A Fc engineering approach to define functional humoral correlates of immunity against Ebola virus

Protective Ebola virus (EBOV) antibodies have neutralizing activity and induction of antibody constant domain (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 could 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, and we therefore applied a rapid, high-throughput Fc engineering platform to define the most protective profiles. We generated a library of Fc variants with identical antigen-binding fragments (Fabs) from an EBOV neutralizing antibody. Fc variants with antibody-mediated complement deposition and moderate natural killer (NK) cell activity demonstrated complete protective activity in a stringent in vivo mouse model. Our findings highlight the importance of specific effector functions in antibody-mediated protection, and the experimental platform presents a generalizable resource for identifying correlates of immunity to guide therapeutic antibody design.

Automated summary

Protective Ebola virus antibodies have neutralizing activity and stimulate innate immune effector functions. By analyzing survivor Fc effector profiles, researchers identified Fc variants with antibody-mediated complement deposition and moderate NK cell activity that showed complete protective activity in a stringent in vivo mouse model. This study emphasizes the importance of specific effector functions in antibody-mediated protection and provides a generalizable resource for therapeutic antibody design.