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Tunable Multivalent Platform for Immune Recruitment to Lower Antigen Expressing Cancers |
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| Authors: | Benjamin P. M. Lake Dr. Ryan G. Wylie Dr. Cyril Bařinka Dr. Anthony F. Rullo |
| Affiliation: | 1. Department of Medicine, Center for Discovery in Cancer Research, McMaster University, Hamilton, Ontario, L8S 4K1 Canada Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, L8S 4L8 Canada;2. Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, L8S 4L8 Canada School of Biomedical Engineering, McMaster University, Hamilton, Ontario, L8S 4M1 Canada;3. Institute of Biotechnology of the Czech Academy of Sciences, Průmyslová 595, 25250 Vestec, Czech Republic;4. Department of Medicine, Center for Discovery in Cancer Research, McMaster University, Hamilton, Ontario, L8S 4K1 Canada |
| 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. |
| Keywords: | Antibodies Cell Recognition Drug Design Immunochemistry Polymers |