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Permalink 02:47:13 pm, by Tom, 1094 words, 1948 views   English (UK)
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The long road to Lucentis

Patients in England suffering from wet form of age related macular degeneration (AMD), a leading cause of blindness, received some good news this week when the National Institute for Health and Clinical Excellence (NICE) announced that they should get access to the drug Lucentis on the NHS thanks to a deal struck with drug's manufacturer, Novartis. A key feature of wet AMD is the excessive growth of blood vessels which tend to leak and damage the tissues of the eye.

This is excellent news since Lucentis has been shown to be highly effective in slowing the progression of wet AMD and preventing blindness. Lucentis is a mouse monoclonal antibody fragment that binds to and inhibits a chemical messenger called vascular endothelial growth factor A (VEGF-A) that is required for the growth of blood vessels, and by doing so prevents the growth of blood vessels that is responsible for the damage seen in wet AMD.

This is perhaps an opportune moment to look at the basic animal research that eventually lead to the development of Lucentis. Doctors and scientists have been interested in the role of blood vessel proliferation, or angiogenesis, in disease for a long time, but in the early days they were mostly interested whether it played a role in cancer. Studies done on rats by Warren Lewis at the Johns Hopkins University in the mid 1920's showed that the growth of blood vessels varied between different tumour types. Shortly after that J. Sandison introduced a key invention, a transparent chamber that could be inserted into an animal tissue and allowed microscopic observation of living tissues underneath a glass coverslip. With this chamber scientists could study the growth of tumours and their effect on the surrounding tissue in living animals. In 1939 Gordon Ide at Rochester University demonstrated that tumours transplanted into rabbits only grew if blood vessels proliferated around the tumour site, a result that was subsequently verified and advanced by Glenn Algire and colleagues at the National Cancer Institute who studied the ability of transplanted tumours to grow in mice and hypothesized that the ability to promote blood vessel growth was a crucial property of aggressive tumours (1). The next major development came in 1968 when two groups, Melvin Greenblatt and Philippe Shubik at Chicago Medical School, and Robert Ehrmann and Mogens Knoth at Harvard Medical School, showed that cancer cells transplanted into hamster cheek pouches promoted blood-vessel proliferation even when a filter was placed between the tumour and the host, demonstrating that a diffusible factor (or factors) was responsible for promoting angiogenesis. Now the search was on to identify those factors.

In 1971 Judah Folkman and colleagues published a paper (2) describing how a factor they named tumour angiogenesis factor (TAF) could be isolated from animal and human tumours and promoted blood vessel growth when injected into rats. Judah Folkman later went on to develop sensitive in vitro assays for angiogenesis, but the rat assay was vital to his early work and angiogenesis and to evaluation of the later in vitro assays. In the decades the discovery of TAF several other angiogenesis factors were identified.

The discovery of VEGF happened when a group of scientists lead by Harold Dvorak noticed that the blood vessels surrounding tumours in guniea pigs were unusually permeable, or leaky, and that that permeability was important to tomour growth(3). They proceeded to isolate a factor, initially named vascular permeability factor (VPF), that was responsible for this increased permeability (4). In 1989 researchers lead by Napoleone Ferrara identified a protein secreted by bovine pituitary cells that promoted angiogenesis and which they named vascular endothelial growth factor (VEGF) (1) . Subsequent gene sequencing demonstrated that VPF and VEGF were the same protein, a key regulator of angiogenesis during both tumour growth and normal processes such as wound healing and embryonic development. The next step was to examine whether it was possible to safely block the activity of VEGF, and in 1993 scientists at Genentech Inc. demonstrated that a monoclonal antibody that bound to VEGF could greatly reduce the growth of tumours that had been implanted in mice by preventing blood vessel proliferation, even though it had no effect on the same tumour cells in vitro(5).

The discovery that by blocking VEGF you could potentially treat cancer lead to the development of drugs such as Genentech's Avastin, but that is perhaps a story for another day. It was known that proliferation of leaky blood vessels was a major factor in wet AMD, and that patients with the disease had high levels of VEGF in their eyes, so VEGF was a tempting target for inhibition. A study published in 2002 demonstrated that a mouse monoclonal antibody fragment, subsequently named Ranibizumab/Lucentis, developed by Genentech could prevent experimental induction of blood vessel formation in the eyes of monkeys (6). Other studies with monkeys were performed to discover the amount of Lucentis that needed to be injected into the eye so that it remained in the retina and vitreous of the eye in sufficient concentrations for long enough to effectively block VEGF (7), and these showed that the amount required was acceptable for trials in humans. They also demonstrated that level of Lucentis subsequently detected in the blood was very low as it was cleared quite rapidly, which was good news given the potential of an anti-VEGF drug to interfere with normal processes such as wound healing. These important results provided the information needed to design clinical trails in human patients.

The process leading to the development of Lucentis is an excellent example of how basic research into "interesting" biological processes leads to medical advances.



1) Ferrara N. "VEGF and the quest for tumour angiogenesis factors." Nat Rev Cancer. Volume 2(10), pages 795-803 (2002).
2) Folkman al. "Isolation of a tumour factor responsible for angiogenesis" J Exp Med. Volume133(2), pages 275–288 (1971).
3) Dvorak H.F. et al."Fibrin gel investment associated with line 1 and line 10 solid tumor growth, angiogenesis, and fibroplasia in guinea pigs. Role of cellular immunity, myofibroblasts, microvascular damage, and infarction in line 1 tumor regression." J Natl Cancer Inst. Volume 62(6), pages1459-1472 (1979).
4) Senger D.R. et al. "Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid." Science Volume 219(4587), pages 983-985 (1983).
5) Kim K.J. et al. "Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo" Nature Volume 362(6423), pages 841-844.
6) Krzystolik M.G. et al. "Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment." Arch Ophthalmol. Volume120(3), pages 338-346 (2002).
7) Gaudreault J. "Preclinical pharmacokinetics of Ranibizumab (rhuFabV2) after a single intravitreal administration" Invest Ophthalmol Vis Sci. Volume 46(2), pages 726-33 (2005)

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