Broadly Neutralizing Influenza Hemagglutinin Stem-Specific Antibody CR8020 Targets Residues that Are Prone to Escape due to Host Selection Pressure
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Broadly Neutralizing.pdf
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Author(s)
Tharakaraman, Kannan
Subramanian, Vidya
Cain, David
Sasisekharan, Viswanathan
Sasisekharan, Ram
Date Issued
May 2014
Journal
Cell Host & Microbe
Publisher
Elsevier
Citation
Tharakaraman, Kannan, Vidya Subramanian, David Cain, Viswanathan Sasisekharan, and Ram Sasisekharan. “Broadly Neutralizing Influenza Hemagglutinin Stem-Specific Antibody CR8020 Targets Residues That Are Prone to Escape Due to Host Selection Pressure.” Cell Host & Microbe 15, no. 5 (May 2014): 644–651.
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Author's final manuscript
Abstract
Broadly neutralizing antibodies (bNAb) that target a conserved region of a viral antigen hold significant therapeutic promise. CR8020 is a bNAb that targets the stem region of influenza A virus (IAV) hemagglutinin (HA). CR8020 is currently being evaluated for prophylactic use against group 2 IAVs in phase II studies. Structural and computational analyses reported here indicate that CR8020 targets HA residues that are prone to antigenic drift and host selection pressure. Critically, CR8020 escape mutation is seen in certain H7N9 viruses from recent outbreaks. Furthermore, the ability of the bNAb Fc region to effectively engage activating Fcγ receptors (FCγR) is essential for antibody efficacy. In this regard, our data indicate that the membrane could sterically hinder the formation of HA-CR8020-FcγRIIa/HA-IgG-FcγRIIIa ternary complexes. Altogether, our analyses suggest that epitope mutability and accessibility to immune complex assembly are important attributes to consider when evaluating bNAb candidates for clinical development.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. School of Engineering
MIT Skoltech Program
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1016/j.chom.2014.04.009
