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

Abstract

Although Interleukin‐22 (IL‐22) is produced by various leukocytes, it preferentially targets cells with epithelial origins. IL‐22 exerts essential roles in modulating various tissue epithelial functions, such as innate host defense against extracellular pathogens, barrier integrity, regeneration, and wound healing. Therefore, IL‐22 is thought to have therapeutic potential in treating diseases associated with infection, tissue injury or chronic tissue damage. A number of in vitro and in vivo nonclinical studies were conducted to characterize the pharmacological activity and safety parameters of UTTR1147A, an IL‐22 recombinant fusion protein that links the human cytokine IL‐22 with the Fc portion of a human immunoglobulin. To assess the pharmacological activity of UTTR1147A, STAT3 activation was evaluated in primary hepatocytes isolated from human, cynomolgus monkey, minipig, rat, and mouse after incubation with UTTR1147A. UTTR1147A activated STAT3 in all species evaluated, demonstrating that all were appropriate nonclinical species for toxicology studies.The nonclinical safety profile of UTTR1147A was evaluated in rats, minipigs, and cynomolgus monkeys to establish a safe clinical starting dose for humans in Phase I trials and to support clinical intravenous, subcutaneous and/or topical administration treatment regimen. Results demonstrate the cross‐species translatability of the biological response in activating the IL‐22 pathway as well as the translatability of findings from in vitro to in vivo systems. UTTR1147A was well tolerated in all species tested and induced the expected pharmacologic effects of epidermal hyperplasia and a transient increase in on‐target acute phase proteins. These effects were all considered to be clinically predictable, manageable, monitorable, and reversible.

IL-10 Family Cytokines IL-10 and IL-22: from Basic Science to Clinical Translation

“…UTTR1147A has modified potency of IL-22 to achieve a preferred therapeutic index. It exhibits therapeutic benefit in mouse colitis models and induces skin acanthosis and wound-healing reaction in minipigs (Rothenberg et al, 2019;Stefanich et al, 2018;Lee et al, 2018). The side effects in human trials with both molecules include dry skin and injection-site reactions.…”

An Open‐Label, Dose‐Escalation Study to Assess the Safety and Efficacy of IL‐22 Agonist F‐652 in Patients With Alcohol‐associated Hepatitis

“…These study subjects were then dichotomized according to their MELD scores and recruited into the study: 9 subjects were placed in the MELD 11-20 group, following demonstration of the absence of side effects in this group, and 9 patients were placed in the MELD 21-28 group. The cutoff of a MELD score of 20 points was used to define moderately severe alcoholassociated hepatitis (MELD [11][12][13][14][15][16][17][18][19][20] and severe AH (21-28). (23,24) Patients were sequentially assigned into three subgroups according to F-652 dose, starting with 10 μg/kg, followed by 30 μg/kg, and finally 45 μg/kg.…”

“…(17) The hepatoprotective effect of the F-652 formulation of IL-22 was demonstrated in acute liver injury models including partial hepatectomy. (16,18) F-652 demonstrated a favorable safety profile in acute and long-term (3-month) studies in rats and monkeys (19) and healthy volunteers. (20) Given its mechanisms of action, the IL-22 agonist F-652 is an excellent candidate for AH treatment.…”

Identification of an IL-22-Dependent Gene Signature as a Pharmacodynamic Biomarker

“…The IL-22 IgG fusion protein, UTR1147A, is currently in clinical development for diseases with epithelial injuries such as IBD. In addition to the assessment of the nonclinical safety and pre-clinical and translational pharmacology [ 21 , 26 ] of UTR1147A, we describe the identification of a sensitive gene signature in a human intestinal epithelial cell line. For a gene signature to act as a clinically translatable biomarker, it must be in an accessible tissue, highly sensitive to low doses of drug, able to differentiate IL-22 from the inflammatory cytokines also present under disease conditions, and dose-dependent across a range of concentrations.…”

“…The safety profile of the IL-22Fc fusion protein UTTR1147A has been established in multiple species [ 26 ], and the pharmacology suggests translatability to clinical use in humans. The pharmacodynamic (PD) biomarkers used in preclinical studies were the serum Reg3β and SAA in rodents, and REG3A, LBP and SAA in cynomolgus monkeys.…”