Human Fcgamma receptors compete for TGN1412 binding that determines the antibody's effector function.

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Dudek S, Weissmuller S, Anzaghe M, Miller L, Sterr S, Hoffmann K, Hengel H, Waibler Z

Human Fcgamma receptors compete for TGN1412 binding that determines the antibody's effector function.

Eur J Immunol. 2019 Jul;49(7):1117-1126. doi: 10.1002/eji.201847924. Epub 2019 Apr 29.

PubMed ID

31002172 [ View in PubMed

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Abstract

The first-in-human clinical trial of the CD28-specific monoclonal antibody (mAb) TGN1412 resulted in a life-threatening cytokine release syndrome. Although TGN1412 was designed as IgG4, known for weak Fc:Fcgamma receptor (FcgammaR) interactions, these interactions contributed to TGN1412-induced T-cell activation. Using cell lines (TFs) expressing human FcgammaRI, -IIa, -IIb, or -III, we show that TGN1412 and TGN1412 as IgG1 and IgG2 are bound by FcgammaRs as it can be deduced from literature. However, upon coculture of TGN1412-decorated T cells with TFs or human primary blood cells, we observed that binding capacities by FcgammaRs do not correlate with the strength of the mediated effector function. FcgammaRIIa and FcgammaRIIb, showing no or very minor binding to TGN1412, mediated strongest T cell proliferation, while high-affinity FcgammaRI, exhibiting strong TGN1412 binding, mediated hardly any T-cell proliferation. These findings are of biological relevance because we show that FcgammaRI binds TGN1412, thus prevents binding to FcgammaRIIa or FcgammaRIIb, and consequently disables T-cell proliferation. In line with this, FcgammaRI(-) FcgammaRII(+) but not FcgammaRI(+) FcgammaRII(+) monocytes mediate TGN1412-induced T-cell proliferation. Collectively, by using TGN1412 as example, our results indicate that binding of monomeric IgG subclasses does not predict the FcgammaR-mediated effector function, which has major implications for the design of therapeutic mAbs.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Natalizumab	High affinity immunoglobulin gamma Fc receptor I	Protein	Humans	Unknown	Ligand	Details