The first thing that comes to mind as an advantage of antibodies is their specificity. The reason monoclonal antibodies such as Genentech Inc.'s Avastin and Biogen Idec Inc.'s Zevalin are hailed is that they are more specific than small molecules and chemotherapy drugs.

That specificity also has led to the use of antibody-small molecule combinations. In their current incarnation, such couplings use the antibody to provide targeting specificity and the small molecule to boost efficacy. One example is Branford, Conn.-based CuraGen Corp.'s CR011-vcMMAE, a fully human monoclonal antibody-drug conjugate (ADC) that received the FDA go-ahead to enter Phase I trials in June.

But scientists from the Scripps Research Institute in San Diego have turned that concept on its head, combining a nonspecific antibody with a specific chemical targeting agent. In a paper to be published in the July 18, 2006, issue of the Proceedings of the National Academy of Sciences, now available online, they report on the methods used to make the unusual combination, and preclinical results achieved in targeting metastatic breast cancer.

Current antibodies "usually remove something," Richard Lerner, president of the Scripps Institute and a co-author on the paper, told BioWorld Today. For example, anti-TNF therapies such as infliximab (Remicade, Centocor Inc.) and etanercept (Enbrel, Amgen Inc.) block TNF alpha. "But there's another piece to the antibody: the effector system."

That effector system is not specific to one antibody, so there is no need to develop a new antibody for each specific antigen, if a targeting system can be devised. Lerner said that the approach described in PNAS combines the biological strength of the effector system with the unlimited targeting diversity of synthetic chemistry.

"There are two general ways that medicine builds diversity," Lerner said - synthetic chemistry and generating biologics. The new approach "borrows the strength of both."

The researchers used a self-assembly process to link small synthetic molecules and a catalytic monoclonal antibody. The synthetic molecule contained a masked binding site that can only be unmasked by the antibody; the antibody unmasks and attaches itself to the binding site.

They used a small molecule to target the antibodies to a cell membrane protein, the integrin alpha-v-beta-3, that is expressed on a variety of cancer cells, as well as on cancer-induced blood vessels. In human breast cancer cells, the combination therapy bound to integrin-expressing cells while the antibody alone did not. The researchers then injected mice that had been pretreated with either the antibody-small molecule combination or the antibody alone. After 41 days, mice that received the combination developed significantly fewer metastases than those treated with other similar compounds or the antibody alone.

In their paper, the scientists noted that because the antibody's reactivity is specific, antibody and small molecule could be tethered before being administered, or given separately to react in the body. Currently, "once a drug leaves the syringe, whatever [its effect] is, you've done it," Lerner said. In contrast, with the new approach, it is theoretically possible to inject the small molecule with an imaging agent attached, and only give the activating antibody if imaging shows that the distribution of the small molecule is favorable to a therapeutic effect: "It's a way of injecting a killing compound and triggering it later."

Lerner pointed out that besides being an efficient way to kill cells, the antibody also provides much better circulation to the small molecule. In their experiments, the half-life of the drug-antibody combination was more than a week, while the small molecule without an antibody was cleared by the body within minutes.

The technology is licensed to private biotechnology firm CovX, which has operations in Dublin, Ireland, and San Diego. The company said it expects to file its lead investigational new drug application based on the technology in 2007.