Tunable Multivalent Platform for Immune Recruitment to Lower Antigen Expressing Cancers

Abstract Chemical immunotherapeutic strategies including Antibody Recruiting Molecules (ARMs ‐ bivalent small molecules containing an antibody‐binding domain (ABD) and a target‐binding domain (TBD)) direct immune‐mediated clearance of diseased cells. Anti‐cancer ARM function relies on high tumor antigen valency, limiting function against lower antigen expressing tumors. To address this limitation, we report a tunable multivalent immune recruitment (MIR) platform 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 demonstrated simultaneous high avidity binding to anti‐dinitrophenyl antibodies and prostate‐specific membrane antigens on prostate cancer. Optimized pARMs mediated enhanced anti‐cancer immune function against lower antigen expressing target cells compared to an analogous ARM.