On the interaction of IgG subclasses with the low affinity Fc gamma RIIa (CD32) on human monocytes, neutrophils, and platelets. Analysis of a functional polymorphism to human IgG2.

Parren, Paul W.H.I.; Warmerdam, Petra A. M.; Boeije, L. C. M.; Arts, J.A.J.; Westerdaal, N. A. C.; Vlug, A.; Capel, P. J. A.; Aarden, Lucien A.; Winkel, Jan G. J. van de

doi:10.1172/jci116022

Cited by 334 publications

(262 citation statements)

References 46 publications

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“…Both mAbs exhibited lower binding to FcgRIIa 131R , and the ranking was reversed in accordance with previous observations (Fig. 3D) (25)(26)(27). TGN1412 and NIB(28SA)-G4 showed negligible binding to both FcgRIIa forms (Fig.…”

Section: Cd28 Recognition By Mabs and Fragmentssupporting

confidence: 91%

Antibody C Region Influences TGN1412-like Functional Activity In Vitro

Ball

Fox

Hufton

et al. 2012

The Journal of Immunology

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The unexpected outcome of the clinical trial of the superagonistic CD28 mAb TGN1412 (IgG4κ) continues to stimulate interest. We show that TGN1412 binds similarly to human and cynomolgus macaque FcγR, eliminating the possibility that differences in Fc-mediated interactions with FcγR contributed to the failure of preclinical testing in macaques to predict toxicity in humans. The influence of the Fc domain and C region structure on the in vitro functional activity of TGN1412 was investigated using F(ab′)2 and Fab fragments derived from TGN1412 recovered from the trial and recombinant TGN1412 subclass variants and mutants. Superagonistic activity, as measured by cytokine release and proliferation, was assessed by exposing PBMCs to immobilized mAbs/fragments or to aqueous mAbs/fragments in the presence of HUVEC monolayers. Removing the Fc generally curtailed or abolished PBMC activation. However, eliminating detectable FcγR-binding of the IgG4 by mutation (L235E) did not abrogate activity. Stabilizing the “wild-type” IgG4 hinge (S228P) enhanced activity without increasing FcγR binding, which could only partially be explained by inhibition of Fab arm–exchange. Subclass switching the IgG4 mAb to IgG1 decreased activity, whereas switching to IgG2 markedly increased activity. We conclude that the C region strongly influences in vitro CD28-mediated superagonistic signaling. Superagonism requires an intact Fc, as shown by the absence of activity of TGN1412 Fab and F(ab′)2 fragments, but, notably, appears to be relatively independent of FcγR-binding properties. We propose that the Fc, potentially through restricting flexibility, maintains a favorable V region conformation to allow superagonistic activity. These findings have important implications for Ab design strategies.

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Section: Cd28 Recognition By Mabs and Fragmentssupporting

confidence: 91%

Antibody C Region Influences TGN1412-like Functional Activity In Vitro

Ball

Fox

Hufton

et al. 2012

The Journal of Immunology

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“…However, in the presence of high-affinity receptors, enhancement or blocking may negate any beneficial Ab function, even though effector cells with such receptors are best able to carry out ADCVI. Our data also suggest a role for vaccineinduced IgG2 or IgG3 in enhancement or blocking because binding of those subclasses are most impacted by the FcRIIa polymorphism (21,22). Further in vitro and in vivo studies will be required to test these possibilities.…”

Section: Discussionmentioning

confidence: 82%

“…Fc␥RIIa is found on several cell types involved in HIV infection, including monocytes, macrophages, and dendritic cells. The H allele of Fc␥RIIa is required for binding to IgG2 and also increases binding to IgG3 (21,22). Fc␥RIIIa is the predominant Fc␥R on NK cells and is also found on some monocytes, macrophages, and dendritic cells (23,(35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

“…Fc␥RIIa is encoded by a gene having two alleles resulting in H or R at aa 131 (21,25). The H allele is required for binding to IgG2 and increases binding to IgG3 (21,22). Fc␥RIIIa is also encoded by a gene having two alleles, resulting in valine (V) or phenylalanine (F) at aa 148 (26).…”

Section: Fc␥riia and Fc␥riiia Gene Polymorphisms Influence The Adcvi mentioning

confidence: 99%

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Recombinant gp120 Vaccine-Induced Antibodies Inhibit Clinical Strains of HIV-1 in the Presence of Fc Receptor-Bearing Effector Cells and Correlate Inversely with HIV Infection Rate

Forthal

Gilbert

Landucci

et al. 2007

The Journal of Immunology

163

159

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Nonneutralizing Abs may play a role in protecting animals and humans from lentiviral infections. We explored the Ab-dependent, cell-mediated virus inhibition (ADCVI) Ab response to recombinant gp120 (rgp120) vaccination in sera from 530 participants in the Vax 004 trial. Serum ADCVI activity was measured against a clinical R5 strain of HIV-1 using peripheral blood mononuclear effector cells from healthy donors. The level of vaccine-induced ADCVI activity correlated inversely with the rate of acquiring HIV infection following vaccination, such that for every 10% increase in ADCVI activity, there was a 6.3% decrease in the hazard rate of infection (p = 0.019). Some vaccinated individuals also mounted an ADCVI response against two other clinical R5 strains of HIV-1. However, ADCVI activity correlated poorly with neutralizing or CD4-gp120-blocking Ab activity measured against laboratory strains. Finally, the degree to which the ADCVI Ab response predicted the rate of infection was influenced by polymorphisms at the FcγRIIa and FcγRIIIa gene loci. These data indicate that rgp120 vaccination can elicit Abs with antiviral activity against clinical strains of HIV-1. However, such activity requires the presence of FcR-bearing effector cells. Our results provide further evidence that ADCVI may play a role in preventing HIV infection.

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“…In the first case, expression is altered, whereas FcgRIIa-His131 binds IgG2 strongly and is considered a heritable risk factor for infectious diseases. [89][90][91] In both cases, phagocytosis is compromised. The FcgRIIIa presents a triallelic change: 48Arg and 48His present stronger binding for human IgG1, IgG3 and IgG4, than 48Leu.…”

Section: Igs and Fcrs Polymorphismsmentioning

confidence: 99%