Scripps Research Institute - Department of Immunology and Microbiology; The Scripps Research Institute - Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery; The Scripps Research Institute - IAVI Neutralizing Antibody Center
Monoclonal antibodies are emerging as effective therapies for viral infections, including for Ebola virus (EBOV). Protective EBOV antibodies have neutralizing activity and induction of Fc-mediated innate immune effector functions. Efforts to enhance Fc-effector functionality often focus on maximizing antibody-dependent cellular cytotoxicity, yet distinct combinations of functions may be critical for antibody-mediated protection. As neutralizing antibodies have been cloned from EBOV disease survivors, we sought to identify survivor Fc-effector profiles to help guide Fc-optimization strategies. Survivors developed a range of functional antibody responses; thus, we applied an Fc-engineering platform to define the most protective profiles. We generated a library of Fc-variants with identical Fabs from an EBOV neutralizing antibody. Fc-variants with antibody-mediated complement deposition and moderate NK cell activity demonstrated complete protective activity in vivo. These data highlight the importance of specific effector functions in antibody-mediated protection and provide a platform for rapid identification of correlates of immunity to guide therapeutic design.
Keywords: Antibody engineering, Ebola virus, Fc effector function
Gunn, Bronwyn M. and Lu, Richard and Slein, Matthew D. and Ilinykh, Philipp A. and Huang, Kai and Atyeo, Caroline and Schendel, Sharon L. and Kim, Jiyoung and Cain, Caitlin and Roy, Vicky and Suscovich, Todd J. and Takada, Ayato and Halfmann, Peter J. and Kawaoka, Yoshihiro and Pauthner, Matthias and Momo, Mambu and Goba, Augustine and Kanneh, Lansana and Andersen, Kristian G. and Schieffelin, John S. and Grant, Donald and Garry, Robert F. and Saphire, Erica Ollmann and Bukreyev, Alexander and Alter, Galit, A Fc-Engineering Approach to Define Functional Humoral Correlates of Immunity Against Ebola Virus. Available at SSRN: https://ssrn.com/abstract=3608385 or http://dx.doi.org/10.2139/ssrn.3608385
This version of the paper has not been formally peer reviewed.
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