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Interleukin-13 receptor alpha 2 peptide-based brain cancer vaccines

a technology of interleukin-13 receptor and brain cancer, which is applied in the direction of antibody medical ingredients, peptide/protein ingredients, immunological disorders, etc., can solve the problems of lack of effective treatment options, difficult treatment of brain tumors, and more difficult treatment of malignant gliomas

Inactive Publication Date: 2012-03-01
UNIVERSITY OF PITTSBURGH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0035]As used herein, the term “effective amount” refers to the amount of a therapy that is sufficient to result in the prevention of the development, recurrence, or onset of brain cancer and / or one or more symptoms thereof, to enhance or improve the prophylactic effect(s) of another therapy, reduce the severity, the duration of brain cancer, ameliorate one or more symptoms of brain cancer, prevent the advancement of brain cancer, cause regression of brain cancer, and / or enhance or improve the therapeutic effect(s) of another therapy.

Problems solved by technology

Brain tumors are particularly difficult to treat using conventional methods such as surgery, radiotherapy, or chemotherapy.
Factors such as invasive growth patterns and the blood-brain barrier make the treatment of malignant gliomas more problematic than other tumors.
The lack of effective treatment options for patients has led to the development of alternative therapies, such as immunotherapy.
However, it remains unclear how efficiently such peptide-based vaccines can induce specific CTLs and whether peptide-analogues can be used for optimal expansion and activation of IL-13Rα2 specific HLA-A2-restricted CTL.

Method used

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  • Interleukin-13 receptor alpha 2 peptide-based brain cancer vaccines
  • Interleukin-13 receptor alpha 2 peptide-based brain cancer vaccines
  • Interleukin-13 receptor alpha 2 peptide-based brain cancer vaccines

Examples

Experimental program
Comparison scheme
Effect test

example 1

7.1 Example 1

[0227]This example demonstrates the identification of modified peptides for IL-13Rα2345-353 that enhance induction of the CTL response against native IL-13Rα2345-353.

[0228]Three modified peptides were synthesized as listed in Table 1. The binding capability of these modified peptides was assessed using an HLA-A2 transfected T2 cell line. Aliquots of T2 cells were incubated with modified peptides or IL-13Rα2345-353 at 1 nM overnight, and then examined for the surface expression levels of HLA-A2 on T2 cells by flow cytometry. Since stable binding of HLA-A2 with peptide epitopes further stabilizes the surface expression of HLA-A2 (Francini et al., 2002; Alves et al., 2003), quantitative expression levels of HLA-A2, which is indicated by Mean Fluorescence Intensity (MFI) in Table 1, correlate with the binding affinity of the peptide-epitopes that are co-incubated with the T2 cells. The modified peptides V9 and A1V9 possess higher binging affinity to HLA-A2 than the native I...

example 2

7.2 Example 2

[0229]This example demonstrates that CTL induced by the agonist analogue V9 recognized peptide IL-13Rα2345-353 presented on HLA-A*0201 more efficiently than CTL induced by the wild type peptide.

[0230]Dendritic cells (DCs) derived from HLA-A*0201+ glioma patients were pulsed with either V9, A1V9, E1V9, a control influenza (flu), or the wild type peptide (10 μg / ml), and used to stimulate autologous CD8+ T cells. On day 7, the individual responder cell cultures were then restimulated once with autologous DCs loaded with the corresponding peptide used in the primary stimulation. Specific CTL activity of the induced T cell lines was first tested with T2 cells loaded with the wild type IL-13Rα2345-353, or no peptide on day 10.

[0231]As depicted in FIG. 1, the T cells that had been stimulated with either wild type (IL-13R) or agonist analogues (V9, A1V9 and E1V9) efficiently lysed T2 target cells pulsed with 100 ng / ml wild type IL-13Rα2345-353; whereas only low background lysis...

example 3

7.3 Example 3

[0233]This example demonstrates that CTL induced by modified peptides lysed HLA-A2+ glioma cells that express IL-13Rα2 more efficiently than CTL induced by the native peptide.

[0234]The ability of modified peptides, such as IL-13Rα2-V9, to enhance the CTL activity against HLA-A2+ human glioma cells that endogenously expressed and presented IL-13Rα2-derived epitopes was examined. Human glioma cell lines U251 and SNB19 express HLA-A2 and IL-13Rα2, whereas human glioma cell line A172 expresses IL-13Rα2 but not HLA-A2 (Okano et al., 2002). Therefore, U251 and SNB 19 were used as relevant target glioma cells, while A172 served as a negative control line to demonstrate HLA-A2-restriction of the response.

[0235]The lytic ability of the peptide-induced CTL lines against these glioma cells was examined using 4-hr 51Cr-release assays. As illustrated in FIG. 3, the U-251 and SNB19 cell lines were highly susceptible to cytotoxic activity of all the CTL lines that had been induced wit...

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Abstract

Provided herein are interleukin-13 receptor α2 peptide-based brain cancer vaccines and methods for treating and vaccinating against brain cancer comprising administering to patients in need thereof interleukin-13 receptor α2 peptide-based brain cancer vaccines. Also provided herein are regimens comprising interleukin-13 receptor α2 peptides and at least one additional peptide and / or immunostimulant.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This patent application is a continuation-in-part of copending U.S. patent application Ser. No. 12 / 561,973, filed Sep. 17, 2009, which is a continuation of U.S. patent application Ser. No. 11 / 231,618, filed Sep. 21, 2005, which issued as U.S. Pat. No. 7,612,162 and which claims the benefit of U.S. Provisional Patent Application No. 60 / 611,797, filed Sep. 21, 2004. This patent application also claims the benefit of U.S. Provisional Patent Application No. 61 / 376,582, filed Aug. 24, 2010. Each of these applications is incorporated herein by reference.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT[0002]This invention was made with Government support under Grant Numbers NS40923 and CA117152 awarded by the National Institutes of Health. The Government has certain rights in this invention.INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY[0003]Incorporated by reference in its entirety herein is a computer-readable ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/17A61P35/00A61K39/00
CPCA61K9/0019A61K38/17A61K38/1709C07K14/4703C07K14/4705C07K14/705A61K38/2086C07K14/7155A61K38/177A61K2300/00A61P25/00A61P35/00A61P37/04A61P43/00A61K39/4615A61K39/46432A61K2239/47A61K39/4622A61K39/001153A61K39/001192A61K39/001119A61K39/001122A61K39/00115A61K2039/572A61K2039/70A61K39/39A61K2039/5154A61K2039/55566A61K2039/55583
Inventor OKADA, HIDEHO
Owner UNIVERSITY OF PITTSBURGH
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