Tunable Synthetic Multivalent Platform for Immune Recruitment to Lower Antigen Expressing Cancers.

Abstract

Chemical immunotherapeutic strategies including Antibody Recruiting Molecules (ARMs) direct immune-mediated clearance of diseased cells or pathogens. ARMs are bivalent small molecules containing an antibody-binding domain (ABD) and a target-binding domain (TBD) to recruit endogenous serum antibodies to highly overexpressed tumour antigens for immune mediated clearance. ARM function relies on a high tumour antigen valency, limiting function against lower antigen expressing tumours. To address this limitation, we report a tuneable multivalent immune recruitment platform (MIR) to amplify/stabilize antibody recruitment to cells with lower antigen valencies. An initial set of polymeric ARMs (pARMs) were synthesized and screened to evaluate ABD/TBD copy number, ratio, and steric occlusion on specific immune induction. Most pARMs demonstrate simultaneous high avidity binding to anti-dinitrophenyl antibodies and prostate specific membrane antigens on prostate cancer. Optimized pARMs mediated enhanced and specific anti-cancer immune function against lower antigen expressing prostate cancer cells compared to an analogous monovalent ARM.