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.

TitleA 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.
Publication TypeJournal Article
Year of Publication2012
AuthorsMoldt B, Shibata-Koyama M, Rakasz EG, Schultz N, Kanda Y, Dunlop CD, Finstad SL, Jin C, Landucci G, Alpert MD, Dugast A-S, Parren PWHI, Nimmerjahn F, Evans DT, Alter G, Forthal DN, Schmitz JE, Iida S, Poignard P, Watkins DI, Hessell AJ, Burton DR
JournalJ Virol
Volume86
Issue11
Pagination6189-96
Date Published2012 Jun
ISSN1098-5514
KeywordsAnimals, Antibodies, Monoclonal, Cells, Cultured, Female, HIV Antibodies, HIV-1, Humans, Macaca mulatta, Receptors, IgG, Simian Acquired Immunodeficiency Syndrome, Simian immunodeficiency virus, Viral Load
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.

DOI10.1128/JVI.00491-12
Alternate JournalJ. Virol.
PubMed ID22457527