Characterization of 7A7, an anti-mouse EGFR monoclonal antibody proposed to be the mouse equivalent of cetuximab.

Xuzhi He,Fiona Simpson,Zewen K Tuong,Margaret Veitch,James W Wells,Shannon Joseph,Nicola Pett,Gabrielle Kelly,Hui Yi Chew,Jazmina L Cruz,Satomi Okano

doi:10.18632/oncotarget.24242

Xuzhi He, Fiona Simpson + Show 9 more

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https://doi.org/10.18632/oncotarget.24242

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Abstract

The Epidermal Growth Factor Receptor (EGFR) is selectively expressed on the surface of numerous tumours, such as non-small cell lung, ovarian, colorectal and head and neck carcinomas. EGFR has therefore become a target for cancer therapy. Cetuximab is a chimeric human/mouse monoclonal antibody (mAb) that binds to EGFR, where it both inhibits signaling and induces cell death by antibody-dependent cell mediated cytotoxicity (ADCC). Cetuximab has been approved for clinical use in patients with head and neck squamous cell carcinoma (HNSCC) and colorectal cancer. However, only 15-20% patients benefit from this drug, thus new strategies to improve cetuximab efficiency are required. We aimed to develop a reliable and easy preclinical mouse model to evaluate the efficacy of EGFR-targeted antibodies and examine the immune mechanisms involved in tumour regression. We selected an anti-mouse EGFR mAb, 7A7, which has been reported to be “mouse cetuximab” and to exhibit similar properties to its human counterpart. Unfortunately, we were unable to reproduce previous results obtained with the 7A7 mAb. In our hands, 7A7 failed to recognize mouse EGFR, both in native and reducing conditions. Moreover, in vivo administration of 7A7 in an EGFR-expressing HPV38 tumour model did not have any impact on tumour regression or animal survival. We conclude that 7A7 does not recognize mouse EGFR and therefore cannot be used as the mouse equivalent of cetuximab use in humans. As a number of groups have spent effort and resources with similar issues we feel that publication is a responsible approach.

Highlights

The Epidermal Growth Factor Receptor (EGFR) is a 170-kDa protein that belongs to the ErbB family of receptor tyrosine kinases
There are several EGFR-targeted drugs currently used in the clinic including therapeutic monoclonal antibodies, which bind to the extracellular domain of EGFR, and small molecule inhibitors that target the EGFR signaling cascade, such as tyrosine kinase inhibitors (TKIs) [5]
NIH-3T3 and TC-1 cells showed no significant evidence of Egfr mRNA expression, TC-1 cells are known to be tumourigenic when injected into mice and TC-1 cells were selected for further study in subsequent experiments

Summary

Introduction

The Epidermal Growth Factor Receptor (EGFR) is a 170-kDa protein that belongs to the ErbB family of receptor tyrosine kinases. It is composed of an extracellular ligand-binding domain, a single hydrophobic transmembrane region and an intracellular domain with intrinsic kinase activity that regulates many developmental, metabolic, and physiological processes [1, 2]. Cetuximab is a chimeric human/mouse mAb that binds to the extracellular domain of EGFR and is approved by the FDA for the treatment of colorectal cancer with KRAS WT status and HNSCC [6]. Previous studies have shown that cetuximab can trigger the innate or adaptive immune system, but the mechanisms are still unclear and need to be further studied [9,10,11,12]

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