Minigene

a technology of minigene and adipose tissue, applied in the field of minigene, can solve the problem of elusive provision of optimal minigenes that maximize epitope-specific immune responses

Inactive Publication Date: 2011-07-28
MSD ITAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Despite extensive studies with the above minigenes, and the use of other strategies, the p...

Method used

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Examples

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example 1

Epitope Identification by EI Suite

[0130]In order to identify epitope candidates that may elicit maximum tumor-specific immune response in a tolerized setting, while minimizing potential for off-target autoimmune activity, the entire CEA protein was scanned with several independent filters, using a proprietary software package called EI Suite (as described in WO 2006 / 124408). EI Suite ranks protein fragments based on binding affinity for a Class I MHC allele (in this case, HLA-A*0201), similarity to fragments of other human and murine proteins, and amenability to immunogenic enhancement.

[0131]A total of 12 HLA-A*0201-restricted peptides and peptide analogs were identified by EI Suite as having the highest potential for use in an epitope-based vaccine or for in vitro monitoring of vaccine-induced CEA-specific CTL responses. The selected CEA peptide epitopes are shown in Table 1

SEQIDPositionPeptideNO.TypeCEA.691IMIGVLVGV 1Wild typeCEA.411V10VLYGPDDPTV 2Anchor-modified analogCEA.690L2GL...

example 2

The A*0201 Binding Affinity Filter

[0132]HLA binding affinity has been shown to correlate with T-cell recognition for peptides derived from viral antigens (Sette et al. J. Immunol. 153: 5586-92 (1994)). More recently, this relationship has also been observed for tumor epitopes (Keogh et al. J. Immunol. 167: 787-796 (2001)). Selecting potential epitopes on the basis of HLA binding affinity is, therefore, an efficient alternative to large-scale epitope mapping or other T cell-dependent strategies.

[0133]Therefore, using EI Suite, the sequence of the CEA protein was scanned for peptides that were predicted to be strong binders to the HLA class I allele A*0201 (referred to as A2.1 below). A total of 1267 peptides representing all possible 9- and 10-mer frames of the 702 amino acid protein were evaluated. Each peptide was scored based on the degree of adherence to a statistical motif inferred from several publicly available epitope databases, including: SYFPEITHI (Rammensee et al. Immunoge...

example 3

Comparison of CEA Peptides with Fragments of Other Human Proteins

[0134]A vaccine containing only CEA-specific epitopes may prevent the off-target T-cell response that sometimes occurs when immune tolerance is broken to a shared antigen. The CTL-mediated destruction of melanocytes (van Elsas et al. J. Exp. Med. 190: 355-366 (1999)) and pancreatic islet β-cells (Ludewig et al. J. Exp. Med. 2000, 191: 795-804 (2000)) following immunotherapy are two examples of such off-target immune response. Moreover, CEA peptides that are also found in other proteins that are expressed in multiple normal tissues are more likely to have been presented to T-cells in a tolerizing setting Immune tolerance to such peptides may therefore be more difficult to overcome. For this reason, EI Suite was used to select, from the 150 top-scoring CEA peptides, those unique to the CEA protein.

[0135]It is known that T-cells can often recognize cognate epitopes comprising modifications at the HLA contact positions (po...

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Abstract

The present invention provides minigenes suitable as a prophylactic or therapeutic vaccine against conditions such as cancer, infectious diseases or autoimmune diseases, and pharmaceutical compositions comprising the minigene. The minigenes of the present invention comprise (a) a human tissue plasminogen signal peptide; (b) at least one T-cell epitope; and (c) an E. coli heat labile enterotoxin B subunit; wherein the at least one T-cell epitope is linked to the rest of the minigene, and to any other epitopes, by furin sensitive linkers. In some embodiments of the invention, the minigene comprises T-cell epitopes from one or more of CEA, her-2/neu and hTERT. Also provided herein are immunogenic peptide epitopes of CEA, her-2/neu and hTERT, as well as immunogenic peptide analogs, and pharmaceutical compositions and vaccines comprising one or more of said peptides and analogs for prophylaxis and/or treatment of cancer or other disorder. Methods of inducing an immune response in a patient, in addition to methods of treatment using the minigenes, immunogenic peptides, and peptide analogs disclosed herein are also provided.

Description

FIELD OF THE INVENTION[0001]The present invention relates to a minigene suitable as a prophylactic or therapeutic vaccine against conditions such as cancer, infectious diseases or autoimmune diseases, pharmaceutical compositions comprising the minigene, and the use of the minigene in therapy.BACKGROUND OF THE INVENTION[0002]It is recognised in the art (Ishioka et al, J. Immunol., 162, 3915-3925, 1999) that immunizations with minigenes containing T-cell epitopes may have several advantages compared to full-length proteins. Proteins may have unknown and potentially toxic biological activity while minigenes deliver only immunologically relevant genetic information. Immunization with a protein usually leads to an immune response that is narrowly focused on a few epitopes (Yewdell and Bennink, Annu. Rev. Immunol., 17, 51-88, 1999), while minigenes can induce significant immune response to multiple (up to 10 or more) epitopes simultaneously (Thomson et al, J. Immunol., 160, 1717-1723, 199...

Claims

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Application Information

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IPC IPC(8): A61K39/00C07K19/00A61P37/04A61P35/00A61P31/00
CPCC07K14/70503C07K2319/02C12N9/6459C07K2319/55C07K2319/50A61P31/00A61P35/00A61P37/04
Inventor LA MONICA, NICOLASCARSELLI, ELISACILIBERTO, GENNAROAURISICCHIO, LUIGIFRIDMAN, ARTHURBAGCHI, ANSUMAN
Owner MSD ITAL
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