Toll-like receptor therapies compete to reduce side effects

[RandyW]

News

Nature Biotechnology

Published online: 6 March 2006; | doi:10.1038/nbt0306-230

Toll-like receptor therapies compete to reduce side effects

An emerging class of highly specific immunomodulator drugs targeting toll-like receptors will be the focus of attention this month at a conference in Salvador, Brazil.

Charlie Schmidt

An emerging class of highly specific immunomodulator drugs targeting toll-like receptors (TLR) will be the focus of attention this month in Salvador, Brazil. The Conference "Toll2006—Recent Advances in Pattern Recognition," to be held March 4–7, will explore the latest scientific progress in the field. Among the most advanced players, two companies, Coley Pharmaceuticals of Wellesley, Massachusetts, and Dynavax Technologies of Berkeley, California, are currently in phase 3 clinical trials to bring their TLR-based products on the market. Biotechs joining the fray must now optimize drug efficacy while keeping unwanted immune side effects at bay.

TLR-targeted drugs trigger the body's innate immune responses.

Dynavax

The first TLR to reach the market, a drug called Aldara (imiquimod) developed by 3M Pharmaceuticals of St. Paul, Minnesota, was approved in 1997 as a cancer therapy before the TLR mechanism of action was well understood. Many drug candidates have since emerged after TLR mechanisms were first described in 1998 (See Box 1). Of these, two are currently in phase 3 clinical trials. The first, PF-3512676, is being developed by Coley Pharmaceuticals for non-small cell lung cancer. The second TLR in phase 3 is called HEPSILAV, a hepatitis B vaccine being developed by Dynavax. There are several other players on the TLR space in less advanced clinical stages (see Table 1).

Table 1. Companies in the race to bring TLRs to market

Full Table

A total of 11 human TLRs have thus far been identified; each with an affinity for specific bacterial or viral components. The most advanced drugs in the TLR pipeline, including the Coley and Dynavax phase 3 candidates, target TLR9. Katherine Xu, an analyst with Pacific Growth Equities in San Francisco, California, who covers Dynavax, estimates the TLR9 market in cancer could reach $1 billion by 2010.

Scientists now say TLRs offer a way to harness our innate immunity for clinical aims. "It's a natural pathway for immune activation that evolved over millions of years," Coley Pharmaceuticals' CEO Art Krieg explains. "Now, we can make synthetic TLR ligands to trigger these pathways so they can be used for therapeutic applications."

It's a natural pathway for immune activation that evolved over millions of years. Now, we can make synthetic TLR ligands to trigger these pathways so they can be used for therapeutic applications.

Art Krieg

Coley Pharmaceuticals

The principle behind Coley's drug targeting TLR9 is to use synthetic forms of cytosine-phosphate-guanine (CpG) to bind and activate the receptor. In turn, that triggers an immune response called T-helper 1 (Th1), dominated by the activation of T cells. Dino Dina, Dynavax's president and CEO, explains that the Th1 responses appear to be cross-regulated with another immune response called Th2 (for T-helper 2)—typically triggered by TLR2 and TLR5. This means that activation of Th1 suppresses Th2, whereas suppression of Th2 activates Th1. Therefore, Dina adds, TLR9's capacity to activate Th1 in the absence of Th2 makes it a particularly attractive mechanism for drug development. Many dangerous immune system side effects—including sepsis—derive from Th2-triggered inflammation, Dina says.

Looking forward, the outlook for TLR drugs is good, but by no means secure. For instance, in the case of TLR9 agonists, developed by Coley and Dynavax, scientists need to ensure the Th1 response doesn't spin out of control, according to Douglas Golenbock, a professor of infectious diseases and immunology at the University of Massachusetts Medical School in Worcester. This could lead, for example, to patients developing autoimmune conditions, such as lupus. "It's all a matter of establishing the right therapeutic index," he says.

Likewise, with TLR antagonists such as the drug for sepsis developed by Tokyo-based Eisai's, the challenge is to supress Th2 without overstimulating Th1, adds Robert Finberg, who is also a professor at the University of Massachusetts Medical School. "These drugs could be beneficial in the short term, but may be bad for the immune system if you give them for too long," he says.

That they have fewer side effects compared with drugs with alternative mechanisms of action could become the main selling point of TLR-targeting drugs. Devron Averett, San Diego, California-based Anadys Pharmaceutical's CSO, claims that ANA975, the company's TLR7 agonist, recently tested in a 28-day clinical trial involving patients with chronic hepatitis C, could produce clinical benefits without triggering the flu-like symptoms observed with TLR9 agonists, including Coley's cancer product. "And we think that will help ensure compliance with therapy," Averett says. "We have an oral route of administration and our adverse events profile is quite favorable."

Many more TLR-targeting drugs could enter development in the future. Sudhir Agrawal, CEO of Cambridge, Massachusetts-based Idera Pharmaceuticals, suggests that researchers could begin expanding investigations into new TLR classes located on cell surfaces. Unlike TLR9, which resides on membranes inside the cell, from where it detects microbial DNA and RNA, surface TLRs detect toxic lipids and proteins. "Surface TLRs have to be exploited, but if their immune response profiles are acceptable, they could be promising," Agrawal says.