A single injection of crystallizable fragment domain-modified antibodies elicits durable protection from SHIV infection.

TitleA single injection of crystallizable fragment domain-modified antibodies elicits durable protection from SHIV infection.
Publication TypeJournal Article
Year of Publication2018
AuthorsGautam R, Nishimura Y, Gaughan N, Gazumyan A, Schoofs T, Buckler-White A, Seaman MS, Swihart BJ, Follmann DA, Nussenzweig MC, Martin MA
JournalNat Med
Volume24
Issue5
Pagination610-616
Date Published05/01/2018
ISSN1546-170X
Abstract

In the absence of an effective and safe vaccine against HIV-1, the administration of broadly neutralizing antibodies (bNAbs) represents a logical alternative approach to prevent virus transmission. Here, we introduced two mutations encoding amino acid substitutions (M428L and N434S, collectively referred to as 'LS') into the genes encoding the crystallizable fragment domains of the highly potent HIV-specific 3BNC117 and 10-1074 bNAbs to increase their half-lives and evaluated their efficacy in blocking infection following repeated low-dose mucosal challenges of rhesus macaques (Macaca mulatta) with the tier 2 SHIV. A single intravenous infusion of 10-1074-LS monoclonal antibodies markedly delayed virus acquisition for 18 to 37 weeks (median, 27 weeks), whereas the protective effect of the 3BNC117-LS bNAb was more modest (provided protection for 11-23 weeks; median, 17 weeks). Serum concentrations of the 10-1074-LS monoclonal antibody gradually declined and became undetectable in all recipients between weeks 26 and 41, whereas the 3BNC117-LS bNAb exhibited a shorter half-life. To model immunoprophylaxis against genetically diverse and/or neutralization-resistant HIV-1 strains, a combination of the 3BNC117-LS plus 10-1074-LS monoclonal antibodies was injected into macaques via the more clinically relevant subcutaneous route. Even though the administered mixture contained an amount of each bNAb that was nearly threefold less than the quantity of the single monoclonal antibody in the intravenous injections, the monoclonal antibody combination still protected macaques for a median of 20 weeks. The extended period of protection observed in macaques for the 3BNC117-LS plus 10-1074-LS combination could translate into an effective semiannual or annual immunoprophylaxis regimen for preventing HIV-1 infections in humans.

DOI10.1038/s41591-018-0001-2
Alternate JournalNat Med
PubMed ID29662199
PubMed Central IDPMC5989326
Grant ListP01 AI100148 / AI / NIAID NIH HHS / United States
R01 AI129795 / AI / NIAID NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
ZIA AI001213-01 / NULL / Intramural NIH HHS / United States
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