Isolation and characterization of IgG3 glycan-targeting antibodies with exceptional cross-reactivity for diverse viral families.

Vukovich MJ, Shiakolas AR, Lindenberger J, Richardson RA, Bass LE, Barr M, Liu Y, Go EP, Park CS, May AJ, Sammour S, Kambarami C, Huang X, Janowska K, Edwards RJ, Mansouri K, Spence TN, Abu-Shmais AA, Manamela NP, Richardson SI, Leonard SEW, Gripenstraw KR, Setliff I, Saunders KO, Bonami RH, Ross TM, Desaire H, Moore PL, Parks R, Haynes BF, Sheward DJ, Acharya P, Sautto GA, Georgiev IS

PLoS Pathog 20 (9) e1012499 [2024-09-00; online 2024-09-18]

Broadly reactive antibodies that target sequence-diverse antigens are of interest for vaccine design and monoclonal antibody therapeutic development because they can protect against multiple strains of a virus and provide a barrier to evolution of escape mutants. Using LIBRA-seq (linking B cell receptor to antigen specificity through sequencing) data for the B cell repertoire of an individual chronically infected with human immunodeficiency virus type 1 (HIV-1), we identified a lineage of IgG3 antibodies predicted to bind to HIV-1 Envelope (Env) and influenza A Hemagglutinin (HA). Two lineage members, antibodies 2526 and 546, were confirmed to bind to a large panel of diverse antigens, including several strains of HIV-1 Env, influenza HA, coronavirus (CoV) spike, hepatitis C virus (HCV) E protein, Nipah virus (NiV) F protein, and Langya virus (LayV) F protein. We found that both antibodies bind to complex glycans on the antigenic surfaces. Antibody 2526 targets the stem region of influenza HA and the N-terminal domain (NTD) region of SARS-CoV-2 spike. A crystal structure of 2526 Fab bound to mannose revealed the presence of a glycan-binding pocket on the light chain. Antibody 2526 cross-reacted with antigens from multiple pathogens and displayed no signs of autoreactivity. These features distinguish antibody 2526 from previously described glycan-reactive antibodies. Further study of this antibody class may aid in the selection and engineering of broadly reactive antibody therapeutics and can inform the development of effective vaccines with exceptional breadth of pathogen coverage.

PubMed 39292703

DOI 10.1371/journal.ppat.1012499

Crossref 10.1371/journal.ppat.1012499

pmc: PMC11410209
pii: PPATHOGENS-D-24-00811