Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Patent
1997-10-02
2000-05-23
Eisenschenk, Frank C.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
4242051, 4241841, 4241861, 4241991, 435 691, 435 693, 536 2372, A61K 3912
Patent
active
060663243
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
The invention relates to recombinantly produced papilloma virus-like particles, proteins, fusion proteins as well as processes for the formation and purification of these particles, proteins and fusion proteins.
Infections with certain (high-risk) types of genital papilloma viruses in humans (HPV), e.g. HPV 16, 18 or 45 are held to be the main risk factor for the formation of malignant tumours of the anogenital tract. Of these, cervical carcinoma is by far the most frequently occurring. According to an estimate by the WHO, about half a million new cases of this disease occur annually. Because of this frequent occurrence, the connection between HPV infection and cervical carcinoma has been the best investigated: neoplasia: CIN) are caused by papilloma virus infections. proven to occur in more than 95% of tumour biopsies as well as in cell lines derived from them. Depending on the geographic origin of the tumors, 50-70% of these contain HPV 16. (Wettstein et al., in Pfister H. (ed): Papilloma viruses and human cancer, pp. 155 to 179, Boca Raton, 1990). cell-lines as well as in in vitro transformed human keratinocytes, and the majority of patients with cervical carcinoma have E6- or E7-specific antibodies. maintain the transformed condition of HPV-positive tumors. following experimental systems:
Other HPV types (principally HPV 6 and 11) cause benign genital warts (condylomata acuminata) and are only extremely rarely associated with malignant tumors (low-risk types).
As a rule, genital papilloma viruses in humans are transmitted during intercourse and in most cases lead to persistent infection in the anogenital mucous membrane. This led to the conclusion that primary infections induce only an insufficient immune response, or that the virus has developed possibilities of avoiding the immune surveillance in the infected cells. On the other hand there are good indications suggesting that the immune system is involved during primary manifestation or during the malignant progression of papilloma virus infections. (For an overview see Altmann et al. (1994) in Minson A., Neil J., McCrae M. (eds): Viruses and cancer, Cambridge University Press, pp. 71 to 80). bovine papilloma virus), the clinical manifestation of primary infections can be avoided by vaccination with viral structural proteins or with wart extracts (autologous vaccines). vaccinia recombinants or by synthetic peptides prior to tumour formation after inoculation of HPV 16-transformed autologous cells. papilloma viruses can be induced by the transfer of lymphocytes of regressor animals. HIV-infected persons), the incidence of genital warts, CIN and anogenital cancer is increased.
This led to the conclusion that papilloma virus-specific vaccinations aimed at preventing the primary infection and the occurrence of genital cancer should be possible. structural proteins L1 and L2 of the papilloma virus (prophylactic vaccination).
Because papilloma viruses cannot be propagated to adequate titres in cell cultures or other experimental systems, the viral proteins can only be produced by means of recombinant vectors. Recently, virus-like particles (VLPs) which, after expression of the viral structure proteins L1 and L2 (or L1 on its own), are formed in recombinant vaccinia or baculo virus, have been described. Purification of the VLPs can be achieved very simply by means of centrifugation in CsCl- or sucrose gradients.
WO 93/02184 describes a method which provides papilloma virus-like particles (VLPs), which are used for diagnostic applications or as a vaccine against infections caused by the papilloma virus.
WO 94/00152 describes a recombinantly produced L1 main capsid protein which mimics the conformational neutralising epitope on human and animal papilloma virions. These recombinant proteins can be used as vaccines which protect against papilloma virus-infections. assisted by early papilloma virus-proteins (principally E6 or E7) which are expressed in the persistently infected cells (therapeutic vaccination).
It is assumed that by this vaccination,
REFERENCES:
Virology, vol. 194, 1993, pp. 210-218, Zhou, J. et al.: "Glycosylation of Human Papillomavirus Type 16 L1 Protein".
WO-A-94/20137, Sept. 9, 1994, University of Rochester: "Production of Human Papillomavirus Capsid Protein and Virus-like Particles".
Virology, vol. 170, 1989, pp. 321-325, Nasseri, M. et al.: "Genetic Analysis of CRPV Pathogenesis: The L1 Open Reading Frame is Dispensable for Cellular Transformation but is Required for Papilloma Formation".
Virology, vol. 178, 1990, pp. 238-246, Crum, C.P. et al.: "Coexpression of the Human Papillomavirus Type 16 E4 and L1 Open Reading Frames in Early Cervical Neplasia".
WO-A-93/00436, Jan. 7, 1993, Cancer Research Campaign Technology Limited: "Papillomavirus L2 Protein".
Virology, vol. 185, 1991, pp. 625-632, Zhou, J. et al.: "Identification of the Nuclear Localization Signal of Human Papillomavirus Type 16 L1 Protein".
WO-A-93/02184, Feb. 4, 1993, The University of Queensland; CLS Limited: "Papilloma Virus Vaccine".
WO-A-94/00152, Jan. 6, 1994, Georgetown University: "Papillomavirus Vaccines".
WO-A-93/20844, Oct. 28, 1993, Cancer Research Campaign Technology Ltd.: "Papillomavirus E7 Protein".
WO-A-93/02184, Feb. 4, 1993, The University of Queensland; CLS Limited: "Papilloma Virus Vaccine".
Gissmann Lutz
Muller Martin
Painstil Jeanette
Zhou Jian
Eisenschenk Frank C.
Loyola University of Chicago
Salimi Ali R.
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