Anti-LRP/LR Antibody W3 Hampers Peripheral PrPSc Propagation in Scrapie Infected Mice

Abstract

Key WordS37kDa/67kDa laminin receptor, LRP/LR, prion, PrP, TSE-therapy AbbrevIAtIonS CJDCreutzfeldt AbStrACtWe identified the 37kDa/67kDa laminin receptor (LRP/LR) as a cell surface receptor for the cellular prion protein (PrP c ) and the infectious prion protein (PrP Sc ). Recently, we showed that anti-LRP/LR antibody W3 cured scrapie infected N2a cells. Here, we demonstrate that W3 delivered by passive immunotransfer into C57BL/6 mice reduced the PrP Sc content in the spleen significantly by 66%, demonstrating an impairment of the peripheral PrP Sc propagation. In addition, we observed a 1.8-fold increase in survival of anti-LRP/LR antibody W3 treated mice (mean survival of 31 days) compared to preimmune serum treated control animals (mean survival of 17 days). We conclude that the significant effect of anti-LRP/LR antibody W3 on the reduction of peripheral PrP Sc propagation might be due to the blockage of the prion receptor LRP/LR which is required, as previously shown in vitro, for PrP Sc propagation in vivo.

Antibody-based immunotherapeutic attempts in experimental animal models of prion diseases

“…However, PrP Sc levels were reduced by 17% in the brains and by 66% in the spleens of the mice, compared to those in control mice, indicating that W3 could interfere with peripheral but not the neuronal formation of PrP Sc [78]. Similar results were reported with anti-LRP/LR scFv fragments, termed S18 [79,80].…”

“…To investigate the prophylactic anti-prion activity of the polyclonal anti-LRP/LR antibody W3 in vivo, W3 was peripherally injected into mice via the intraperitoneal route once a week over a period of 12 weeks [78]. The mice were intraperitoneally inoculated with RML prions 1 week after the first W3 injection.…”

Anti-LRP/LR-Specific Antibody IgG1-iS18 Significantly Reduces Adhesion and Invasion of Metastatic Lung, Cervix, Colon and Prostate Cancer Cells

“…Following the success of these experiments, clinical studies are planned to commercialize the antibody for tumor metastasis treatment. Since other LRP/LR-specific antibodies such as W3 revealed no side effects in C57BL/6 mice, 26 we do not expect any side effects with IgG1-iS18 in animal models.…”

Prion Diseases

“…295 In addition to using antibodies that target PrP, a beneficial effect has been demonstrated by blocking the laminin receptor, which has been shown to also act as a receptor for PrP. 296 In cell culture, this antibody (pAb W3) prevented propagation of PrP Sc , 134 and when the pAb W3 was administered to mice a week prior to prion inoculation, their survival time nearly doubled. 296 The potential involvement of autophagy in prion disease has led to a handful of studies in cultured cells and in vivo models of scrapie infection, 153,297 and in Tg mouse models of genetic prion disease, 154 that support therapies directed at enhancing autophagy to mitigate sporadic disease and delay onset of genetic disease and symptoms.…”