Broadly neutralizing influenza hemagglutinin stem-specific antibody CR8020 targets residues that are prone to escape due to host selection pressure.
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.
Department of Biological Engineering, Skolkovo-MIT Center for Biomedical Engineering, Koch Institute of Integrative Cancer Research, Infectious Diseases Interdisciplinary Research Group, and Singapore-MIT Alliance for Research and Technology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Kannan
K
Tharakaraman
Department of Biological Engineering, Skolkovo-MIT Center for Biomedical Engineering, Koch Institute of Integrative Cancer Research, Infectious Diseases Interdisciplinary Research Group, and Singapore-MIT Alliance for Research and Technology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Vidya
V
Subramanian
Department of Biological Engineering, Skolkovo-MIT Center for Biomedical Engineering, Koch Institute of Integrative Cancer Research, Infectious Diseases Interdisciplinary Research Group, and Singapore-MIT Alliance for Research and Technology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
David
D
Cain
Department of Biological Engineering, Skolkovo-MIT Center for Biomedical Engineering, Koch Institute of Integrative Cancer Research, Infectious Diseases Interdisciplinary Research Group, and Singapore-MIT Alliance for Research and Technology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Viswanathan
V
Sasisekharan
Department of Biological Engineering, Skolkovo-MIT Center for Biomedical Engineering, Koch Institute of Integrative Cancer Research, Infectious Diseases Interdisciplinary Research Group, and Singapore-MIT Alliance for Research and Technology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: rams@mit.edu.
Ram
R
Sasisekharan
D020816:Amino Acid Motifs; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D000914:Antibodies, Viral / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D018604:Epitope Mapping; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D053122:Influenza A Virus, H3N2 Subtype / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D064766:Influenza A Virus, H7N9 Subtype / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology* / Q000821:virology; D008958:Models, Molecular; D009500:Neutralization Tests
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus