Covalent Immune Recruiters (CIRs): Tools To Gain Chemical Control Over Immune Recognition.

Unprecedented progress made in the treatment of cancer using the body’s own immune system has encouraged the development of synthetic molecule based immunotherapeutics. An emerging class of these compounds, called Antibody Recruiting Molecules (ARMs) or Antibody Engagers (AEs), function by reversibly binding antibodies naturally present in human serum and recruiting these to cancer cells to form quaternary complexes with immune cells that drive cancer cell destruction. Despite their promise, the requirement to form quaternary complexes governed by multiple equilibria complicates an understanding of their in vivo efficacy. Particularly problematic are low endogenous serum antibody concentrations and rapid clearance of AEs from circulation. Here we describe a new class of bifunctional chemical tools we call covalent immune recruiters (CIRs). CIRs covalently label specific serum antibodies in a selective manner to a target protein binding ligand. CIRs thereby exert well defined control over antibody recruitm...