EGFR-homing double-stranded RNA vector for systemic cancer treatment
Inventors
Levitzki, Alexander • Shir, Alexei
Assignees
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Publication Number
US-9006406-B2
Publication Date
2015-04-14
Expiration Date
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.
Core Innovation
The invention relates to EGFR-homing vectors for systemic cancer therapy that target EGFR-overexpressing tumor cells. The disclosed vectors use polyinosinic-polycytidylic acid double stranded RNA (polyIC, pIC) complexed with a PEI-PEG carrier to form EGFR-homing dsRNA vectors.
EGFR binding is provided by EGFR-binding ligands coupled to the PEI-PEG carrier complex, including EGF or GE11. The targeted polyIC is described as mobilizing and locally attracting immune cells and inducing cytokines/chemokines such as IFN-β/γ, IL-2, TNF-α, Gro-α, and IP-10.
The invention further describes enhanced bystander effects and apoptosis mediated by PBMCs in vitro, and immune-cell infiltration into EGFR+ tumors in vivo. The disclosed approach is stated to eradicate disseminated tumors in SCID-NOD mice when followed by PBMC administration.
A second-generation format is described that uses linear PEI-based vectors, including pIC/PPE and pIC/PPGE11, replacing branched PEI and, in one embodiment, using GE11 instead of mEGF. The document states improved cancer-killing efficiency and simplified production versus the first-generation pIC/MPPE while maintaining selectivity for EGFR-low/negative cells.
Claims Coverage
The partial independent claim set includes 2 independent claims. Both independent claims focus on EGFR-homing vectors used in systemic administration, selected from two specific vector formulations, namely pIC/PPE and pIC/PPGE11.
Systemic EGFR-homing pharmaceutical composition
A pharmaceutical composition for systemic administration comprising a pharmaceutically acceptable carrier and an EGFR-homing vector selected from a vector comprising polyinosinic-polycytidylic acid double stranded RNA; unbranched polyethyleneimine covalently linked to polyethylene glycol; and mEGF (pIC/PPE), and a vector comprising polyinosinic-polycytidylic acid double stranded RNA; unbranched polyethyleneimine covalently linked to polyethylene glycol; and peptide GE11 (pIC/PPGE11).
EGFR-homing vector selection
An EGFR-homing vector selected from a vector comprising polyinosinic-polycytidylic acid double stranded RNA; unbranched polyethyleneimine covalently linked to polyethylene glycol; and mEGF (pIC/PPE), and a vector comprising polyinosinic-polycytidylic acid double stranded RNA; unbranched polyethyleneimine covalently linked to polyethylene glycol; and peptide GE11 (pIC/PPGE11).
Across the independent claims, the core claim coverage is the use of polyinosinic-polycytidylic acid double stranded RNA with an unbranched polyethyleneimine covalently linked to polyethylene glycol, combined with EGFR targeting via mEGF (pIC/PPE) or peptide GE11 (pIC/PPGE11), in either a systemic pharmaceutical composition context or as an EGFR-homing vector itself.
Stated Advantages
Mobilizes and locally attracts immune cells.
Induces cytokines/chemokines such as IFN-β/γ, IL-2, TNF-α, Gro-α, and IP-10.
Enhances PBMC-mediated bystander effects and apoptosis in vitro.
Enables immune-cell infiltration into EGFR+ tumors in vivo.
Eradicates disseminated tumors in SCID-NOD mice when followed by PBMC administration.
Improved cancer-killing efficiency versus first-generation pIC/MPPE.
Simplified production versus first-generation pIC/MPPE.
Maintains selectivity for EGFR-low/negative cells.
Documented Applications
Systemic cancer therapy targeting EGFR-overexpressing tumor cells using EGFR-homing dsRNA vectors.
Treatment context described as inducing PBMC-mediated bystander effects and apoptosis in vitro and enabling immune-cell infiltration into EGFR+ tumors in vivo.
Use in a xenograft model context stated as eradication of disseminated tumors in SCID-NOD mice when followed by PBMC administration.
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