New discovery platforms are connecting the mechanisms of tumor cells with synthetic peptide therapies in search for cancer vaccines.
The time has come for hybrids. For the world of transportation, that means a vehicle that runs on different fuels. For the universe of healthcare, it’s a drug with the properties of more than one vehicle. Both approaches tip their hat to the reality that, like it or not, nature knows best.
One of the earliest examples where nature was used to solve a natural problem is the vaccine: a molecular display of a captured enemy soldier that alerts the body to the coming, full-on invasion. For polio, the creation of a vaccine was fairly straightforward: polio doesn’t look like us. Designing a vaccine for cancer, however, is not so simple—the tumor is us.
The fundamental question is, then, how are cancer cells different? Exploring this frontier is Harpreet Singh, PhD, chief scientific officer and cofounder of immatics biotechnologies, Tübingen, Germany. “The company was formed around a technology that was first developed at the University of Tübingen—a new platform combining different aspects of peptidomics, genomics, and immunology such that, for the first time, we are able to identify peptides directly from the HLA molecules found on primary tumor cells,” Singh explains. The HLA (human leukocyte antigen) system is the name of the major histocompatibility complex in humans—proteins that are expressed on the surface of all cell types that display peptide swatches from all proteins currently decorating the cell. The immune system, by way of circulating T-cells, screens HLA-bound peptides to determine a cell’s health status. “It’s like a window into the cell for the immune system to see what’s happening inside,” he says.
Mass spectrometry specialists analyze tumor samples from cancer patients in the search for novel peptide antigens. The best peptides that are commonly found on a large number of cancer samples are combined to a product and synthesized for treatment in clinical trials. (Source: immatics)
immatics’ platform, called XPRESIDENT, is able to identify large numbers of HLA-bound tumor-associated peptides (TUMAPS) directly from primary tumor tissue. “This sort of work has been done in cell lines,” says Singh, “but nobody’s ever done it with primary tissues from patients.” The objective is then to compare TUMAPS data (the output are peptide spectra) to the molecular signature of healthy cells. “In glioma, we initially identified 15,000 peptides,” he says. “After a comparison to normal cells, we selected 10 to 15 peptides that are considered highly immunogenic, and are known to have a vital function in a tumor cell.” Peptides were then generated via solid-state synthesis for incorporation into a cancer vaccine, antigen cocktail.
Synthesis was straightforward. “Even our longest peptides are generally not longer than 18 to 20 residues,” Singh explains. With his background in biochemistry, he had to resist the temptation to complicate the process. “In my experience, you might find that you can induce a stronger T-cell response (through chemical modification), but the result will be less effective at killing tumor cells.” It turns out that nature’s selection was already the best choice.
EXPRESIDENT still has some convincing to do, though. Many cancer vaccines have been developed with alternate platforms, and nearly all have failed. But Singh is convinced his is the right approach: immatics lead vaccine candidate, IMA901, has already shown in a Phase 1 study that 74% of patients with kidney cancer had a vaccine-induced, specific T-cell response.
A real phage turner
Another new discovery platform to help populate the map of the therapeutic peptide frontier is the Minicell Peptide Display (MPD) from Sopherion Therapeutics, Princeton, N.J. “MPD is a research platform that has a variety of advantages over existing technologies,” says Salvatore Forenza, PhD, vice president of research and development at Sopherion, who adds that the most significant of which is the independent expression of the peptide of interest. “Peptides are not incorporated in the cell wall like in a phage display, and that allows you to produce much larger peptides—up to 450 amino acids—while maintaining native confirmation,” he says.
MPD is then utilized in the same way as a phage display: a library of peptide sequences is expressed within minicells, and then run through a standard binding assay to determine associations between the expressed peptide and a membrane-bound receptor target. “Hits” can then be isolated and further characterized. These hits are informative, but in oncology, they’re usually not viable drugs. “There’s never only one target that is capable of modulating the life cycle of a tumor cell, there are multiple signals,” says Forenza. Using MPD, he hopes to identify multiple binding domains, and then combine those domains into a single (small) peptide to modulate signaling pathways subject to multiple stimuli. “We call these ‘Sophins’—multifunctional peptides generated by our platform,” says Forenza. Once the variable functionalities are stitched together, further modifications might be made to stabilize the molecule, such as the substitution of amino acids for those not susceptible to proteolytic enzymes.
Though this technology has multiple applications in oncology and beyond, Sopherion is keeping it in-house for the moment while they focus their resources. Their lead oncology compound, Myocet, is currently in a Phase 3 trial. Once finished, MPD will head for primetime.
That’s a wrap
A more advanced, if not more crowded area of peptide therapeutics is the histone deacetylase (HDAC) inhibitors. HDACs play a role in the organization and packaging of the genome, helping to coil DNA around molecules called histones. The inhibitors discovered thus far have a natural affinity for the mechanisms of oncology. “You would expect the whole genome to be involved,” says Simon Kerry, PhD, CEO of Karus Therapeutics, Southhampton, UK, “but as it happens, those genes regulated by known HDAC inhibitors are the ones involved in cellular proliferation.” And that’s cancer.
With so many HDAC inhibitors in development, it’s a wonder the Karus should choose such a deep pool in which to wade, but Kerry feels he has the method to stay afloat. “These agents fall into four categories: the aliphatic acids, like valproic acid, that have a lot of off-target activity; hydoxamates, like vorinostat (from Merck, the only approved HDAC inhibitor to date) lacks potency; benzamides, which have good activity also lack the necessary potency; and then there’s the depsipeptides,” Kerry says. These are naturally-produced compounds, often from microbes, that contain both peptide and ester bonds. The most promising of these in development is romidepsin from Gloucester Pharmaceuticals, Cambridge, Mass. “This agent is bacterial in origin, a cyclic molecule with disulphide bridge. It looks very different from other HDACs,” says Kerry.
Karus has taken this parent compound and optimized it. “We’ve managed to increase potency into the tens of picomolar range, while at the same time engineering out some of the natural disadvantages, such as its ability to induce drug resistance mechanisms,” he explains.
Efforts thus far have produced several synthetic analogues to romidepsin, and in vitro data suggests these compounds have anticancer activity at doses that would be toxic for the parent compound. Karus hopes to take its lead candidate into the clinic in Q4 2008.
Staples? We’ve got that.
Peptide therapies are often limited by where they can go. Small molecules can diffuse across a cell membrane; peptides generally cannot. Joe Yanchik, CEO of Aileron Therapeutics, Cambridge, Mass., is trying to fix that. “What we’ve done is use a closing metathesis reaction to bring stability to alpha helices in a peptide structure,” a so-called stapled peptide. This modification was initially investigated as a way to shield a peptide against proteolysis—and it was successful in that regard, “but the most surprising observation—utterly unanticipated by the inventors—was that this allowed the helix to cross the cell membrane,” says Yanchik. “This gives us the opportunity to create a whole new class of drugs that are capable of targeting intercellular protein-protein interactions—all presently un-druggable using current drug modalities.”
One of the innovators of the stapled peptide approach, the late Stanley Korsmeyer, MD, was also a pioneer in the investigation of the mitochondrial, apoptosis-associated protein BCL-2, and that target is now the focus of Aileron’s clinical development program. The lead compound is derived from endogenous resources, taking advantage of the known intercellular protein players in the cascade of BCL-2 associated apoptosis. “We identified the tool that already knows what to do when it gets into the cell. What we need to do is to give it the stability to get where it will do the most good,” Yanchik says.
About the Author
Neil Canavan is a freelance journalist of science and medicine based in New York.
This article was published in Drug Discovery & Development magazine: Vol. 10, No. 9, September, 2008, pp. 16-20.
Filed Under: Drug Discovery