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EGFR-homing double-stranded rna vector for systemic cancer treatment

Inactive Publication Date: 2012-01-18
YISSUM RES DEV CO OF THE HEBREW UNIV OF JERUSALEM LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of the non-targeted PolyIC may diffuse through normal tissues into non-cancerous cells and induce toxic responses

Method used

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  • EGFR-homing double-stranded rna vector for systemic cancer treatment
  • EGFR-homing double-stranded rna vector for systemic cancer treatment
  • EGFR-homing double-stranded rna vector for systemic cancer treatment

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] Example 1. PolyIC / MPPE induces the expression of immunocompetent cytokines in A431 and MDA-MB-468 cells. Expression of IFN-α, IP-10 and Gro-α in glioblastoma cells (U87MGwtEGFR), but not in cells with low levels of EGFR (U87MG). These data support the notion that cells produce these cytokines only when a certain threshold level of dsRNA is internalized, a dose that is only reached in cells that overexpress EGFR. In this study, we extended the analysis to two additional EGFR overexpressing cancer cell lines: A431 (vulvar cancer) and MDA-MB-468 (breast cancer). When these cells were transfected with PolyIC / MPPE (2.5 μg / ml), we detected up to 5.1 pg / ml of IFN-β; 148 pg / ml of Gro-α and 188 pg / ml of IP-10 (Table 2). Gro-α and IP-10 are chemokines responsible for the recruitment of T cells to areas where they are expressed. Thus, after challenge with PolyIC / MPPE, A431 and MDA-MB-468 cells, such as U87MGwtEGFR cells, secreted cytokines into the medium.

[0093] Table 2. Cyt...

Embodiment 2

[0095] Example 2. In vitro activation of human immune cells.

[0096] Considering the above results, we hypothesized that cytokine-enriched media from A431 and MDA-MB-468 cells treated with PolyIC / MPPE would stimulate the immune system. We checked whether this was the case by testing the effect of culture medium from PolyIC-transfected cancer cells on healthy human peripheral blood mononuclear cells (PBMC). PBMCs are composed of several types of immune cells (NK, T cells, NK-T cells, macrophages). When activated, these cells produce toxic cytokines, eg, IFN-γ and TNF-α, known to be effective against various cancer cells. PBMC also interact, causing a synergistic, highly antiproliferative effect. For example, activated T cells and NK cells produce IFN-γ, which activates macrophages and stimulates TNF-α production. The release of IL-2 into the medium is directly related to PBMC activation and can be conveniently quantified by ELISA. PBMCs are thus a convenient system to stud...

Embodiment 3

[0098] Example 3. Activation of PBMCs in vivo.

[0099] Selective expression of these cytokines in tumors overexpressing EGFR was also demonstrated in vivo (Table 3). SCID-NOD mice bearing subcutaneous tumors overexpressing EGFR in the right flank and U138MG tumors in the left flank were treated intravenously with 4 consecutive daily injections of PolyIC / MPPE, and finally a single peritoneal dose of four million PBMCs Injection. Expression, at much higher concentrations, in tumors overexpressing EGFR (Table 3). These cytokines are expected to selectively attract PBMCs to EGFR-overexpressing tumors, where PBMCs will be activated.

[0100] Table 3 Cytokine expression patterns in vivo.

[0101]

[0102] We then asked whether the concentration of cytokines on vector-transfected EGFR-overexpressing tumors was high enough to actually attract and activate immune cells. In separate experiments, cells were injected s.c. into the right flank (A431 or MDA-MB-468) and left flank (U...

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Abstract

An epidermal growth factor receptor (EGFR)-homing vector comprising a double-stranded RNA (dsRNA) molecule with an EGFR-binding peptide or polypeptide, is disclosed for use in combination with immune cells for treatment of cancer overexpressing EGFR.

Description

field of invention [0001] The present invention belongs to the field of cancer therapy and relates to a carrier comprising a double-stranded RNA (dsRNA) with an EGFR-binding agent capable of directing the dsRNA specifically to cancer cells overexpressing EGFR, thereby mobilizing the immune system for for the treatment of tumors overexpressing EGFR. [0002] Abbreviations: dsRNA: double-stranded RNA; EGF: epidermal growth factor; EGFR: EGF receptor; PBMC: peripheral blood mononuclear cells; PEG: poly(ethylene glycol); PEI: polyethyleneimine; nucleotide-polycytidylic acid double-stranded RNA; pIC / MPPE: PolyIC / melitin-branched polyethyleneimine-polyethylene glycol-EGF; pIC / PPE: PolyIC / linear polyethyleneimine-polyethylene Diol-EGF; pIC / PPGE11: PolyIC / linear polyethyleneimine-polyethylene glycol-(peptide)GE11. Background of the invention [0003] Epidermal growth factor receptor (EGFR) is overexpressed in various solid human tumors, including non-small cell lung cancer, breast...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C12N15/117
CPCC12N2310/17C12N15/117A61P35/00A61P35/04A61P37/04A61P43/00
Inventor A.莱维茨基A.席尔
Owner YISSUM RES DEV CO OF THE HEBREW UNIV OF JERUSALEM LTD
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