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Open Access Publications from the University of California

A Nonfucosylated Variant of the anti-HIV-1 Monoclonal Antibody b12 Has Enhanced Fc RIIIa-Mediated Antiviral Activity In Vitro but Does Not Improve Protection against Mucosal SHIV Challenge in Macaques

  • Author(s): Moldt, B.;
  • Shibata-Koyama, M.;
  • Rakasz, E. G;
  • Schultz, N.;
  • Kanda, Y.;
  • Dunlop, D. C;
  • Finstad, S. L;
  • Jin, C.;
  • Landucci, G.;
  • Alpert, M. D;
  • Dugast, A.-S.;
  • Parren, P. W. H. I;
  • Nimmerjahn, F.;
  • Evans, D. T;
  • Alter, G.;
  • Forthal, D. N;
  • Schmitz, J. E;
  • Iida, S.;
  • Poignard, P.;
  • Watkins, D. I;
  • Hessell, A. J;
  • Burton, D. R
  • et al.

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.

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