National Editor

Drosophila melanogaster sounds like the name of a medieval king's fairy tale daughter, cursed by deformity and locked away in a distant castle.

In actuality, of course, it's the genus and species of the fruit fly - a tiny insect that has genetic peculiarities and a brief life span, which makes Drosophila ideal for research.

One of the most promising yields is Toll-like receptors, or TLRs, which appear on the surfaces of antigen-presenting cells. TLRs, first located in Drosophila, recognize structures that are common to infectious agents and, when bound to them, trigger innate immune responses in the body.

Earlier this month, New Haven, Conn.-based VaxInnate Corp. netted $23.1 million in a Series B financing, partly to advance its early stage work with TLR-based drugs. (See BioWorld Today, March 12, 2004.)

But another company further along in the field is privately held Coley Pharmaceutical Group Inc., of Wellesley, Mass., with the cancer compound ProMune, which targets TLR9, in Phase II studies for melanoma, non-small-cell lung cancer and cutaneous T-cell lymphoma. Data are expected in June from the lung cancer study.

"We're seeing levels of immune activity that are fabulous," Arthur Krieg, chief scientific officer of Coley, told BioWorld Today. "Using it with a vaccine, we're seeing higher antibody responses than have ever been reported before," along with T-cell responses, he said.

Targeting TLR9 works in allergies and asthma, as well as cancer, he added. Coley has partnered its allergy/asthma program with Aventis Pharma AG, of Frankfurt, Germany, in a 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. ProMune also is known as CpG 7909; the cancer program is not yet partnered.

Vaccine adjuvants are a big part of Coley's world. Its efforts in that area have yielded 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 Emeryville, Calif.-based Chiron Corp., and a deal with GlaxoSmithKline plc, of London, was broadened 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.

Back to TLRs, specifically. Named for the Toll gene in Drosophila, the receptors help the insect fight fungal infections. When researchers discovered the gene shares cytoplasmic sequences with the interleukin-2 receptor, its potential in humans began to emerge. German scientist Christiane Nüesslein-Volhard, who first found the gene, tagged it "Toll" - slang in her country for "cool."

TLRs first attained the limelight in the 1990s, and they're hot in biotechnology now, with 10 human TLRs discovered so far. The first five might be direct homologues to the fruit-fly molecule, but that doesn't necessarily make them more promising, Krieg pointed out. A fruit fly is hardly the same as a human.

"Even between the human and a mouse, a mouse cannot afford to lose more than a few milligrams of tissue or it's going to be dead," he said - noting that reports have surfaced in the past few weeks of new TLRs found in mice - and the differences between flies and humans are even more daunting.

The main point with TLRs is the possibility that ancient, innate human 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, at which much biotechnology research has been aimed.

Enter Coley's TLR9, found on dendritic cells, the key initiators of the innate immune response.

"People used to talk about nonspecific immune activators [such as bacterial extracts] and it was kind of a dirty phrase," Krieg said. "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. When you stimulate TLR9, you're stimulating a very small fraction of the immune cells," thus reducing toxicity risks.

A drug from a different class of TLR9 agonists, Actilon, is in Phase II trials against hepatitis C, Krieg said, adding that TLRs could even be useful against heart disease.

"We used to think about [heart disease] as being remote from immunology," he said, but now inflammation has become part of the picture in coronary trouble. "I'm not saying inflammation is mediated by TLRs - probably not," Krieg said. "I'm saying this is a key regulatory pathway for the immune system in general."

No Comments