Pretender to Avastin throne poised to enter clinical trails
enter clinical trials and could prove a serious rival to
VEGF-blocking drugs, due to fewer side-effects and less drug
resistance.
The overall affect of TB-403 is to starve cancer tumours by cutting off their blood supply. In this way, it is similar to Genentech and Roche's Avastin (bevacizumab), a blockbuster antibody that targets vascular endothelial growth factor (VEGF). However, the pretender to the Avastin throne exerts its effect through a totally different target - placental growth factor (PlGF). The drug's developers believe this new target gives TB-403 a couple of advantages over VEGF drugs. The first is that VEGF inhibitors act on normal, as well as diseased, tissue causing side-effects such as blood clots, high blood pressure, blood vessel pruning in healthy organs, interruption of pregnancy, and other side effects, according to scientists at the University of Leuven, Belgium, and the Flanders Institute for Biotechnology (VIB). Writing in the latest edition of the journal Cell, the researchers explain that, by comparison, PlGF levels are virtually undetectable and dispensable in normal, healthy tissue. "PlGF knockout mice survive and are healthy," said Peter Carmeliet from the University of Leuven. "With no VEGF, they die before birth." PlGF is overexpressed in cancer and chronic inflammatory conditions and induces new vessel formation in tissues under stress. This means that, unlike VEGF, PlGF does not seem to affect normal blood vessel growth, according to BioInvent. "This mode of action, which is different from and complementary to current anti-VEGF inhibitors, makes it attractive as both a stand-alone and combination therapy," said Prof. Desire Collen, CEO of Belgium-based ThromboGenics. The hope is that PlGF inhibitors could cause limited side-effects yet still provide the desired efficacy. The second potential advantage to attacking this new target in preference to VEGF paradoxically stems from the fact that PlGF inhibitors don't seem to be as effective as their more established rivals. Avastin and others do their job to such an extent that the body begins to produce other molecules that promote new blood vessel growth (angiogenesis), including PlGF. This effectively 'rescues' the tumour from the effects of Avastin and can lead to some patients becoming resistant to the therapy. By working less well, TB-403 doesn't induce this rescue attempt and the developers hope patients won't become resistant to it. The antibody has now been tested in more than 12 mouse models of cancer, including ones resistant to VEGF-inhibiting therapy. TB-403 blocked angiogenesis and the ability of tumour cells to move. It also prevented infiltration of blood vessel-promoting immune cells, called macrophages. It will be several years before TB-403 makes it anywhere near approval but Svein Mathisen, CEO of BioInvent, is confident enough to have proclaimed that "TB-403 will secure a prominent place in the oncology armoury." The first step of the process is ready to start, with a humanised form of the antibody having already been created. The two companies say they expect to begin a Phase I clinical trial before the end of this year. "It needs to stand the test of time and rigorous clinical testing, but the findings in mice look promising," said Carmeliet. Clinical trials to assess the drug's ability to block blood vessel growth in conditions such as age-related macular degeneration (AMD) and diabetic retinopathy - two of the developed world's leading causes of blindness - are also planned.
