The interactions between bacteria and their hosts may have been under scrutiny for more than a century, but a solid understanding of the specifics of the signaling processes involved has only recently started to develop. Opsona Therapeutics, a spinoff from Trinity College Dublin in 2004, is one of several biotechnology firms around the globe that is staking a claim to this hotly contested area.

Opsona Therapeutics

The firm is building on a considerable body of expertise in immunology and in Toll-like receptor (TLR) signaling amassed by its scientific founders, Dermot Kelleher, Kingston Mills, and Luke O'Neill. Its CEO, Australian biotechnology entrepreneur Mark Heffernan, is putting the package together as a commercial proposition. Cormac Kilty, founder and CEO of Biotrin, is chairman.

The company has made solid progress so far. Its internal pipeline of drug candidates is expected to enter the clinic over the next couple of years. First up is a "prodrug" consisting of an undisclosed steroid, which is conjugated to a carrier molecule that ensures its delivery to the colon. The drug activity is released following cleavage by an enzyme that is expressed by bacteria present in the large intestine.

"It's a novel, innovative way of getting a drug specifically to the colon," says Heffernan. Ulcerative colitis is the initial indication, but the same basic method is applicable to other compounds and to other indications. "It'd be a new use for oral drugs that have failed in the clinic," he says.

The company has secured a major alliance with Wyeth, based on the discovery and development of antagonists to TLRs and on finding new targets within TLR-signaling pathways. In an Irish context, deals on this scale have been few and far between. "I think it's probably one of the largest - certainly of the companies I'm aware of," says Seamus O'Hara, partner at Seroba BioVentures, an early investor.

Since the first TLR was characterized around a decade ago, the proteins - 10 have been identified so far in humans - have quickly become hot targets for drug developers. They function as specialist pattern-recognition receptors that bind a specific, highly conserved molecular motif associated with microbial pathogens. That event triggers a signaling process, which, in turn, kick-starts the innate immune response.

Opsona's second preclinical candidate is a monoclonal antibody that binds an undisclosed TLR target. It has potential in a range of acute and chronic inflammatory conditions. The company also has an earlier-stage program in peptidomimetic research.

Late last year, Opsona also added a novel asset to its preclinical pipeline. It in-licensed from Swiss firm Nestlé a protein found in human breast milk and serum that exerts immunomodulatory effects by inhibiting TLRs. The contact with the food giant came about through its €6.25 million ($10 million US) Series A round, in which the Nestlé-backed fund, Inventages Venture Capital, participated - along with GenenFund, the corporate venture arm of Genentech, and Enterprise Ireland and Seroba, both of Dublin

The early movers in the TLR field, such as Coley Pharmaceuticals (now owned by Pfizer), Anadys Pharmaceuticals, and Idera Pharmaceuticals, have mainly concentrated on upregulating TLR signaling with small-molecule drugs and adjuvants, in order to boost the immune response against infection or tumors.

Opsona, in contrast, aims to dampen the immune response in patients with autoimmune conditions. Others undertaking this approach include Eisai, a Japanese firm whose TLR-4 antagonist E5564 (eritoran) is undergoing a Phase III trial in sepsis, as is TAK-242 (resatorvid), a TRR-4 signal blocker, which another Japanese company, Takeda, is developing.

For now, Opsona is holding most of its cards close to its chest. "We haven't disclosed to the world yet what our compounds actually are," says Heffernan. The company aims to raise around €10 million in a Series B round over the summer. Its entry into the clinic should follow shortly afterwards, a move that will be keenly followed.