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Prion. 2007 Jul-Sep; 1(3): 207–212.
PMCID: PMC2634594

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

Abstract

We identified the 37kDa/67kDa laminin receptor (LRP/LR) as a cell surface receptor for the cellular prion protein (PrPc) and the infectious prion protein (PrPSc). 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 PrPSc content in the spleen significantly by 66%, demonstrating an impairment of the peripheral PrPSc 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 PrPSc propagation might be due to the blockage of the prion receptor LRP/LR which is required, as previously shown in vitro, for PrPSc propagation in vivo.

Key Words: 37kDa/67kDa laminin receptor, LRP/LR, prion, PrP, TSE-therapy

Introduction

Transmissible spongiform encephalopathies (TSE) are a group of neurodegenerative protein-misfolding diseases, also known as prion diseases affecting both animals including scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and chronic wasting disease (CWD) in elk and deer as well as humans (e.g., Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome and fatal familial insomnia (FFI)) (for review see refs. 14). Affected individuals display rapidly progressive symptoms due to various effects such as gliosis, astrocytosis, neuronal loss and spongiosis.

TSEs are associated with an abnormal form of the prion protein, termed PrPSc. The conversion of the host encoded PrPc into the disease associated isoform (PrPSc) results in accumulation which is perpetuated by an autocatalytic process.5,6 Although various therapeutic approaches have already been developed (for review see refs. 711), no treatment was available until now, which is able to cure affected individuals. The first successful approach in antibody-based therapies was the passive immunotransfer of a monoclonal anti-PrP antibody which cured rodents peripherally infected with PrPSc.12 Besides monoclonal antibodies targeting the prion protein,13,14 also single chain anti-PrP antibodies are currently investigated for a TSE therapy.15

Among many interaction partners identified for PrPc,10,1618 the non-integrin 37/67 kDa laminin receptor (LRP/LR) has been discovered as a receptor for both the cellular PrPc 19,20 and the disease associated PrPSc.21,22 Downregulation of LRP/LR by antisense LRP RNA or siRNAs directed against LRP mRNA abrogates PrPSc propagation in ScN2a cells.23 Secretion of a transdominant negative LRP mutant also abolishes PrPSc propagtion in neuronal cells.24 A polyclonal anti-LRP/LR antibody termed W3 interferes with PrP27–30 cell binding21 and internalization of bovine PrPSc by human enterocytes.22 Most notably, W3 has been shown to cure PrPSc propagating cells from scrapie.23 In order to investigate whether W3 is able to hamper prion propagation in vivo, we delivered W3 into mice by passive immunization. Spleen analysis confirmed a significant reduction in peripheral PrPSc propagation in W3 treated mice. Moreover, W3 treated mice revealed a 1.8-fold increase in survival (the time span from the day one of the four TSE-relevant symptoms occur until the day mice show two of the four TSE-relevant symptoms over three days25) compared to the control group injected with preimmune serum. Our results suggest that LRP/LR plays an important role for PrPSc propagation in vivo and that targeting LRP/LR is a relevant strategy for therapy in prion diseases.

Materials and Methods

Antibodies and preimmune serum.

In order to get the polyclonal anti-LRP antibody pAb W3, we immunized albino rabbits [(New Zealand; ZRL:kbl (nzw)br; Charles River Breeding Laboratories, Wilmington, Massachusets)]. One mililiter of a mixture of GST:: LRP fusion protein expressed in E. coli system26 and CWS adjuvant (RIBI adjuvant, Sigma) was subcutaneously injected into rabbits (see ref. 27). After 28 days, animals were boosted and after additional 14 days the animals were immunized a third time. Eleven days later 200 ml of blood were collected and coagulated for one hour at 37°C and incubated over night at 4°C followed by two centrifugation steps ten minutes at 9,000 rpm and 10.500 rpm at 4°C. Purification was done using a protein A sepharose column (Pierce, Rockford, Illinois). W3 was selected from several anti-LRP sera tested for recognition efficiency of LRP/LR by FACS and western analysis.27 Preimmune serum was obtained from rabbit prior to immunization.

Passive immunotransfer of anti-LRP/LR antibody W3 into mice.

Animals were maintained and treated in accordance with ethical guidelines of Bavaria. Experiments were approved by the Regierung von Oberbayern (Munich, Germany, Ar.: 209.1/211-2531-83/04). For infection studies C57BL/6 mice were injected intraperitoneally (i.p.) with a total amount of 1 mg of W3 or preimmune serum. Treatment was performed once per week over a period of 12 weeks. One week after the first antibody injection mice were inoculated i.p. with 100 µl 10% RML Scrapie homogenate. The time span from the day of RML inoculation until one of the four symptoms: ataxia of gait, tremor, difficulty righting from a supine position and rigidity in the tail occured (termed as symptom onset) and survival (the time span from the day one of the four TSE-relevant symptoms occur until the day mice show two of the four TSE-relevant symptoms over three days25) were monitored. In all monitoring procedures the investigators were blinded as to the experimental groups individual mice belonged to.

Analysis of PrPSc and total PrP levels in the spleen of RML inoculated mice.

Ninety days post RML inoculation six mice per group were sacrificed for analysis of peripheral PrPSc propagation. Spleens were collected and homogenized in PBS buffer. Adjusting the total protein amount to 200 µg, samples were digested with Proteinase K to a final concentration of 20 µg/ml for 60 minutes at 37°C. Samples were analysed on a 12% SDS PAGE and blotted onto a PVDF membrane. Immunodetection was performed using SAF83 as the primary and anti-mouse-POD conjugate (Jackson Immunoresearch) as the secondary antibody. Blots were developed using an enhanced chemiluminescence system (Perkin Elmer Lifescience) and exposed on Kodak Biomax light films. Quantification of the western blot signals was carried out by densitometric measurements using the Image J software. To determine the total PrP amount, spleen samples were treated as described for the PrPSc detection but without a Proteinase K treatment. For total PrP detection SAF32 was used as the primary and anti-mouse-IgG-POD as the secondary antibody.

Analysis of PrPSc and total PrP levels in the brain of terminal mice.

Mice were sacrified after two of the four characteristical TSE symptoms25 were detected for a period of three days. Total brain samples of six mice per group were collected and homogenized in PBS buffer. Protein levels were adjusted to 200 µg per sample and digested with Proteinase K to a final concentration of 20 µg/ml for 60 minutes at 37°C. The PrPSc content was determined by analysis on a 12% SDS PAGE and blotted onto a PVDF membrane. Immunodetection was performed using SAF83 as the primary and anti-mouse-IgG-POD (Jackson Immunoresearch) as the secondary antibody. Blots were developed using an enhanced chemiluminescence system (Perkin Elmer Lifescience) and exposed on Kodak Biomax light films. Quantification of the western blot signals was carried out by densitometric measurements using the Image J software. To determine the total PrP amount total brain samples were treated as described for PrPSc detection in the absence of Proteinase K treatment. Detection for total PrP was carried out using SAF32 as the primary and anti-mouse-IgG-POD as the secondary antibody.

Statistical analysis.

Statistical analyses were performed employing a Student's t test with two tailed distribution and two-sample unequal variance.

Results

Anti-LRP/LR antibody W3 reduces peripheral PrPSc propagation.

One milligram per week of anti-LRP/LR antibody W3 and preimmune serum was intraperitoneally injected into scrapie infected mice for a period of 12 weeks (Fig. 1). One week after the first injection mice were intraperitoneally inoculated with RML Scrapie homogenate and monitored for symptom onset (incubation times) and survival (Fig. 1). W3 and preimmune serum treated mice were controlled daily and showed normal behavior till they were sacrificed. No side effects were detectable at any time points.

Figure 1
Schematic overview of the passive immunotransfer modalities. One milligram of antibody (either W3 or preimmune serum) per C57BL/6 mouse was intraperitoneally injected seven days prior to intraperitoneal inoculation with 10% RML brain homogenate. Antibodies ...

Western blot analysis of the spleen of W3 treated mice 90 days post inoculation revealed a significant reduction of the PrPSc level by 66% compared to the preimmune serum treated mice (Fig. 2A and andB),B), suggesting that W3 reduces significantly peripheral PrPSc propagation. The amount of total PrP (PrPSc plus PrPc) was reduced by approx. 40% (Fig. 2C and andD)D) in W3 treated mice, suggesting that PrPc levels remain unaffected by the antibody treatment.

Figure 2
Analysis of total PrP and PrPSc levels in the spleen of scrapie infected mice treated with polyclonal anti-LRP antibody W3 and preimmune serum 90 days post infection. LRP/LR antibody W3 and preimmune serum was intraperitoneally injected into C57BL/6 mice ...

Anti-LRP/LR antibody W3 prolongs the survival in scrapie infected mice.

Anti-LRP/LR antibody W3 treated mice did not show a prolongation of incubation times compared to the preimmune serum treated control group (Fig. 3A and Table 1). However, the anti-LRP/LR antibody W3 treated mice revealed a mean survival of 31 days, which represents a 1.8-fold prolongation of the survival in comparison with the preimmune serum (mean survival 17 days) treated control group (Fig. 3B, ,CC and Table 1).

Figure 3
Symptom onset (Incubation times) and survival in scrapie infected C57BL/6 mice treated with polyclonal anti-LRP antibody W3 and preimmune serum. C57BL/6 mice were intraperitoneally inoculated with RML prions one week after the first antibody/preimmune ...
Table 1
Incubation times and survival of scrapie infected mice treated with W3 and preimmune serum

At the terminal state the PrPSc level in the brain of W3 treated mice was reduced by 17% compared to preimmune serum treated mice (Fig. 4A and andB),B), whereas W3 and preimmune serum treated mice showed no alteration in the total PrP content (Fig. 4C and andD),D), suggesting that PrPc levels remained unaltered in both experimental groups.

Figure 4
Analysis of total PrP and PrPSc levels in the brain of scrapie infected mice treated with polyclonal anti-LRP antibody W3 and preimmune serum at the terminal state. LRP/LR antibody W3 and preimmune serum was intraperitoneally injected into C57BL/6 mice ...

Discussion

At present no therapeutic strategy is available for the treatment of TSEs which cures prion diseases.8,9,11,28,29 Since the laminin receptor acts as a receptor for PrPc,30 and PrPSc,21 LRP/LR exhibits a promising target for therapeutic strategies in prion diseases. The anti-laminin receptor polyclonal antibody W3 was well efficient in vitro by curing scrapie propagating cells from PrPSc.23 In order to prove an in vivo effect of W3 on (1) peripheral PrPSc propagation and (2) prolongation of survival, we passively transferred W3 into C57BL/6 mice by intraperitoneal injections followed by i.p. RML prion inoculations. W3 treated mice revealed a significant reduction (66%) of the peripheral PrPSc propagation compared to preimmune serum treated mice as analyzed by determining the PrPSc levels in the spleen. Total PrP levels (PrPSc plus PrPc) in the spleen were reduced by approx. 40%, suggesting that W3 treatment has no or only a weak influence on the reduction of PrPc levels in the spleen.

In addition, W3 treated mice revealed a 1.8-fold increase in survival (31 days) compared to the preimmune serum treated control group (17 days), suggesting that W3 also hampers PrPSc propagation in the central nervous system contributing to prolongation of survival. Moreover, this is of potential interest for treatment of CJD patients because the effects were observed during the clinical stages, when mice had already neurological symptoms (prolongation of survival time from onset of the disease to death). Due to the limited amount of the polyclonal antibody W3, which was raised against LRP in a rabbit,27 we could not elongate the antibody treatment over the 12 weeks treatment period and could not increase the number of animals and/or the dose of antibody applied (1 mg) which all together might have resulted in an even more obvious effect on the increase in survival. In contrast to survival, incubation times were not affected. We assume that by increasing the antibody amount and the time period of treatment, the incubation time might also be prolonged. Application of a monoclonal anti-PrP antibody in mice with 2 mg of antibody twice a week resulted in a delayed onset of the disease.12 Many promising anti-prion drugs which are effective in vitro failed to be active also in vivo (reviewed in ref. 9). Among them, are the antimalaria drugs mefloquine31 and quinacrine.32 In contrast, W3 is effective both in vitro23 and in vivo. Currently, the efficacy of doxycyclin in the treatment of CJD is under investigation in observational studies in Milano (Italy) and Göttingen (Germany). First data indicate that administration of doxycyclin might prolong the survival by two-fold. In the German study on 23 patients, the survival was prolonged from four months (median in sCJD) to eight months. Whether the prolongation time is due to a specific prion effect, will be tested in a prospective double blind study. No conclusions can be drawn, however, regarding a potential prolongation of incubation times in CJD patients by doxycyclin. A combination therapy with doxycyclin and antibodies targeting LRP/LR might have some additive or even synergistic effects.

On the molecular level LRP/LR specific antibody W3 blocks (1) PrPc binding to neuronal cells,30 (2) PrP27-30 binding to mammalian cells21 and (3) BSE prion internalization by human enterocytes,22 suggesting that the antibody interferes with PrPc and PrPSc internalization processes prohibiting as a consequence PrPSc propagation, which might occur in compartments of the endocytic pathway rather than on the cell surface (for review see refs. 8 and 10). In scrapie infected mice, we show that W3 is able to interfere efficiently with peripheral PrPSc propagation, which takes place in organs of the lymphoreticular system such as the spleen. At the time point when the animals were sacrificed (at the day when two TSE-associated symptoms appeared for three days25) the detected PrPSc levels in the brain were not significantly different between W3 treated and preimmune serum-treated mice, suggesting that PrPSc propagation was not delayed in the brain of W3 treated animals. The total PrP content at the terminal state in the brain of mice treated with W3 and preimmune serum was unchanged, suggesting that also PrPc levels in the brain were not affected by W3 treatment.

Taken together, this pilot study revealed important results regarding an antibody therapy or post-exposure prophylaxis with W3 resulting in a signifcant reduction of peripheral PrPSc propagation and a slight prolongation of survival. Since we started the antibody treatment seven days prior to PrPSc inoculation and terminated the treatment 77 days post PrPSc inoculation (long before first symptoms occur) (Fig. 1), we preformed in this study a post-exposure prophylaxis rather than a therapy, which is usually initiated at the stage when first symptoms appeared.

Since the amount of W3 is limited, we generated in a parallel study single chain antibodies (scFv) directed against LRP/LR by phage display.33 Passive immunotransfer of the scFv S18 by intraperitoneal injections into scrapie infected mice also resulted in a reduction of the PrPSc level in the spleen by approx. 40% without a significant prolongation of incubation times and survival.33 W3 reduced PrPSc levels in the spleen significantly by 66% and slightly prolonged the survival 1.8-fold. One of the reasons for the slightly better efficacy of W3 compared to scFv S18 might be the longer half-life of full-length IgGs in the blood (approximately 14 days) compared to single chain antibodies (approximately 12 hours). The amount of antibody (1 mg per week) was the same for both studies although the duration of antibody treatment was different (eight weeks for scFv S18 versus 12 weeks for W3). A polyclonal serum raised against a specific antigen (here LRP/LR) contains approximately 5–10% antibodies directed against this antigen.34 Therefore approximately 50–100 mg of LRP/LR specific antibodies per week were injected in the present study, i.e. 10 to 20-fold less compared to the scFv S18 trial (1 mg/week), suggesting that full-length IgG molecules are more potent than scFv fragments in passive immunotherapy.

Our results demonstrated that the polyclonal antibody W3 significantly impaired PrPSc replication in the spleen. These findings are an incentive to pursue with studies of antibodies directed against LRP/LR to obtain more effective results on the neuroinvasion phases of the infection. Passive immunotransfer studies with improved versions of the single chain antibody S18, as well as full-length IgG versions thereof might represent promising regimens for an efficient treatment of prion diseases.

Acknowledgements

We thank Katharina Krüger, Tina Hallas and Jennifer Hentrich for excellent technical assistance. This work was supported by the Bundesministerium für Bildung und Forschung (grant 01-KO-0514), the European Commission (grant NoE-NeuroPrion FOOD-CT-2004-506579) and the Deutsche Forschungsgemeinschaft (DFG) (grant WE 2664/2-1).

Abbreviations

CJD
Creutzfeldt-Jakob disease
CWD
chronic wasting disease
FFI
fatal familial insomnia
GSS
Gerstmann-Sträussler-Scheinker
LR
high affinity laminin receptor
LRP
laminin receptor precursor
RML
rocky mountain laboratory
TSE
transmissible spongiform encephalopathy
W3
polyclonal anti-LRP/LR antibody

Footnotes

Previously published in a Prion E-publication: http://www.landesbioscience.com/journals/prion/article/5273

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