Therapeutic Antibody Effector Function Engineering

Monoclonal antibodies (mAbs) often exert therapeutic effects by binding to and blocking natural protein -- protein interactions -- however, the effector functions encoded by the Fc portion of a mAb can contribute either beneficially or detrimentally to the desired overall effect. Antibody-directed cellular cytotoxicity (ADCC) has been shown to contribute significantly to anti-tumor mAb efficacy via engagement of Fcγ receptors (FcγRs) on effector cell types such as natural killer (NK) cells; however, antagonism of surface receptors involved in autoimmune disease is more typically pursued without the objective of destroying the associated cell.

In this project, we will develop and explore a strategy for constructing bispecific mAbs entirely lacking native Fc/FcγR interaction, and modularly incorporate FcγR binding domains expressed as polypeptide fusions to the IgG. These FcγR binding domains will be isolated by yeast surface display of small (12 kDa) Fn3 domains possessing randomized surface loops. Anticancer efficacy of these bispecific antibodies will be tested in a syngeneic mouse tumor model. We predict that the capability to specifically engage activating FcγRs while leaving inhibitory FcγRs untouched will lead to significantly improved ADCC.