Papillomavirus L2 N-terminal peptides for the induction of broadly cross-neutralizing antibodies
Inventors
Schiller, John T. • Pastrana, Diana V. • Roden, Richard B. S. • Gambhira, Ratish • Lowy, Douglas R.
Assignees
Johns Hopkins University • US Department of Health and Human Services
Publication Number
US-9388221-B2
Publication Date
2016-07-12
Expiration Date
2026-02-01
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Abstract
The invention comprises a method for inducing broadly cross-neutralizing antibodies against cutaneous and mucosal papillomavirus types or against heterologous papillomavirus types in humans comprising administering to a human in need thereof an immunogenic peptide or protein (or polynucleotide encoding therefor), where the immunogenic peptide or protein is: (a) a peptide or protein of at least 10 amino acid residues in length having a sequence corresponding to either a sequence from the N terminal amino acids 1-200 of papillomavirus L2 protein (for cross-neutralizing antibodies against cutaneous and mucosal papillomavirus types) or a sequence from the N terminal amino acids 1-88 of papillomavirus L2 protein (for cross-neutralizing antibodies against heterologous papillomavirus types), (b) a peptide or protein of at least 10 amino acid residues in length with at least 55% identity with the sequence from (a), or (c) a peptide or protein as defined in either (a) or (b) which is conjugated or fused to a protein or peptide other than a papillomavirus L2 protein or peptide.
Core Innovation
The invention relates to a method for inducing broadly cross-neutralizing antibodies against cutaneous and mucosal papillomavirus types or against heterologous papillomavirus types in humans by administering to a human an immunogenic peptide or protein (or polynucleotide encoding the same). The immunogenic peptide or protein is characterized as having at least 10 amino acid residues corresponding to sequences from the N-terminal amino acids 1-200 or 1-88 of the papillomavirus L2 protein, or at least 55% identity with these sequences, and may be conjugated or fused to a non-L2 protein or peptide.
Human papillomaviruses cause various diseases including common warts, genital warts, and cervical cancer, with oncogenic HPV types being responsible for most cervical cancer cases. Current L1-based vaccines generate primarily type-specific neutralizing antibodies requiring multivalent formulations to cover multiple HPV types. There is a need for effective vaccination strategies yielding cross-protective antibodies against multiple HPV types with reduced complexity and expense.
Vaccination with L2 proteins or peptides can provide immunity and cross-neutralization against some genital HPV types, but neutralizing antibody titers are generally lower than those elicited by L1 VLPs. The invention solves the problem of broad protection against multiple HPV types by focusing on highly conserved cross-neutralizing epitopes located in the N-terminus of the L2 protein, specifically amino acid residues 1-88 or 1-200, which induce broadly cross-neutralizing antibodies across cutaneous and mucosal papillomavirus types including heterologous types.
Claims Coverage
The patent includes one independent claim defining a method that encompasses multiple inventive features related to inducing broadly cross-neutralizing antibodies by administering nucleic acid-expressed immunogenic peptides or proteins.
Use of N-terminal L2 protein sequence for inducing broadly cross-neutralizing antibodies
Administering to a human an immunogenically effective dose of a composition containing a polynucleotide encoding an immunogenic peptide or protein of at least 10 and up to 88 amino acids in length, with sequence corresponding to N-terminal amino acids 1-88 of papillomavirus L2 protein, to induce broadly cross-neutralizing antibodies against cutaneous and mucosal papillomavirus types.
Encoding peptides from HPV16 L2 N-terminus
The polynucleotide encodes a peptide or protein from the N-terminal amino acids 1-88 of HPV16 L2 protein to induce cross-neutralizing antibodies.
Encoding peptides within residues 17-36 of HPV16 L2
The polynucleotide encodes a peptide or protein comprising or consisting of the N-terminal amino acids 17-36 of HPV16 L2, which includes a conserved neutralizing epitope critical for neutralization.
Conjugation or fusion to non-L2 proteins or peptides
The polynucleotide encodes a peptide or protein conjugated or fused to an amino acid, protein, or peptide other than a papillomavirus L2 protein or peptide, potentially enhancing immunogenicity or delivery.
The claims cover methods of inducing broadly cross-neutralizing antibodies by administering nucleic acid sequences encoding immunogenic L2 peptides from the conserved N-terminal region, particularly amino acids 1-88 or 17-36 of HPV16 L2, including configurations conjugated or fused to other proteins or peptides, facilitating broad cross-type protection.
Stated Advantages
The BPV1 L2 1-88 region is exceptionally effective at inducing broadly cross-neutralizing antibodies to conserved epitopes shared by cutaneous and mucosal papillomavirus types, enabling broad protection.
Vaccination with the N-terminal L2 peptides yields broadly cross-neutralizing antibodies, significantly reducing the complexity and expense compared to multivalent L1 VLP vaccines.
Low titers of L2-specific neutralizing antibodies are sufficient to confer protective immunity against experimental papillomavirus challenge in animal models.
Documented Applications
Use as vaccine compositions for immunization against papillomavirus and papillomavirus-related diseases in mammals, particularly humans, to prevent or reduce papillomavirus infection.
Prophylaxis and treatment of human papillomavirus infections causing cutaneous and mucosal warts, genital warts, and cervical intraepithelial neoplasia associated with oncogenic HPV types.
Use in serological assays to detect or measure antibodies to papillomavirus L2 peptides, and immunoassays for papillomavirus detection and diagnosis.
Production of monoclonal and polyclonal antibodies for research tools, passive immunization, and therapeutic interventions.
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