Anti-epidermal growth factor receptor monoclonal antibodies in cancer therapy

Abstract

The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor involved in the proliferation and survival of cancer cells. EGFR is the first molecular target against which monoclonal antibodies (mAb) have been developed for cancer therapy. Here we review the mechanisms underlying the effects of EGFR-specific mAb in cancer therapy. The efficacy of EGFR-specific mAb in cancer occurs thanks to inhibition of EGFR-generated signalling; furthermore, the effects of antibodies on the immune system seem to play an important role in determining the overall anti-tumour response. In this review, attention is focused on cetuximab and panitumumab, two mAb introduced recently into clinical practice for treatment of metastatic colorectal and head and neck cancer which target the external part of EGFR.

Fig. 1

Signal transduction pathway mediated by epidermal growth factor receptor (EGFR). The interaction with ligand that occurs in the extracellular portion of the EGFR family induces the formation of a functionally active EGFR–EGFR homodimer or of an EGFR–human epidermal receptor 2 (HER2), EGFR–HER3 or EGFR–HER4 heterodimer. As explained in the text, this results in conformational changes that allow the EGFR tyrosine kinase to be activated with the phosphorylation of specific tyrosine residues within the EGFR intracellular carboxyl-terminal domain. Phosphorylated tyrosine residues trigger a complex programme of intracellular signals to the cytoplasm and then to the nucleus that stimulates cell proliferation, loss of differentiation, invasion and angiogenesis, and blocks the apoptosis.

Fig. 2

Effects of monoclonal antibody (mAb) therapies on the immune system. (a) The mAb bind the epidermal growth factor receptor (EGFR) expressed on the surface of the tumour cell; this binding activates antibody dependent cellular cytotoxicity by engaging Fc receptors on the surface of natural killer (NK) cells. Some T cells may also be activated by specific recognition of the FAb portion of the mAb. Finally, the binding mAb/EGFR can allow, by trogocytosis, the internalization of part of EGFR by antigen-presenting cells as the dendritic cells. (b) Dendritic cells present peptides derived from the internalized portion of EGFR to T cells, priming an immune response more efficient in recognition of EGFR peptides associated with major histocompatibility complex expressed by tumour cells. As reported in the text, Fc receptors are expressed on the surface of many cells (mast cells, eosinophils, etc.) that can secrete a variety of different cytokines and chemokines, thus amplifying the overall immune response induced by mAb.