Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1996-12-17
1999-02-02
Chambers, Jasemine C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
4353201, 4351723, 536 231, A01N 4304
Patent
active
058665536
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to the production and use of a novel pharmaceutical product: a nucleic acid which, when directly introduced into living vertebrate tissue, induces an immune response which specifically recognizes papilloma virus.
BACKGROUND OF THE INVENTION
Papilloma virus (PV) infections occur in a variety of animals, including humans, sheep, dogs, cats, rabbits, monkeys, snakes and cattle. Papilloma viruses infect epithelial cells, generally inducing benign epithelial or fibroepithelial tumors at the site of infection. Papilloma viruses are species specific infective agents; e.g., a human papillomavirus generally does not infect a nonhuman animal.
Papilloma viruses may be classified into distinct groups based on the host that they infect. Human papilloma viruses (HPV) are further classified into more than 60 types based on DNA sequence homology (for a review, see Papilloma Viruses and Human Cancer, H. Pfister (ed.), CRC Press, Inc., 1990). Papilloma virus infections appear to induce type-specific immunogenic responses in that a neutralizing immunity to infection to one type of papilloma virus may not confer immunity against another type of papilloma virus.
In humans, different HPV types cause distinct diseases. HPV types 1,2, 3, 4, 7, 10 and 26-29 cause benign warts in both normal and immunocompromised individuals. HPV types 5, 9, 9, 12, 14, 15, 17, 19-25, 36 and 46-50 cause flat lesions in immunocompromised individuals. HPV types 6, 11, 34, 39, 41-44 and 51-55 cause nonmalignant condylomata of the genital tract. HPV types 16 and 18 cause epithelial dysplasia of the genital tract and are associated with the majority of in situ and invasive carcinomas of the cervix, vagina, vulva and anal canal.
Immunological studies in animal systems have shown that the production of neutralizing antibodies to papilloma virus antigens prevents infection with the homologous virus. The development of effective human papilloma virus vaccines has been slowed by the inability to cultivate papilloma viruses in vitro. The development of an effective HPV vaccine has been particularly slowed by the absence of a suitable animal host for the direct study of HPV.
Neutralization of papilloma virus by antibodies appears to be type-specific and dependent upon conformational epitopes on the surface of the virus.
Papilloma viruses are small (50-60 nm), nonenveloped, icosahedral DNA viruses that encode for early and late genes. The open reading frames (ORFs) of the virus genomes are designated E1 to E7 and L1 and L2, where "E" denotes early and "L" denotes late. L1 and L2 encode virus capsid proteins. E1 to E3 and E5 to E7 are associated with functions such as viral replication and transformation.
The L1 protein is the major capsid protein and has a molecular weight of 55-60K. L2 protein is a minor capsid protein which has a predicted molecular weight of approximately 55K and an apparent molecular weight of 75-100K as determined by polyacrylamide gel electrophoresis. Electron microscopic and immunologic data suggest that most of the L2 protein is internal to the L1 protein. The L2 proteins are highly conserved among different papilloma viruses, especially the 10 basic amino acids at the C-terminus. The L1 ORF is highly conserved among different papilloma viruses.
The L1 and L2 genes have been used to generate recombinant proteins for potential use in the prevention and treatment of papilloma virus infections. Zhou et al. cloned HPV type 16 L1 and L2 genes into a vaccinia virus vector and infected CV-1 mammalian cells with the recombinant vector to produce virus-like particles (VLP). These studies were interpreted as establishing that the expression of both HPV type 16 L1 and L2 proteins in epithelial cells is necessary and sufficient to allow assembly of VLP. The expression of L1 protein alone or L2 protein alone or double infection of cells with single recombinant vaccinia virus vectors containing L1 and L2 genes did not produce particles.
Bacterially-derived recombinant bovine papilloma virus L1 and L2 h
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Donnelly John J.
Liu Margaret A.
Martinez Douglas
Montgomery Donna L.
Chambers Jasemine C.
Clark Deborah J. R.
Giesser Joanne M.
Merck & Co. , Inc.
Tribble Jack L.
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