15 August 2001. While therapeutic Aβ antibodies are wending their way through
clinical trials, researchers studying other offending brain proteins have been
racing to work out similar strategies. In the August 16 Nature, Anthony Williamson
and Dennis Burton at the Scripps Research Institute in La Jolla, California, working
with Stanley Prusiner at the University of California, San Francisco, describe
antibodies that can essentially eradicate a prion infection. A smaller study reporting
similar results appeared last month in PNAS (Enari et al.)
"[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