Passive antibody immunization against prion protein prevents the spread of clinical disease to the brain of mice, even though the antibody works primarily by reducing prion replication in peripheral tissues, including the spleen. This is the astonishing news in a report in today’s Nature by Anthony White, John Collinge, Simon Hawke, and colleagues at Imperial College and University College, both in London, as well as David Anstee of the National Blood Service.
Prion diseases and Alzheimer’s share key features in that both involve natural proteins that somehow misfold, aggregate, and destroy brain cells. Consequently, researchers are pursuing some parallel treatment strategies to interfere with this process, immunotherapy being one of them. Today’s report takes into mice prior work showing that antibodies can eradicate prion infection in cultured cells (see ARF related news story).
In the present study, White and colleagues used a model that develops fatal clinical scrapie after inoculation with scrapie brain homogenate. Peripheral inoculation models an earlier infection stage and slower disease course; intracerebral inoculation models a more advanced stage and rapid course. The researchers treated these mice repeatedly with two monoclonal antibodies: ICSM 35 is an IgG2b isotype that has high affinity to both the normal cellular and the infectious forms of the offending protein, PrPc and PrPSc, respectively. ICSM 18 is a IgG1 with high affinity only for PrPc. Western blots, immunoblots, immunohistochemistry, and bioassays of splenic homogenates all yielded similar results, namely that both antibodies depleted PrPSc in the spleen in scrapie-infected mice, with ICSM 18 slightly outperforming 35.
PrPSc levels in the spleen decreased markedly, regardless of whether the mice had received the scrapie inoculation intraperitoneally or intracerebrally. But did that do the mice any good? It did not help those that had received intracerebral inoculation; these mice survived to around 150 days after inoculation, as did untreated controls. It also did nothing for mice that had been infected intraperitoneally but were already developing clinical scrapie by the time they received the antibody; these mice died at around 197 days after inoculation, as did untreated controls. By contrast, mice that received antibody up to a month after intraperitoneal scrapie inoculation-even those in whom splenic scrapie replication was occurring at full speed-all survived to more than 500 days at submission of the paper. At 500 days, the treated mice had not yet shown signs of clinical scrapie, and treated mice that were killed 230 days after intraperitoneal infection had no detectable PrPSc in their brains. The scientists are currently assessing whether the prion infection is suppressed or eradicated in these mice.
Previous therapeutic interventions work only when given before or right around the time of inoculation, probably because they simply neutralize the injected material, the authors write (e.g., Sigurdsson et al., 2002, but see also Sigurdsson et al., 2003). That the present treatment works later, at the height of splenic prion accumulation, suggests it truly suppresses prion replication. This raises hope that there might be a window of opportunity after infection but before clinical signs appear, where immunization might be effective. However, a diagnostic test capable of identifying those people who harbor early-stage prion infections would be required, as well. The antibodies’ lack of success after clinical onset of disease likely results from their inability to cross the blood-brain barrier, the authors note. Finally, they caution that autoimmune reactions, which are now under intense study for AD immunization after they derailed a phase II trial (see ARF related online discussion) could well develop in patients with Creutzfeldt-Jakob or other prion diseases.—Gabrielle Strobel
- Sigurdsson EM, Brown DR, Daniels M, Kascsak RJ, Kascsak R, Carp R, Meeker HC, Frangione B, Wisniewski T. Immunization delays the onset of prion disease in mice. Am J Pathol. 2002 Jul;161(1):13-7. PubMed.
- Sigurdsson EM, Sy MS, Li R, Scholtzova H, Kascsak RJ, Kascsak R, Carp R, Meeker HC, Frangione B, Wisniewski T. Anti-prion antibodies for prophylaxis following prion exposure in mice. Neurosci Lett. 2003 Jan 23;336(3):185-7. PubMed.
- White AR, Enever P, Tayebi M, Mushens R, Linehan J, Brandner S, Anstee D, Collinge J, Hawke S. Monoclonal antibodies inhibit prion replication and delay the development of prion disease. Nature. 2003 Mar 6;422(6927):80-3. PubMed.