Capturing and Recreating Diverse Antibody Repertoires as Multivalent Recombinant Polyclonal Antibody Drugs

Plasma-derived polyclonal antibodies are polyvalent drugs used for many important clinical indications that require modulation of multiple drug targets simultaneously, including emerging infectious disease and transplantation. However, plasma-derived drugs suffer many problems, including impurities, constraints on supply, and batch-to-batch variation. In this study, we demonstrated proof-of-concept for a technology that uses microfluidics and molecular genomics to capture diverse mammalian antibody repertoires as multivalent recombinant drugs. These "recombinant hyperimmune" drugs were derived from convalescent human donors, or human donors or mice that are vaccinated with immunogens, and comprised thousands or tens of thousands of antibodies. For example, we used our technology to build a potent recombinant hyperimmune for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) in less than three months. We also validated a recombinant hyperimmune for Zika virus disease that abrogates antibody-dependent enhancement (ADE) through Fc engineering. For patients with primary immune deficiency (PID), we built high potency polyvalent recombinant hyperimmunes against pathogens that commonly cause serious lung infections. Finally, to address the limitations of rabbit-derived anti-thymocyte globulin (rabbit ATG), we generated a recombinant human anti-thymocyte globulin (rhATG) and showed in vivo function against graft-versus-host disease (GVHD). In the future, our technology could be used to target a wide variety of other clinical applications, including cancer and autoimmunity.