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Targeted chimeric molecules for cancer therapy

A technology of chimeric molecules, targeting moieties, applied in the fields of cancer biology and pharmacy, cell biology, molecular biology

Inactive Publication Date: 2008-06-18
RES DEVMENT FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0030] Although some chimeric protein compositions have been described, there is still a need for other methods and compositions for improved therapy related to killing cells

Method used

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  • Targeted chimeric molecules for cancer therapy
  • Targeted chimeric molecules for cancer therapy
  • Targeted chimeric molecules for cancer therapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0451] Exemplary Materials and Methods for Examples 2-8

[0452] Cell Lines and Culture

[0453] Four species were cultured in Dulbecco's modified Eagle's medium (DMEM, Life Technologies Inc., Rockville, MD) supplemented with 10% heat-inactivated fetal bovine serum (FBS), 100 units / ml penicillin, and 100 μg / ml streptomycin. Human pancreatic cancer cell lines (AsPc-1, Capan-1, Capan-2 and L3.6pl).

[0454] Chemotherapeutics and scFV23 / TNF fusion constructs

[0455]5-Fluorouracil (5-FU) was purchased from Roche Laboratories (Nutley, NJ). Cisplatin and etoposide (VP-16) were purchased from Bristol Laboratories (Princeton, NJ). Doxorubicin was purchased from Cetus Corporation (Emeryville, CA). Gemcitabine was purchased from Eli Lilly Co. (Indianapolis, IN). scFv23 / TNF fusion constructs were produced in bacterial expression hosts, purified to homogeneity and evaluated for biological activity as described above (Rosenblum et al., 1995).

[0456] Antibody

[0457] Monoclonal A...

Embodiment 2

[0466] Status of HER-2 / NEU, HER-1, TNFR-1, TNFR-2 and P-AKT in four human pancreatic cancer cell lines

[0467] HER-2 / neu was previously found to be overexpressed in pancreatic tumor biopsy samples and HER-2 / neu expression was considered a marker of poor prognosis in pancreatic intraepithelial tumors (Tomaszewska et al., 1998). The expression of HER-2 / neu was determined in four pancreatic cancer cell lines. All four pancreatic cancer cell lines (AsPc-1, Capan-1, Capan-2 and L3.6pl) expressed HER-2 / neu, TNFR-1, TNFR-2 and phospho-Akt. Compared with AsPc-1 cells, L3.6pl cells expressed 3.7-fold higher levels of HER-2 / neu, 3.1-fold higher levels of TNFR-1, and 1.6-fold higher levels of TNFR-2. Three of the four pancreatic cell lines (Capan-1, Capan-2 and L3.6pl) also showed elevated baseline levels of activated Akt. Compared with AsPc-1 cells, Capan-1 cells were found to express the highest level of p-Akt (Figure 1 and Table 1).

[0468] Epidermal growth factor receptor (HER-1...

Embodiment 3

[0476] Effects of SCFV23 / TNF, TNF and chemotherapy drugs on the growth of human pancreatic cancer cell lines

[0477] The chemotherapeutics differed markedly in their ability to inhibit cell proliferation in vitro among the four cell lines tested. All pancreatic cancer cell lines were highly resistant to the cytotoxic effects of TNF (IC 50 >1600nM). IC of 5-fluorouracil, cisplatin and etoposide 50 The value is 1-300mM, while in comparison, the activities of doxorubicin, gemcitabine and scFv23 / TNF are higher, IC 50 Values ​​were 6-700 nM (Figures 2A-2D and Table 2).

[0478] Table 2: IC of various drugs against four exemplary human pancreatic cancer cell lines 50

[0479]

[0480] * highest concentration reached.

[0481] Measure the IC after 72 hours of exposure to the drug 50 value, IC 50 Values ​​are defined as the concentration causing 50% growth inhibition in treated cells compared to control cells.

[0482] Interestingly, L3.6pl cells with the highest express...

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Abstract

The present invention concerns chimeric cancer therapeutic molecules comprising a targeting moiety and an anti-cell proliferation moiety. The anti-cell proliferation moiety may comprise a cytotoxic agent or an apoptosis-inducing factor, in specific embodiments. In particular embodiments, the anti-cell proliferation mechanism of the chimeric molecules comprises apoptotic pathways. In additional embodiments, the chimeric molecules of the present invention provide sensitivity to chemotherapy in a cell that is resistant to the chemotherapy.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application Serial No. 60 / 643,337, filed January 10, 2005, which is hereby incorporated by reference in its entirety. [0003] This invention was developed at least in part with support from Department of Defense grants DAMD17-99-1-9259-3 and DAMD17-02-1-0457-1. The United States Government may have certain rights in this invention. field of invention [0004] The present invention relates to the fields of cell biology, molecular biology, cancer biology and pharmacy. More specifically, the invention relates to targeting chimeric molecules for cancer therapy, including targeting cytotoxic agents such as TNF, and targeting pro-apoptotic molecules such as granzyme B. Background of the invention [0005] High rates of cancer morbidity and mortality have fueled the need for improved therapies, not only for new cancer cases, but also for those already treated and re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48C07K16/32A61P35/00
CPCA61K47/48561A61K47/486C07K2319/00C07K2317/622A61K41/0038C07K2317/77C07K16/32C07K2317/73C07K16/30A61K47/6849A61K47/6859A61P35/00A61P43/00
Inventor M·G·罗森布拉姆A·D·埃林顿
Owner RES DEVMENT FOUND
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