Polyplex of double-stranded RNA and polymeric conjugate

Inventors

Levitzki, Alex • Joubran, Salim • Shir, Alexei • Zigler, Maya • Talhami, Alaa • LANGUT, Yael

Assignees

Targimmune Therapeutics AG

Abstract

A polyplex of a double stranded RNA (dsRNA) and a polymeric conjugate consists of a linear polyethyleneimine (PEI) covalently linked to one or more polyethylene glycol (PEG) moieties. Each PEG moiety is conjugated via a linker to a targeting moiety capable of binding to a cancer antigen. Exemplary cancer antigens include epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2) and prostate surface membrane antigen (PSMA).

Core Innovation

The invention describes a polyplex of polyinosinic-polycytidylic acid double stranded RNA (poly I:C) and a polymeric conjugate consisting of linear polyethyleneimine (LPEI) covalently linked to one or more polyethylene glycol (PEG) moieties, where each PEG moiety is conjugated via a linker to a targeting moiety capable of binding to a cancer antigen. The polymeric conjugate is further defined as a diconjugate of the formula (i)-(viii), with m and n being 51 or greater in one described scope.

The targeted polyplex is configured so that PEGylation level and the resulting physicochemical properties alter targeted nucleic-acid delivery and nuclease protection. The properties include particle size, zeta potential, and shape heterogeneity, and the nuclease protection is described with DNase I protection. Embodiments include specified dsRNA strand-length ranges together with defined LPEI and PEG sizes and named targeting moieties that bind cancer antigens.

The disclosed linker chemistry connects the PEG moiety to the cancer-antigen targeting moiety through specified bond types, including —S—S—, NH—CO—, —CO—NH—, —S—C—, O—CO—, —CO—O—, or urea (—NH—CO—NH), and peptide moieties having sequences identified as SEQ ID NO: 2 or SEQ ID NO: 3. The targeting moieties include examples such as EGFR, HER2, PSMA, hEGF, and a DUPA residue, and the disclosed polymeric conjugate structures include exemplary named complexes such as LPEI-PEG2k-HER2 and related diconjugate and tri-conjugate architectures.

Claims Coverage

The independent claims cover polyplexes made from poly I:C dsRNA and an LPEI-PEG polymeric conjugate conjugated to a cancer-antigen targeting moiety, with added limitations in linker type, targeting moiety identity, and dsRNA strand length. The inventive features across the independent claims total 4 independent claim scopes.

Across the independent claims, coverage centers on a targeted poly I:C dsRNA polyplex built from covalently linked LPEI-PEG conjugates, with PEG linked to a cancer-antigen targeting moiety. The principal claim-specific inventive features further narrow the scope by defining a diconjugate architecture, specifying peptide linker sequences and allowed bond types, specifying hEGF targeting with a defined linker connection and parameter ranges, and specifying DUPA residue targeting with a defined conjugate formula and dsRNA strand length.

Stated Advantages

Documented Applications