title: 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.
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.
authors.affiliation: Department of Immunology and Microbial Science and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Moldt
authors.forename: Mami
authors.initials: M
authors.lastname: Shibata-Koyama
authors.forename: Eva G
authors.initials: EG
authors.lastname: Rakasz
authors.forename: Niccole
authors.initials: N
authors.lastname: Schultz
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kanda
authors.forename: D Cameron
authors.initials: DC
authors.lastname: Dunlop
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Finstad
authors.forename: Chenggang
authors.initials: C
authors.lastname: Jin
authors.forename: Gary
authors.initials: G
authors.lastname: Landucci
authors.forename: Michael D
authors.initials: MD
authors.lastname: Alpert
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Dugast
authors.forename: Paul W H I
authors.initials: PW
authors.lastname: Parren
authors.forename: Falk
authors.initials: F
authors.lastname: Nimmerjahn
authors.forename: David T
authors.initials: DT
authors.lastname: Evans
authors.forename: Galit
authors.initials: G
authors.lastname: Alter
authors.forename: Donald N
authors.initials: DN
authors.lastname: Forthal
authors.forename: Jörn E
authors.initials: JE
authors.lastname: Schmitz
authors.forename: Shigeru
authors.initials: S
authors.lastname: Iida
authors.forename: Pascal
authors.initials: P
authors.lastname: Poignard
authors.forename: David I
authors.initials: DI
authors.lastname: Watkins
authors.forename: Ann J
authors.initials: AJ
authors.lastname: Hessell
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D015483:HIV Antibodies / Q000008:administration & dosage* / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008253:Macaca mulatta; D017452:Receptors, IgG / Q000276:immunology* / Q000378:metabolism; D016097:Simian Acquired Immunodeficiency Syndrome / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology* / Q000472:pathogenicity; D019562:Viral Load
chemical_list: D000911:Antibodies, Monoclonal; C496124:FCGR3A protein, human; D015483:HIV Antibodies; D017452:Receptors, IgG