Methods and compositions for nucleic acid and protein payload delivery
Inventors
WATSON, Andre Ronald • Foster, Christian
Assignees
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Publication Number
US-12123012-B2
Publication Date
2024-10-22
Expiration Date
Abstract
Provided are methods and compositions for delivering a nucleic acid, protein, and/or ribonucleoprotein payload to a cell. Also provided are delivery molecules that include a peptide targeting ligand conjugated to a protein or nucleic acid payload (e.g., an siRNA molecule), or conjugated to a charged polymer polypeptide domain (e.g., poly-arginine such as 9R or a poly-histidine such as 6H, and the like). The targeting ligand provides for (i) targeted binding to a cell surface protein, and (ii) engagement of a long endosomal recycling pathway. As such, when the targeting ligand engages the intended cell surface protein, the delivery molecule enters the cell (e.g., via endocytosis) but is preferentially directed away from the lysosomal degradation pathway.
Core Innovation
The invention provides a delivery molecule that includes a targeting ligand comprising an amino acid SEQ ID NO: 171 that specifically binds to cKit. The targeting ligand is conjugated to a protein payload, a nucleic acid payload, and/or a charged polymer polypeptide domain.
The delivery molecule is configured to engage the long endosomal recycling pathway upon binding of the targeting ligand to a cell surface protein and subsequent endocytosis of the delivery molecule. By biasing trafficking toward the long endosomal recycling pathway, the delivery molecule reduces lysosomal degradation.
The disclosure supports conjugation architectures in which the targeting ligand is conjugated to payloads using a linker. In particular implementations, the linker comprises amino acid sequence SEQ ID NO: 17, and the charged polymer polypeptide domain is selected from poly-arginine and poly-histidine.
Claims Coverage
The claim set covers one cKit-binding delivery molecule with five inventive features across the independent and dependent claims.
cKit-binding targeting ligand configured to engage long endosomal recycling pathway
A delivery molecule comprising a targeting ligand comprising amino acid SEQ ID NO: 171 that specifically binds to cKit, configured to engage the long endosomal recycling pathway upon binding of the targeting ligand to a cell surface protein and subsequent endocytosis of the delivery molecule.
Conjugated payloads including protein and/or nucleic acid and/or charged polymer domain
The cKit-binding targeting ligand is conjugated to a protein payload, a nucleic acid payload, and/or a charged polymer polypeptide domain.
RNAi agent nucleic-acid payload optionally as siRNA
The targeting ligand is conjugated to a nucleic acid payload that is an RNAi agent, optionally an siRNA molecule.
Linker-based conjugation with linker comprising SEQ ID NO:17
The targeting ligand is conjugated to the protein payload, nucleic acid payload, and/or charged polymer polypeptide domain via a linker, wherein the linker comprises the amino acid sequence SEQ ID NO:17.
Charged polymer domain selection from poly-arginine or poly-histidine
The charged polymer polypeptide domain is selected from poly-arginine and poly-histidine.
The coverage centers on a cKit-binding targeting ligand defined by amino acid SEQ ID NO: 171 that is conjugated to payloads and configured to engage the long endosomal recycling pathway after binding and endocytosis. The dependent claims further specify an RNAi agent nucleic-acid payload, linker-based conjugation with a linker comprising amino acid sequence SEQ ID NO:17, and charged polymer polypeptide domains restricted to poly-arginine or poly-histidine.
Stated Advantages
Biases trafficking toward the long endosomal recycling pathway to reduce lysosomal degradation.
Documented Applications
Therapeutic contexts are described at a high level, including hematopoietic editing and targeting contexts such as pancreatic/neuronal targeting, Von Willebrand disease, sickle cell, B-thalassemia, and HIV.
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