Jeffrey Ravetch, cofounder of MacroGenics.

The beauty of monoclonal antibodies as therapeutics is that they can be generated against a limitless variety of protein targets. To date, it has been this flexibility and specificity—conferred by the antibodies' “variable region”—that has generated the most interest within the industry. However, MacroGenics believes that the “stem” or constant (Fc) region of the antibody plays an equally important role and one that has, to date, been overlooked. (Click here for company profile.)

One of MacroGenics' cofounders, Jeffrey Ravetch of the Rockefeller University (New York), was the first to show that the biological outcome of an antigen–antibody reaction in vivo depended on the way in which the Fc region interacted with effector cells, such as macrophages, mast cells, and neutrophils. Effector cells possess stimulatory and inhibitory Fc receptors, both of which are engaged by the antibody–antigen complex, and the balance between these opposing signals determines the strength of the immune response evoked. It's a new concept, and offers MacroGenics a unique and distinctive position within what is currently a crowded antibody arena. Ravetch explains that most of its competitors are still focused on the “front end” of the antibody, and are modulating antigen-binding sites.

Recent data from Ravetch's laboratory has brought home the importance of the Fc region. In collaboration with Genentech (S. San Francisco, CA), Ravetch and his team revealed the role of effector Fc receptors in the efficacy of two therapeutic antibodies—Rituxan and Herceptin. Mice lacking inhibitory Fc receptors were 10 times more sensitive to the antitumor effects of Herceptin than wild-type animals, whereas animals lacking stimulatory Fc receptors were relatively resistant to the drug's effects (Nat. Med. 6, 373, 2000).

“Companies are now approaching us about the technology ... always a good sign,” says Ravetch. In theory, the clinical activity of many therapeutic antibodies is influenced by effector receptors, and so MacroGenics technology could be applied widely throughout the industry. Another key advantage of the technology is that it offers a means to both upregulate and downregulate the activation of the immune system, providing novel routes to control inflammatory and autoimmune diseases.

However, Macrogenics' primary goal is to develop its own antibodies using its understanding of the function of the Fc effector receptor. The most advanced product is a blocking antibody for an activation Fc receptor for the treatment of inflammatory disorders, which could offer competition for the market for gamma globulins. The company will also develop antibodies for prostate and lung cancers, drawing on its close links with the Institute for Systems Biology (Seattle, WA), which was set up last year by local University of Washington scientists and MacroGenics' cofounders Leroy Hood, Ruedi Aebersold, and Alan Aderem, for integrating genomics, proteomics, and bioinformatics for identifying disease targets.