Method of treating cancer
Inventors
Levitzki, Alex • Joubran, Salim • Shir, Alexei • Zigler, Maya • Talhami, Alaa • LANGUT, Yael
Assignees
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Publication Number
US-11298376-B2
Publication Date
2022-04-12
Expiration Date
Abstract
A method of treating cancer can include administering a polyplex of a double stranded RNA and a polymeric conjugate. The polymeric conjugate can consist of a linear polyethyleneimine covalently linked to one or more polyethylene glycol (PEG) moieties. Each PEG moiety can be conjugated via a linker to a targeting moiety capable of binding to a cancer antigen.
Core Innovation
The invention provides a non-viral cancer treatment using a polyplex formed from double stranded RNA (dsRNA) and a polymeric conjugate containing linear polyethyleneimine (LPEI) and polyethylene glycol (PEG). The polymeric conjugate further includes one or more PEG moieties linked to a tumor-targeting moiety capable of binding a cancer antigen.
The polymeric conjugate is selected from specific formulas (i) through (viii), including LPEI-PEG constructs where PEG is associated with defined peptide or other linker segments and an LPEI backbone. The described targeting moieties include EGFR, HER2, PSMA, and other receptor antigens, with supported instantiations including di-/tri-conjugates such as LPEI-PEG2k-HER2 and LPEI-(PEG2k-HER2)3 as well as DUPA/PSMA-targeted variants.
PEGylation is described as altering polyplex properties, including increased size/heterogeneity and decreased zeta potential, which affects DNA protection and targeted transfection. The document reports differences in DNase I protection and presents selective gene delivery and cytotoxicity patterns in cells differing by receptor expression, with anti-tumor activity reported in cell-based and in vivo models for EGFR-, HER2-, and PSMA/DUPA-targeted poly I:C payloads.
Claims Coverage
The provided independent claim covers a method for treating selected cancers by administering a dsRNA-containing polyplex together with a PEGylated polymeric conjugate defined by specific formulas (i)-(viii) and including a targeting moiety capable of binding a cancer antigen. The claim includes at least three inventive coverage axes: (1) the cancer selection, (2) the dsRNA polyplex payload combined with a PEG-LPEI polymeric conjugate of defined formula types, and (3) targeting via a targeting moiety X.
Treatment of EGFR-overexpressing, HER2-overexpressing, or prostate cancer with a dsRNA polyplex
A method for treating a cancer selected from the group consisting of a cancer characterized by EGFR-overexpressing cells, a cancer characterized by HER2-overexpressing cells and prostate cancer, by administering to a subject a polyplex of dsRNA and a polymeric conjugate.
PEG-LPEI polymeric conjugate selected from defined formulas including a targeting moiety X
Administering a polyplex where the polymeric conjugate is selected from formulas (i)-(viii), including PEG2k-LPEI structures in which X is included in the conjugate and is a targeting moiety capable of binding a cancer antigen.
PEG-LPEI conjugate architecture with peptide-linked PEG2k-LPEI segments
Using specific formula embodiments such as X-(NH—(CH2)7—CO)-Phe-Phe-(NH—(CH2)—CH(NH2)—CO)-Asp-Cys-PEG2k-LPEI and X-(NH—(CH2)7—CO)-Phe-Gly-Trp-Trp-Gly-Cys-PEG2k-LPEI, with X being a targeting moiety.
Targeting-moiety binding to cancer antigen
Employing a targeting moiety X capable of binding to a cancer antigen, including EGFR/HER2/PSMA-specific targeting.
Across the independent claim coverage, the inventive focus is on treating EGFR-overexpressing, HER2-overexpressing, or prostate cancer by administering a dsRNA polyplex together with a PEGylated LPEI-based polymeric conjugate defined by specific formulas and incorporating a targeting moiety X capable of binding a cancer antigen.
Stated Advantages
PEGylation is described as altering polyplex properties, including increased size/heterogeneity and decreased zeta potential.
PEGylation affects DNA protection and targeted transfection.
The document reports differences in DNase I protection.
Selective gene delivery and cytotoxicity patterns are reported in cells differing by receptor expression.
Anti-tumor activity is reported in cell-based and in vivo models for EGFR-, HER2-, and PSMA/DUPA-targeted poly I:C payloads, including effects of immune-cell combinations such as T-TILs/PBMCs and bystander killing with PBMCs.
Documented Applications
Treatment of cancers characterized by EGFR-overexpressing cells.
Treatment of cancers characterized by HER2-overexpressing cells.
Treatment of prostate cancer.
Cell-based and in vivo models for EGFR-, HER2-, and PSMA/DUPA-targeted poly I:C payloads.
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