1887

Journal of General Virology header logo

Volume 91, Issue 6

Immunotherapeutic effect of anti-PrP monoclonal antibodies in transmissible spongiform encephalopathy mouse models: pharmacokinetic and pharmacodynamic analysis Free

Abstract

Prion diseases are transmissible neurodegenerative disorders for which no therapeutic or prophylactic regimens exist. Passive immunization with appropriate antibodies directed against the cellular form of the prion protein (PrPC) can delay the onset of prion disease after peripheral infection, but mechanisms and parameters determining their efficacy remain unknown. In the present study, we characterized the main pharmacokinetic properties of anti-PrP antibodies in different mouse models expressing various levels of PrPC (, C57BL/6 and tga20 mice) in correlation with therapeutic effect. Plasma levels of free antibodies, total endogenous PrPC and PrPC–antibody complexes were monitored after a single intraperitoneal monoclonal antibody (mAb) injection. Efficacy in delaying PrPSc peripheral accumulation seemed to be associated with mAb capacity to form long-lasting complexes with endogenous PrPC in the plasma. In agreement with previous observations on cellular models of transmissible spongiform encephalopathy infection, we observed that injection of anti-PrP antibodies induced a large (up to 100-fold) increase in circulating PrPC. Finally, the most efficient antibody extended the lifespan of infected animals greatly. These results allowed us to define critical characteristics of anti-PrP mAbs associated with therapeutic efficacy and could constitute a useful reference for designing optimized passive immunotherapies for prion diseases.

  • Received:
  • Accepted:
  • Published Online:
© SGM
Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.018077-0
2010-06-01
2024-04-20
Loading full text...

Full text loading...

/deliver/fulltext/jgv/91/6/1635.html?itemId=/content/journal/jgv/10.1099/vir.0.018077-0&mimeType=html&fmt=ahah

References

  1. Aguzzi, A. & Polymenidou, M.(2004). Mammalian prion biology: one century of evolving concepts. Cell 116, 313–327.[CrossRef] [Google Scholar]
  2. Aguzzi, A. & Sigurdson, C. J.(2004). Antiprion immunotherapy: to suppress or to stimulate? Nat Rev Immunol 4, 725–736.[CrossRef] [Google Scholar]
  3. Andreoletti, O., Berthon, P., Marc, D., Sarradin, P., Grosclaude, J., van Keulen, L., Schelcher, F., Elsen, J. M. & Lantier, F.(2000). Early accumulation of PrPSc in gut-associated lymphoid and nervous tissues of susceptible sheep from a Romanov flock with natural scrapie. J Gen Virol 81, 3115–3126. [Google Scholar]
  4. Beringue, V., Vilette, D., Mallinson, G., Archer, F., Kaisar, M., Tayebi, M., Jackson, G. S., Clarke, A. R., Laude, H. & other authors(2004). PrPSc binding antibodies are potent inhibitors of prion replication in cell lines. J Biol Chem 279, 39671–39676.[CrossRef] [Google Scholar]
  5. Bueler, H., Fischer, M., Lang, Y., Bluethmann, H., Lipp, H. P., DeArmond, S. J., Prusiner, S. B., Aguet, M. & Weissmann, C.(1992). Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356, 577–582.[CrossRef] [Google Scholar]
  6. Bueler, H., Aguzzi, A., Sailer, A., Greiner, R. A., Autenried, P., Aguet, M. & Weissmann, C.(1993). Mice devoid of PrP are resistant to scrapie. Cell 73, 1339–1347.[CrossRef] [Google Scholar]
  7. Cardinale, A., Filesi, I., Vetrugno, V., Pocchiari, M., Sy, M. S. & Biocca, S.(2005). Trapping prion protein in the endoplasmic reticulum impairs PrPC maturation and prevents PrPSc accumulation. J Biol Chem 280, 685–694.[CrossRef] [Google Scholar]
  8. Collins, S. J., Lawson, V. A. & Masters, C. L.(2004). Transmissible spongiform encephalopathies. Lancet 363, 51–61.[CrossRef] [Google Scholar]
  9. Demart, S., Fournier, J. G., Creminon, C., Frobert, Y., Lamoury, F., Marce, D., Lasmezas, C., Dormont, D., Grassi, J. & Deslys, J. P.(1999). New insight into abnormal prion protein using monoclonal antibodies. Biochem Biophys Res Commun 265, 652–657.[CrossRef] [Google Scholar]
  10. Enari, M., Flechsig, E. & Weissmann, C.(2001). Scrapie prion protein accumulation by scrapie-infected neuroblastoma cells abrogated by exposure to a prion protein antibody. Proc Natl Acad Sci U S A 98, 9295–9299.[CrossRef] [Google Scholar]
  11. Feraudet, C., Morel, N., Simon, S., Volland, H., Frobert, Y., Creminon, C., Vilette, D., Lehmann, S. & Grassi, J.(2005). Screening of 145 anti-PrP monoclonal antibodies for their capacity to inhibit PrPSc replication in infected cells. J Biol Chem 280, 11247–11258.[CrossRef] [Google Scholar]
  12. Fischer, M., Rulicke, T., Raeber, A., Sailer, A., Moser, M., Oesch, B., Brandner, S., Aguzzi, A. & Weissmann, C.(1996). Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie. EMBO J 15, 1255–1264. [Google Scholar]
  13. Fishburn, C. S.(2008). The pharmacology of PEGylation: balancing PD with PK to generate novel therapeutics. J Pharm Sci 97, 4167–4183.[CrossRef] [Google Scholar]
  14. Grassi, J., Frobert, Y., Pradelles, P., Chercuitte, F., Gruaz, D., Dayer, J. M. & Poubelle, P. E.(1989). Production of monoclonal antibodies against interleukin-1α and -1β. Development of two enzyme immunometric assays (EIA) using acetylcholinesterase and their application to biological media. J Immunol Methods 123, 193–210.[CrossRef] [Google Scholar]
  15. Grassi, J., Creminon, C., Frobert, Y., Etienne, E., Ezan, E., Volland, H. & Pradelles, P.(1996). Two different approaches for developing immunometric assays of haptens. Clin Chem 42, 1532–1536. [Google Scholar]
  16. Grassi, J., Creminon, C., Frobert, Y., Fretier, P., Turbica, I., Rezaei, H., Hunsmann, G., Comoy, E. & Deslys, J. P.(2000). Specific determination of the proteinase K-resistant form of the prion protein using two-site immunometric assays. Application to the post-mortem diagnosis of BSE. Arch Virol Suppl 16, 197–205. [Google Scholar]
  17. Haik, S., Brandel, J. P., Salomon, D., Sazdovitch, V., Delasnerie-Laupretre, N., Laplanche, J. L., Faucheux, B. A., Soubrie, C., Boher, E. & other authors(2004). Compassionate use of quinacrine in Creutzfeldt–Jakob disease fails to show significant effects. Neurology 63, 2413–2415.[CrossRef] [Google Scholar]
  18. Hill, A. F., Desbruslais, M., Joiner, S., Sidle, K. C., Gowland, I., Collinge, J., Doey, L. J. & Lantos, P.(1997). The same prion strain causes vCJD and BSE. Nature 389, 448–450.[CrossRef] [Google Scholar]
  19. Irani, D. N., Otto, M. & Weber, T.(2003). Prion diseases: current and future therapeutic approaches. Curr Treat Options Infect Dis 5, 477–485. [Google Scholar]
  20. Kim, C. L., Karino, A., Ishiguro, N., Shinagawa, M., Sato, M. & Horiuchi, M.(2004). Cell-surface retention of PrPC by anti-PrP antibody prevents protease-resistant PrP formation. J Gen Virol 85, 3473–3482.[CrossRef] [Google Scholar]
  21. Llewelyn, C. A., Hewitt, P. E., Knight, R. S., Amar, K., Cousens, S., Mackenzie, J. & Will, R. G.(2004). Possible transmission of variant Creutzfeldt–Jakob disease by blood transfusion. Lancet 363, 417–421.[CrossRef] [Google Scholar]
  22. Lobo, E. D., Hansen, R. J. & Balthasar, J. P.(2004). Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci 93, 2645–2668.[CrossRef] [Google Scholar]
  23. Mallucci, G. & Collinge, J.(2005). Rational targeting for prion therapeutics. Nat Rev Neurosci 6, 23–34.[CrossRef] [Google Scholar]
  24. Meggio, F., Negro, A., Sarno, S., Ruzzene, M., Bertoli, A., Sorgato, M. C. & Pinna, L. A.(2000). Bovine prion protein as a modulator of protein kinase CK2. Biochem J 352, 191–196.[CrossRef] [Google Scholar]
  25. Meier, P., Genoud, N., Prinz, M., Maissen, M., Rulicke, T., Zurbriggen, A., Raeber, A. J. & Aguzzi, A.(2003). Soluble dimeric prion protein binds PrPScin vivo and antagonizes prion disease. Cell 113, 49–60.[CrossRef] [Google Scholar]
  26. Morel, N., Simon, S., Frobert, Y., Volland, H., Mourton-Gilles, C., Negro, A., Sorgato, M. C., Creminon, C. & Grassi, J.(2004). Selective and efficient immunoprecipitation of the disease-associated form of the prion protein can be mediated by nonspecific interactions between monoclonal antibodies and scrapie-associated fibrils. J Biol Chem 279, 30143–30149.[CrossRef] [Google Scholar]
  27. Otto, M., Cepek, L., Ratzka, P., Doehlinger, S., Boekhoff, I., Wiltfang, J., Irle, E., Pergande, G., Ellers-Lenz, B. & other authors(2004). Efficacy of flupirtine on cognitive function in patients with CJD: a double-blind study. Neurology 62, 714–718.[CrossRef] [Google Scholar]
  28. Peden, A. H., Head, M. W., Ritchie, D. L., Bell, J. E. & Ironside, J. W.(2004). Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 364, 527–529.[CrossRef] [Google Scholar]
  29. Peretz, D., Williamson, R. A., Kaneko, K., Vergara, J., Leclerc, E., Schmitt-Ulms, G., Mehlhorn, I. R., Legname, G., Wormald, M. R. & other authors(2001). Antibodies inhibit prion propagation and clear cell cultures of prion infectivity. Nature 412, 739–743.[CrossRef] [Google Scholar]
  30. Perrier, V., Solassol, J., Crozet, C., Frobert, Y., Mourton-Gilles, C., Grassi, J. & Lehmann, S.(2004). Anti-PrP antibodies block PrP replication in prion-infected cell cultures by accelerating PrP degradation. J Neurochem 89, 454–463.[CrossRef] [Google Scholar]
  31. Prusiner, S. B.(1982). Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144.[CrossRef] [Google Scholar]
  32. Prusiner, S. B.(1998). Prions. Proc Natl Acad Sci U S A 95, 13363–13383.[CrossRef] [Google Scholar]
  33. Sigurdsson, E. M., Sy, M. S., Li, R., Scholtzova, H., Kascsak, R. J., Kascsak, R., Carp, R., Meeker, H. C., Frangione, B. & Wisniewski, T.(2003). Anti-prion antibodies for prophylaxis following prion exposure in mice. Neurosci Lett 336, 185–187.[CrossRef] [Google Scholar]
  34. Solforosi, L., Criado, J. R., McGavern, D. B., Wirz, S., Sanchez-Alavez, M., Sugama, S., DeGiorgio, L. A., Volpe, B. T., Wiseman, E. & other authors(2004). Cross-linking cellular prion protein triggers neuronal apoptosis in vivo. Science 303, 1514–1516.[CrossRef] [Google Scholar]
  35. Trevitt, C. R. & Collinge, J.(2006). A systematic review of prion therapeutics in experimental models. Brain 129, 2241–2265.[CrossRef] [Google Scholar]
  36. Volland, H., Pradelles, P., Ronco, P., Azizi, M., Simon, D., Creminon, C. & Grassi, J.(1999). A solid-phase immobilized epitope immunoassay (SPIE-IA) permitting very sensitive and specific measurement of angiotensin II in plasma. J Immunol Methods 228, 37–47.[CrossRef] [Google Scholar]
  37. Weissmann, C. & Aguzzi, A.(2005). Approaches to therapy of prion diseases. Annu Rev Med 56, 321–344.[CrossRef] [Google Scholar]
  38. White, A. R., Enever, P., Tayebi, M., Mushens, R., Linehan, J., Brandner, S., Anstee, D., Collinge, J. & Hawke, S.(2003). Monoclonal antibodies inhibit prion replication and delay the development of prion disease. Nature 422, 80–83.[CrossRef] [Google Scholar]
  39. Whittle, I. R., Knight, R. S. & Will, R. G.(2006). Unsuccessful intraventricular pentosan polysulphate treatment of variant Creutzfeldt–Jakob disease. Acta Neurochir (Wien) 148, 677–679.[CrossRef] [Google Scholar]
  40. Will, R. G., Ironside, J. W., Zeidler, M., Cousens, S. N., Estibeiro, K., Alperovitch, A., Poser, S., Pocchiari, M., Hofman, A. & Smith, P. G.(1996). A new variant of Creutzfeldt–Jakob disease in the UK. Lancet 347, 921–925.[CrossRef] [Google Scholar]
  41. Wroe, S. J., Pal, S., Siddique, D., Hyare, H., Macfarlane, R., Joiner, S., Linehan, J. M., Brandner, S., Wadsworth, J. D. & other authors(2006). Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt–Jakob disease associated with blood transfusion: a case report. Lancet 368, 2061–2067.[CrossRef] [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.018077-0
Loading
Immunotherapeutic effect of anti-PrP monoclonal antibodies in transmissible spongiform encephalopathy mouse models: pharmacokinetic and pharmacodynamic analysis
J. Gen. Virol. 91, 1635 (2010); https://doi.org/10.1099/vir.0.018077-0
/content/journal/jgv/10.1099/vir.0.018077-0
/content/journal/jgv/10.1099/vir.0.018077-0
Loading

Data & Media loading...

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error