It's a Mab, Mab, Mab, Mab World

By Edwin Colyer, QX Health (www.qxhealth.com)

Once upon a time, and not very long ago, antibodies were shunned. They were great in theory, fine for the textbooks, but definitely undesirable in a pharmaceutical company's pipeline. But judging by recent licensing deals, pharma now can't wait to get its hands on them. Edwin Colyer assesses the impact of recent moves into the monoclonal market.

Until very recently, the antibody arena was the sole realm of a few pioneers: Genentech, Centocor, Xoma. Times have changed. Those companies that kept the faith now have something to shout about—and this time the industry is listening. At one time, the word "antibody" sent licensing managers turning round and exploring other options; now companies can't wait to sign deals, and not just for products. Pharma is going back to the bench.

The turnaround in temperament is a tale of two companies and one technology—the monoclonal mouse. Mice have been genetically modified to produce fully human antibodies that pose no risk of immunogenicity in patients. To produce novel, specific antibodies against selected target proteins, one simply injected the mouse with the target antigen and let the mouse's immune system raise human antibodies against it. Any antibody with the required specificity can be harvested and manufactured as a monoclonal.

Two companies hold patents to the monoclonal mouse technology. Abgenix has developed its proprietary XenoMouse, and Medarex owns the HuMab-Mouse. While the two technologies are similar, the patents differ sufficiently to avoid any possible conflicts.

Between them, Abgenix and Medarex boast a glittering cast of collaborators. Medarex boasts 19 mouse collaborators, surpassing Abgenix's 18 collaborations at the beginning of May by signing a deal with Centocor. Most of these deals were signed only within the last 12 to 18 months, yet some collaborations have already been extended.

The cast list alone is revealing. Naturally, you have the veterans, those venerable players who persevered and who now relish the renewed interest in antibodies. But it appears that big pharma will steal the show this time. There's no more sitting in the wings, waiting for antibodies to prove themselves in clinical trials, then snapping them up in late-stage deals. Instead, the pharmaceutical companies have taken center stage.

Most of the biggest stars have joined the ever-growing troupe: Bristol-Myers Squibb, Merck KgaA, Schering, Novartis, BASF, Pfizer, and Schering-Plough. Hardly a month goes by without another signing up.

Several factors account for the U-turn. Firstly, monoclonals are now proven as therapeutics. At least eight are currently on the market in the US, including the best selling ReoPro, used to prevent blood clots, with 1999 sales estimated at around $445 million. Another antibody, Rituxan, is used to treat relapsed or unresponsive low-grade non-Hodgkin's lymphoma. In only its second full year on the market, sales totaled $263 million.

So, with antibodies therapeutically proven and a mouse in which to make them—and you can produce antibodies against practically any protein or peptide you choose—it is small wonder that Medarex and Abgenix have spent most of the last 12 months signing licensing deals.

It is the genomics revolution, however, that has pushed drug companies back to antibody technologies. The monoclonal mouse only epitomizes the rejuvenation of the antibody market, but many other companies have suddenly discovered that their antibody technologies are in demand. Several years into the genomics era of drug discovery, pharmaceutical and biotech companies find themselves wading through a sea of target genes and proteins. Antibodies are the natural answer to the problem, the simplest means of assessing and validating the best candidates for further research. Furthermore, as antibodies have a shorter lead time, they can be available as a first-to-market therapeutic relatively quickly, buying time to conduct further research and screen for small molecule drugs too.

The pharmaceutical companies with a strong history in genomics, and whose genomics programs are beginning to bear fruit, have been the first of the new wave to approach the antibody engineers. But immediately behind you discover some real newcomers: the genomics companies themselves.

Most genomics companies, while licensing out their technology in collaborative research, also conduct their own in-house genomics programs with the aim to develop drugs as a future revenue source. These in-house programs have progressed and identified candidate targets. Validation is necessary first, followed by a search for functional therapeutic agents. Antibodies are the answer.

Abgenix thus added Human Genome Sciences to its list of licensees for XenoMouse in December 1999. HGS followed up this agreement in February this year, signing a deal with Cambridge Antibody Technology. With access to two significant antibody technologies, HGS could conceivably begin human trials of an antibody therapeutic within the next two years. It is also likely that other similar genomics companies will soon follow suit and enter into similar deals with antibody technology companies.

It won't be long before the sea of genomics targets in early drug discovery becomes a flood of monoclonals products on the market. According to recent surveys, there are now over 260 companies worldwide developing more than 700 antibodies. Even if only as little as 5% progress to full development, that's still 35 new antibodies—four times as many as currently available.

One thing is certain: while licensing deals at the moment focus on antibody production technologies, soon the antibodies themselves will be up for grabs in a monoclonal mass market. First, the monoclonal experts—companies like Antisoma, which focus on antibody therapeutics—will peddle their wares. These companies are often small and require larger partners to take their products through clinical trials. But how will they set out their stall to differentiate their products? Most likely they will specialize in niche markets and seek orphan drug status.

Next will come larger companies that take products through development and onto the market. Pharma's resources should allow accelerated development of the products with the best market potential.

Following close behind will be "pure" genomics companies, proud of their first therapeutic products. Will they need development partners, or will the genomics craze have provided them with enough revenue to complete clinical trials themselves? Will we begin to see these companies hiring sales forces, or will they seek marketing partners?

And finally you find the antibody engineers: Abgenix, Medarex, CAT and Co. With such powerful technology, they are unable to resist making some monoclonals of their own. But these companies are short of targets, and need to buy some in. Already, Abgenix has teamed up with Corixa. "We believe the marriage of Corixa's antigens with our XenoMouse technology... represents an exciting opportunity for both companies," said R. Scott Greer, president and CEO of Abgenix. "We look forward to a productive relationship that could result in the discovery and commercialization of multiple novel products." Medarex , meanwhile, has collaborated with Regeneron, gaining access to Regeneron's target identification expertise.

In short, the combination of genomics and monoclonal antibodies creates a hotbed for partnerships and licensing. Antigens need antibodies and vice versa. Collaboration is a necessity. We now just have to wait to see who wins in the race to market.

(Find more information on monoclonal antibodies in the QX Health Strategic Brief archive by following the links from the QX home page, www.qxhealth.com).

For more information: Edwin Colyer, Editor, QX Health, Enterprise House, Manchester Science Park, Lloyd Street North, Manchester M15 6SE, UK. Tel: +44 161 232 3300. Fax: +44 161 232 0000. Email: info@qxhealth.com. Web: http://www.qxhealth.com.

Copyright, 2000, QX Health. All rights reserved.