Antifugetactic agents for the treatment of brain cancers

a brain cancer and anti-cancer technology, applied in the field of anti-cancer agents for brain cancer, to achieve the effect of increasing immune cell migration, inhibiting immune cell-specific fugetactic activity, and increasing immune cell migration

Inactive Publication Date: 2016-06-16
THE GENERAL HOSPITAL CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent describes a group of compounds called fugetactic agents that prevent the action of chemokines, which are also known as chemoattractants. These agents can inhibit the dimerization of chemokines and their receptors, which can cause a negative signal in cells. By blocking this negative signal, the agents can increase the movement of immune cells towards tumors and help fight cancer. The patent also describes a method for using these agents to enhance the immune response to tumors.

Problems solved by technology

For example, the anti-fugetactic compound can interfere with fugetactic ligand activity or receptor binding, thereby allowing the receptor to receive chemoattractant signals.

Method used

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  • Antifugetactic agents for the treatment of brain cancers
  • Antifugetactic agents for the treatment of brain cancers
  • Antifugetactic agents for the treatment of brain cancers

Examples

Experimental program
Comparison scheme
Effect test

example i

Anti-Fugetactic Agents Decrease Immune Evasion by Melanomas

[0127]T-cells are repelled by SDF-1 by a concentration-dependent and CXCR4 receptor-mediated mechanism. Repulsion of tumor antigen-specific T-cells from a tumor expressing SDF-1 allows the tumor cells to evade immune control. As shown herein, anti-fugetactic agents restore immune defenses against tumors.

I. Materials and Methods

[0128]A. C57B1 / 6 and OT-I Mice

[0129]C57B1 / 6 mice between 6 and 10 weeks old were used in all experiments (Jackson Laboratory, Bar Harbor, Me.). The OT-ITCR transgenic mice were kindly provided by W. R. Heath and F. Carbone (Walter and Eliza Hall Institute, Melbourne, Australia). The OT-I TCR is expressed on CD8+ T cells and is specific for the peptide OVA257-264 (SIINFEKL) bound to the class I MHC molecule H2-Kb (Hogquist, K. A., et al. 1994 Cell 76:17-2).

[0130]B. Cell Lines and Preparation of OT-I CTLs

[0131]B16 melanoma cells (H2b) stably expressing chicken OVA (B16 / OVA.pc) were provided by Drs. E. Lo...

example ii

Emigration of CD4 Cells from the Fetal Thymus is Abrogated by the Anti-fugetactic, CXCR4Antagonist AMD3100

[0216]Developing thymocytes undergo maturation whilst migrating through the thymus and, ultimately, emigrate from the thymus to populate peripheral lymphoid organs. The process of thymic emigration is controlled in part by the receptor / ligand interaction between SDF-1 and its cognate receptor CXCR-4. The precise mechanism by which CXCR4 / SDF-1 contributes to thymic emigration has now been determined to be regulated by a CXCR4-dependent fugetactic signal that can be abrogated by the anti-fugetactic agent AMD3100.

I. Materials and Methods

[0217]A. Mice

[0218]E15.5 CXCR4− / − embryos were generated by breeding CXCR4-deficient heterozygous mice on a C57BL / 6 background. Presence of the vaginal plug was considered to represent gestational day 0.5. Mice and embryos were genotyped as previously described (Ma, Q., et al. 1998. Proc Natl Acad Sci USA 95:9448; Ma, Q., et al. 1999. Immunity 10:46...

example iii

Protein Kinase C Inhibitors have Anti-Fugetactic Effects on Neutrophils

[0228]Neutrophil chemotaxis can serve as a prototype for understanding higher eukaryotic cell migration and gradient sensing (Iijima, M., et al. 2002. Dev Cell 3:469-78; Parent, C. A., et al. 1999. Science 284:765-70). It is well established that neutrophils undergo chemoattraction, or persistently directionally biased movement towards a number of chemokinetic agents elaborated at sites of tissue injury, including the chemokine IL-8 (Baggiolini, M., et al. 1992. FEBS Lett 307: 97-101; Rot, A. 1993. Eur J Immunol 23:303-6; Luster, A. D. 1998. N Engl J Med 338:436-45). It has now been determined that neutrophil fugetaxis can be abrogated by anti-fugetactic Protein Kinase C inhibitors such as GF109203X.

I. Materials and Methods

[0229]A. Neutrophil Isolation

[0230]Human whole blood was obtained from healthy volunteers by venipuncture into tubes containing sodium heparin (Becton Dickinson, San Jose, Calif.). Neutrophils ...

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Abstract

This invention provides methods and compositions for modulating movement of eukaryotic cells with migratory capacity. More specifically, the invention provides antifugetactic agents and methods for the use thereof in enhancing an immune response.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a Continuation application of U.S. Ser. No. 11 / 667,410, filed Apr. 11, 2008, which is the U.S. National Phase Application, pursuant to 35 U.S.C. §371, of PCT International Patent Application No. PCT / US2005 / 040218, filed Nov. 4, 2005, which claims priority to U.S. Provisional Patent Application No. 60 / 625,733, filed Nov. 5, 2004. The entire contents of the aforementioned patent applications are incorporated by reference in their entirety herein.STATEMENT OF GOVERNMENTAL INTEREST[0002]This work was funded in part by grant number NHLBI-44851 from the National Institutes of Health. Accordingly, the United States Government may have certain rights to this invention.BACKGROUND OF THE INVENTION[0003]Cell movement in response to specific stimuli is observed to occur in prokaryotes and eukaryotes (Doetsch R N and Seymour W F., 1970; Bailey G B et al., 1985). Cell movement seen in these organisms has been classified into three t...

Claims

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Application Information

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Patent Type & AuthorityApplications(United States)
IPC IPC(8): A61K31/395A61K31/337A61K33/24A61K33/243
CPCA61K31/395A61K31/337A61K33/24A61K38/19C07K16/2866A61K31/00G01N2333/726G01N2500/02A61K31/33A61P31/04A61P35/00A61P35/02A61P37/04A61K33/243
InventorPOZNANSKY, MARK C.POTTS, JR., JOHN T.VIANELLO, FABRIZIOPAPETA, NATALIA
OwnerTHE GENERAL HOSPITAL CORP