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

ABSTRACT: 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.

SUBMITTER: Gunn BM

PROVIDER: S-EPMC8111768 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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

Gunn Bronwyn M BM Lu Richard R Slein Matthew D MD Ilinykh Philipp A PA Huang Kai K Atyeo Caroline C Schendel Sharon L SL Kim Jiyoung J Cain Caitlin C Roy Vicky V Suscovich Todd J TJ Takada Ayato A Halfmann Peter J PJ Kawaoka Yoshihiro Y Pauthner Matthias G MG Momoh Mambu M Goba Augustine A Kanneh Lansana L Andersen Kristian G KG Schieffelin John S JS Grant Donald D Garry Robert F RF Saphire Erica Ollmann EO Bukreyev Alexander A Alter Galit G

Immunity 20210401 4

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 ...[more]

PMID: 33852832

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Project description:Purpose of the reviewIn this review, we will discuss the field of engineered humoral immunity with an emphasis on recent work using viral vectors to produce antibodies in vivo. As an alternative to passive transfer of monoclonal antibody protein, a transgene encoding an antibody is delivered to cells via vector transduction, resulting in expression and secretion by the host cell. This review will summarize the evidence in support of this strategy as an alternative to traditional vaccines against infection and as novel therapeutics for a variety of diseases.Recent findingsHistorically, humoral immunity has been engineered through vaccination and passive transfer of monoclonal antibodies. However, recent work suggests that vectors can be used to deliver transgenes encoding broadly neutralizing antibodies to non-hematopoietic tissues and can mediate long-term expression that is capable of preventing or treating infectious diseases. The production of engineered monoclonal antibodies allows for precise targeting and elimination of aberrant self-proteins that are characteristic of certain neurodegenerative disease. This approach has also been successfully used to combat cancer and addiction in several animal models. Despite the wide array of expression platforms that have been described, adeno-associated virus vectors have emerged as the frontrunner for rapid clinical translation.SummaryRecent advances in vector-mediated antibody expression have demonstrated the potential for such interventions to prevent infection and treat disease. As such, it offers an alternative to immunogen-based vaccine design and a novel therapeutic intervention by enabling precise manipulation of humoral immunity. Success translating these approaches to patients may enable the development of effective prevention against previously intractable pathogens that evade immunity such as HIV, influenza, malaria or HCV and may also enable new treatment options for neurodegenerative diseases such as Alzheimer's disease.

Dataset Information

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

Publications

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

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