"[This study] is important because it provides a usable in vitro assay for screening antibody reagents that might be useful in vivo. But it falls far short of showing that such treatment might be clinically useful," says Harvey Cantor, who chairs the department of cancer immunology and AIDS at the Dana-Farber Cancer Institute in Boston, Massachusetts.

Williamson and colleagues added a series of antigen-binding fragments (Fabs) to mouse neuroblastoma cells and then measured the levels of the pathogenic prion protein in the cells at various time points afterwards. The antibodies proved to inhibit pathogenic prion formation in a dose-dependent way.

When the scientists introduced previously infected and then Fab-treated cells into the brains of mice, the animals remained healthy up to 350 days after the experiment (and counting,) whereas mice receiving untreated cells fell sick after about 165 days, said Williamson.

The antibody fragments were directed against different epitopes of the surface-bound, normal version of the prion protein, whose direct interaction with its pathogenic cousin is thought to drive the formation of additional infectious particles. The researchers also identified the peptide region recognized by the most potent antibody, and they recommend this region as a target for drug development and for further studies into the mechanism of prion propagation.

Moreover, Williamson, et al., found that once the antibody halted the production of further pathogenic prions, the cells degraded the preexisting infection. "That surprised us. Because prion particles are notoriously difficult to destroy-they withstand radiation, enzymatic attack, and extreme heat-we wondered what would happen to the particles that were there before we began treating," Williamson said. Apparently the cells were able to clear these preexisting prions once the degradation pathways were no longer overwhelmed by continually generated pathogenic prion protein.

Developing a therapy based on these data would require a humanized antibody engineered to avoid the recruitment of immune effector cells, which could cause inflammation. Instead of eliciting a classic immune response, the antibody would compete with the pathogenic prion protein for binding to the cellular protein, much like many conventional drugs work.

"Delivering such an antibody to the brain may be the biggest problem, but we are encouraged by Aβ vaccination in AD, where the antibodies appear to enter the brain," Williamson said. Even so, the approach is not currently being developed because the therapeutic market for prion diseases remains small, he added. Most industry efforts are currently focused on diagnostics.

After early clinical trials on therapeutic antibodies failed, the prospects for this approach have improved again in the past five years, mostly in cancer. "This is in part because companies have learned to pay close attention to technical issues, such as potential antigenicity, the type of immune reaction involved (T1 versus T2) and, most important, the development of better in-vitro assays to pinpoint the precise biologic activity of the antibody," says Cantor. "Hopefully companies engaged in AD research will fully absorb these lessons," he adds.-Gabrielle Strobel.

Reference:Peretz D, Williamson RA, Kaneko K, Vergara J, Leclerc E, Schmitt-Ulms G, Mehlhorn IR, Legname G, Wormald MR, Rudd PM, Dwek RA, Burton DR, Prusiner SB. Antibodies inhibit prion propagation and clear cell cultures of prion infectivity. Nature. 2001 Aug 16;412(6848):739-43. Abstract