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

Academic Article
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Overview

authors

  • Gavrilyuk, J.
  • Ban, H.
  • Uehara, H.
  • Sirk, S. J.
  • Saye-Francisco, K.
  • Cuevas, A.
  • Zablowsky, E.
  • Oza, A.
  • Seaman, M. S.
  • Burton, Dennis
  • Barbas III, Carlos

publication date

  • May 2013

journal

  • Journal of Virology  Journal

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.

subject areas

  • Antibodies, Neutralizing
  • Benzoates
  • CD4 Immunoadhesins
  • Cell Line
  • HIV Antibodies
  • HIV Infections
  • HIV-1
  • Humans
  • Immunoconjugates
  • Neutralization Tests
  • Piperazines
  • Spiro Compounds
  • Virus Internalization
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Identity

PubMed Central ID

  • PMC3624287

International Standard Serial Number (ISSN)

  • 0022-538X

Digital Object Identifier (DOI)

  • 10.1128/jvi.03146-12

PubMed ID

  • 23427154
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Additional Document Info

start page

  • 4985

end page

  • 4993

volume

  • 87

issue

  • 9

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