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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

AI Technical Summary

Problems solved by technology

Despite extensive studies with the above minigenes, and the use of other strategies, the provision of an optimal minigene that maximizes epitope-specific immune responses remains elusive.

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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