Topologically engineered antibodies and Fc-fusion proteins: a new class of multifunctional therapeutic candidates for SARS-CoV-2, cancer, and other disease

The ability of antibodies and Fc-fusion proteins to bind multiple targets cooperatively is limited by their topology. Here we describe our discovery that ACE2 Fc-fusion proteins spontaneously cross-dimerize, forming topologically distinct “superdimers” that demonstrate extraordinary SARS-CoV-2 intra-spike cooperative binding and potently neutralize Omicron B.1.1.529 at least 100-fold better than eight clinically authorized antibodies. We also exploited cross- dimerization to topologically engineer novel superdimeric antibodies and Fc-fusion proteins with antibody-like plasma half-lives to address cancer and infectious disease therapy. These include bispecific ACE2-antibody superdimers that potently neutralize all major SARS-CoV-2 variants, and bispecific anti-cancer and anti-viral antibody superdimers that are more potent than two-antibody cocktails. Superdimers are efficiently produced from single cells, providing a new therapeutic approach to many disease indications. ### Competing Interest Statement D.J.C, L.T., N.L.S.C., M.F., U.E., and B.F. are employees, M.L.G. and D.J.C. are directors, and B.Z.C. is a consultant of Hinge Bio, Inc., and each may hold shares in Hinge Bio, Inc. D.J.C. is an inventor on patent applications on this work and a member of Biomolecular Holdings LLC which has a financial interest in these patent applications. The Simmons laboratory has received a sponsored research agreement from Hinge Bio, Inc.