Covalent Stabilization of Antibody Recruitment Enhances Immune Recognition of Cancer Targets

Abstract

Antibody recruiting molecules (ARMs) represent an important class of chemical tools with therapeutic potential. ARMs function by simultaneously binding to a hapten specific serum antibody (Ab) and a cancer cell surface protein, thereby forming ARM:Ab complexes on the cancer cell surface. These complexes activate immune cell recognition and elimination of the cancer cell. Problematically, ARM function in human patients may be limited by conditions that drive the dissociation of ARM:Ab complexes; namely intrinsically low binding affinity of anti-hapten antibodies in human serum. To address this potential limitation, we applied covalent ARM (cARM) chemical tools to eliminate the ARM:Ab equilibrium through a covalent linkage. In the current study we determine to what extent stabilizing ARM:Ab complexes via cARMs enhances target immune recognition. We observe cARMs significantly enhance immune function relative to ARMs and demonstrate ARM therapeutic function can be dramatically enhanced by increasing the stability of ARM:antibody complexes on cancer cells.