Multifunctional antibody-derived IL-12 mimetics: prospects of future clinical development

INTRODUCTION: Cytokines are important immunomodulatory proteins for therapeutic applications but display several limitations due to their pleiotropic nature, sometimes systemic toxicities, and suboptimal pharmacokinetics. Recent advances in protein engineering have enabled the development of antibody-derived cytokine mimetics which elicit cytokine-like signaling by targeting specific cytokine receptor subunits. AREAS COVERED: In this special report, we summarize our current knowledge of antibody-based cytokine mimetics. We discuss antibody-derived mimetics for several cytokines such as IL-2 an IL-18 and put emphasis on IL-12 receptor agonists with biased cell subset specificities. Furthermore, we provide an overview of next-generation engineering possibilities, including conditionally active cytokine mimetics which convert an anti-inflammatory stimulus into a pro-inflammatory agonism. EXPERT OPINION: Antibody-derived cytokine mimetics represent an emerging class of immunomodulatory agents in a bi- or multispecific architecture which might complement conventional cytokine engineering approaches. While these entities can be highly tailor-made for precise receptor engagement, enabling the modulation of downstream signaling, cell-type specificity, and functional bias, challenges remain, such as potential immunogenicity, preclinical model limitations, and differences in receptor binding affinities compared with natural cytokines.