Despite intense scientific scrutiny since the outbreak of variant Creutzfeldt-Jakob disease (vCJD) in the mid-1990s, no effective treatment is available for human prion disease. The passive transfer of anti-PrP monoclonal antibodies (mAbs) in prion-infected mice has been demonstrated to extend the murine lifespan significantly. However, prior to considering clinical trials in humans, further understanding the mechanism of action, the optimal dose, and side-effect profile is essential. As vCJD prion infection begins peripherally before CNS invasion, we developed a comparable therapeutic model when peripheral infection is well established before experimental treatments are tested. The in vivo half-life of the therapeutic mAbs used, ICSM18 and ICSM35, was defined and a suitable biweekly treatment was established. To determine the optimal therapeutic dose with least toxicity, the anti-PrP mAbs (or isotype controls) were then titrated in infected FVB/N mice, and the highest dose was also tested in BALB/c and Prnp0/0 mice for the detection of side effects. While phosphate-buffered saline (PBS) control treated RML prion-infected FVB/N mice all succumbed to prion disease at a mean of 194 (+/- 4 SEM) days, >50% of ICSM18 (1-3mg/week) and ICSM35 (4mg/week) treated mice survived >350 days without scrapie signs (p≤0.035 Log-Rank test vs. PBS). Lower doses of either mAb resulted in only a modest increase in survival. Consistent with this outcome, ICSM18 provided maximal early splenic PrPSc clearance at doses of 4mg and 1mg/week whereas ICSM35 was only this effective at 4mg/week. Unexpectedly, all FVB/N mice treated with ICSM18 at 4mg/week developed a fatal ataxic illness at PID134-163. Pathologically, little or no PrPSc was detected in the spleens or brains of these mice, but they all had inflammatory demyelination of the fornix and brainstem with activation of microglial cells. FVB/N mice treated with ICSM35 at 4mg/week, which survived for >450 days were found to have mild focal CNS inflammation without overt demyelination suggesting the effect is related to the specific mAb and dose administered. This side effect is also PrPC and mouse strain dependent, as Prnp0/0 mice and BALB/c mice were unaffected. We have therefore established a safe and effective therapeutic window for using anti-PrP mAb treatment in mice with established peripheral prion replication, and have demonstrated a significant decrease in mortality without side effects in the surviving mice. Future human anti-PrP mAbs trials can be guided by translating these studies to provide a dosing regimen to which provides benefit without deleterious effects. This thesis will discuss the pharmacokinetic properties of the anti-PrP mAbs, the location of the therapeutic action, the competence of the immune system in mAb treated mice, and the relevance of these factors to both anti-PrP effect and CNS inflammation.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:625641 |
| Date | January 2011 |
| Creators | Carswell, C. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1324517/ |
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