AUTHOR=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. TITLE=Anti-idiotype isolation of a broad and potent influenza A virus-neutralizing human antibody JOURNAL=Frontiers in Immunology VOLUME=15 YEAR=2024 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1399960 DOI=10.3389/fimmu.2024.1399960 ISSN=1664-3224 ABSTRACT=

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.