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Publication Number
US-11912747-B2
Publication Date
2024-02-27
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
A chimeric recombinant protein is disclosed that comprises a double stranded RNA (dsRNA) binding domain and a target binding moiety that binds to prostate surface membrane antigen (PSMA). The protein further comprises a spacer peptide between the dsRNA binding domain and the target binding moiety, and the target binding moiety is an antibody or antigen-binding fragment of an antibody.
The disclosure specifies dsRNA binding domain architectures that include dsRNA-binding motifs (dsRBM) and corresponding sources, including PKR, TRBP, PACT, Staufen, NFAR1, NFAR2, SPNR, RHA, and NREBP. A human PKR sequence is set forth in SEQ ID NO: 18, and the chimeric recombinant protein is also provided as a polypeptide identical to a sequence set forth as SEQ ID NO: 3.
The disclosure further provides complexes comprising the chimeric recombinant protein and dsRNA as cargo, including poly(I:C) with polyinosinic/polycytidylic strands (poly IC). Targeting to PSMA is coupled to dsRNA association, and the disclosure describes PSMA-selective binding and internalization in cell assays, as well as induced apoptosis and cytokine induction, including caspase-3 and PARP cleavage and cytokines including IP-10, RANTES, and IFN-β.
The disclosure also describes direct and immune-mediated bystander effects in prostate cancer cell models and tumor spheroid models, including enhanced destruction in the presence of PBMCs.
Claims Coverage
The partial content identifies one independent claim (clm-00001). The independent claim covers one inventive feature: a chimeric recombinant protein combining a dsRNA-binding domain, a PSMA-targeting antibody(-fragment) moiety, and an ARG9 spacer peptide between the domains.
ARG9-spaced dsRNA-binding and PSMA-targeting chimeric recombinant protein
A chimeric recombinant protein comprising a double stranded RNA (dsRNA) binding domain and a target binding moiety that binds to prostate surface membrane antigen (PSMA), wherein a spacer peptide between the dsRNA binding domain and the target binding moiety is ARG9 as set forth in SEQ ID NO: 5, and wherein the target binding moiety is an antibody or antigen-binding fragment of an antibody.
The claims focus on linking PSMA binding to dsRNA binding using an ARG9 (SEQ ID NO: 5) spacer, with additional refinements specifying particular dsRBM sources and sequence-defined protein formats, including SEQ ID NO: 18 and SEQ ID NO: 3.
Stated Advantages
PSMA-selective binding and internalization are described in cell assays.
Induced apoptosis and cytokine induction are described, including caspase-3 and PARP cleavage and cytokines including IP-10, RANTES, and IFN-β.
Direct and immune-mediated bystander effects are described in prostate cancer cell models and tumor spheroid models, including enhanced destruction in the presence of PBMCs.
Documented Applications
Prostate cancer cell models.
Tumor spheroid models.
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