pH-Dependent Grafting of Cancer Cells with Antigenic Epitopes Promotes Selective Antibody-Mediated Cytotoxicity

A growing class of immunotherapeutics
work by redirecting components
of the immune system to recognize markers on the surface of cancer
cells. However, such modalities will remain confined to a relatively
small subgroup of patients because of the lack of universal targetable
tumor biomarkers among all patients. Here, we designed a unique class
of agents that exploit the inherent acidity of solid tumors to selectively
graft cancer cells with immuno-engager epitopes. Our targeting approach
is based on pHLIP, a unique peptide that selectively targets tumors in vivo by anchoring to cancer cell surfaces in a pH-dependent
manner. We established that pHLIP–antigen conjugates trigger
the recruitment of antibodies to the surface of cancer cells and induce
cytotoxicity by peripheral blood mononuclear and engineered NK cells.
These results indicate that these agents have the potential to be
applicable to treating a wide range of solid tumors and to circumvent
problems associated with narrow windows of selectivity.