Abstract
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.
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