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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

Clinical trials and combinations: BI 836880 is currently being investigated as monotherapy in two Phase I clinical studies in patients with solid tumours,2,3 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 programmed cell death ligand-1 (PD-L1) expression >1%.4

About BI 836880

VEGF/Ang2

VEGF and Ang2 signalling have different but complementary functions in tumour angiogenesis:5–7

  • Ang2 destabilises established blood vessels through interruption of vascular tyrosine protein kinase receptor Tie2 signalling, which promotes vessel remodelling – a prerequisite for sprouting angiogenesis
  • Signalling via VEGF regulates endothelial cell proliferation and migration, and vessel sprouting

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

VEGF and Ang2 have complementary roles in tumour angiogenesis6,7

Role of Ang2 and VEGF in angiogenesis

Ang2, angiopoietin-2; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

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 PD-1 inhibitors (e.g. BI 754091).

BI 836880’s mechanism of action1,5–7

BI 836880: mechanism of action

Ang2, angiopoietin-2; CD, cluster of differentiation; PD-1, programmed cell death protein-1; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Preclinical and clinical development

Monotherapy

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 as monotherapy in two Phase I clinical trials involving patients with solid tumours.2,3

Combination therapy

BI 836880 is also being investigated in a Phase I clinical trial 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 solid tumours trial status

NSCLC

image

AE, adverse event; Ang2, angiopoietin-2; DCR, disease control rate; 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 2019).

3

ClinicalTrials.gov. NCT02689505. http://clinicaltrials.gov/ct2/show/NCT02689505 (Accessed: September 2019).

4

ClinicalTrials.gov. NCT03468426. https://clinicaltrials.gov/ct2/show/NCT03468426 (Accesssed: September 2019).

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.

 

© 2019 Boehringer Ingelheim International GmbH. All rights reserved.

 

Page last updated: September 2019