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InOncology.com

VEGF/Ang2 inhibitor

BI 836880: A dual inhibitor of two key pathways mediating tumour angiogenesis

BI 836880* is a humanised bispecific nanobody® comprising blocking domains for vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2).1 It is a potent and selective inhibitor of VEGF and Ang2.1

BI 836880 is currently being investigated as monotherapy in two Phase I clinical studies in patients with solid tumours2,3 and in combination with the programmed cell death protein-1 (PD-1) inhibitor BI 754091* in a Phase I trial involving patients with non-squamous non-small cell lung cancer (NSCLC) with PD-L1 expression >1%.4

About BI 836880

VEGF/Ang2

VEGF and Ang2 signalling have different but complementary functions in tumour angiogenesis:5,6 Ang2 destabilises established blood vessels through interruption of vascular tyrosine protein kinase receptor Tie2 signalling, which promotes vessel remodelling – a prerequisite for sprouting angiogenesis.6,7

Ang2 destabilises established blood vessels through the interruption of Tie2

Ang1 growth factor and the receptor, Tie2

Signalling via VEGF regulates endothelial cell proliferation and migration, and vessel sprouting. 6,7

VEGF stimulation causes endothelial cells to sprout and proliferate to form new vessel structures

VEGF and receptor, sprouting angiogenesis

Preclinical studies in mouse models of various solid tumours have shown that combined VEGF/Ang2 blockade increases animal survival compared with blockade of either pathway alone.5

Mechanism of action

BI 836880 is a humanised bispecific nanobody® (antibody fragments consisting of a single variable antibody domain) comprising blocking domains for VEGF and Ang2 and an additional portion for extending the half-life.1 By binding to VEGF and Ang2, BI 836880 inhibits tumour angiogenesis and vascularisation, and enhances the tumour microenvironment to support T-cell trafficking and function in the tumour,1 making it a potential candidate for use in combination with PD1 inhibitors.

BI 836880’s mechanism of action

VEGF and receptor, sprouting angiogenesis

Preclinical and clinical development

Preclinical data have shown that BI 836880 can potently and selectively neutralise VEGF and Ang2 in models of pancreatic, lung, renal, ovarian and colon cancer.1 Furthermore, it showed superior inhibition of tumour growth and angiogenesis in vivo than either the VEGF inhibitor bevacizumab, or the Ang1/2 inhibitor AMG 368 alone.1

BI 836880 is currently being investigated in three Phase I clinical trials: two investigating BI 836880 monotherapy in patients with solid tumours2,3 and one investigating BI 836880 in combination with the PD-1 inhibitor BI 754091 in patients with advanced non-squamous NSCLC and PD-L1 expression >1%.4

Solid tumours

VEGF/Ang2 Clinical Trials

NSCLC

image

AE, adverse event; Ang2, angiopoietin 2; DLT, dose-limiting toxicity; DoR, duration of response; MTD, maximum tolerated dose; OR, objective response; PD, pharmacodynamics; PD-1, programmed cell death protein-1; PFS, progression free survival; PK, pharmacokinetics; VEGF, vascular endothelial growth factor.

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References

1

Hofmann I, et al. Poster presentation at the 8th Euro Global Summit on Cancer Therapy 2015.

2

ClinicalTrials.gov. NCT02674152. http://clinicaltrials.gov/ct2/show/NCT02674152 (Accessed: September 2018).

3

ClinicalTrials.gov. NCT02689505. http://clinicaltrials.gov/ct2/show/NCT02689505 (Accessed: September 2018).

4

ClinicalTrials.gov. NCT03468426. https://clinicaltrials.gov/ct2/show/NCT03468426 (Accesssed: September 2018).

5

Fukumura D, et al. Nat Rev Clin Oncol 2018;15(5):325–40.

6

Gerald D, et al. Cancer Res 2013;73(6):1649–57.

7

Huang H, et al. Nat Rev Cancer 2010;10(8):575–85.

*This is an investigational compound and has not been approved. Its safety and efficacy have not been established.

 

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Page last updated: May 2019