Anti-idiotype isolation of a broad and potent influenza A virus-neutralizing human antibody

Olia, Adam S.; Prabhakaran, Madhu; Harris, Darcy R.; Cheung, Crystal Sao-Fong; Gillespie, Rebecca A.; Gorman, Jason; Hoover, Abigayle; Morano, Nicholas C.; Ourahmane, Amine; Srikanth, Abhinaya; Wang, Shuishu; Wu, Weiwei; Zhou, Tongqing; Andrews, Sarah F.; Kanekiyo, Masaru; Shapiro, Lawrence; McDermott, Adrian B.; Kwong, Peter D.

doi:10.3389/fimmu.2024.1399960

Anti-idiotype isolation of a broad and potent influenza A virus-neutralizing human antibody

Journal Article · Thu May 30 00:00:00 EDT 2024 · Frontiers in Immunology

DOI:https://doi.org/10.3389/fimmu.2024.1399960· OSTI ID:2470055

Olia, Adam S. ^[1]; Prabhakaran, Madhu ^[1]; Harris, Darcy R. ^[1]; Cheung, Crystal Sao-Fong ^[1]; Gillespie, Rebecca A. ^[1]; Gorman, Jason ^[2]; Hoover, Abigayle ^[1]; Morano, Nicholas C. ^[3]; Ourahmane, Amine ^[1]; Srikanth, Abhinaya ^[1]; Wang, Shuishu ^[1]; Wu, Weiwei ^[1]; Zhou, Tongqing ^[1]; Andrews, Sarah F. ^[1]; Kanekiyo, Masaru ^[1]; Shapiro, Lawrence ^[3]; McDermott, Adrian B. ^[1]; Kwong, Peter D. ^[4]

National Institutes of Health (NIH), Bethesda, MD (United States)
National Institutes of Health (NIH), Bethesda, MD (United States); US Food and Drug Administration (USFDA), Silver Spring, MD (United States)
Columbia Univ., New York, NY (United States)
National Institutes of Health (NIH), Bethesda, MD (United States); Columbia Univ., New York, NY (United States)

The VH6-1 class of antibodies includes some of the broadest and most potent antibodies that neutralize influenza A virus. Here, we elicit and isolate anti-idiotype antibodies against germline versions of VH6-1 antibodies, use these to sort human leukocytes, and isolate a new VH6-1-class member, antibody L5A7, which potently neutralized diverse group 1 and group 2 influenza A strains. While its heavy chain derived from the canonical IGHV6-1 heavy chain gene used by the class, L5A7 utilized a light chain gene, IGKV1-9, which had not been previously observed in other VH6-1-class antibodies. The cryo-EM structure of L5A7 in complex with Indonesia 2005 hemagglutinin revealed a nearly identical binding mode to other VH6-1-class members. The structure of L5A7 bound to the isolating anti-idiotype antibody, 28H6E11, revealed a shared surface for binding anti-idiotype and hemagglutinin that included two critical L5A7 regions: an FG motif in the third heavy chain-complementary determining region (CDR H3) and the CDR L1 loop. Surprisingly, the chemistries of L5A7 interactions with hemagglutinin and with anti-idiotype were substantially different. Overall, we demonstrate anti-idiotype-based isolation of a broad and potent influenza A virus-neutralizing antibody, revealing that anti-idiotypic selection of antibodies can involve features other than chemical mimicry of the target antigen.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); Simons Foundation; USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-06CH11357; W-31109-ENG-38

OSTI ID:: 2470055

Journal Information:: Frontiers in Immunology, Journal Name: Frontiers in Immunology Vol. 15; ISSN 1664-3224

Publisher:: Frontiers Research FoundationCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
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cryo-EM
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