Role of immunoglobulin G fragment C receptor polymorphism-mediated antibody-dependant cellular cytotoxicity in colorectal cancer treated with cetuximab therapy

F V Negri,B Bortesi,G Missale,N Naldi,F Loupakis,R Camisa,T M Neri,G Bisagni,A Ardizzoni,N Chernyschova,A Musolino,A Zerbini,A Ruzzo,D Laccabue

doi:10.1038/tpj.2012.54

Abstract

Antibody-dependent cellular cytotoxicity (ADCC), which is activated by effector cells via immunoglobulin G (IgG) fragment C receptors (FcRs), was proposed as a mechanism of cetuximab efficacy. Peripheral blood mononuclear cells (PBMCs) from 23 healthy donors and 13 patients with metastatic colorectal cancer (mCRC) treated with cetuximab were tested for FcγR polymorphisms and cetuximab-mediated ADCC. ADCC was measured by chromium-51 release on a epidermal growth factor receptor (EGFR)-positive human colon cancer cell line. Overall, 86 mCRC patients were genotyped for study purposes. PBMCs harbouring the FcγRIIIa 158 V/V genotype had a significantly higher cetuximab-mediated ADCC. No correlation was found between FcγR polymorphisms and response rate or time to progression after cetuximab-based therapy. Despite the in vitro analysis showing that the FcγRIIIa 158 V/V genotype is associated with higher ADCC, clinical data do not support a predictive role of FcγRIIIa polymorphisms in mCRC treated with cetuximab.

Highlights

The clinical success of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in the treatment of colorectal cancer (CRC) was closely related to their ability to target and block the EGFR, preventing the activation of the complex network of EGFR-associated intracellular signals.[1]
Cetuximab-mediated antibody-dependent cellular cytotoxicity (ADCC) was detected in all Peripheral blood mononuclear cells (PBMCs) samples
PBMCs bearing immunoglobulin G fragment C receptor (FcgR) genotypes with a lower affinity to immunoglobulin G1 (IgG1) (FcgRIIIa F/F and/or FcgRIIa R/R) showed a significantly worse cetuximab-mediated ADCC than other genotypes (P 1⁄4 0.003; Figure 2)

Summary

Introduction

The clinical success of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in the treatment of colorectal cancer (CRC) was closely related to their ability to target and block the EGFR, preventing the activation of the complex network of EGFR-associated intracellular signals.[1]. In ADCC, the antibody binds to tumour cells and bridges the effector cells via their receptors for immunoglobulin G (FcgRs).[5] Several FcR subtypes have been identified, including FcgRI, FcgRIIa/IIb/IIc and FcgIIIa/IIIb.[6] Owing to the presence of an immunoreceptor tyrosine-based activation pattern either in the cytoplasmic domain (FcgRIIa) or in the accessory signalling g chain (FcgRIIIa), FcgRIIIa and FcgRIIa can stimulate immune cells. Previous investigations suggested that FcgRIIIa gene single-nucleotide polymorphisms may influence the response to rituximab and trastuzumab in patients with non-Hodgkin’s lymphoma and breast cancer, respectively.[7,8,9,10] Compared with the phenylalanine (F) allele, the FcgRIIIa of valine (V) allele displays a higher affinity to human IgG1, and cells bearing the FcgRIIIa V allele mediate enhanced ADCC activity.[11,12] polymorphisms corresponding to the expression of histidine (H) or arginine (R) at amino acid 131 in FcgRIIa affect the binding affinity of IgG1.13

Methods

Results

Conclusion