Antibody conjugation approach enhances breadth and potency of neutralization of anti-HIV-1 antibodies and CD4-IgG.

TitleAntibody conjugation approach enhances breadth and potency of neutralization of anti-HIV-1 antibodies and CD4-IgG.
Publication TypeJournal Article
Year of Publication2013
AuthorsGavrilyuk J, Ban H, Uehara H, Sirk SJ, Saye-Francisco K, Cuevas A, Zablowsky E, Oza A, Seaman MS, Burton DR, Barbas CF
JournalJ Virol
Volume87
Issue9
Pagination4985-93
Date Published05/01/2013
ISSN1098-5514
KeywordsAntibodies, Neutralizing, Benzoates, CD4 Immunoadhesins, Cell Line, HIV Antibodies, HIV Infections, HIV-1, Humans, Immunoconjugates, Neutralization Tests, Piperazines, Spiro Compounds, Virus Internalization
Abstract

Broadly neutralizing antibodies PG9 and PG16 effectively neutralize 70 to 80% of circulating HIV-1 isolates. In this study, the neutralization abilities of PG9 and PG16 were further enhanced by bioconjugation with aplaviroc, a small-molecule inhibitor of virus entry into host cells. A novel air-stable diazonium hexafluorophosphate reagent that allows for rapid, tyrosine-selective functionalization of proteins and antibodies under mild conditions was used to prepare a series of aplaviroc-conjugated antibodies, including b12, 2G12, PG9, PG16, and CD4-IgG. The conjugated antibodies blocked HIV-1 entry through two mechanisms: by binding to the virus itself and by blocking the CCR5 receptor on host cells. Chemical modification did not significantly alter the potency of the parent antibodies against nonresistant HIV-1 strains. Conjugation did not alter the pharmacokinetics of a model IgG in blood. The PG9-aplaviroc conjugate was tested against a panel of 117 HIV-1 strains and was found to neutralize 100% of the viruses. PG9-aplaviroc conjugate IC50s were lower than those of PG9 in neutralization studies of 36 of the 117 HIV-1 strains. These results support this new approach to bispecific antibodies and offer a potential new strategy for combining HIV-1 therapies.

DOI10.1128/JVI.03146-12
Alternate JournalJ. Virol.
PubMed ID23427154
PubMed Central IDPMC3624287
Grant ListAI095038 / AI / NIAID NIH HHS / United States
AI100663 / AI / NIAID NIH HHS / United States
AI33292 / AI / NIAID NIH HHS / United States
R01 AI033292 / AI / NIAID NIH HHS / United States
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