Mymetics Corp (MYMX)

[Work Harder]

Structural Basis for Broad HIV-1 Neutralization by the MPER-Specific Human Broadly Neutralizing Antibody LN01

Georgia Tomaras David C Montefiori

Antonio Lanzavecchia

Lausanne University Hospital

University of Milan

Potent and broadly neutralizing antibodies (bnAbs) are the hallmark of HIV-1 protection by vaccination. The membrane-proximal external region (MPER) of the HIV-1 gp41 fusion protein is targeted by the most broadly reactive HIV-1 neutralizing antibodies. Here, we examine the structural and molecular mechansims of neutralization by anti-MPER bnAb, LN01, which was isolated from lymph-node-derived germinal center B cells of an elite controller and exhibits broad neutralization breadth. LN01 engages both MPER and the transmembrane (TM) region, which together form a continuous helix in complex with LN01. The tilted TM orientation allows LN01 to interact simultaneously with the peptidic component of the MPER epitope and membrane via two specific lipid binding sites of the antibody paratope. Although LN01 carries a high load of somatic mutations, most key residues interacting with the MPER epitope and lipids are germline encoded, lending support for the LN01 epitope as a candidate for lineage-based vaccine development.

https://www.researchgate.net/publication/336733608_Structural_Basis_for_Broad_HIV-1_Neutralization_by_the_MPER-Specific_Human_Broadly_Neutralizing_Antibody_LN01

A public antibody lineage that potently inhibits malaria infection through dual binding to the circumsporozoite protein

Immunization with attenuated Plasmodium falciparum sporozoites (PfSPZs) has been shown to be protective against malaria, but the features of the antibody response induced by this treatment remain unclear. To investigate this response in detail, we isolated IgM and IgG monoclonal antibodies from Tanzanian volunteers who were immunized with repeated injection of Sanaria PfSPZ Vaccine and who were found to be protected from controlled human malaria infection with infectious homologous PfSPZs. All isolated IgG monoclonal antibodies bound to P. falciparum circumsporozoite protein (PfCSP) and recognized distinct epitopes in its N terminus, NANP-repeat region, and C terminus. Strikingly, the most effective antibodies, as determined in a humanized mouse model, bound not only to the repeat region, but also to a minimal peptide at the PfCSP N-terminal junction that is not in the RTS,S vaccine. These dual-specific antibodies were isolated from different donors and were encoded by VH3-30 or VH3-33 alleles that encode tryptophan or arginine at position 52. Using structural and mutational data, we describe the elements required for germline recognition and affinity maturation. Our study provides potent neutralizing antibodies and relevant information for lineage-targeted vaccine design and immunization strategies.

https://www.researchgate.net/publication/323865360_A_public_antibody_lineage_that_potently_inhibits_malaria_infection_through_dual_binding_to_the_circumsporozoite_protein

Seattle Institute for Biomedical and Clinical Research and other places

Swiss Tropical and Public Health Institute and other places

https://www.researchgate.net/scientific-contributions/42662106-Antonio-Lanzavecchia

Citing article

Apr 2018

Antonio Lanzavecchia

https://www.irb.usi.ch/irb-people/lanzavecchia-antonio/?id=8930

Crystal structure and size-dependent neutralization properties of HK20, a human monoclonal antibody binding to the highly conserved heptad repeat 1 of gp41

https://pubmed.ncbi.nlm.nih.gov/21124990/