Building on safe ground

Since the advent of technologies to generate antibodies in the lab in 1975, a great many companies have been founded on the premise that these platforms could easily be used to crank out treatments for a huge variety of diseases. But while the technologies to generate antibodies have become more and more sophisticated, moving from mouse to humanized to human to engineered, the road to drug development has been far bumpier. Indeed, the majority of successful MAbs have not come from the platform companies.

The lesson of this experience is that the biology matters, and the initial failures could be laid to poor choices of targets.

The latest generation of antibody companies has absorbed this lesson. But that doesn't mean that they're starting out with large biology groups. In fact, most of these 4th generation companies have gone in the opposite direction, taking a very conservative approach to focus on targets that have been validated by marketed products. As a result, most think they don't need a lot of in-house biology or clinical expertise - at least in their early years.

Their most popular target is TNF alpha, a target validated by several approved biologics, including Enbrel etanercept from Amgen Inc. (AMGN, Thousand Oaks, Calif.), Remicade infliximab from Johnson & Johnson (JNJ, New Brunswick, N.J.) and Humira adalimumab from Abbott Laboratories (ABT, Abbott Park, Ill.).

John Edwards, vice president of commercial development of Compound Therapeutics Inc., summed up the rationale. "TNF is a very well known target," he said. "There are well established preclinical models tied to clinical outcome so that they show very early on what the product candidate can do. Also, there is a low regulatory risk. Besides, the rheumatoid arthritis market is expected to grow considerably, and existing products are far from being perfect."

Other new-generation companies pursuing TNF are Ablynx N.V., Affibody AB, Borean Pharma A/S, and Domantis Ltd.

Most of these companies are relying on external advice in picking their targets, mostly from academic collaborators, although a few are also doing some in-house evaluation. None is doing target discovery, finding it too costly and too time-consuming.

Round four

The rationale for developing next-generation antibody technologies is quite clear, as conventional antibodies have innate limitations. MAbs are bulky molecules - they can't enter cells, penetrate deep into tissue or reach targets buried in other structures. They can't be administered orally. And manufacturing is expensive, as they have to be produced in cell culture. Moreover, their binding to targets is reversible, so that they have to be given in concentrations on the order of 5,000-10,000 times the concentration of their targets to be effective.

On the other hand, MAbs have desirable properties that researchers want to conserve: High specificity accompanied by low toxicity and an ability not only to directly induce cancer cell death, but also to activate the immune

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