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Compositions and methods for treatment of cancer

a technology of adhesion protein and peptide, which is applied in the field of animal cell adhesion protein peptidomimetics, can solve the problems of long time-consuming and laborious treatment of cancer, affecting the development of anti-adhesion therapy for the treatment of disease processes for which there is no effective treatment, and affecting the study of these processes. it can reduce the adhesion of tumor cells and reduce the metastasis of cancer

Inactive Publication Date: 2005-08-18
THE WISTAR INST OF ANATOMY & BIOLOGY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0024] In still another aspect, the invention provides a method of treating cancer in a mammal by administering an effective amount of a peptido-mimetic of a carbohydrate ligand to the mammal. The ligand is preferably a Lewis antigen. Administration of the peptido-mimetic reduces adhesion of tumor cells to endothelial cells in the mammal, thereby reducing metastasis of the cancer.

Problems solved by technology

Although recent studies suggest the importance of carbohydrate ligand-cell adhesion interactions in tumor metastasis, angiogenesis and inflammatory responses, the complex nature of the carbohydrate ligands involved has long hampered studies of these processes.
The difficult chemical or enzymatic synthesis required by these complex carbohydrate ligands and the technical complexity involved in analyzing the functional / structural interactions of these ligands with selectins at the molecular level have severely hindered the development of anti-adhesion therapeutics for treatment of these disease processes for which there is no effective treatment.

Method used

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  • Compositions and methods for treatment of cancer
  • Compositions and methods for treatment of cancer
  • Compositions and methods for treatment of cancer

Examples

Experimental program
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Effect test

example 1

Screening of a Random Peptide Library

[0091] To develop novel molecules to inhibit the adhesion of human adenocarcinoma cells to EC and, ultimately, to inhibit metastasis in vivo, peptides were derived from a 12-mer random peptide library. A diverse library of random dodecapeptides, displayed as flagellin-thioredoxin fusion proteins (FLITRX) on the surfaces of E. Coli bacterial cells, was obtained from Invitrogen (Carlsbad, Calif.) [LaVallie et al., 1993, Bio / Technology, 11:187-193]. This library enables efficient isolation of bacteria displaying peptides with affinity to immobilized antibodies or to other binding proteins. The use of this library offered advantages over phage display in which the level of expression of phage coat protein genes is low and the selected peptides are usually unconstrained molecules with many degrees of conformational freedom. Moreover, no phage infection or isolation steps are necessary using, the FLITRX fusion protein system. Such highly diverse pepti...

example 2

Protein Expression, Isolation and Sequencing

[0093] In the final selection cycle described above, the clones were tested for protein expression using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) followed by Western blotting [Towbin et al., 1979, Proc. Natl. Acad. Sci. USA 76:4350-4354] as follows. Specifically, each bacterial pellet was collected and dissolved directly in SDS-PAGE sample buffer containing SDS and P-mercaptoethanol. Proteins were separated using 12% polyacrylamide gel and transferred into nitrocellulose filters according to standard procedures. Expression of the FLITRX fusion protein-containing peptide sequences mimicking carbohydrate structures expressed by the bacterial clones was detected using one of the following monoclonal antibodies (10 pg / ml): [0094] (1) MAb BR15-6A, which is specific for the carbohydrate ligand LeY [Rodeck et al., 1987, Hybridoma 6:389-401], [0095] (2) MAb NS19-9, which is specific for the carbohydrate ligand SA-Lea [...

example 3

Competition Enzyme-Linked Immunosorbent Assay

[0102] The peptide competition / inhibition assays referred to throughout the following examples are performed as follows: Test peptides at concentrations ranging from 10 nM to 1 mM were preincubated with 100 μl of the MAb NS19-9 (5 μg / ml) diluted in 10% μ-globulin free horse serum / PBS at room temperature. Fifty μl of preincubated inhibition complex antibody-peptide is added to each well of 96-well plate and incubated at 30-37° C. for 1 hour. After 1 hour of incubation, MAb / peptide complex mixtures were transferred to wells precoated with a constant amount of neoglycoprotein containing coupled multivalent carbohydrate determinant (SA-Lea-polyacrylamide matrix (SA-LeX-PAA or LeY-PAA) (5 μg / well) and allowed to bind for 1 hour followed by blocking with 10% γ-globulin-free horse serum for 2 hours at room temperature. Wells were washed with 100 μl PBS four times. Goat anti-mouse immunoglobulin G conjugated to horse radish peroxidase (Boehringe...

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Abstract

Compositions containing one or more peptido-mimetics or modified peptido-mimetics of a carbohydrate ligand of an adhesion molecule in a physiologically acceptable carrier are useful for methods of reducing metastasis in a mammal and for inhibiting inflammatory response in a mammal. Particularly useful are embodiments in which the ligand is a Lewis antigen and / or the adhesion molecule is a selectin, e.g., E-selectin. Methods are disclosed for identifying peptido-mimetics of carbohydrate ligands, which may be involved in binding of tumor cells to other cells, such as endothelial cells.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. patent application Ser. No. 09 / 831,047, filed May 3, 2001, which is a 371 of International Patent Application No. PCT / US99 / 26277, filed Nov. 5, 1999, which claims the benefit of the priority of U.S. Provisional Patent Application No. 60 / 107,478, filed Nov. 6, 1998, now abandoned.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [0002] This invention was supported in part by funds from the U.S. Government (United States Army Grant DAMD 17-96-1-6232 and NIH Grant No. A145133). The U.S. Government may therefore have certain rights in the invention.BACKGROUND OF THE INVENTION [0003] The invention relates generally to animal cell adhesion, and more specifically to peptido-mimetics of carbohydrate ligands of animal cell adhesion proteins and methods of using the same. [0004] Tumor metastasis is a multistep process requiring detachment of malignant cells from the primary tumor, penetrati...

Claims

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Application Information

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IPC IPC(8): A61K38/17
CPCA61K38/177A61K38/10A61K38/12
Inventor BLASZCZYK-THURIN, MAGDALENAKIEBER-EMMONS, THOMAS
Owner THE WISTAR INST OF ANATOMY & BIOLOGY
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