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Apoe peptide dimers and uses thereof

a technology of apoe peptide and dimers, which is applied in the direction of peptide sources, metabolic disorders, extracellular fluid disorders, etc., can solve the problems of limited efficacy, adverse side effects or limited effects, and the efficacy of surgical removal of tumors from cancerous tissue is often limited, so as to increase the potency and increase the biological activity of the compound

Inactive Publication Date: 2013-01-03
CORNERSTONE BIOSCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes a treatment for breast cancer using a combination of two drugs, COG4-49 and MDA-MB-231. The treatment was effective in reducing the growth of tumors in mice with triple negative breast cancer. The treatment was given either subcutaneously or through the tail vein, and the results showed a significant reduction in tumor size compared to control groups.

Problems solved by technology

Although these treatment methods have been successful in some cases, they are hindered by adverse side effects or limited efficacy.
For example, the efficacy of eliminating cancerous tissue by surgical removal of tumors is often limited by the tendency of cancers to invade adjacent tissue and metastasize to other sites in the body.
Chemotherapy, as well as radiation treatment, is often limited by toxicity or damage to other tissues in the body.

Method used

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  • Apoe peptide dimers and uses thereof
  • Apoe peptide dimers and uses thereof
  • Apoe peptide dimers and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

The Cytotoxic Activity of ApoE Peptides is Enhanced by Formation of Disulfide Dimers

[0099]We have previously shown that the addition of a protein transduction domain (PTD), such as an antennapedia peptide, to the apoE-mimetic COG133 peptide (LRVRLASHLRKLRKRLL (SEQ ID NO: 3)) enhances its anti-inflammatory activity. A series of fusion peptides with COG133 conjugated to a PTD were prepared by chemical synthesis. Notably, we found that COG112 with the sequence RQIKIWFQNRRMKWKKCLRVRLASHLRKLRKRLL (SEQ ID NO: 1), was effective in suppressing production of NO, TNFα and IL-6 with IC50s of 21 nM, 58 nM, and 12 nM, respectively, in BV2 cells following stimulation with LPS (FIG. 1). These results demonstrate a significant safety window for COG112 where effective suppression occurs at concentrations of 12-58 nM while the LD50 is >120-fold higher at 7 μM.

[0100]During the course of testing various compounds for cytotoxicity against CLL cells, we found that COG112 had an ED50 of 220 nM. These data...

example 2

Non-Reducible COG112 Dimer Peptides Activate PP2A and are Cytotoxic to Cancer Cells

[0104]After discovery that COG112 was active as a disulfide-linked dimer, we sought a method to stabilize the dimer state of COG112. We initially treated the reduced COG112 peptide with a 5-fold molar excess of bismaleimidoethane (BMOE) in dilute solution. The peptide was precipitated by addition of ether, collected by filtration, and the unreacted BMOE removed by washing prior to drying under vacuum. The BMOE-linked peptide was dissolved in buffer and mixed with a 1.5-2.0 molar excess of freshly reduced COG112. Coupling was monitored by HPLC until the reaction was complete and the resultant peptide-BMOE-linker-peptide dimer was precipitated with ether, collected, washed, and purified by reverse phase HPLC to a purity of 98%. The identity of this peptide (known as COG449) was confirmed by MS and was assayed in the BV2 NO release assay. As shown in FIG. 3, we observed an IC50 of 9.4 nM for nitric oxide...

example 3

Creation of an ApoE Peptide Dimer Library

[0112]Based on the results demonstrated in Examples 1 and 2 that dimers of ApoE peptides are more potent in inducing cytotoxicity of cancer cells and activating PP2A, twenty eight different monomer ApoE peptides are synthesized that can be coupled with two different coupling chemistries to create a dimer library of sixty four unique compounds. The goal of this Example is to establish a library of chemically stable peptide dimers designed to explore the structure activity relationship between apoE-mimetic peptides and cytotoxicity for CLL cells. Our initial screens with COG peptides were limited to a single dimer peptide, COG112, which has the sequence Ac-RQIKIWFQNRRMKWKKCLRVRLASHLRKLRKRLL-amide (SEQ ID NO: 1) that contained a disulfide bridge through the cysteine at position 17. This peptide has an antennapedia-derived PTD domain at the N-terminal end and an apoE-mimetic domain in the C-terminal portion such that the dimerized peptide contain...

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Abstract

The present invention provides novel pharmaceutical compositions comprising ApoE-derived peptide dimers. In particular, the ApoE peptide dimers of the invention comprise at least two ApoE mimetic domains and can comprise one or more protein transduction domains. Methods of treating various conditions, such as cancer, inflammatory conditions, and neurodegenerative diseases, by administering the pharmaceutical compositions of the invention are also disclosed.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 292,668, filed Jan. 6, 2010, which is herein incorporated by reference in its entirety.DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY[0002]The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: COGO—022—01WO_SeqList_ST25.txt, date recorded: Jan. 6, 2011, file size 40 kilobytes).FIELD OF THE INVENTION[0003]The present invention relates to pharmaceutical compositions comprising peptide dimers derived from apolipoprotein E (ApoE). The present invention also relates to methods of treating various disease states, such as cancer and neurodegenerative diseases, with the novel compositions.BACKGROUND OF THE INVENTION[0004]Cancer is a class of diseases in which a group of cells exhibit uncontrolled growth, invasion and destruction of adj...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/17A61P35/00A61P25/00A61P25/28A61P9/10A61P35/02A61P25/16A61P25/18A61P29/00A61P17/06A61P1/00A61P1/04C07K14/775A61P7/10
CPCC07K14/775A61K38/00A61K38/1709A61P1/00A61P1/04A61P7/10A61P9/10A61P17/06A61P25/00A61P25/16A61P25/18A61P25/28A61P29/00A61P35/00A61P35/02A61K47/64
Inventor VITEK, MICHAEL P.CHRISTENSEN, DALE J.
Owner CORNERSTONE BIOSCI INC
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