic transplantation. Ruxolitinib is the only FDA-approved therapy for SR aGVHD, and patients in whom ruxolitinib is ineffective or poorly tolerated have limited treatment options and high mortality. Interleukin-22 (IL-22) has been shown to promote epithelial survival, regeneration, and production of innate antimicrobial molecules within the GI tract. F-652, a recombinant human (rh)IL-22 fusion protein showed a promising day 28 treatment response rate in a phase 2 trial for newly diagnosed lower GI aGVHD. We sought to investigate the potential use of rhIL-22 in SR GI aGVHD after ruxolitinib failure. Three patients with SR lower GI aGVHD received weekly doses of F-652. All patients were initially treated with methylprednisolone 2 mg/kg/day without response and failed 5-7 prior lines of therapy including ruxolitinib (Table). They also had multiple episodes of bacteremia and GVHD-associated GI bleeding. Patients were allowed to continue belumosudil concurrently with F-652 since in vitro studies suggested rho kinase inhibition did not impair the trophic effects of IL-22 on intestinal epithelium. Since IL-22’s signaling through JAK/STAT raised the question that JAK inhibition could compromise IL-22 activity, ruxolitinib continuation was considered on a case-by-case basis. IL-22 induces C-reactive protein (CRP) and we measured blood CRP concentrations as a marker of in vivo F-652 activity. Consistent CRP elevations were observed 3 days after F-652 doses in Pts A and C (Figure). These CRP elevations occurred despite concurrent use of belumosudil in Pt A and ruxolitinib in Pt C. By day 28 following F-652 initiation, both Pts achieved a partial response, with resolution of GI bleeding. Pt A had experienced 21 episodes of bacteremia before F-652. Following F-652, resolution of bacteremias and overall improvement allowed for patient discharge following a 14-month hospitalization. Pt B had persistent diarrhea and GI bleeding after F-652, and died at day 149 post-HCT. Pt C received 6 doses of F-652 and achieved a partial response before eventually experiencing disease progression. Overall, F-652 treatment was well tolerated without significant drug-related adverse events. This is the first report of IL-22 therapy in SR aGVHD. Whereas most GVHD treatments involve immunosuppresion, IL-22 acts on epithelial cells where it can support tissue recovery, improve barrier function, and promote innate antimicrobial immunity. CRP elevations post-treatment suggest that IL-22 may be able to exert such effects even with concurrent ruxolitinib. These findings support further development of the tissue-supportive strategies to enhance the recovery of damaged gastrointestinal mucosa in advanced lower GI aGVHD.

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