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

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.

Mouse Antibodies with Activity Against the SARS-CoV-2 D614G and B.1.351 Variants (preprint)

With the rapid spread of SARS-CoV-2 variants, including those that are resistant to antibodies authorized for emergency use, it is apparent that new antibodies may be needed to effectively protect patients against more severe disease. Differences between the murine and human antibody repertoires may allow for the isolation of murine monoclonal antibodies that recognize a different or broader range of SARS-CoV-2 variants than the human antibodies that have been characterized so far. We describe mouse antibodies B13 and O24 that demonstrate neutralizing potency against SARS-CoV-2 Wuhan (D614G) and B.1.351 variants. Such murine antibodies may have advantages in protecting against severe symptoms when individuals are exposed to new SARS-CoV-2 variants.