By David N. Leff
Way back before the dawn of human history, Homo flintstonienis lived in caves, and carved his large-mammal meals with stone cutlery.
Those cavemen paid no attention to the cholesterol in their high-fat diets. They didn¿t have to.
¿In early humans,¿ observed veteran vascular biologist Una Ryan, ¿regulation of cholesterol must have been very useful when you ate bison one week and didn¿t get your woolly mammoth till a month later. You needed a molecule called CETP ¿ cholesteryl ester transfer protein ¿ to adjust its levels in your blood plasma. CETP,¿ she explained, ¿is sort of a shuttle bus that takes cholesterol from high-density lipoproteins ¿ that¿s LDL, the good¿ cholesterol ¿ to LDL, the bad actor.¿ (See BioWorld Today, Aug. 18, 1996, p. 1.)
¿Nowadays,¿ Ryan pointed out, ¿CETP is just a pain in the neck, because we consume such high cholesterol three times a day. CETP is clearly no longer useful to modern humans.¿
Ryan is president and CEO of Avant Immunotherapeutics Inc., of Needham, Mass. Her company has just completed construction of a vaccine against atherosclerosis, which works by knocking out CETP¿s function.
Avant immunologist Larry Thomas was scheduled to present the novel vaccine Monday to a minisymposium on atherosclerosis at FASEB, the Federation of American Societies of Experimental Biology, in Washington. His abstract bore the title: ¿A vaccine to produce anti-cholesteryl ester transfer protein antibodies for the prevention and treatment of atherosclerosis.¿
¿One tends to think of atherosclerosis,¿ Ryan told BioWorld Today, ¿as a disease that¿s best managed by diet, exercise and ¿ if you want to lower your ¿bad¿ LDL ¿ the best drugs now are the statins such as mevastatin and lovastatin. Like many chronically administered medications, patient compliance is not great. And they¿re very expensive. Avant¿s vaccine will cost much less.
¿The statins have been enormously successful,¿ she pointed out, ¿but they don¿t do a good job of elevating HDL, which I believe is an extremely important protective risk factor for the disease.
¿There are populations of people in Japan,¿ Ryan went on, ¿who have lived to a ripe old age, with very high HDLs, and a low incidence of atherosclerosis They were found to have mutations in CETP, which disabled its cholesterol-trafficking function. That experiment of nature replicates our anti-CETP vaccine¿.
Avant¿s candidate vaccine consists of a dimeric, chimeric synthetic doublet peptide, 31 amino acids long, directed to a small piece of CETP, the functional fragment that does the cholesterol shuttling. One peptide molecule is coupled at the B-cell epitope, which produces antibodies. The other binds a T-cell epitope, which is actually tetanus toxin. ¿Because,¿ Ryan explained, ¿we all have an immune response to tetanus, against which we¿ve all had shots as children.
¿So that¿s how we trick the immune system into providing the T-cell help. Because there¿s no T-cell help when you¿re trying to do a vaccine against self antigens. That¿s the clever bit about it, and it¿s also very novel.¿
¿You think of vaccines for pathogens and outside invaders,¿ Ryan observed. ¿This is one where we are directing it towards the self antigen, so we have to break immune tolerance.¿
As Avant¿s Thomas¿ abstract reported to the FASEB session, the vaccine¿s creators tested their product in vivo in New Zealand White rabbits, the preferred animal model for cardiovascular drug development. ¿On the vaccine designing team,¿ Ryan recalled, ¿Larry was in charge of the animal experiments.
¿Our final experiment,¿ she continued, ¿fed the rabbits fairly high levels of cholesterol, like a human high-cholesterol Big Mac diet. This was where we saw a 35 percent improvement in HDL cholesterol concentrations, atherotic lesions lessened by 40 percent, and significantly reduced CETP activity The animals also had considerably smaller areas of streak lesions in their aortas than did untreated controls.¿
Arterial fatty streaks are a heads-up predictor of incipient atherosclerosis, decades before it becomes a diagnosable disease of the elderly.
¿As one develops the kinds of plaques in humans that give us heart attacks, stroke and peripheral vascular disease,¿ Ryan pointed out, ¿those take a period of 60 years or so to develop.¿ She recalled a study years ago of pathogenetic determinants of atherosclerosis in youth, funded by the NIH.
¿They looked at the arteries of young people who had died of non-cardiovascular events, such as automobile or motorcycle accidents, and also of babies. And they found that as these complex plaques developed early in life, they start out as fatty streaks, which are deposits of fat and some other cells in the arteries. So if you feed these rabbits high cholesterol, you find fatty streaks. They¿re not the same as those old-age plaques that you see in humans who have to have heart surgery. But they are the beginnings of the process.¿
A Streak That Foretells The Future
The aorta is not a unique site of streak occurrence, but a convenient place to look for them. Nor do they run like stripes down the arteries along their inner walls, but rather as elongated patches of cholesterol, lipid and foam cells in and around the cells of the vessel wall.
Ryan made the added point that, ¿You have to be careful. Animal models are only models. And the only time you really see the human disease is in humans. ¿
She perceives an important role of the atherosclerosis vaccine as ¿allowing us to access people who are now sort of average, without high-risk cholesterol levels. We will try to move them into the protective levels of HDLs, which seems to be over 60 milligrams per deciliter.
¿When you take a shot for measles for example,¿ Ryan pointed out, ¿you¿re protected for life, or a long time. We picture this vaccine as something where you go in for your annual physical checkup, or once or twice a year, you get your booster shot. Much like going in for your seasonal flu shot, you¿d get your atherosclerosis inoculation at the same time.
¿Avant aims to move the vaccine into the clinic shortly,¿ Ryan said. ¿This will be just a Phase I safety trial, for which we¿ll be ready to go this summer. Initially it will vaccinate reasonably healthy people without symptoms, and not at high risk of atherosclerosis, but who need to have their HDLs improved.
¿Later we will just be seeing how to ultimately expand, when some of the groups who are resistant to cholesterol-lowering statin drugs could be helped. Of course,¿ she concluded, ¿we¿d love to see it go to everybody, but I don¿t want to be unrealistic.¿ n