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P418 Pharmacodynamic biomarkers demonstrate dose-dependent pharmacological activity of the IL-22Fc fusion protein UTR1147A in healthy volunteers in a phase 1a clinical trial

Lekkerkerker A., Harder B., Kulkarni P., Zhao R., Choi M., Noyes A., Polihrom A., Fillos D., Rae J., Danilenko D., Stefanich E., Herman A., Lu T.

Genentech, Research and Early Development, South San Francisco, United States

Background

Interleukin-22 (IL-22) belongs to the IL 10 cytokine family [1] and binds specifically to the IL-22 receptor (IL-22R) heterodimer, expressed on a variety of epithelial cells [2]. IL-22 modulates innate immunity via activation of STAT3 and induces subsequent regenerative and protective properties [3]. UTTR1147A, IL-22Fc, is a recombinant fusion protein in development for IBD.

In cynomolgus monkeys, UTTR1147A demonstrated dose-dependent increases in serum levels of regenerating islet-derived protein 3A (REG3A), an antimicrobial C-type lectin as well as serum amyloid protein A (SAA), a STAT3-dependent anti-microbial protein and acute phase protein C-reactive protein (CRP). This observation was corroborated in mice where murine IL-22Fc induced dose-dependent increases in serum REG3β, the murine homologue of Reg3A, and SAA. Therefore, REG3A, SAA, and CRP are attractive pharmacodynamic (PD) biomarkers that are supportive of IL 22R target engagement.

Methods

The safety and tolerability of UTTR1147A was assessed in a first-in-human observer-blinded, placebo-controlled single ascending dose Phase 1a study in healthy volunteers at a single center. Subjects were given either intravenously (IV) placebo or subcutaneous (SC) UTTR1147A at doses ranging from 1 to 120 μg/kg. To assess pharmacological activity of UTTR1147A, exploratory PD biomarker levels of REG3A, SAA and CRP were measured in serum samples obtained predose and at defined postdose time points.

Results

UTTR1147A induced dose-dependent increases in serum SAA, REG3A and CRP levels compared to placebo. Levels of all three biomarkers peaked at higher concentrations and at earlier time points following IV compared to SC administration. Increases of REG3A were sustained longer compared to increases seen with SAA and CRP. Normalized Reg3A levels remained slightly above baseline at end of study following 90 and 120 μg/kg IV and 120 μg/kg SC dose levels, whereas lower dose groups were near baseline by day 43. The observed increases in CRP were a direct pharmacologic effect of exposure to UTTR1147A. Consistent with nonclinical studies, no signs or symptoms of systemic inflammation accompanied these increases in CRP.

Conclusion

In conclusion, dose-dependent increases in serum levels of PD biomarkers REG3A, SAA, and CRP were observed following treatment with UTTR1147A compared to placebo. These PD biomarker data provide evidence that UTTR1147A effectively engaged its target receptor IL-22R and demonstrate dose-dependent pharmacological activity of UTTR1147A in healthy volunteers.

References:

[1] Ouyang W et al. (2011), Regulation and functions of the IL-10 family of cytokines in inflammation and disease, Annul Rev Immunol

[2] Gurney AL, (2004), IL-22, a Th1 cytokine that targets the pancreas and select other peripheral tissues, Int Immunopharmacol

[3] Wolk K et al. (2004), IL-22 increases the innate immunity of tissues, Immunity