Randomized Phase I Healthy Volunteer Study of UTTR1147A (IL‐22Fc): A Potential Therapy for Epithelial Injury

Abstract

Most treatments for epithelial injury target hematopoietic mechanisms, possibly causing immunosuppression. Interleukin (IL)-22 promotes tissue regeneration, acting directly on epithelial cells. UTTR1147A, a human IL-22Fc (immunoglobulin G (IgG)4) fusion protein, activates IL-22 signaling. This phase I placebo-controlled trial of single, ascending, i.v. (1-120 μg/kg) and s.c (3-120 μg/kg) doses of UTTR1147A analyzed its effects on safety, tolerability, pharmacokinetics, and pharmacodynamic biomarkers in healthy volunteers. Most adverse events (AEs) were mild or moderate. The maximum tolerated i.v. dose in healthy volunteers was 90 μg/kg. Predominant AEs were dose-dependent reversible skin effects consistent with IL-22 pharmacology. UTTR1147A exposure increased approximately dose-proportionally, with a half-life of ~1 week. IL-22 biomarkers (regenerating islet protein 3A (REG3A), serum amyloid A (SAA), and C-reactive protein (CRP)) increased dose-dependently. Neither inflammatory symptoms and signs nor cytokines increased with CRP elevations. UTTR1147A demonstrated acceptable safety, pharmacokinetics, and IL-22R engagement, supporting further clinical development.

Nonclinical safety assessment of a human interleukin‐22FC IG fusion protein demonstrates in vitro to in vivo and cross‐species translatability

“…While the functional aspects of the increase in REG3A in cynomolgus monkeys given UTTR1147A were not explored in the toxicity studies reported here, systemic administration of recombinant REG3γ, a murine homologue of REG3A, partially protected against weight loss and mortality in IL22−null mice infected with Citrobacter rodentium . As with the skin findings, these transient dose‐dependent elevations in acutephase proteins as well as in REG3A were observed in human clinical trials …”

“…5 As with the skin findings, these transient dose-dependent elevations in acutephase proteins as well as in REG3A were observed in human clinical trials. 22 Doses of 75 μg/kg and above in monkey studies presented here produced C max at or above the in vitro and in vivo EC50 level estimated from human hepatocytes (~3 μg/mL) and cynomolgus monkeys (~1 μg/mL), respectively. 19 In general, the doses of IL-22Fc required to elicit measurable serum biomarker elevations in healthy mice and monkeys (muIL-22Fc or UTTR1147A, respectively) were associated with a serum C max above 1 μg/mL and these biomarkers returned to baseline when serum levels were below the 10-100 ng/mL range.…”

“…Thus, the toxicology program has appropriately identified relevant toxicities associated with UTTR1147A as reversible, minimal to mild epidermal hyperplasia with minimal inflammation, and a reversible acute‐phase inflammatory response. All toxicities are considered monitorable, manageable, and reversible; and have reliably translated to the toxicities observed in humans in ongoing clinical trials …”

“…and have reliably translated to the toxicities observed in humans in ongoing clinical trials. 22 Lastly, it is also important to note, that depending on the tissue environment in which IL-22 is being upregulated, the functional consequence of activating the IL-22 pathway can lead to either further inflammation or tissue repair. 11 More recently, contributions of IL-22 from mast cells 28 and innate lymphoid cells (ILCs; 29 have been postulated to contribute to the pathophysiology of diseases such as psoriasis and colon cancer.…”

The role of IL-22 in intestinal health and disease

“…As no preclinical model recapitulates all aspects of human IBD, high-quality clinical data will be critical to elucidate the role of IL-22 in human disease. In one approach, an IL-22 IgG4 Fc fusion protein (UTTR1147A) was developed and shown to elicit systemic pharmacodynamic effects when administered to human volunteers (Rothenberg et al, 2019). UTTR1147A is currently being tested in patients with moderate-to-severe ulcerative colitis and Crohn’s disease (NCT03558152).…”