By David N. Leff
Sooner or later, Hollywood will get around to filming the ultimate action drama — the human immune response.
Except for sex, this never-ending thriller has everything that turns an audience on: violence, deception, invasion, attack, mass murder, treason, revenge.
The movie opens on a police identification line-up. Someone in the row of individuals presented for inspection by potential witnesses is the perpetrator, suspected of breaking and entering, with intent to kill.
That culprit is the foreign antigen — viral, bacterial, fungal, cancer, whatever.
Before the immune system can deal with the invader, it has to recognize the antigen, which is presented to the line-up by an antigen-presenting cell. This molecular bailiff exhibits the antigen on its surface so that T cells, the immune system's constabulary, can recognize the invader.
"First of all," explained pathologist Ben Bronstein, "a white blood cell called an antigen-presenting cell swallows the protein antigen and chops it into peptide fragments. Inside the cell, these bind to major histocompatibility class II [MHC II] molecules. This complex is transported to the cell's surface. There, receptors on helper T lymphocytes recognize the antigenic complex and bind to it.
"Subsequently," he continued, "it signals T cells to attack the alien intruder. It may enlist B cells — the immune system's humoral arm — as an additional immune weapon." Bronstein is president and CEO of Peptimmune Inc., of Cambridge, Mass.
As in so much larger-scale warfare, the defending forces sometimes mistake their body's own troops for those of a foreign interloper. When the immune system directs friendly fire at its "self" proteins, autoimmune diseases ensue.
Paradoxically, the very opposite can also occur: When an extra-high dose of an antigenic peptide floods into the body, it may produce tolerance rather than rejection. Bronstein cites hayfever as an example of this so-called "high-zone tolerance."
"Say you have hayfever and go in for an allergy shot," he told BioWorld Today. "If you get a low dose of whatever is causing your allergic response, you tend to mount a pretty strong immune reaction. But the more that dose increases, the more you tend to tolerate it. Your helper T cells go into an anergic (dormant) stage, rather than an activated stage. It's like a hair of the dog that bit you."
Attempting to unravel that high-zone paradox four years ago led molecular immunologist Jack Strominger, of Harvard University, in Cambridge, Mass., to devise an approach that has the potential of fighting autoimmune disease, by depressing T cell depredation, and infectious diseases, such as HIV, by stepping up its potency.
He founded Peptimmune in 1995 to commercialize his invention under a worldwide, exclusive license from Harvard.
Strominger is senior author of a paper in today's Proceedings of the National Academy of Sciences (PNAS), dated Dec. 23, 1997. Its title: "Superactivation of an immune response triggered by oligomerized T cell epitopes."
Potential Drugs Called Peptimers
"In 1993," Strominger recalled, "we crystallized Class II MHC proteins. They crystallized as dimers. So we asked whether the dimer has any physiological role, and tried to figure out how we could link peptides to force dimerization or oligomerization. We've since done it in several ways, chemical and biosynthetic, all covered by our pending patent.
"You can read into this PNAS paper," Strominger told BioWorld Today, "the idea that the dimer itself isn't big enough for physiological relevance."
He and his co-authors constructed higher oligomers of three, four and more identical subunits. "My hunch is," he observed, "that the effective one has more than two."
Peptimmune has developed variants of "those effective ones" into potentially therapeutic compounds it calls "Peptimers."
"Consider multiple sclerosis [MS]," said biochemist James Rasmussen, the company's vice president of research and development and chief scientific officer. "Many people consider that myelin basic protein [MBP] is involved in inducing that autoimmune disease. MBP is made up of a series of antigenic peptides. Certain ones are particularly prominent in inducing the MS response, so we incorporated into our Peptimers multi-copies of those presumed immunodominant epitopes. They range from tetramers to 32-mers. We're looking at those different lengths to see which are the most potent."
In vitro, Strominger's laboratory has contrived Peptimers with potency up to 10,000-fold greater than the peptide monomer measured in proliferation of helper T cells.
Rare Skin Disease Also Targeted
Besides MS and rheumatoid arthritis, Rasmussen cites another less well known therapeutic target: "It's pemphigus vulgaris," he said, "a very interesting and rare autoimmune disorder not mentioned in the PNAS paper.
"This serious blistering skin disease," he went on, "is found predominantly in elderly Ashkenazi Jews. Because of its involvement in the skin and its exact disease mechanism, we understand pemphigus about as completely as any autoimmune disease I can think of." (See BioWorld Today, Dec. 16, 1997, p. 1.)
He continued: "We know the HLA types found in these patients. We know which protein is clearly responsible for the autoimmune response. And we know which peptide epitopes within that protein are the keys. So if you have the appropriate HLA class II type, your risk of developing pemphigus goes up 15 times."
Rasmussen pointed out that "there are no animal models for pemphigus, and only suboptimal therapies available. So after some in vitro and safety testing, we think our Peptimers would be applicable for human trials."
He added an epidemiological puzzler: "Pemphigus vulgaris is not 100 percent exclusive to people of Ashkenazi lineage. There is an enclave of it among Japanese and elsewhere in the world."
The company also is gearing up to develop Peptimers as "superactivator" therapeutic vaccines against infectious diseases, starting with HIV, based on peptide antigens identified by immunologist Bruce Walker, of Boston-based Massachusetts General Hospital. (See BioWorld Today, Nov. 21, 1997, p. 1.)
"Peptimmune really started up in July 1996," Bronstein recalled. "Its first financing came on March 6, 1997, and we will shortly go out for a second round of venture funding." *