Hapten/Myristoyl Functionalized Poly(propyleneimine) Dendrimers as Potent Cell Surface Recruiters of Antibodies for Mediating Innate Immune Killing

Abstract Recruiting endogenous antibodies to the surface of cancer cells using antibody‐recruiting molecules has the potential to unleash innate immune effector killing mechanisms against antibody‐bound cancer cells. The affinity of endogenous antibodies is relatively low, and many currently explored antibody‐recruiting strategies rely on targeting over‐expressed receptors, which have not yet been identified in most solid tumors. Here, both challenges are addressed by functionalizing poly(propyleneimine) (PPI) dendrimers with both multiple dinitrophenyl (DNP) motifs, as anti‐hapten antibody‐recruiting motifs, and myristoyl motifs, as universal phospholipid cell membrane anchoring motifs, to recruit anti‐hapten antibodies to cell surfaces. By exploiting the multivalency of the ligand exposure on the dendrimer scaffold, it is demonstrated that dendrimers featuring ten myristoyl and six DNP motifs exhibit the highest antibody‐recruiting capacity in vitro. Furthermore, it is shown that treating cancer cells with these dendrimers in vitro marks them for phagocytosis by macrophages in the presence of anti‐hapten antibodies. As a proof‐of‐concept, it is shown that intratumoral injection of these dendrimers in vivo in tumor‐bearing mice results in the recruitment of anti‐DNP antibodies to the cell surface in the tumor microenvironment. These findings highlight the potential of dendrimers as a promising class of novel antibody‐recruiting molecules for use in cancer immunotherapy.