Differential inhibition of trastuzumab- and cetuximab-induced cytotoxicity of cancer cells by immunoglobulin G1 expressing different GM allotypes

作者：Namboodiri A M; Pandey J P^*

来源：Clinical and Experimental Immunology, 2011, 166(3): 361-365.

DOI：10.1111/j.1365-2249.2011.04477.x

• ADCC
• cetuximab
• Fc gamma receptor
• GM allotypes
• trastuzumab

Antibody-dependent cell-mediated cytotoxicity (ADCC), which links the innate and the adaptive arms of immunity, is a major host immunosurveillance mechanism against tumours, as well as the leading mechanism underlying the clinical efficacy of therapeutic antibodies such as cetuximab and trastuzumab, which target tumour antigens, human epidermal growth factor receptor (HER)1 and HER2, respectively. Immunoglobulin (Ig)G antibody-mediated ADCC is triggered upon ligation of Fc gamma receptor (Fc gamma R) to the Fc region of IgG molecules. It follows that genetic variation in Fc gamma R and Fc could contribute to the differences in the magnitude of ADCC. Genetic variation in Fc gamma R is known to contribute to the differences in the magnitude of ADCC, but the contribution of natural genetic variation in Fc, GM allotypes, in this interaction has hitherto not been investigated. Using an ADCC inhibition assay, we show that IgG1 expressing the GM 3+, 1-, 2- allotypes was equally effective in inhibiting cetuximab-and trastuzumab-mediated ADCC of respective target cells, in the presence of natural killer (NK) cells expressing either valine or phenylalanine allele of Fc gamma RIIIa. In contrast, IgG1 expressing the allelic GM 17+, 1+, 2+ allotypes was significantly more effective in inhibiting the ADCC - mediated by both monoclonal antibodies - when NK cells expressed the valine, rather than the phenylalanine, allele of Fc gamma RIIIa. These findings have important implications for engineering antibodies (with human gamma 1 constant region) against malignancies characterized by the over-expression of tumour antigens HER1 and HER2 - especially for patients who, because of their Fc gamma RIIIa genotype, are unlikely to benefit from the currently available therapeutics.

• 出版日期2011-12