Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector
Patent
1997-12-18
1999-11-23
Eisenschenk, Chris
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
4241851, 530300, 530403, 536 2372, 930220, 935 88, A61K 3900, C07K 100, C07H 2104
Patent
active
059895489
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a peptide-based vaccine against papillomavirus infection.
BACKGROUND
The human papillomaviruses (HPVs) cause a variety of proliferative epithelial lesions, from common warts to premalignant intraepithelial neoplasias of the anogenital region (zur Hausen, 1991). Thus far, 68 different types of human papillomavirus (HPV) have been isolated (de Villiers, 1992). HPV type 16 is the predominant type found in human anogenital cancers and highgrade intraepithelial neoplasias (Lorinoz et al., 1992). The HPV capsid contains two proteins encoded by the L1 and L2 open reading frames (ORFs). The major protein of the PV capsid is an approximately 57 kDa protein encoded by L1 (Li et al., 1987); Pliacinski et al., 1984; Tomita et al., 1987). The L2 ORF codes for a 76 kDa protein which is the minor structural protein of the PV capsid (Komly et al., 1986). The HPV virion consists of an icosahedral capsid with 72 capsomeres composed of pentamers of the major capsid protein L1 (Baker et al., 1991). The function and structural location of the minor capsid protein L2 is unclear.
Neutralizing monoclonal antibodies against cottontail rabbit papillomavirus (CRPV) (Christensen & Kreider, 1991), bovine papillomavirus (BPV) (Christensen & Kreider, 1993) and HPV11 (Christensen et al., 1990) have hitherto only been generated against conformation-dependent epitopes on intact virions and it has not been possible to map their location due to the conformational dependence of these epitopes.
Immunization with an L2 protein of CRPV induces low-titered neutralizing antibodies, indicating that at least part of L2 is exposed on the virion surface (Christensen et al., 1991).
However, no specific sequences have been identified which are exposed on the virion surface of HPV. It was hypothesized that intact virions may contain surface exposed linear epitopes which could be identified by antibodies generated by immunization with peptides. A knowledge of the specific amino acid sequences of antigenic sites--exposed on intact virus particles and present in neutralizing epitopes--should enable design of effective immunogenes for vaccination.
It is well recognized that the structure of neutralizing epitopes with the ability of conferring protection is an essential requirement for the design of effective vaccines. Extensive attempts have been made to identify such neutralizing epitopes, however, without success. The problems are: 1) Immunization with an intact capsid containing conformationally sensitive epitopes may induce mostly antibodies to conformational epitopes which cannot be mapped for practical reasons. 2) Immunization with a denatured whole capsid protein will not induce antibodies against conformationally sensitive epitopes, but antibodies are preferentially made against immunodominant epitopes which are found at the inside of the capsid and these epitopes are thus not useful for vaccination.
Since it has not been possible to experimentally define the surface-exposed neutralizing epitopes, previous attempts to identify surface-exposed epitopes had to rely on computer algorithms that may identify evolutionarily variable or hydrophilic amino acid stretches which might conceivably be surface-exposed. Such algorithms have been unreliable, since they have either not worked or have only had a limited success.
DESCRIPTION OF THE INVENTION
In the experimental work, on which the present invention is based, antisera against 77 overlapping synthetic peptides from the L1 and L2 proteins of HPV16 were used to generate antipeptide antisera in guinea pigs. The resulting hyperimmune sera were tested for reactivity with intact HPV16 particles in order to identify surface-exposed epitopes. Finally, antisera against synthetic peptides from the corresponding surface-exposed sites of rabbit papillomavirus were tested for their ability to neutralize infectious rabbit papillomavirus.
A hypothesis that was made was the proposal that it should be possible to bypass the problems caused by immunodominant epitopes (either of confor
REFERENCES:
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Eisenschenk Chris
Euro-Diagnostica AB
Salimi Ali R.
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