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SimultaneousTargeting of FcγRsand FcαRI EnhancesTumor Cell Killing Arianne M. BrandsmaToine ten BroekeMaaike Nederend2015 год

Simultaneous Targeting of FcγRs and FcαRI Enhances Tumor Cell Killing
статья из журнала

Страница публикацииПубликация в OpenAlex
Аннотация: Efficacy of anticancer monoclonal antibodies (mAb) is limited by the exhaustion of effector mechanisms. IgG mAbs mediate cellular effector functions through FcγRs expressed on effector cells. IgA mAbs can also induce efficient tumor killing both in vitro and in vivo. IgA mAbs recruit FcαRI-expressing effector cells and therefore initiate different effector mechanisms in vivo compared with IgG. Here, we studied killing of tumor cells coexpressing EGFR and HER2 by the IgG mAbs cetuximab and trastuzumab and their IgA variants. In the presence of a heterogeneous population of effector cells (leukocytes), the combination of IgG and IgA mAbs to two different tumor targets (EGFR and HER2) led to enhanced cytotoxicity compared with each isotype alone. Combination of two IgGs or two IgAs or IgG and IgA against the same target did not enhance cytotoxicity. Increased cytotoxicity relied on the presence of both the peripheral blood mononuclear cell and the polymorphonuclear (PMN) fraction. Purified natural killer cells were only cytotoxic with IgG, whereas cytotoxicity induced by PMNs was strong with IgA and poor with IgG. Monocytes, which coexpress FcγRs and FcαRI, also displayed increased cytotoxicity by the combination of IgG and IgA in an overnight killing assay. Coinjection of cetuximab and IgA2-HER2 resulted in increased antitumor effects compared with either mAb alone in a xenograft model with A431-luc2-HER2 cells. Thus, the combination of IgG and IgA isotypes optimally mobilizes cellular effectors for cytotoxicity, representing a promising novel strategy to improve mAb therapy.
Год издания: 2015
Авторы: Arianne M. Brandsma, Toine ten Broeke, Maaike Nederend, Laura A.P.M. Meulenbroek, Geert van Tetering, Saskia Meyer, J.H. Marco Jansen, M. Alejandra Beltrán Buitrago, Sietse Q. Nagelkerke, István Balázs Németh, Ruud Ubink, Gerard Rouwendal, Stefan Lohse, Thomas Valerius, Jeanette H.W. Leusen, Péter Boross
Издательство: American Association for Cancer Research
Источник: Cancer Immunology Research
Ключевые слова: Monoclonal and Polyclonal Antibodies Research, T-cell and B-cell Immunology, Glycosylation and Glycoproteins Research
Другие ссылки: Cancer Immunology Research (HTML)
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