Thursday, November 15, 2007
Trapping the wily VEGF
A significant challenge in pharmacology is the correct dosing of the drug. "The dose makes the poison" is an adage in toxicology, but "the dose makes the drug" just as much. Too little drug and insufficient effect will occur; too much and the patient is likely to suffer from toxic side-effects.
Traditionally, drug dosages evolved completely empirically. Many drugs have profiles allowing very crude dosing -- "take two aspirins and call me in the morning" is remarkable advice, remarkable because it generally works. Other drugs, particularly in trials, are dosed by body size. This makes rough sense, as if you wish to obtain a certain concentration of drug the amount of body it will be diluted in should be taken into account.
Over time various influences on dosing have been realized. I ate a grapefruit today pondering whether one day this small pleasure will be forbidden to me; the metabolism of many drugs is altered by natural compounds present in grapefruit. Individual variation plays a major role as well, with some chemotherapy drugs at normal doses near-lethal to small fractions of the population, because those individuals metabolize the drug differently. Some drugs have notoriously narrow dosing windows: underdose a heart patient and they may have angina or other nasty events; overdose them and they can have nosebleeds which simply won't end.
It is hard enough to dose drugs for which there are decades of experience or which are relatives of drugs with long pedigrees. Dosing brand new agents with new activity profiles is far more difficult. Hence, there is a real need for compasses which could point the way to the correct dose.
VEGF is an important soluble signaling factor which stimulates angiogenesis, the formation of new blood vessels. Anti-angiogenesis agents have emerged as an important tool in oncology and also in the vision-robbing disease macular degeneration. VEGF can be targeted in a number of ways: the antibody drug Avastin (bevacizumab) directly binds VEGF, whereas multi-targeted ("dirty") kinase inhibitors such as Nexavar (sorafanib) and Sutent (sunitinib) knock out the cellular receptors for VEGF (which are tyrosine kinases) among their many targets.
VEGF-Trap is an investigation drug being developed by Regeneron, one of those feline biotech companies (9 lives!) which keep plugging along. VEGF-Trap is a pastiche of carefully chosen protein parts: pieces of two different human VEGF receptors plus a bit from a human antibody (IgG1) constant region.
In a new paper in PNAS (open access) the Regeneron folks show that VEGF-Trap forms stable, inert, monomeric complexes with VEGF which remain in circulation. By measuring the amount of free and VEGF-complexed VEGF-Trap in circulation they can measure VEGF levels and identify a dose which ensures that maximal trapping occurs. If insufficient drug is applied, then little or no free VEGF-Trap is detected.
One significant surprise, in both mice and humans, is that VEGF levels are higher than previously reported. Furthermore, VEGF levels do not differ greatly between individuals with cancer (human patients or xenografted mice) and those without. Human and mouse VEGF levels were very similar, when normalized for body mass. Maximal anti-tumor effects were observed in the mouse models at the dosing point where free VEGF-Trap was observed, suggesting that this method of VEGF measurement can guide dosing.
Can you do the same trick with bevacizumab? Not according to the paper: antibodies form multivalent complexes with their targets, and these complexes are removed from circulation by various mechanisms. Measurements of bound complex are therefore difficult and not informative.
During my previous job I got interested in whether VEGF, or other angiogenic mediators, might be useful for patient stratification. Several papers claimed that soluble angiogenesis factor levels were useful in predicting cancer outcome, but when I compared the measurements in the papers they weren't even on the same scale: the reported baseline measurements in normal individuals were completely different. It didn't invalidate the concept, but certainly prevented any useful synthesis of various papers.
John S. Rudge, Jocelyn Holash, Donna Hylton, Michelle Russell, Shelly Jiang, Raymond Leidich, Nicholas Papadopoulos, Erica A. Pyles, Al Torri, Stanley J. Wiegand, Gavin Thurston, Neil Stahl, and George D. Yancopoulos
VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade
PNAS published November 13, 2007, DOI: 10.1073/pnas.0708865104