Rewiring innate immune defence to eradicate cancer is one of the mechanisms of action of several monoclonal antibodies used in the clinic. Binding of monoclonal antibodies onto a cancer cell surface triggers antibody-mediated effector killing by innate immune cells and through complement activation. As an alternative to monoclonal antibodies, which face inherent issues with cost of production and stability, synthetic systems that can recruit endogenous antibodies from the blood stream to a cancer cell surface could be of great relevance. We explore antibody recruiting polymers (ARPs) as a novel type of biomaterials for immune-engineering. ARPs combine a cell surface binding strategy with multiple copies of hapten motifs that can bind to endogenous antibodies that are present in human serum. Clustering of antibodies on the cancer cell surface will trigger Fc-mediated innate immune killing. To generate ARPs that can bind to cell surfaces, we explored both hydrophobic anchoring as well as covalent binding to a synthetically introduced cell surface receptor. For hydrophobic anchoring, we synthesized a lipid-functionalized RAFT CTA that mediates hydrophobic insertion into the phospholipid membrane. As an alternative to cell surface anchoring we explored metabolic labeling of cancer cells with azido-sugars to introduce azides onto the glycocalyx that subsequently serve as synthetic receptors for cyclooctyne-functionalized ARPs. Using dinitrophenol (DNP) as a hapten we demonstrate efficient antibody recruitment to ARP treated cells in 2D and 3D cell cultures and show that ARPs outperform monovalent antibody recruiting molecules by several orders of magnitude. Furthermore, in vitro co-culturing of ARP-treated cancer cells with primary human macrophages, showed that ARPs are potent mediators of innate effector killing by promoting phagocytosis of cancer cells by macrophages.

Engineering innate immune mediated cancer cell killing by antibody recruiting polymers

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.