ANTI-ATHEROSCLEROSIS VACCINE AIMS TO TURNAUTOIMMUNITY FROM PATHOGENIC TO PREVENTIVE
By David N. LeffScience Editor
CAMBRIDGE, Mass. _ Strange as it may seem, a leading biotechcompany which has a research program on combating autoimmunediseases, is considering how to generate autoimmunity in humans.
Immunologist Charles Rittershaus, associate director of cell biologyat T Cell Sciences Inc. here, called his idea _ inducingautoreactivity to control cholesterol metabolism _ "a crazy idea."
Rittershaus told a session on autoimmunity at the 1995 scienceseminar of the Massachusetts Technology Institute here that "Theobjective of this project we've been working on the past five monthsis to attempt to induce anti-atherogenic plasma of the lipoprotein profile _ that is, high levels ofHDL [high-density lipoprotein] _ the `good' cholesterol."
By now almost everyone knows that HDL earns its white-hatreputation by shunting excess cholesterol to the liver, which hustles itout of the body. Meanwhile, HDL's black-hat adversary, LDL, triesto divert that cholesterol back into the metabolic pathway, where itcan build up artery-clogging plaque, and cause atherosclerosis andheart attack.
HDL and LDL may be household acronyms, but CETP is not _ yet.CETP _ cholestyrl ester transfer protein _ is the molecule thathijacks cholesterol off the straight and narrow path to the liver, andputs it on the low road to cardiovascular disease.
Vaccine Target: Not LDL, But CETP
"What we're attempting to do," Rittershaus explained, "is blockCETP trafficking. Hyperlipidemia patients," he noted, "have elevatedCETP activity, whereas athletes _ who tend not to developatherosclerosis _ have low CETP activity." To clinch thiscorrelation, he observed: "Individuals who have a genetic deficiencyof CETP chalk up markedly elevated HDL levels," and added,"Anecdotally, these people live to be very old, and don't seem tohave problems with atherosclerosis."
Rittershaus cited in vivo evidence from hamsters and rabbits thatCETP correlates with the disease. "Infusion of anti-CETP antibodiesinto the blood of those animals," he said, "elevated HDL levels inboth species. "In rabbits, the good-guy HDL level had doubled within48 hours."
Taking hints from the rabbits and hamsters, the T Cell Sciencesresearcher recalled, "we thought we would try to block CETP byvaccination. This approach would induce endogenous antibodies withspecificity similar to the monoclonals infused into the animals."
But because the target CETP is a "self" protein, he looked in theliterature for a precedent. This turned up current clinical trials inIndia of a contraceptive vaccine, in which fertile women arevaccinated against their own human chorionic gonadotropin, ahormone necessary to sustain pregnancy. (See BioWorld Today, Aug.31, 1994, p. 1.)
As long as booster shots maintained an optimum antibody level, hefound, "these women remained functionally sterile. But withoutboosters, they soon became pregnant.
"So we came up with these questions: "Could we induce endogenous,anti-CETP antibody? Could these autoreactive antibodies modify theplasma lipoprotein level or profile? If so, would vaccination againstCETP affect these levels?"
He and his colleagues put together a CETP-specific vaccine, whichcombined T cell and B cell epitopes with a tetanus toxoid adjuvant.Its first component is a recombinant amino acid sequence of thehuman CETP protein's functional region, which resides on its Cterminus. This sequence presumably serves as a B cell epitope.
They coupled this with a universal T cell epitope, consisting of partof the tetanus toxoid peptide, to stimulate T cells to help the B cellsthat generate anti-CETP antibodies grow and differentiate.
"We then decided to look for an animal model we could try this in,"Rittershaus told his audience here.
They found a clinical testing facility, Pharmakon USA, of Waverley,Pa. (a subsidiary of Princeton, N.J.-based DNX Corp.) that hadtransgenic mice expressing human CETP. On a high-cholesterol diet,these animals evolved 40 to 50 percent lower HDL levels, and aheightened susceptibility to atherosclerosis.
"Their human CETP," Rittershaus reasoned, "should act as a self-antigen."
Pharmakon inoculated T Cell Sciences' anti-CETP vaccine into six ofthese transgenic rodents, and an adjuvant dummy into six controls.
After two booster shots, on days 28 and 42, they bled the mice on day63 for analysis. Compared to controls, all six animals generated veryhighly specific recognition of the CETP, which declined in level,while their HDL went up.
"This experiment," Rittershaus observed, "demonstrated that thesetransgenic mice could be induced to produce inhibitory antibodiesdirected against a self-protein."
Thus encouraged, he and his team started "a small pilot study in fourNew Zealand rabbits _ three vaccinees and one control. Theseduplicated the responses seen in the mice.
"In future, with these rabbits," Rittershaus summed up, "we want tosee if we can demonstrate a type of antibody response similar to whatwe see in contraceptive vaccine. And we're currently examining theeffects of our vaccine in cholesterol-fed rabbits, looking for atheroticstreaks and lesions in their blood vessels."
Responding to a question from the floor, he allowed that it will alsobe necessary to confirm that the anti-CETP effect is reversible.
"Chuck [Rittershaus] had this idea," T Cell Sciences president andCEO Alan Tuck told BioWorld Today. "It came out of the work weare doing in autoimmune diseases with T cell receptor, in which weare trying to suppress autoimmunity."
Tuck added: "It's still too early-stage to say if the CETP vaccine ideais for real. We didn't do it just for a hobby, but because it'sinteresting. If it works, we'll pursue it. We think it's exciting." n
(c) 1997 American Health Consultants. All rights reserved.