Development of a Human Antibody Cocktail that Deploys Multiple Functions to Confer Pan-Ebolavirus Protection

Anna Z Wec; Zachary A Bornholdt; Shihua He; Andrew S Herbert; Eileen Goodwin; Ariel S Wirchnianski; Bronwyn M Gunn; Zirui Zhang; Wenjun Zhu; Guodong Liu; Dafna M Abelson; Crystal L Moyer; Rohit K Jangra; Rebekah M James; Russell R Bakken; Natasha Bohorova; Ognian Bohorov; Do H Kim; Michael H Pauly; Jesus Velasco; Robert H Bortz 3rd; Kevin J Whaley; Tracey Goldstein; Simon J Anthony; Galit Alter; Laura M Walker; John M Dye; Larry Zeitlin; Xiangguo Qiu; Kartik Chandran

doi:10.1016/j.chom.2018.12.004

Development of a Human Antibody Cocktail that Deploys Multiple Functions to Confer Pan-Ebolavirus Protection

Cell Host Microbe. 2019 Jan 9;25(1):39-48.e5. doi: 10.1016/j.chom.2018.12.004.

Authors

Anna Z Wec¹, Zachary A Bornholdt², Shihua He³, Andrew S Herbert⁴, Eileen Goodwin⁵, Ariel S Wirchnianski¹, Bronwyn M Gunn⁶, Zirui Zhang⁷, Wenjun Zhu⁷, Guodong Liu⁷, Dafna M Abelson², Crystal L Moyer², Rohit K Jangra¹, Rebekah M James⁴, Russell R Bakken⁴, Natasha Bohorova², Ognian Bohorov², Do H Kim², Michael H Pauly², Jesus Velasco², Robert H Bortz 3rd¹, Kevin J Whaley², Tracey Goldstein⁸, Simon J Anthony⁹, Galit Alter⁶, Laura M Walker⁵, John M Dye⁴, Larry Zeitlin¹⁰, Xiangguo Qiu¹¹, Kartik Chandran¹²

Affiliations

¹ Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
² Mapp Biopharmaceutical, San Diego, CA 92121, USA.
³ Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada.
⁴ U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA.
⁵ Adimab, LLC, Lebanon, NH 03766, USA.
⁶ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
⁷ Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; Department of Medical Microbiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
⁸ One Health Institute and Karen C. Drayer Wildlife Health Center, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA.
⁹ Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.
¹⁰ Mapp Biopharmaceutical, San Diego, CA 92121, USA. Electronic address: larry.zeitlin@mappbio.com.
¹¹ Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; Department of Medical Microbiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada. Electronic address: xiangguo.qiu@canada.ca.
¹² Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: kartik.chandran@einstein.yu.edu.

Abstract

Passive administration of monoclonal antibodies (mAbs) is a promising therapeutic approach for Ebola virus disease (EVD). However, all mAbs and mAb cocktails that have entered clinical development are specific for a single member of the Ebolavirus genus, Ebola virus (EBOV), and ineffective against outbreak-causing Bundibugyo virus (BDBV) and Sudan virus (SUDV). Here, we advance MBP134, a cocktail of two broadly neutralizing human mAbs, ADI-15878 from an EVD survivor and ADI-23774 from the same survivor but specificity-matured for SUDV GP binding affinity, as a candidate pan-ebolavirus therapeutic. MBP134 potently neutralized all ebolaviruses and demonstrated greater protective efficacy than ADI-15878 alone in EBOV-challenged guinea pigs. A second-generation cocktail, MBP134^AF, engineered to effectively harness natural killer (NK) cells afforded additional improvement relative to its precursor in protective efficacy against EBOV and SUDV in guinea pigs. MBP134^AF is an optimized mAb cocktail suitable for evaluation as a pan-ebolavirus therapeutic in nonhuman primates.

Keywords: Ebola glycoprotein; Ebola virus; antibody cocktail; antibody engineering; antiviral drug; broadly neutralizing antibodies; ebolavirus; filovirus; human monoclonal antibodies; immunotherapy.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animal Welfare
Animals
Antibodies, Monoclonal / administration & dosage
Antibodies, Monoclonal / immunology*
Antibodies, Monoclonal / isolation & purification
Antibodies, Monoclonal / therapeutic use
Antibodies, Neutralizing / administration & dosage
Antibodies, Neutralizing / immunology
Antibodies, Neutralizing / isolation & purification
Antibodies, Neutralizing / therapeutic use
Antibodies, Viral / administration & dosage
Antibodies, Viral / immunology*
Antibodies, Viral / therapeutic use
Antiviral Agents
Disease Models, Animal
Ebolavirus / immunology*
Ebolavirus / pathogenicity
Epitopes / immunology
Female
Filoviridae / immunology
Guinea Pigs
Hemorrhagic Fever, Ebola / immunology*
Hemorrhagic Fever, Ebola / prevention & control*
Hemorrhagic Fever, Ebola / virology
Humans
Immunotherapy
Mice
Mice, Inbred BALB C
Mice, Knockout
Recombinant Proteins / immunology
Treatment Outcome

Substances

Antibodies, Monoclonal
Antibodies, Neutralizing
Antibodies, Viral
Antiviral Agents
Epitopes
Recombinant Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding