Methods and reagents for efficient and targeted delivery of therapeutic molecules to CXCR4 cells
Inventors
Villaverde Corrales, Antonio Pedro • Vazquez Gomez, Esther • CESPEDES NAVARRO, Maria Virtudes • CASANOVA RIGAT, ISOLDA • FERRER MIRALLES, Neus • Mangues Bafalluy, Ramon • Unzueta Elorza, Ugutz
Assignees
Universitat Autonoma de Barcelona UAB • Centro de Investigacion Biomedica en Red en Bioingenieria Biomateriales y Nanomedicina CIBERBBN • Fundacio Institut de Recerca de lHospital de La Santa Creu i Sant Pau
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Publication Number
US-10265371-B2
Publication Date
2019-04-23
Expiration Date
Abstract
Conjugates comprising a targeting moiety specific for the CXCR4 and based on the polyphemusin-derived peptide and a therapeutic or imaging agent are provided. Therapeutic and diagnostic methods with the conjugates which require specific targeting to CXCR4+ cells are provided as well.
Core Innovation
The invention relates to a conjugate comprising a targeting peptide selected from a peptide comprising the sequence RRWCYRKCYKGYCYRKCR (SEQ ID NO: 5) and peptides with at least one conservative amino acid substitution in the sequence SEQ ID NO: 5. The targeting peptide specifically binds to CXCR4 and promotes internalization of an attached therapeutic agent in a cell expressing CXCR4.
The targeting peptide is attached to a therapeutic agent selected from a polynucleotide and a small organic molecule by a protein domain. The described scope includes delivery of the therapeutic agent to CXCR4-expressing cells via internalization promoted by the T22-derived targeting peptide, including functional variants and defined classes of therapeutic and diagnostic/imaging agents.
The document further characterizes CXCR4-directed behavior in terms of internalization, defined endosomal escape, and selective in vivo biodistribution to tumor sites including colorectal cancer xenografts/metastases. Example embodiments include targeting-peptide fusion and reporter contexts, and targeting-related inhibition of a CXCR4 ligand interaction, including SDFalpha inhibition, supporting the CXCR4-binding and internalization function.
Claims Coverage
The document identifies one independent claim. The independent claim covers a CXCR4-binding conjugate that links a T22-derived targeting peptide (SEQ ID NO: 5 or conservative-substitution variants) to a therapeutic agent (polynucleotide or small organic molecule) via a protein domain, with the therapeutic agent internalized in CXCR4-expressing cells; the claims include multiple dependent refinements that constrain peptide substitutions, attachment protein domains, therapeutic agent categories, and specific nanotransporter classes and cancer-treatment contexts.
CXCR4-binding T22-derived targeting peptide with conservative substitutions
A targeting peptide selected from a peptide comprising the sequence RRWCYRKCYKGYCYRKCR (SEQ ID NO: 5) and a peptide with at least one conservative amino acid substitution in the sequence SEQ ID NO: 5.
Protein domain attachment of targeting peptide to therapeutic agent
A therapeutic agent selected from the group consisting of a polynucleotide and a small organic molecule, wherein the therapeutic molecule is attached to the targeting peptide by a protein domain.
CXCR4-specific binding and internalization of therapeutic agent
The targeting peptide specifically binds to CXCR4 and promotes internalization of the therapeutic agent in a cell expressing CXCR4.
Overall, the claim set centers on a conjugate built from a T22 (SEQ ID NO: 5) or conservative-substitution variant targeting peptide that specifically binds CXCR4 and promotes internalization, with attachment to a therapeutic polynucleotide or small organic molecule via a protein domain; dependent claims further narrow protein domain types, therapeutic agent categories, and nanotransporter classes and treatment to particular CXCR4-expressing cancer contexts.
Stated Advantages
Promotes internalization of the therapeutic agent in a cell expressing CXCR4.
Enables CXCR4-specific binding of the targeting peptide to direct the conjugate.
Documented Applications
Antitumor therapeutic uses, including colorectal cancer contexts, supported by selective in vivo biodistribution to colorectal cancer xenografts/metastases.
Anti-HIV therapeutic uses using CXCR4/CD4+ targeting.
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