New technologies for detection and prevention of prion diseases

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D-Gen anti-PrP monoclonal antibodies

D-Gen provides high-quality antibodies against prion proteins, which are ideally suited for immunohistochemistry, FACS analysis, ELISA, Western blotting and immunoprecipitation. A long standing limitation of anti-PrP monoclonal antibodies has been their inability to recognise the disease associated isoform of PrP, PrP^Sc. Although several commercial antibodies are capable of reacting with denatured PrP^C and PrP^Sc on western blots, antibodies capable of detecting native PrP^Sc for use in FACS analysis, immunoprecipitation or in vivo studies have not been available.  

By using a novel immunogen D-Gen has identified several unique antibody specificities which are now available.

Conditions under which recombinant human PrP can switch between the native a-PrP conformation, characteristic of PrP^C, and a compact, highly soluble, monomeric form, rich in beta-sheet structure have been established. This conformer, designated b-PrP, has many properties in common with PrP^Sc. It displays partial resistance to proteolysis with proteinase K, is composed of beta-sheet secondary structure and it readily aggregates into structures that form highly regular amyloid fibrils.

Antibodies raised against b-PrP

Immunisation of mice with recombinant a-PrP and b-PrP produces very different polyclonal responses and results in the generation of distinctive populations of monoclonal antibodies (Mabs).

In particular, several monoclonals raised against b-PrP (but not a-PrP) have high affinity for, and can efficiently immunoprecipitate native PrP^Sc. These Mabs have already been applied to develop a cattle BSE diagnostic test which proved 100% specific and sensitive on rigorous independent evaluation by the European Commission (ICSM18, ICSM35). ICSM18 is also particularly useful in detecting mouse PrP against which there have been limited reagents available. D-Gen's antibodies raised against recombinant PrP have also been used successfully in both in vitro and in vivo therapeutic studies (ICSM18, ICSM35).

 ICSM18 and ICSM35 have become the antibodies of choice within prion research due to their high affinity and specificity and due to their ability to detect PrP from a wide variety of species including hamster, mouse, sheep, cattle and human.

We have also isolated monoclonal antibodies that, without denaturation, differentially distinguish between prion protein glycoforms (ICSM3, ICSM4 and ICSM10).

D-Gen's antibodies are raised against recombinant human prion proteins. The high purity of the recombinant PrP antigen as well as the culture methods used to produce the antibodies result in antibodies of high specificity which do not cross-react with other proteins.

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Examples of references citing use of D-Gen's ICSM range of monoclonal antibodies:

1. Mallucci GR, Ratté S, Asante EA, Linehan J, Gowland I, Jefferys JGR, Collinge J: Post-natal knockout of prion protein alters hippocampal CA1 properties, but does not result in neurodegeneration. EMBO J. 2002, 21:202-210.

2. Mallucci G, Dickinson A, Linehan J, Klohn PC, Brandner S, Collinge J: Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis. Science 2003, 302:871-874.

3. Hill AF, Joiner S, Linehan J, Desbruslais M, Lantos PL, Collinge J: Species barrier independent prion replication in apparently resistant species. Proc Natl Acad Sci (USA) 2000, 97:10248-10253.

4. 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, 422:80-83.

5. Asante EA, Linehan JM, Desbruslais M, Joiner S, Gowland I, Wood A, Welch J, Hill AF, Lloyd SE, Wadsworth JDF, Collinge J: BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein. EMBO J. 2002, 21 (23):6358-6366.

6. Lloyd SE, Onwuazor ON, Beck JA, Mallinson G, Farrall M, Targonski P, Collinge J, Fisher EMC: Identification of multiple quantitative trait loci linked to prion disease incubation period in mice. Proc.Natl.Acad.Sci.USA 2001, 98:6279-6283.

7. Prinz M, Heikenwalder M, Junt T, Schwarz P, Glatzel M, Heppner FL, Fu YX, Lipp M, Aguzzi A: Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion. Nature 2003.

8. Klohn PC, Stoltze L, Flechsig E, Enari M, Weissmann C: A quantitative, highly sensitive cell-based infectivity assay for mouse scrapie prions. Proc.Natl.Acad.Sci U.S.A 2003.

9. Meier P, Genoud N, Prinz M, Maissen M, Rulicke T, Zurbriggen A, Raeber AJ, Aguzzi A: Soluble Dimeric Prion Protein Binds PrP(Sc) In Vivo and Antagonizes Prion Disease. Cell 2003, 113:49-60.

10. Heppner FL, Musahl C, Arrighi I, Klein MA, Rülicke T, Oesch B, Zinkernagel RM, Kalinke U, Aguzzi A: Prevention of scrapie pathogenesis by transgenic expression of anti-prion protein antibodies. Science 2001, 294:178-182.

11. Schimmel H, Catalani P, Le Guern L, Prokisch J, Philipp W, Trapmann S, Zeleny R: The evaluation of five rapid tests for the diagnosis of transmissible spongiform encephalopathy in bovines. European Commission Report 2002.

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