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

• Published in: bioRxiv 2020-08
• Main Authors: Keating, Sheila M, Mizrahi, Rena A, Adams, Matthew S, Asensio, Michael A, Benzie, Emily, Carter, Kyle P, Chiang, Yao, Edgar, Robert C, Gautam, Bishal K, Gras, Ashley, Jackson, Leong, Leong, Renee, Yoong Wearn Lim, Manickam, Vishal A, Medina-Cucurella, Angelica V, Niedecken, Ariel R, Saini, Jasmeen, Simons, Jan Fredrik, Spindler, Matthew J, Stadtmiller, Kacy, Tinsley, Brendan, Wagner, Ellen K, Wayham, Nicholas, Laree Tracy, Vingsbo Lundberg, Carina C, Buscher, Dirk, Jose Vicente Terencio, Roalfe, Lucy, Pearce, Emma, Richardson, Hayley, Goldblatt, David, Ramjag, Anushka T, Carrington, Christine Vf, Simmons, Graham, Muench, Marcus, Chamow, Steven, Monroe, Bryan, Olson, Charles, Oguin, Thomas H, Lynch, Heather, Jeanfreau, Robert, Meyer, Everett H, Adler, Adam S, Johnson, David S
• Format: Article
• Language: English
• Subjects: Antibodies; Antibody libraries; Autoimmunity; Bronchopulmonary infection; Cloning; Coronaviruses; COVID-19; Drugs; Globulins; Graft-versus-host reaction; Immunoglobulins; Immunology; Immunosuppressive agents; Impurities; Infectious diseases; Microfluidics; Patent applications; Severe acute respiratory syndrome coronavirus 2; Therapeutic targets; Thymocytes; Transplantation
• ISSN: 2692-8205
• DOI: 10.1101/2020.08.05.232975

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 low potency, impurities, constraints on supply, and batch-to-batch variation. In this study, we demonstrated proofs-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 comprised thousands to tens of thousands of antibodies and were derived from convalescent human donors, or vaccinated human donors or immunized mice. Here we used our technology to build a highly 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 (ATG), we generated a recombinant human version and demonstrated in vivo function against graft-versus-host disease (GVHD). Recombinant hyperimmunes are a novel class of drugs that could be used to target a wide variety of other clinical applications, including cancer and autoimmunity. Competing Interest Statement S.M.K., R.A.M., M.S.A., M.A.A., E.B., K.P.C., Y.C., R.C.E., B.K.G., A.G., J.L., R.L., Y.W.L., V.A.M., A.V.M-C., A.R.N., J.S., J.F.S., M.J.S., K.S., B.T., E.K.W., N.W., E.H.M., A.S.A., and D.S.J., have received shares and salary from GigaGen, Inc. C.V.L. receives a salary from Statens Serum Institut. D.B. and J.V.T. receive salaries from Grifols. C.V.F.C. and A.T.R. receive salary from The University of the West Indies. L.R., E.P., H.R., and D.G. receive salary from University College London. G.S. and M.O.M. receive salary from Vitalant. L.T., S.M.C., B.M., and C.O. received consulting fees from GigaGen, Inc. T.H.O. and H.L. receive salary from Duke University Medical Center and were paid by GigaGen, Inc. to perform SARS CoV-2 neutralization studies. R.J. is an employee of MedPharmics, which received payments for convalescent COVID-19 samples from GigaGen, In