Therapeutic Application of Monoclonal Antibodies in Pancreatic Cancer: Advances, Challenges and Future Opportunities

Abstract

Pancreatic cancer remains as one of the most aggressive cancer types. In the absence of reliable biomarkers for its early detection and more effective therapeutic interventions, pancreatic cancer is projected to become the second leading cause of cancer death in the Western world in the next decade. Therefore, it is essential to discover novel therapeutic targets and to develop more effective and pancreatic cancer-specific therapeutic agents. To date, 45 monoclonal antibodies (mAbs) have been approved for the treatment of patients with a wide range of cancers; however, none has yet been approved for pancreatic cancer. In this comprehensive review, we discuss the FDA approved anticancer mAb-based drugs, the results of preclinical studies and clinical trials with mAbs in pancreatic cancer and the factors contributing to the poor response to antibody therapy (e.g. tumour heterogeneity, desmoplastic stroma). MAb technology is an excellent tool for studying the complex biology of pancreatic cancer, to discover novel therapeutic targets and to develop various forms of antibody-based therapeutic agents and companion diagnostic tests for the selection of patients who are more likely to benefit from such therapy. These should result in the approval and routine use of antibody-based agents for the treatment of pancreatic cancer patients in the future.

Keywords: mAbs; monoclonal antibodies; pancreatic cancer; target antigens; targeted therapy.

Figure 1

Mechanisms of action of monoclonal antibody-based products. (A) Targeting growth factor receptors, blocking the binding of an activating ligand and inhibiting receptor homo- and heterodimerization; (B) Targeting of tumour vasculature receptor or its ligands inhibiting angiogenesis; (C) Induction of apoptosis by recruitment of immune effector cells (ADCC) or activation of the complement cascade (CDC), and the use of antibody-based molecules to engineer T lymphocytes (CAR T cells); (D) Immune checkpoint inhibition by blockade of the PD-1/PD-L1 axis or CTLA-4 inhibitory receptors, increasing cytotoxic T cell activity; (E) Simultaneous targeting of two antigens, one on tumour cells and one on effector T cells, by using bispecific antibodies (BITE, bispecific T-cell enhancing); and (F) Delivery of payloads such as toxins and radioisotopes to tumour cells. Created with BioRender.com (accessed on 17 March 2021).

Figure 2

Antigens targeted by antibodies in patients with pancreatic cancer. Created with BioRender.com (accessed on 17 March 2021).