* This list only includes agreements concerning the discovery and development of therapeutic antibodies. It does not include agreements covering marketing and sales, diagnostics applications, ex vivo cell therapy or production methods.



Never ones to shirk a challenge, biotech companies have come up with ways to alleviate the mouse problem -- either by replacing about half (chimeric) or most (humanized) of the murine amino acids with human ones (although Idec Pharmaceuticals Corp. is also creating primatized monoclonals, which contain monkey sequences) or by producing fully human antibodies in transgenic mice which have been engineered with human antibody genes (instead of their own). Advances in genetic engineering have also led to superior, and much less expensive, methods for producing the large quantities of monoclonals that are needed for therapeutic regimens.



Even so, why have so many biotech and pharma companies jumped on the monoclonal antibody bandwagon again? Because such drugs really are the magic bullets that German physician Paul Erlich dreamed about in the early 1900s: They can be tailored specifically and precisely to kill their targets without harming the normal cells surrounding them. (Erlich, however, was thinking of chemicals, not antibody molecules, that could attack bacterial pathogens.) And monoclonals elicit far fewer side effects than many other drugs (especially when compared to chemotherapy, for instance). Plus, monoclonal drugs are big sellers: In 1999, ReoPro hauled in $447 million, MedImmune Inc.'s Synagis (for RSV infection) reaped $293 million, and Genentech Inc. and Idec Pharmaceuticals' Rituxan (for non-Hodgkin's lymphoma) garnered $279 million. (For details of all nine FDA-approved monoclonal antibody drugs, plus sales figures, see the charts in the Signals article, "The Payoff: Betting On Protein Drugs.") There's another important reason for the current enthusiasm surrounding monoclonal antibodies: "Antibodies are the fastest way to take advantage of discoveries in genomics," explained Abgenix's Greer.

* This list only includes agreements concerning the discovery and development of therapeutic antibodies. It does not include agreements covering marketing and sales, diagnostics applications, ex vivo cell therapy or production methods.


Today, the vast majority of companies developing monoclonal-based therapeutics are focused on creating fully human molecules. Yet, not one fully human antibody drug has made it all the way through the regulatory process. (All nine that have been approved are either murine, chimeric or humanized.) That's not because some have tried and failed but rather because the technology for creating fully human antibodies is still so new. There are about eight such potential drugs now in the clinic, according to Greer. It wasn't until February of this year that the first fully human monoclonal entered Phase III trials. That product, BASF Pharma's anti-TNF antibody D2E7 for treating rheumatoid arthritis, was initially isolated and optimized as part of a research collaboration with Cambridge Antibody Technology plc.

Consequently, it's not clear yet whether fully human antibodies will, in the end, offer any significant advantage over their mousy counterparts. Companies that are already heavily invested in murine antibodies are making efforts to humanize them. (For instance, refer to the charts in this article to see the many firms that have licensed Protein Design Labs Inc.'s humanization technology this year.) Companies that are starting from scratch, however, all seem to be placing their bets on fully human products. (Again, check the charts for the deals that Abgenix Inc. and Medarex Inc., in particular, have signed this year.)



A quick scan of the alliances detailed in the charts in this article will make it quite clear that many target-discovery companies do, indeed, feel that antibodies may be the quickest way to capitalize on their discoveries. And, in concert with the wealth of new drug development targets being spawned by genomics research, there are now more ways to generate antibodies to them. The use of bacterial viruses (in a technique called phage display) to generate combinatorial libraries of antibodies rapidly has become increasingly popular.

And start-up Raven biotechnologies inc., based in San Carlos, CA, has devised yet another approach which not only is able to identify new targets but also is capable of generating monoclonals. The company has developed 10 human disease- and organ-specific progenitor stem cell lines, which it uses as immunogens to generate libraries of monoclonals to cell surface proteins (antigens). Since these are progenitor cells, many of their surface proteins will not be expressed in the mature organs they go to form -- but they can get turned on again if malignancy sets in. Raven's monoclonals can potentially be used as therapeutics in their own right, but they're also helpful in probing the expression or function of the targeted antigen or even purifying it.

"Right now we're screening for five different cancers," explained Jennie Mather, Raven's founder and CEO. "We screen the antibodies [in the generated library] to see what's unique. We don't identify what genes are involved until we've narrowed them down from thousands to two or three" that are relevant for the disease. The library of antibodies can be prioritized by checking their reactivity with normal and diseased human tissue samples; what results is a small number of physiologically relevant antibodies.

Although Raven has developed its own, in vitro technology for producing human monoclonals, on which it filed a patent application late last year, "We're mainly a target discovery company," Mather explained. Raven is certainly not averse to exploring the utility of other technologies for generating human monoclonals. "No one technology is good for everything," Mather explained. In fact, Raven's already using Medarex's HuMAb-Mouse technology for producing fully human antibodies against certain of its cell surface antigens, with an initial focus on ovarian cancer. This is only the first of several alliances, said Mather: Although she couldn't provide the specifics, a number of deals are in the works, with both biotech firms and big pharmas.



Medarex has signed 12 therapeutic-based alliances this year. So has Abgenix, the other major player in fully human antibody technology, Two of Abgenix's alliances are expansions of earlier agreements; one (not listed in the table) is for the production of one of Abgenix's antibodies in transgenic animals; and four are licensing deals. But five involve true collaborations in product development. The first of these, with Immunex Corp., signaled the beginning of an evolution in Abgenix's business development strategy, explained chairman and CEO Greer. The company still inks straight licensing deals, but is also moving towards profit-sharing arrangements. And those come in two varieties: One is based on the partner's targets. "Companies that are target-wealthy, like Corixa, need access to XenoMouse [for making antibodies]. And, Abgenix needs the targets. We scratch each other's back," Greer said. In these deals, "we often add a co-development twist," he continued. The deal with Human Genome Sciences (which was signed in December 1999) is a good example; the partners will jointly pick and jointly develop a certain number of targets.

The other profit-sharing deals are based on Abgenix's own product pipeline. "We are the source of the target and we will bring it into the clinic. We also retain a significant economic interest in the product " by retaining the rights through early clinical trials (as far as Phase II) before seeking a partner, Greer said.