Antibody-Recruiting Small Molecules: Synthetic Constructs as Immunotherapeutics

The ability to harness one's endogenous immune response against a pathogen has significantly advanced the treatment of many serious diseases. While immune-based therapeutic strategies have traditionally been dominated by biologics, recent advances at the interface of organic chemistry and immunology have yielded new classes of small molecules that can direct and regulate immune responses. This chapter focuses on the development and application of one such class of small molecules called antibody-recruiting small molecules (ARMs) for the treatment of cancer and infectious diseases. ARMs are bifunctional small molecules that simultaneously bind to a pathogen-associated cell surface biomarker and endogenous antibodies, forming a ternary complex. Formation of the ternary complex then directs antibody dependent, immune effector functions, resulting in targeted cytotoxicity. Here, we present an overview of the conception and evolution of ARMs, including key case studies highlighting their in vitro and in vivo efficacies, as well as some key challenges and perspectives of this area of research in the context of drug discovery and clinical application.