Ang2 inhibitors and Tie2 activators: potential therapeutics in perioperative treatment of early stage cancer

Abstract

Anti-angiogenic drugs targeting the VEGF pathway are most effective in advanced metastatic disease settings of certain types of cancers, whereas they have been unsuccessful as adjuvant therapies of micrometastatic disease in numerous phase III trials involving early-stage (resectable) cancers. Newer investigational antiangiogenic drugs have been designed to inhibit the Angiopoietin (Ang)-Tie pathway. Acting through Tie2 receptors, the Ang1 ligand is a gatekeeper of endothelial quiescence. Ang2 is a dynamically expressed pro-angiogenic destabilizer of endothelium, and its upregulation is associated with poor prognosis in cancer. Besides using Ang2 blockers as inhibitors of tumor angiogenesis, little attention has been paid to their use as stabilizers of blood vessels to suppress tumor cell extravasation and metastasis. In clinical trials, Ang2 blockers have shown limited efficacy in advanced metastatic disease settings. This review summarizes preclinical evidence suggesting the potential utility of Ang2 inhibitors or Tie2 activators as neoadjuvant or adjuvant therapies in the prevention or treatment of early-stage micrometastatic disease. We further discuss the rationale and potential of combining these strategies with immunotherapy, including immune checkpoint targeting antibodies.

Ang2-Targeted Combination Therapy for Cancer Treatment

“…Antiangiogenic therapy is one of the important means of tumor treatment at present (102) It does not only block the nutrition and oxygen required by tumor cells but also normalize abnormal blood vessels and increase the sensitivity of radiotherapy and chemotherapy (9,92). Bevacizumab, erlotinib, apatinib and other drugs are widely used in clinic, especially in combination with chemotherapy drugs, which significantly improves the curative effect in the treatment of colorectal cancer, small cell lung cancer and other cancers, but its side effects and drug resistance have not been solved (103)(104)(105). In recent years, Ang2 has become a new target of anti-angiogenesis therapy.…”

Spatial expression of an mRNA encoding Tie2-agonist in the capillary endothelium of the lung prevents pulmonary vascular leakage

“…Our new approach and technology thus overcome the limitations of efficaciously administering recombinant multimeric proteins for activating Tie2 signaling. In the past, a promising therapeutic approach to overcome Ang2 repression of the normal Tie2 signaling pathway has been to drive Tie2 activation to supra-physiological levels using recombinant Ang1 protein itself as well as derivatives thereof, such as COMP-Ang1 (Cho et al 2004a) or CMP-Ang1 (Khan et al 2021; Cho et al 2004b). Additionally, either an unrelated Tie2 agonist such as Vasculotide (Wu et al 2015; Gutbier et al 2017) or applying cell-based Ang1 gene therapy (McCarter et al 2007) have been used to that purpose.…”

“…However, an Ang2 neutralization dependent restoration of basal Tie2 phosphorylation has not been shown so far. The second promising therapeutic approach to overcome Ang2 repression of the normal Tie2 signaling pathway has been to drive Tie2 activation to supra-physiological levels using recombinant Ang1 protein itself as well as derivatives thereof, such as COMP-Ang1 (Cho et al 2004a) or CMP-Ang1 (Khan et al 2021; Cho et al 2004b). Additionally, either an unrelated agonist such as Vasculotide (Wu et al 2015; Gutbier et al 2017) or administration of cells expressing Ang1 (McCarter et al 2007) were shown to be applicable and effective to that purpose.…”

Structural insights into the clustering and activation of Tie2 receptor mediated by Tie2 agonistic antibody

“…Therefore, the therapeutic potential of our Tie2-agonistic antibodies— hTAAB and hzTAAB-H2L2—should be further explored in appropriate animal models of disease such as non-human primates and mouse models that express human Tie2. Despite Angpt1 variants, ABTAA and our Tie2-activating antibody (hTAAB) having the same ultimate goal of activating Tie2, they function in slightly different ways, thus likely to lead to somewhat different therapeutic outcome under pathological condition 47 . Therefore, it will be of interest in future studies to examine the therapeutic effects of hzTAAB under pathological conditions in which Angpt2 is elevated and to compare the effect of hzTAAB to that of other Tie2 agonists (COMP-Angpt1, ABTAA, etc.).…”