Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Dec;3(12):1316-24.
doi: 10.1158/2326-6066.CIR-15-0099-T. Epub 2015 Sep 25.

Simultaneous Targeting of FcγRs and FcαRI Enhances Tumor Cell Killing

Arianne M Brandsma  1 , Toine Ten Broeke  1 , Maaike Nederend  1 , Laura A P M Meulenbroek  1 , Geert van Tetering  1 , Saskia Meyer  1 , J H Marco Jansen  1 , M Alejandra Beltrán Buitrago  1 , Sietse Q Nagelkerke  2 , István Németh  3 , Ruud Ubink  4 , Gerard Rouwendal  4 , Stefan Lohse  5 , Thomas Valerius  5 , Jeanette H W Leusen  6 , Peter Boross  1
Affiliations

Simultaneous Targeting of FcγRs and FcαRI Enhances Tumor Cell Killing

Arianne M Brandsma et al. Cancer Immunol Res. 2015 Dec.

Abstract

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.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

Publication types

MeSH terms

LinkOut - more resources