Design of De Novo Mimetic Protein of Interleukin-21

Abstract

Interleukin-21 (IL-21) is crucial in coordinating immune cells and has pleiotropic effects in their immune responses. It has established clinical anti-tumor activity in many cancer models. Despite its efficacy, its therapeutic window has been limited due to its systemic toxicity and poor protein engineerability, resulting in the molecule with suboptimal biodistribution and pharmacokinetic properties. In addition, the limited cross-reactivity of human IL-21 in mice complicates the use of animal models to study the toxicity and activity of candidate IL-21 therapeutics. Here, we created de novo IL-21 mimetic proteins that can fully recapitulate its interaction with receptors and the biology of native IL-21 in both humans and mice.