A Review of Anti-Angiogenic Targets for Monoclonal Antibody Cancer Therapy

Abstract

Tumor angiogenesis is a key event that governs tumor progression and metastasis. It is controlled by the complicated and coordinated actions of pro-angiogenic factors and their receptors that become upregulated during tumorigenesis. Over the past several decades, vascular endothelial growth factor (VEGF) signaling has been identified as a central axis in tumor angiogenesis. The remarkable advent of recombinant antibody technology has led to the development of bevacizumab, a humanized antibody that targets VEGF and is a leading clinical therapy to suppress tumor angiogenesis. However, despite the clinical efficacy of bevacizumab, its significant side effects and drug resistance have raised concerns necessitating the identification of novel drug targets and development of novel therapeutics to combat tumor angiogenesis. This review will highlight the role and relevance of VEGF and other potential therapeutic targets and their receptors in angiogenesis. Simultaneously, we will also cover the current status of monoclonal antibodies being developed to target these candidates for cancer therapy.

Keywords: VEGF; antibody; cancer therapy; therapeutic target; tumor; tumor angiogenesis.

Figure 1

Mechanisms of action of monoclonal antibodies targeting VEGF, PDGF, HGF, Ang, and their receptors for suppressing tumor growth and angiogenesis. Under pathological conditions, including hypoxia, most tumor cells and/or adjacent cells upregulate the expression of many angiogenic factors, including VEGF, PDGF, HGF, and Ang, and secrete them within the tumor microenvironment. When these molecules bind their cognate receptors, receptor dimerization and autophosphorylation stimulate downstream signaling molecules including phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/v-Akt murine thymoma viral oncogene (Akt) and MAPK (dash lines) for the promotion of tumor growth and angiogenesis. Currently, most antibody therapeutics are being developed to block the interaction between agonists and their receptors (T arrows).

Figure 2

Dual mode of action of a monoclonal antibody targeting the CLEC14a (C-type domain family 14 member) CTLD (C-type lectin-like domain) in cancer. (A) In tumor angiogenesis, the CLEC14a CTLD (red) plays a key role in mediating endothelial cell-cell contacts. When a targeting antibody binds to the CTLD of CLEC14a on tumor vessels, endothelial cell-cell contacts are inhibited, resulting in inhibition of tumor angiogenesis; (B) Simultaneously, binding of the antibody to CLEC14a on endothelial cells induces internalization of CLEC14a and eventually leads to its downregulation. These molecular mechanisms are important for suppressing CLEC14a-mediated tumor angiogenesis.