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Compounds and Methods Useful for Detection and Treatment of Cancer

a technology of frameshift peptides and compounds, applied in the field of compounds and methods useful for cancer detection and treatment, can solve the problems of inability to achieve the failure of promising immune responses directed against frameshift peptides in tumor tissues in a not yet determined number, and the inability to achieve vaccine therapy for cancer mediated by frameshift peptides. the approach to the use of cancer vaccination therapy may be limited

Inactive Publication Date: 2019-08-29
ROCHE MTM LAB AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent is about compounds and methods for detecting and treating disorders associated with frameshift mutations in coding microsatellite regions. These mutations can lead to the expression of new peptide sequences in tumor cells, which can be used as detection markers for disorders and also elicit a specific cellular immune response that can be used for prevention and therapy of cancers. The patent describes the use of compounds that target these frameshift peptides for immunotherapy, which involves the use of cytotoxic T lymphocytes or FS8-specific antibodies to specifically attack and eliminate tumor cells. The patent also discusses the identification of genes containing coding microsatellites that show mutations with certain frequencies in sporadic tumors and the use of these mutations for diagnosis and therapy of cancers.

Problems solved by technology

The accumulation of genetic alterations and resulting mutant proteins represent a major obstacle for tumor cells to escape immune surveillance.
As a consequence the promising therapies based on immune response directed against frameshift peptides in tumor tissues may fail in a not yet determined number of cases of tumors.
So the approaches for the use of the vaccination therapy of cancer mediated by frameshift peptides might be limited by the fact, that the potential immunogenic frameshift peptides are not always detectable by the immune system due to mutations in the antigen presenting and processing properties of the cancer cells.
Even supposed, that during specific stages of tumor development cells express the aberrant proteins and thus are vulnerable to the immune surveillance, there potentially remains a population of tumor cells, that is not eliminated by the therapy.
This state is quite undesirable for any therapy of cancers, for the remaining cells may continue growing and thus the tumor is not eliminated from the organism.
Thus it was suspected, that components of the immune system directed against novel peptides, characteristic for e.g. tumor cells, are not suitable for the detection of the disorders especially in the case of frameshift mutation peptides.
This is due to the fact, that MSI disorders are frequently associated with DNA mismatch repair deficiency and thus are especially prone to mutations.

Method used

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  • Compounds and Methods Useful for Detection and Treatment of Cancer
  • Compounds and Methods Useful for Detection and Treatment of Cancer
  • Compounds and Methods Useful for Detection and Treatment of Cancer

Examples

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example 1

Analysis of The Mutation Frequency of Genes Harbouring Repeat Tracts

[0136]Investigations were performed regarding the mutation frequencies of unpublished coding microsatellite regions. Nine novel coding microsatellites residing in genes not yet analyzed for frameshift mutations in MSI colorectal, endometrial or gastric tumors have been examined in the course of the studies leading to the present invention. They include three genes containing Al 1 repeats (TAF1B, MACS, HT001), five genes with A10 repeats (CHD2, UVRAG, TCF6L1, ABCF1, AIM2) and one gene harboring a G9 repeat (ELAVL3). The MSI status of these specimen was determined using the NCI ICG-HNPCC microsatellite reference marker panel (8). PCR reactions were performed as follows:

[0137]Genomic DNA was isolated from 5-8 haematoxylin and eosin stained 5 μm sections after microdissection, using the Qiamp Tissue Kit (Qiagen, Hilden, Germany). Preparation of DNA from cell lines was performed according to standard protocols. PCR prime...

example 2

Detection of the Expression of Frameshift Mutated mRNA From Genes Harbouring Coding Microsatellite Regions Using PCR

[0140]Samples of colon, gastric and endometrial carcinomas are used to determine the expression of mRNA showing frameshift mutations in coding microsatellite regions using PCR and subsequent sequencing of the amplified nucleic acid products.

[0141]Tumors are collected, snap frozen, and stored at −80° C. They are verified to be composed predominantly of neoplastic cells by histopathological analysis. mRNA is isolated from tumors using Qiagen reagents (Qiagen, Hilden, Germany), and single-stranded cDNA is synthesized using Superscript II (Life Technologies, Inc.).

[0142]PCR reactions were performed in a total volume of 25 μI containing 50 ng cDNA, 2.5 μl 10× reaction buffer (Life Technologies, Karlsruhe, Germany), 1.5 mM MgCl2, 200 μM dNTPs, 0.3 μM of each primer, and 0.5 U Taq DNA polymerase (Life Technologies) and using the following conditions: initial denaturation at 9...

example 3

Stimulation of Cellular Immune Response by Frameshift Peptides

[0145]The present experiments were performed in order to determine, whether the frameshift peptides arising from mutations in coding microsatellite regions according to the present invention are suited to stimulate a cellular immune response. The experiments were performed as follows:

[0146]Peptides displaying HLA-A2.1-binding motifs were selected by taking advantage of specific computer programs [(Parker, Bednarek, & Coligan 1994); bimas.dcrt.nih.gov / molbio / hla_bind / and (Rammensee et al. 1999); 134.2.96.221 / scripts / MHCServerdll / home.htm].

TABLE 3Frameshift Peptides analyzed for in vitro stimulation of a cellular immune response.All analyzed peptides (SEQ ID NOs: 75-106, as listed in Table 3 in order) arederived from (−1) mutations in microsatellites of the cognate proteins; theprotein or nucleotide accession numbers are indicated within the table; the positionof the start amino acid in the protein is indicated in the tabl...

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Abstract

The present invention relates to compounds and methods useful for the detection and treatment of disorders associated with frameshift mutations in coding microsatellite regions. The compounds and methods are applicable in cancers, especially of DNA mismatch repair deficient (MMR) sporadic tumors and HNPCC associated tumors. The compounds are useful for detection of disorders and in therapy such as immuno-therapy. The diagnostic methods relate to diagnosis and prognostic assessment of disorders associated with frameshift polypeptides originating from frameshift mutations in coding microsatellite regions of genes based on the detection of immunological entities directed against said frameshift polypeptides in body fluids. With respect to the treatment of cancer, the invention pertains to methods which use immuno therapy with combinatorial mixtures of tumor specific frameshift peptides to elicit a cytotoxic T-cell response specifically directed against tumor cells for prevention and curative treatment of cancers and pre-cancers.

Description

[0001]This application is a continuation of U.S. Ser. No. 14 / 340,467, filed Jul. 24, 2014; which is a continuation of U.S. application Ser. No. 13 / 284,660 filed Oct. 28, 2011; which is a divisional of U.S. patent application Ser. No. 10 / 511,698, filed Jun. 2, 2005, U.S. Pat. No. 8,053,552; which is a National Stage of International Application PCT / EP03 / 04083, filed Apr. 17, 2003, published Oct. 23, 2003, under PCT Article 21(2) in English; which claims the priority of EP 02008773.0, filed Apr. 18, 2002, EP 02008771.4, filed Apr. 18, 2002, and EP 02008774.8, filed Apr. 18, 2002. The contents of the above-identified applications are incorporated herein by reference in their entirety.FIELD OF THE INVENTION[0002]The present invention relates to compounds and methods useful for the detection and treatment of disorders associated with frameshift mutations in coding microsatellite regions. The compounds and methods are applicable in cancers, especially of DNA mismatch repair deficient (MMR...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): G01N33/574C07K14/47
CPCG01N33/57419A61K2039/53C07K14/47A61P37/04A61P43/00
Inventor VON KNEBEL-DOEBERITZ, MAGNUSGEBERT, JOHANNESLINNEBACHER, MICHAELWOERNER, STEFANRIDDER, RUEDIGERBORK, PEERYUAN, YAN PING
Owner ROCHE MTM LAB AG