Human papillomavirus / Ii-Key hybrids and methods of use
Inventors
Assignees
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Publication Number
US-8748130-B2
Publication Date
2014-06-10
Expiration Date
Abstract
The present invention is directed towards compositions comprising Ii-Key/HPV hybrid peptides. The hybrid peptides of the present invention are effective in the generation of CD4+ helper T cell immune responses directed towards the specific HPV epitopes encoded in the hybrid peptide. The inclusion of the Ii-key peptide in the hybrid causes the peptide to have greater immunogenicity as compared to control peptide. The inclusion of Ii-Key/HPV hybrid in a peptide vaccine formulation composing both HPV hybrid and HPV CTL epitope peptide (administered concurrently or sequentially) leads to a greater CTL activity against HPV CTL epitopes. The hybrid peptides of the present invention may be useful, for example, for the immunization of subjects against HPV.
Core Innovation
The invention relates to Ii-key/HPV16 E7 hybrid peptide compositions and compositions comprising nucleic acid encoding an Ii-key/HPV16E7 hybrid peptide. The hybrid peptide is selected from HPV2 represented by SEQ ID NO: 4, HPV3 represented by SEQ ID NO: 5, and HPV4 represented by SEQ ID NO: 6. The compositions are administered to stimulate an immune reaction in a subject.
The compositions enhance antigen-specific CD4+ helper T-cell responses and thereby boost CTL responses against HPV CTL epitopes. The Ii-key interaction with MHC class II bypasses normal processing and supports enhanced T helper activity and subsequent CTL activity.
The hybrid architecture links Ii-key residues LRMK (SEQ ID NO:11) or YRMK (SEQ ID NO:16) via spacers/linkers to HPV MHC class II epitopes, and embodiments include nucle-acid-encoded constructs. HLA-DR4 transgenic mouse results show greater than 5-fold CD4+ IFN-γ ELISPOT enhancement for HPV4 compared with an epitope-only control, together with improved binding of a hybrid to HLA-DR4+ cells.
In vivo co-immunization produces dose-dependent augmentation of co-immunized HPV CTL epitope activity by HPV4, with HPV4 described as superior to epitope-only control in in vivo CTL assays. The document also describes co-immunization and concurrent or sequential administration.
Claims Coverage
The independent claim is directed to a method of stimulating an immune reaction by administering, or causing administration of, a composition comprising an Ii-key/HPV16 E7 hybrid peptide or nucleic acid encoding that hybrid peptide. The independent claim specifies one inventive selection set consisting of three sequence-defined hybrid-peptide variants.
Administering an Ii-key/HPV16 E7 hybrid peptide or nucleic-acid-encoded hybrid peptide
A method of stimulating an immune reaction comprising administering to a subject or causing to be administered to a subject a composition comprising an Ii-key/HPV16 E7 hybrid peptide or nucleic acid encoding an Ii-key/HPV16E7 hybrid peptide.
Selected hybrid-peptide variants for HPV16 E7 hybrid peptides
The Ii-key HPV16 E7 hybrid peptide is selected from the group consisting of HPV2 represented by SEQ ID NO: 4, HPV3 represented by SEQ ID NO: 5 and HPV4 represented by SEQ ID NO: 6.
Across the independent claim scope, the core inventive structure is a method of immune stimulation using an Ii-key/HPV16 E7 hybrid peptide or nucleic acid encoding it, limited to one of three specified Ii-key hybrid sequence-defined variants.
Stated Advantages
Enhances antigen-specific CD4+ helper T-cell responses.
Boosts CTL responses against HPV CTL epitopes.
Improves CD4+ IFN-γ ELISPOT responses, described as greater than 5-fold enhancement for HPV4 versus epitope-only control.
Improves binding of a hybrid to HLA-DR4+ cells.
Augments co-immunized HPV CTL epitope activity in vivo in a dose-dependent manner.
HPV4 is described as superior to epitope-only control in in vivo CTL assays.
Documented Applications
Stimulating an immune reaction in a subject by administering Ii-key/HPV16 E7 hybrid peptide compositions or nucleic-acid-encoded Ii-key/HPV16E7 hybrid peptide compositions.
Enhancing antigen-specific CD4+ helper T-cell responses and boosting CTL responses against HPV CTL epitopes, including co-immunized HPV11 CTL epitope activity.
Use of HLA-DR4 transgenic mice to evaluate CD4+ IFN-γ ELISPOT enhancement and hybrid binding to HLA-DR4+ cells.
In vivo CTL assay evaluation in the context of co-immunization using HPV CTL epitopes augmented by HPV4 versus epitope-only control.
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