"Toll-like receptor" sounds like a cop waiting at a highway coin basket to catch those who pass through without paying. And, in a way, that's what toll-like receptors, or TLRs, are.
Found on the surfaces of antigen-presenting cells, they are glycoprotein molecules that recognize microbial structures and, when bound to them, trigger innate immune responses in the body.
Officially, TLRs are named for the Toll gene in Drosophila fruit fly, helping the insect fight fungal infections - a gene that became interesting with regard to humans when researchers found it shares cytoplasmic sequences with the interleukin-2 receptor. How cool is that? Enough to make the German scientist Christiane Nüesslein-Volhard, who first found the gene, name it "Toll" - slang in her country for "cool."
The science is moving along, and TLR research gained new attention earlier this month when VaxInnate Corp. pulled down $23.1 million in a Series B financing to expand its scientific team and advance trials. VaxInnate's platform, known as VaxIne, exploits innate and adaptive immune responses by combining a disease-specific antigen with compounds called Pathogen-Associated Molecular Patterns to start the disease-battling activity. Two infectious disease programs and one cancer program will launch this year, based on TLR discoveries.
Carlo Russo, VaxInnate's newly appointed president and CEO, said the round gives his company enough cash to get an investigational new drug application filed and start a trial, but more money likely will be needed to go beyond that.
VaxInnate is hardly alone in TLRs. Probably the farthest along in the area is Coley Pharmaceutical Group Inc., with the cancer compound ProMune, which targets TLR9, in Phase II studies for melanoma, non-small-cell lung cancer and cutaneous T-cell lymphoma, said Arthur Krieg, Coley's chief scientific officer.
Anadys Pharmaceuticals Inc. is working on ANA245, a nucleoside analogue believed to interact with TLR7, in early stage trials. The government has taken note. NovaScreen Biosciences Corp. recently netted a biodefense contract worth about $13 million based on TLRs, and Corixa Corp. is investigating TLRs in respiratory-tract infections with a National Institutes of Health grant of $11.6 million.
"There is lots known in terms of the TLRs and the ligands, but most of what's been done is by serendipity," Russo told BioWorld Financial Watch. "What [researchers] found turned out to be a ligand for the TLRs, but you need to have the fusion between the ligand and antigen."
Russo formerly oversaw vaccines with Merck Research Laboratories, the division of Merck & Co. Inc., of which he was executive director and head of global regulatory development.
Immune response comes in two basic types: innate and acquired. Acquired immunity is made possible by T cells and B cells, on which biotechnology research has focused for years. Innate immunity is a separate beast, not specific but still able to identify and deal with pathogens by way of TLRs, 10 of which have been identified since the 1990s.
The first five of those human TLRs might be direct homologues to the fruit-fly molecule, researchers say. Many scientific papers on TLRs have been published, and most have lurking within them the tantalizing suggestion that ancient, innate immunity - far from being the imprecise "shotgun" defense previously believed - might precede and help focus the acquired immunity gained by way of T cells and B cells.
Coley's Krieg called TLRs "a very hot field right now." The targets are good, and they're validated.
"One of the exciting things about immunology in general is that it affects every organ in the body," he said. Thus, TLRs might be useful in cancer, infectious disease, even allergies and asthma. Actilon, Coley's drug from a different class of TLR9 agonists than ProMune, is in Phase II trials against hepatitis C, Krieg said.
"People used to talk about nonspecific immune activators [such as bacterial extracts] and it was kind of a dirty phrase," he told BioWorld Financial Watch. "What's happened with the discovery of the TLR system is that we've gone to targeted stimulation of single TLRs. Those crude bacterial extracts that had limited activity are made of thousands of constituents, of course, but only a handful that directly activate the innate immune system. We can now synthesize ligands that will turn on a single TLR. Depending on which one you activate, you get a completely different response."
Coley is "seeing levels of immune activity that are fabulous," he said. "Using it with a vaccine, we're seeing higher antibody responses than have ever been reported before," along with T-cell responses, he said.
Where will TLRs likely be most beneficial?
"That's the million-dollar question," Krieg said. "Cancer is the hardest of the targets. Most people look at cancer and say, No immunotherapy is going to work there.' But then you look at allergies and asthma, and that's perfect."
Coley has partnered its allergy/asthma program with Aventis Pharma AG in a licensing relationship through which Aventis has developed an asthma product called CpG 7279. ("CpG" means cytosine and guanine separated by a phosphate linking the pair of nucleotides together.)
"I guess I would distinguish [the question of] where is the greatest medical need from where is the greatest possibility of success," Krieg said. "The development risk in allergy/asthma is that you'll find some kind of toxicity that will kill the drug. And you need a very large sales force to market a drug like that" - hence the Aventis deal. The pharma company is "taking at least one compound into the clinic this year," Krieg said.
"With cancer, on the other hand, we knew it would take a very bad toxicity profile before that would kill the drug, and you can market it with a relatively small sales force," he said. "I think we're going to succeed in cancer, too, but I wouldn't want to set our bar too high. We haven't made a big push to go out and find a partner."
The promise of TLRs is strong enough that some even talk about going after sepsis, declared by cliché-mongers as the Holy Grail of biotechnology.
Putting their chips on that indication "has killed so many biotech companies that I would probably jinx Coley if I said we should go after it," Krieg said.
Coley has plenty to keep it busy, anyway. Its vaccine adjuvant work has borne a $12 million partnership with the government to develop CpG immunostimulatory TLR9 agonists to enhance anthrax vaccines.
Late last year, the company licensed its VaxImmune adjuvant for incorporation into multiple vaccine candidates at Chiron Corp., and a deal with GlaxoSmithKline plc was expanded in November 2002.
Begun in early 2000, the GSK deal first involved a worldwide coexclusive license to CpG compounds for use in certain therapeutic and prophylactic vaccines for infectious diseases, and later came to include cancer vaccines made by combining Coley's CpG immunostimulatory oligonucleotides with GSK's cancer antigens.
First results from Coley's own cancer program are expected at the American Society of Clinical Oncology in June, Krieg said. Those will be data from the Phase II trial in NSCLC. Partnering the cancer program is hardly out of the question.
"After ASCO, we expect to be in very active discussions," he said.