tetano
Editor, Senior Moderator
Front Immunol
. 2024 May 30:15:1399960.
doi: 10.3389/fimmu.2024.1399960. eCollection 2024. Anti-idiotype isolation of a broad and potent influenza A virus-neutralizing human antibody
Adam S Olia[SUP] #[/SUP][SUP] 1 [/SUP], Madhu Prabhakaran[SUP] #[/SUP][SUP] 1 [/SUP], Darcy R Harris[SUP] 1 [/SUP], Crystal Sao-Fong Cheung[SUP] 1 [/SUP], Rebecca A Gillespie[SUP] 1 [/SUP], Jason Gorman[SUP] 1 2 [/SUP], Abigayle Hoover[SUP] 1 [/SUP], Nicholas C Morano[SUP] 3 4 [/SUP], Amine Ourahmane[SUP] 1 [/SUP], Abhinaya Srikanth[SUP] 1 [/SUP], Shuishu Wang[SUP] 1 [/SUP], Weiwei Wu[SUP] 1 [/SUP], Tongqing Zhou[SUP] 1 [/SUP], Sarah F Andrews[SUP] 1 [/SUP], Masaru Kanekiyo[SUP] 1 [/SUP], Lawrence Shapiro[SUP] 3 4 5 [/SUP], Adrian B McDermott[SUP] 1 [/SUP], Peter D Kwong[SUP] 1 3 4 [/SUP]
Affiliations
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.
Keywords: MEDI8852; VH6-1 class; anti-idiotype; broadly neutralizing antibody; cryo-EM; influenza A virus.
. 2024 May 30:15:1399960.
doi: 10.3389/fimmu.2024.1399960. eCollection 2024. Anti-idiotype isolation of a broad and potent influenza A virus-neutralizing human antibody
Adam S Olia[SUP] #[/SUP][SUP] 1 [/SUP], Madhu Prabhakaran[SUP] #[/SUP][SUP] 1 [/SUP], Darcy R Harris[SUP] 1 [/SUP], Crystal Sao-Fong Cheung[SUP] 1 [/SUP], Rebecca A Gillespie[SUP] 1 [/SUP], Jason Gorman[SUP] 1 2 [/SUP], Abigayle Hoover[SUP] 1 [/SUP], Nicholas C Morano[SUP] 3 4 [/SUP], Amine Ourahmane[SUP] 1 [/SUP], Abhinaya Srikanth[SUP] 1 [/SUP], Shuishu Wang[SUP] 1 [/SUP], Weiwei Wu[SUP] 1 [/SUP], Tongqing Zhou[SUP] 1 [/SUP], Sarah F Andrews[SUP] 1 [/SUP], Masaru Kanekiyo[SUP] 1 [/SUP], Lawrence Shapiro[SUP] 3 4 5 [/SUP], Adrian B McDermott[SUP] 1 [/SUP], Peter D Kwong[SUP] 1 3 4 [/SUP]
Affiliations
- PMID: 38873606
- PMCID: PMC11169713
- DOI: 10.3389/fimmu.2024.1399960
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.
Keywords: MEDI8852; VH6-1 class; anti-idiotype; broadly neutralizing antibody; cryo-EM; influenza A virus.