Multi-epitope TARP peptide vaccine and uses thereof
Inventors
Wood, Lauren V. • Berzofsky, Jay A. • Roberson, Brenda D. • Terabe, Masaki
Assignees
US Department of Health and Human Services
Publication Number
US-10286050-B2
Publication Date
2019-05-14
Expiration Date
2034-12-12
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Abstract
Immunogenic T cell receptor γ alternate reading frame protein (TARP) peptide compositions that include multiple epitopes of the TARP protein are described. The disclosed compositions can be used for the treatment of TARP-expressing cancers, such as prostate cancer, breast cancer and mesothelioma. In some embodiments, the TARP peptide compositions disclosed herein include sets of overlapping TARP peptides that each have a length of about 15 to about 25 amino acids, and comprise about 5 to about 15 amino acids that are identical to at least another overlapping peptide in the set. In particular examples, the combination of the overlapping TARP peptides in the set encompasses the complete amino acid sequence of human TARP. The multi-epitope peptide compositions described herein include both CD4 and CD8 epitopes, a feature that is important for eliciting CD4+ T cell and CD8+ T cell, as well as humoral, immune responses.
Core Innovation
The invention provides compositions comprising immunogenic T cell receptor γ alternate reading frame protein (TARP) peptides that include multiple overlapping epitopes of the TARP protein. These compositions are designed to elicit immune responses, including CD4+ T cell, CD8+ T cell, and humoral responses, against TARP-expressing cells, especially tumor cells. The overlapping peptides are between 15 and 25 amino acids in length and share 5 to 15 identical consecutive amino acids with other peptides in the set, collectively encompassing the complete 58 amino acid human TARP protein.
The compositions can include combinations of three to seven overlapping TARP peptides, with examples comprising five overlapping peptides spanning the entire TARP sequence. These peptides may be delivered alone, in combination with antigen presenting cells (APCs) such as dendritic cells loaded with the peptides, or with pharmaceutically acceptable carriers and/or adjuvants. Methods for eliciting immune responses and for treating subjects with TARP-expressing cancers, including prostate cancer, breast cancer, and mesothelioma, by administering therapeutically effective amounts of these compositions are also provided.
The problem addressed is that prior cancer vaccines using tumor-associated antigens often elicit suboptimal and short-lived CD8+ T cell responses due to lack of specific T-cell help, which is partially caused by vaccination strategies restricted to MHC class I peptides that may induce tolerance instead of tumor immunity. Limited peptide usage in vaccines also permits immune escape by tumors. The invention overcomes these limitations by employing multi-epitope overlapping synthetic peptides that include both CD4+ and CD8+ T cell epitopes, thus enhancing helper T cell activation and broader immune responses, and by covering the entire TARP protein sequence to circumvent HLA restriction and reduce immune escape.
Claims Coverage
The patent comprises one independent composition claim and one independent method claim, featuring multiple inventive aspects of multi-epitope TARP peptide compositions and their therapeutic use in treating TARP-expressing cancers.
Composition comprising five non-identical overlapping TARP peptides
The composition includes exactly five overlapping TARP peptides, specifically SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9, covering the entire TARP protein sequence.
Inclusion of additional TARP peptides to enhance composition
The composition further comprises the TARP peptides consisting of SEQ ID NO: 3 and SEQ ID NO: 4, which are 9-mer peptides binding to HLA-A*0201, enhancing immunogenicity.
Composition optionally comprising a pharmaceutically acceptable carrier or adjuvant
The vaccine formulations may include pharmaceutically acceptable carriers and/or adjuvants to improve delivery and immune response.
Incorporation of antigen presenting cells loaded with TARP peptides
The compositions can include APCs, such as dendritic cells, loaded with the TARP peptides to enhance antigen presentation and immune activation.
Unit dose and formulation of composition
The composition may be presented in unit dose form, including as a lyophilized powder for administration.
Method of treating prostate or breast cancer with the TARP peptide composition
Therapeutic administration of a composition comprising the five overlapping TARP peptides to a subject with TARP-expressing prostate or breast cancer, thus treating the subject.
Method using APCs loaded with TARP peptides for treatment
Treatment method involving administration of APCs, specifically dendritic cells, loaded with TARP peptides, including autologous cells, within a therapeutically effective viable cell count range (1×10^6 to 30×10^6).
Administration routes for therapeutic method
The composition can be administered intradermally, intravenously, intramuscularly, or subcutaneously for therapeutic effect.
The patent claims cover compositions comprising a full set of overlapping TARP peptides, optionally including additional immunogenic peptides, formulated with carriers, adjuvants, and antigen presenting cells, as well as therapeutic methods using these compositions or peptide-loaded APCs to treat TARP-expressing cancers such as prostate and breast cancer, with various administration routes specified.
Stated Advantages
Coverage of the entire TARP protein sequence by overlapping peptides enables induction of a multivalent immune response without HLA restriction.
Inclusion of CD4+ T cell helper epitopes in longer overlapping peptides enhances CD8+ T cell responses with improved functional avidity and longevity as well as humoral immune responses.
Use of synthetic long peptides processed by professional antigen presenting cells avoids tolerance and induces broader T cell responses, minimizing immune escape.
Documented Applications
Treatment of TARP-expressing cancers such as prostate cancer, breast cancer, and mesothelioma using multi-epitope overlapping TARP peptide vaccines.
Generating immune responses, including CD4+ and CD8+ T cell and humoral responses, in subjects against TARP-expressing tumor cells.
Administration of peptide-loaded antigen presenting cells, such as dendritic cells, for boosting antitumor immunity.
Use in clinical trials for Stage D0 prostate cancer involving multi-epitope TARP peptide dendritic cell vaccination.
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