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

View ORCID ProfileSheila M. Keating, View ORCID ProfileRena A. Mizrahi, Matthew S. Adams, Michael A. Asensio, Emily Benzie, Kyle P. Carter, Yao Chiang, Robert C. Edgar, Bishal K. Gautam, Ashley Gras, Jackson Leong, Renee Leong, View ORCID ProfileYoong Wearn Lim, Vishal A. Manickam, Angelica V. Medina-Cucurella, Ariel R. Niedecken, Jasmeen Saini, Jan Fredrik Simons, Matthew J. Spindler, Kacy Stadtmiller, Brendan Tinsley, Ellen K. Wagner, Nicholas Wayham, View ORCID ProfileLaRee Tracy, Carina Vingsbo Lundberg, Dirk Büscher, Jose Vicente Terencio, Lucy Roalfe, Emma Pearce, Hayley Richardson, View ORCID ProfileDavid Goldblatt, Anushka T. Ramjag, Christine V.F. Carrington, View ORCID ProfileGraham Simmons, View ORCID ProfileMarcus O. Muench, Steven M. Chamow, Bryan Monroe, Charles Olson, Thomas H. Oguin, Heather Lynch, Robert Jeanfreau, Everett H. Meyer, View ORCID ProfileAdam S. Adler, View ORCID ProfileDavid S. Johnson
doi: https://doi.org/10.1101/2020.08.05.232975
Sheila M. Keating
1GigaGen Inc., South San Francisco, CA, USA
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Rena A. Mizrahi
1GigaGen Inc., South San Francisco, CA, USA
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Matthew S. Adams
1GigaGen Inc., South San Francisco, CA, USA
2Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA, USA
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Michael A. Asensio
1GigaGen Inc., South San Francisco, CA, USA
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Emily Benzie
1GigaGen Inc., South San Francisco, CA, USA
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Kyle P. Carter
1GigaGen Inc., South San Francisco, CA, USA
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Yao Chiang
1GigaGen Inc., South San Francisco, CA, USA
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Robert C. Edgar
1GigaGen Inc., South San Francisco, CA, USA
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Bishal K. Gautam
1GigaGen Inc., South San Francisco, CA, USA
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Ashley Gras
1GigaGen Inc., South San Francisco, CA, USA
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Jackson Leong
1GigaGen Inc., South San Francisco, CA, USA
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Renee Leong
1GigaGen Inc., South San Francisco, CA, USA
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Yoong Wearn Lim
1GigaGen Inc., South San Francisco, CA, USA
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Vishal A. Manickam
1GigaGen Inc., South San Francisco, CA, USA
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Angelica V. Medina-Cucurella
1GigaGen Inc., South San Francisco, CA, USA
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Ariel R. Niedecken
1GigaGen Inc., South San Francisco, CA, USA
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Jasmeen Saini
1GigaGen Inc., South San Francisco, CA, USA
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Jan Fredrik Simons
1GigaGen Inc., South San Francisco, CA, USA
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Matthew J. Spindler
1GigaGen Inc., South San Francisco, CA, USA
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Kacy Stadtmiller
1GigaGen Inc., South San Francisco, CA, USA
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Brendan Tinsley
1GigaGen Inc., South San Francisco, CA, USA
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Ellen K. Wagner
1GigaGen Inc., South San Francisco, CA, USA
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Nicholas Wayham
1GigaGen Inc., South San Francisco, CA, USA
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LaRee Tracy
3PHASTAR, Inc., San Diego, CA, USA
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Carina Vingsbo Lundberg
4Statens Serum Institut, Copenhagen, Denmark
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Dirk Büscher
5Grifols S.A., Sant Cugat del Vallès, Spain
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Jose Vicente Terencio
5Grifols S.A., Sant Cugat del Vallès, Spain
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Lucy Roalfe
6Immunobiology Section, Great Ormond Street Institute of Child Health, University College London, London, England
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Emma Pearce
6Immunobiology Section, Great Ormond Street Institute of Child Health, University College London, London, England
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Hayley Richardson
6Immunobiology Section, Great Ormond Street Institute of Child Health, University College London, London, England
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David Goldblatt
6Immunobiology Section, Great Ormond Street Institute of Child Health, University College London, London, England
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Anushka T. Ramjag
7Department of Preclinical Sciences, Faculty of Medical Sciences, The University of the West Indies, St. Augustine Campus, Trinidad and Tobago
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Christine V.F. Carrington
7Department of Preclinical Sciences, Faculty of Medical Sciences, The University of the West Indies, St. Augustine Campus, Trinidad and Tobago
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Graham Simmons
8Vitalant Research Institute, San Francisco, CA, USA
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Marcus O. Muench
8Vitalant Research Institute, San Francisco, CA, USA
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Steven M. Chamow
9Chamow & Associates, Inc., San Mateo, CA, USA
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Bryan Monroe
9Chamow & Associates, Inc., San Mateo, CA, USA
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Charles Olson
9Chamow & Associates, Inc., San Mateo, CA, USA
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Thomas H. Oguin
10Regional Biocontainment Laboratory, Duke University Medical Center, Durham, NC, USA
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Heather Lynch
10Regional Biocontainment Laboratory, Duke University Medical Center, Durham, NC, USA
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Robert Jeanfreau
11MedPharmics, Inc., Metairie, LA, USA
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Everett H. Meyer
12Stanford Diabetes Research Center, Stanford University Medical Center, Stanford, CA, USA
13Stanford Cancer Institute, Stanford University Medical Center, Stanford, CA, USA
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Adam S. Adler
1GigaGen Inc., South San Francisco, CA, USA
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David S. Johnson
1GigaGen Inc., South San Francisco, CA, USA
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  • For correspondence: djohnson@gigagen.com
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ABSTRACT

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, Inc. E.H.M. is a salaried employee of Stanford University Medical Center. Methods for linkage of heavy and light chain Ig in emulsion droplets are granted in patents US20200140947A1 and EP2652155B1, to D.S.J. and E.H.M. Methods for cloning antibody libraries are granted in patents US20190256841A1, US10689641, WO2018170013A1, WO2016200577A1, and US20160362681A1, to D.S.J., A.S.A., M.J.S., and R.A.M. Antibody library compositions are described in patent applications US63/038,470 and US62/841,097, to D.S.J., A.S.A., R.A.M., Y.W.L., S.M.K., R.L., J.L., and M.A.A.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Capturing and Recreating Diverse Antibody Repertoires as Multivalent Recombinant Polyclonal Antibody Drugs
Sheila M. Keating, Rena A. Mizrahi, Matthew S. Adams, Michael A. Asensio, Emily Benzie, Kyle P. Carter, Yao Chiang, Robert C. Edgar, Bishal K. Gautam, Ashley Gras, Jackson Leong, Renee Leong, Yoong Wearn Lim, Vishal A. Manickam, Angelica V. Medina-Cucurella, Ariel R. Niedecken, Jasmeen Saini, Jan Fredrik Simons, Matthew J. Spindler, Kacy Stadtmiller, Brendan Tinsley, Ellen K. Wagner, Nicholas Wayham, LaRee Tracy, Carina Vingsbo Lundberg, Dirk Büscher, Jose Vicente Terencio, Lucy Roalfe, Emma Pearce, Hayley Richardson, David Goldblatt, Anushka T. Ramjag, Christine V.F. Carrington, Graham Simmons, Marcus O. Muench, Steven M. Chamow, Bryan Monroe, Charles Olson, Thomas H. Oguin, Heather Lynch, Robert Jeanfreau, Everett H. Meyer, Adam S. Adler, David S. Johnson
bioRxiv 2020.08.05.232975; doi: https://doi.org/10.1101/2020.08.05.232975
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Capturing and Recreating Diverse Antibody Repertoires as Multivalent Recombinant Polyclonal Antibody Drugs
Sheila M. Keating, Rena A. Mizrahi, Matthew S. Adams, Michael A. Asensio, Emily Benzie, Kyle P. Carter, Yao Chiang, Robert C. Edgar, Bishal K. Gautam, Ashley Gras, Jackson Leong, Renee Leong, Yoong Wearn Lim, Vishal A. Manickam, Angelica V. Medina-Cucurella, Ariel R. Niedecken, Jasmeen Saini, Jan Fredrik Simons, Matthew J. Spindler, Kacy Stadtmiller, Brendan Tinsley, Ellen K. Wagner, Nicholas Wayham, LaRee Tracy, Carina Vingsbo Lundberg, Dirk Büscher, Jose Vicente Terencio, Lucy Roalfe, Emma Pearce, Hayley Richardson, David Goldblatt, Anushka T. Ramjag, Christine V.F. Carrington, Graham Simmons, Marcus O. Muench, Steven M. Chamow, Bryan Monroe, Charles Olson, Thomas H. Oguin, Heather Lynch, Robert Jeanfreau, Everett H. Meyer, Adam S. Adler, David S. Johnson
bioRxiv 2020.08.05.232975; doi: https://doi.org/10.1101/2020.08.05.232975

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