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Dual inhibitor of two key pathways mediating tumour angiogenesis
BI 836880* is a humanised bispecific Nanobody® that is a dual inhibitor of vascular endothelial growth factor (VEGF) and angiopoietin-2 growth factor (Ang-2), early members of two key tumour angiogenesis pathways. BI 836880 is currently being investigated in Phase I trials in patients with solid tumours.1,2
About BI 836880
BI 836880’s mechanism of action
BI 836880 is a humanised Nanobody®; nanobodies® are engineered antibody fragments consisting of variable antibody domains.3 BI 836880 comprises two single variable domains that inhibit VEGF and Ang-2, and an additional albumin module that extends half-life in vivo.4 Both VEGF and
Ang‑2 are key angiogenic factors that are induced by hypoxia and often overexpressed in cancer.5,6 Activation of the Ang-2/Tie-2 pathway promotes vascular destabilisation and enables VEGF-induced angiogenesis to take place.6 As there is cross-talk between the two signalling pathways, inhibition of both pathways may be a superior approach compared to targeting either pathway alone.4
The role of VEGF/Ang-2 signalling
The VEGF family are soluble growth factors secreted by tumour cells which bind to the extracellular domain of the VEGF receptors (VEFGRs).5 VEGF has the ability to regulate vessel permeability and activation of the VEGFR pathway triggers downstream signalling cascades that result in endothelial cell growth, migration and survival.5 VEGF is a key mediator of tumour angiogenesis, with expression levels playing an important role in the speed and extent of metastatic development.7,8 Overexpression of VEGF correlates with tumour progression and poor prognosis in patients with different cancers including non-small cell lung cancer, breast cancer and colorectal cancer.7-9
The Ang-1 and Ang-2 growth factors and their receptor, Tie-2, are primarily expressed by endothelial cells and play essential roles in vascular development.10 Ang-1 binds to Tie-2 to promote vascular maturity and integrity, while Ang-2 is a naturally occurring antagonist of Ang-1 and promotes vascular destabilisation to enable VEGF-induced angiogenesis.6 Inhibition of Ang-2 has been shown to reduce tumour vascularity.10
Preclinical and clinical development: solid tumours
BI 836880 has shown promising in vitro and in vivo activity in oncology.4 Preclinical data have shown that BI 836880 can potently and selectively neutralise VEGF and Ang-2 in models of pancreatic, lung, renal, ovarian and colon cancer. When compared with bevacizumab, a VEGF inhibitor, and AMG 368, an Ang-2 inhibitor, BI 836880 showed superior percentage tumour growth inhibition and inhibition of angiogenesis in vivo.4 BI 836880 is currently being investigated in Phase I dose finding trials in patients with solid tumours.1,2
AE, adverse event; DLT, dose-limiting toxicity; MTD, maximum tolerated dose
ClinicalTrials.gov. NCT02674152. http://clinicaltrials.gov/ct2/show/NCT02674152. Accessed: July 2017.
ClinicalTrials.gov. NCT02689505. http://clinicaltrials.gov/ct2/show/NCT02689505. Accessed: July 2017.
Ablynx NV. Understanding Nanobodies®. http://www.ablynx.com/technology-innovation/understanding-nanobodies/. Accessed: July 2017.
Hofmann I, et al. Presented at the 8th Euro Global Summit on Cancer Therapy, Valencia, Spain, 3–5 November 2015.
Hicklin DJ, et al. J Clin Oncol 2005;23(5):1011–27.
Albini A, et al. J Natl Cancer Inst 2012;104(6):429–31.
Lee JC, et al. Eur J Cancer 2000;36(6):748–53.
Gasparini G. Oncologist 2000;5 Suppl 1:37–44.
Zhan P, et al. J Thorac Oncol 2009;4(9):1094–103.
Falcon BL, et al. Am J Pathol 2009;175(5):2159–70.
*This is an investigational compound and has not been approved. Its safety and efficacy have not been established.
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