Pharmacogenetics of anticancer monoclonal antibodies

Abstract

Pharmacogenetics is the study of therapeutic and adverse responses to drugs based on an individual's genetic background. Monoclonal antibodies (mAbs) are a rapidly evolving field in cancer therapy, however a number of newly developed and highly effective mAbs (e.g., anti-CTLA-4 and anti-PD-1) possess pharmacogenomic profiles that remain largely undefined. Since the first chemotherapeutic mAb Rituximab was approved in 1997 by the US Food and Drug Administration for cancer treatment, a broad number of other mAbs have been successfully developed and implemented into oncological practice. Nowadays, mAbs are considered as one of the most promising new approaches for cancer treatment. The efficacy of mAb treatment can however be significantly affected by genetic background, where genes responsible for antibody presentation and metabolism, for example, can seriously affect patient outcome. This review will focus on current anticancer mAb treatments, patient genetics that shape their efficacy, and the molecular pathways that bridge the two.

Keywords: Pharmacogenetics; cancer immunotherapy; immune-checkpoint proteins; monoclonal antibodies; personalized medicine; pharmacogenomics.

Figure 1

Structure of a monoclonal antibody

Figure 2

Mechanism of anticancer activity of anti-EGFR mAbs. Cetuximab and panitumumab bind to EGF receptors, thus preventing further signalling transduction via PI3K/mTOR and RAS/ERK pathways. Inactivation of growth signalling pathways prevents cell proliferation and survival. EGFR: epidermal growth factor receptor; mAbs: monoclonal antibodies

Figure 3

The effect of bevacizumab on VEGF signalling pathway. This figure shows, that bevacizumab is primarily directed to bind VEGF signalling molecules. Such interaction leads to inactivity of VEGF binding to its receptors and as a result it reduces neoangiogenesis. VEGF: vascular endothelial growth factor