A nonfucosylated variant of the anti-HIV-1 monoclonal antibody b12 has enhanced FcγRIIIa-mediated antiviral activity in vitro but does not improve protection against mucosal SHIV challenge in macaques

J Virol. 2012 Jun;86(11):6189-96. doi: 10.1128/JVI.00491-12. Epub 2012 Mar 28.

Abstract

Eliciting neutralizing antibodies is thought to be a key activity of a vaccine against human immunodeficiency virus (HIV). However, a number of studies have suggested that in addition to neutralization, interaction of IgG with Fc gamma receptors (FcγR) may play an important role in antibody-mediated protection. We have previously obtained evidence that the protective activity of the broadly neutralizing human IgG1 anti-HIV monoclonal antibody (MAb) b12 in macaques is diminished in the absence of FcγR binding capacity. To investigate antibody-dependent cellular cytotoxicity (ADCC) as a contributor to FcγR-associated protection, we developed a nonfucosylated variant of b12 (NFb12). We showed that, compared to fully fucosylated (referred to as wild-type in the text) b12, NFb12 had higher affinity for human and rhesus macaque FcγRIIIa and was more efficient in inhibiting viral replication and more effective in killing HIV-infected cells in an ADCC assay. Despite these more potent in vitro antiviral activities, NFb12 did not enhance protection in vivo against repeated low-dose vaginal challenge in the simian-human immunodeficiency virus (SHIV)/macaque model compared to wild-type b12. No difference in protection, viral load, or infection susceptibility was observed between animals given NFb12 and those given fully fucosylated b12, indicating that FcγR-mediated activities distinct from FcγRIIIa-mediated ADCC may be important in the observed protection against SHIV challenge.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / isolation & purification
  • Antibodies, Monoclonal / metabolism
  • Cells, Cultured
  • Female
  • HIV Antibodies / administration & dosage*
  • HIV Antibodies / immunology
  • HIV Antibodies / isolation & purification
  • HIV Antibodies / metabolism
  • HIV-1 / immunology*
  • Humans
  • Macaca mulatta
  • Receptors, IgG / immunology*
  • Receptors, IgG / metabolism
  • Simian Acquired Immunodeficiency Syndrome / pathology
  • Simian Acquired Immunodeficiency Syndrome / prevention & control*
  • Simian Acquired Immunodeficiency Syndrome / virology
  • Simian Immunodeficiency Virus / immunology*
  • Simian Immunodeficiency Virus / pathogenicity
  • Viral Load

Substances

  • Antibodies, Monoclonal
  • FCGR3A protein, human
  • HIV Antibodies
  • Receptors, IgG