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  • Review Article
  • Published:

Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer

Key Points

  • The idea that inhibiting tumour angiogenesis might be an effective anticancer strategy was proposed by Folkman over thirty years ago.

  • A number of molecules involved in angiogenesis have now been identified, including vascular endothelial growth factor (VEGF), which is an essential regulator of normal and pathological angiogenesis.

  • This article overviews the biology of VEGF, and then focuses on the path from the identification of VEGF and the establishment of its key role in tumour angiogenesis to the clinical development of the humanized anti-VEGF monoclonal antibody bevacizumab.

  • Bevacizumab was approved by the FDA as a first-line treatment for metastatic colorectal cancer in February 2004 — the first approval by the FDA of a therapeutic developed to target tumour angiogenesis.

Abstract

The existence of factors that stimulate blood vessel growth, thereby recruiting a neovascular supply to nourish a growing tumour, was postulated many decades ago, although the identification and isolation of these factors proved elusive. Now, vascular endothelial growth factor (VEGF), which was identified in the 1980s, is recognized as an essential regulator of normal and abnormal blood vessel growth. In 1993, it was shown that a monoclonal antibody that targeted VEGF results in a dramatic suppression of tumour growth in vivo, which led to the development of bevacizumab (Avastin; Genentech), a humanized variant of this anti-VEGF antibody, as an anticancer agent. The recent approval of bevacizumab by the US FDA as a first-line therapy for metastatic colorectal cancer validates the ideas that VEGF is a key mediator of tumour angiogenesis and that blocking angiogenesis is an effective strategy to treat human cancer.

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Figure 1: Role of the VEGF receptor tyrosine kinases in endothelial cells.
Figure 2: Duration of survival in a Phase III study of previously untreated patients with metastatic colorectal cancer in two arms of the study*.

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Correspondence to Napoleone Ferrara.

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Competing interests

N.F., K.J.H., H.-P.G. and W.N. are employees of Genentech, Inc., which developed and markets bevacizumab (Avastin).

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DATABASES

LocusLink

aFGF

bFGF

angiogenin

EGF

PDGF-B

PlGF

TNF-α

VEGF-A

VEGF-B

VEGF-C

VEGF-D

Glossary

ENDOTHELIAL CELLS

The main type of cell in the inside lining of blood vessels, lymph vessels and the heart.

HEPARIN

Naturally occurring acidic glycosaminoglycan. Heparin-like moieties are common in proteoglycans in the cell surface and extracellular matrix.

PERICYTES

Support cells of capillaries (believed by many to be the equivalent of smooth muscle cells in larger vessels).

DOMINANT-NEGATIVE

A defective protein that retains interaction capabilities and so distorts or competes with normal proteins, inhibiting their function.

XENOGRAFTS

Tumour specimens can be grown in immunocompromised rodents to provide tumour models with many of the complexities of human tumours.

HUMANIZATION

A technique used to circumvent the immunogenicity of murine monoclonal antibodies for human therapy. In the simplest case, the complementary determining regions of a mouse monoclonal antibody are transferred to a human antibody that therefore acquires the binding characteristics of the original murine antibody. The amino-acid sequence of the humanized antibody is 93–95% human.

TORTUOSITY

The characteristic serpiginous appearance of newly formed and tumour-associated vessels. In tumour vessels, tortuosity is believed to be a hallmark of defective structural properties.

APTAMER

Oligonucleotide ligand selected in vitro to bind specific proteins.

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Ferrara, N., Hillan, K., Gerber, HP. et al. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3, 391–400 (2004). https://doi.org/10.1038/nrd1381

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