Chimeric proteins for targeting dsRNA
Inventors
Levitzki, Alexander • LANGUT, Yael • Edinger, Nufar
Assignees
Targimmune Therapeutics AG • ALEX LEVITZKI MANAGEMENT AND HOLDINGS Ltd
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Publication Number
US-11230580-B2
Publication Date
2022-01-25
Expiration Date
Abstract
Described herein are recombinant chimeric proteins comprising a double stranded RNA (dsRNA) binding domain and a cancer-cell targeting domain for targeting of dsRNA to cancer cells. Methods of use of the described chimeric proteins are also provided herein.
Core Innovation
The disclosed subject matter provides recombinant proteins that combine a double stranded RNA (dsRNA) binding domain with a target-binding moiety. The dsRNA binding domain comprises one or more double-stranded RNA-binding motifs (dsRBM), and at least one dsRBM is a dsRBM of dsRNA dependent protein kinase R (PKR). The target-binding moiety is EGF.
A linker is included between the dsRNA binding domain and the EGF target-binding moiety. In particular, the linker is defined as a peptide of sequence ACSGSACSGSAGNRVRRSVGSSNG (SEQ ID NO:26). Dependent refinements further constrain the dsRNA binding domain to specific dsRNA binding domain sequences and/or human PKR-derived forms.
The disclosure further describes complexes and pharmaceutical compositions that include dsRNA cargos with the recombinant proteins. The dsRNA cargo is described as polyinosinic acid/polycytidylic acid (poly IC) and related dsRNA material, and the recombinant protein-dsRNA combinations are described for use in connection with cancers associated with EGFR.
Claims Coverage
The disclosed family centers on one independent claim covering a recombinant protein architecture that fuses a dsRNA binding domain, including a PKR-derived dsRBM, to an EGF target-binding moiety via a defined peptide linker. Dependent claim refinements further narrow the dsRNA binding domain definition, specify human EGF, and add constrained dsRNA complex embodiments.
Recombinant dsRNA-binding protein with PKR dsRBM and EGF target moiety
A recombinant protein comprises a double stranded RNA (dsRNA) binding domain and a target-binding moiety, where the target-binding moiety is EGF; the dsRNA binding domain comprises one or more dsRNA-binding motifs (dsRBM); and at least one dsRBM is a dsRBM of dsRNA dependent protein kinase R (PKR).
Peptide linker between PKR-derived dsRNA binding domain and EGF
The recombinant protein further comprises a linker between the dsRNA binding domain and the target-binding moiety, where the linker is a peptide of sequence ACSGSACSGSAGNRVRRSVGSSNG (SEQ ID NO: 26).
PKR-derived dsRNA binding domain sequence limitation
The dsRNA binding domain is specified as a dsRNA binding domain selected from human PKR-derived dsRNA binding domain sequences or full length human PKR, including embodiments characterized by an amino acid sequence corresponding to SEQ ID NO:18 and/or amino acid residues 1-197 of human PKR, and related motif/linker arrangements.
Human EGF target-binding moiety
The recombinant protein is characterized in that the EGF is human EGF.
Poly IC dsRNA cargo for recombinant protein complexes
A dsRNA recombinant-protein complex is described in which the dsRNA consists of a polyinosinic acid strand and a polycytidylic acid strand (poly IC).
Overall claim coverage defines a recombinant fusion protein architecture that links a PKR-derived dsRNA binding domain to an EGF target-binding moiety through a specific peptide linker, and it further narrows the dsRNA binding domain, constrains the EGF to human EGF, and specifies poly IC as the dsRNA cargo for recombinant protein complexes.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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