BioWorld International Correspondent

LONDON - An antibody that interferes with the action of a molecule that helps blood vessels to grow in tumors and other diseases - but not in healthy tissue - could enter clinical trials in humans before the end of the year.

The molecule blocked by this potential therapy is placental growth factor (PlGF), a member of the same family of molecules as VEGF. Drugs that inhibit VEGF are already in clinical use for the treatment of some types of cancer, because of their ability to switch off the growth of new blood vessels (angiogenesis), thus starving tumors of oxygen and nutrients.

Recent studies have shown that PlGF, unlike VEGF, switches on the production of new blood vessels only in disease. Such observations suggested that PlGF inhibitors might reduce pathological angiogenesis without affecting healthy blood vessels, and could form a new class of anticancer drugs with fewer side effects than those that inhibit VEGF.

Now a new study, published in Cell, provides evidence from more than 12 mouse models of cancer that antibodies that inhibit PlGF can slow the growth of tumors, including those that are resistant to VEGF-inhibiting therapies.

The PlGF antibodies blocked angiogenesis and the ability of tumor cells to move. Unlike VEGF inhibitors, anti-PIGF also blocked the infiltration of pro-angiogenic macrophages - cells that may cause resistance to VEGF inhibitors, as the Cell paper showed.

Anti-PIGF antibodies also prevented the development of severe oxygen deprivation within the tumors, so avoiding the hypoxia that normally triggers release of other angiogenic factors, which also leads to resistance to therapies that block the action of VEGF.

Peter Carmeliet, professor of medicine at the University of Leuven in Belgium, told BioWorld International: "These data suggest that, at least in mice, there is less resistance to anti-PlGF than there is to anti-VEGF. We can start to think about combination therapy with anti-PlGF and anti-VEGF, to increase the efficacy of treatment and inhibit tumor growth without causing more toxicity."

Carmeliet and his colleagues, including researchers at the Flanders Institute for Biotechnology (VIB), in collaboration with Thrombogenics NV, also of Leuven, published their findings in the Nov. 2, 2007, Cell in a paper titled: "Anti-PlGF Inhibits Growth of VEGR(R)-Inhibitor-Resistant Tumors without Affecting Healthy Vessels".

Thrombogenics holds the rights to develop anti-PlGF as a therapy. With its development partner, BioInvent International, of Lund, Sweden, Thrombogenics has started manufacturing a humanized anti-PlGF antibody, which is known as TB-403.

Désiré Collen, CEO and chairman of Thrombogenics, told BioWorld International: "We have already done extensive toxicology testing, so we are ready to begin trials in humans. We hope to have approval very soon and begin trials before the end of this year."

Carmeliet said that more than 95 percent of all therapies that are in development for anti-angiogenesis target VEGF or its main receptor, VEGF(R)2. Yet if interfering with those molecules causes side effects, or results in treatments that allow resistance to develop, he said, all these approaches will encounter the same problems.

"This is where PlGF comes into play, because it acts on a different receptor, the PlGF(R)1, which stimulates cancer growth in different and more divergent ways," Carmeliet said. "The most likely way forward is to give cocktails of these inhibitors, so long as they all work through different mechanisms."

VEGF-inhibiting therapies represent a major breakthrough, he added, but they still pose several problems. First, depending on the type of tumor, up to 70 or 80 percent of patients may not respond because of resistance to the drug. Secondly, the therapy does not cure the disease although it prolongs survival. Thirdly, the side effects include hypertension, bleeding, thrombosis, hypothyroidism, fatigue, stroke and myocardial infarction. Although these side effects are acceptable for most patients with cancer, they mean that the therapies cannot be used for children with cancer, pregnant women with cancer or people who have both ischemic heart disease and cancer.

Carmeliet said: "As reported in Cell, we found no side effects whatsoever with anti-PlGF treatment. This is entirely consistent with the genetic data, because knock-out mice lacking functional PlGF are completely healthy and show impaired angiogenesis only in disease, but not in development or in healthy tissue. Because of this attractive safety profile, we can start considering to use anti-PlGF in children or pregnant women with cancer."

Based on its anti-antiangiogenic properties, Thrombogenics and BioInvent also intend to develop TB-403 for eye diseases, to block uncontrolled blood vessel growth in conditions such as age-related macular degeneration and diabetic retinopathy.