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mRNA-LNP prime boost evolves precursors toward VRC01-like broadly neutralizing antibodies in preclinical humanized mouse models

Science immunology. 2024-05; 
Xuesong Wang, Christopher A Cottrell, Xiaozhen Hu, Rashmi Ray, Maria Bottermann, Paula Maldonado Villavicencio, Yu Yan, Zhenfei Xie, John E Warner, Jordan Renae Ellis-Pugh, Oleksandr Kalyuzhniy, Alessia Liguori, Jordan R Willis, Sergey Menis, Sebastian Rämisch, Saman Eskandarzade, Michael Kubitz, Ryan Tingle Nicole Phelps, Bettina Groschel, Sunny Himansu, Andrea Carfi, Kathrin H Kirsch, Stephanie R Weldon, Usha Nair, William R Schief, Facundo D Batista
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Gene Synthesis Genes encoding the antibody Fv regions were synthesized by GenScript and cloned into antibody expression vectors pCW-CHIg-hG1 and pCW-CLIg-hk.  Get A Quote

摘要

Germline-targeting (GT) protein immunogens to induce VRC01-class broadly neutralizing antibodies (bnAbs) to the CD4-binding site of the HIV envelope (Env) have shown promise in clinical trials. Here, we preclinically validated a lipid nanoparticle-encapsulated nucleoside mRNA (mRNA-LNP) encoding eOD-GT8 60mer as a soluble self-assembling nanoparticle in mouse models. In a model with three humanized B cell lineages bearing distinct VRC01-precursor B cell receptors (BCRs) with similar affinities for eOD-GT8, all lineages could be simultaneously primed and undergo diversification and affinity maturation without exclusionary competition. Boosts drove precursor B cell participation in germinal centers; the accumulat... More

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