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-11590198-B2
Publication Date
2023-02-28
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 that includes a targeting peptide comprising the sequence RRWCYRKCYKGYCYRKCR (SEQ ID NO: 5) or a peptide with at least one conservative amino acid substitution in that sequence. The targeting peptide specifically binds chemokine receptor type 4 (CXCR4) and promotes internalization of the therapeutic agent in a cell expressing CXCR4. In the stated conjugate, the therapeutic agent is a polypeptide or protein.
The conjugate framework is described for CXCR4 receptor targeting using a polyphemusin-derived T22 peptide (SEQ ID NO: 5) fused to or coupled with therapeutic or diagnostic agents. The description emphasizes receptor-specific binding and internalization, and discusses promotion of internalization associated with endosomal escape.
The disclosed conjugates provide coverage for different therapeutic payload formats in which the therapeutic agent can be a polypeptide or protein or a nucleic acid or small molecule, including high-molecular-weight agents. The description further discusses delivery via nanotransporters, including nanoparticles, lipid nanoparticles or liposomes, viral vectors, VLPs, and protein cages, as well as peptide variants using conservative substitutions and preferences related to disulfide bridge designs, together with linker or cleavage strategies.
Claims Coverage
The independent claim clm-00001 covers CXCR4-targeted conjugates comprising the T22 (polyphemusin-derived) targeting peptide (SEQ ID NO: 5) or conservative substitution variants linked to a therapeutic polypeptide or protein, where CXCR4 binding and internalization are functional requirements. Based on the provided claim set, no other independent claims are explicitly included, while dependent claims refine the targeting peptide identity and therapeutic agent categories and delivery formats.
CXCR4-binding T22 targeting peptide for CXCR4 internalization
A targeting peptide comprising the sequence RRWCYRKCYKGYCYRKCR (SEQ ID NO: 5) or a peptide with at least one conservative amino acid substitution in the sequence SEQ ID NO: 5, wherein the targeting peptide specifically binds chemokine receptor type 4 (CXCR4) and promotes internalization of the therapeutic agent in a cell expressing CXCR4.
Therapeutic polypeptide or protein as the therapeutic agent
A conjugate wherein the therapeutic agent is a polypeptide or protein that is promoted for internalization by the CXCR4-binding targeting peptide.
The claim coverage provided is centered on CXCR4-specific targeting using the RRWCYRKCYKGYCYRKCR (SEQ ID NO: 5) peptide or conservative substitution variants, combined with an internalization-promoting mechanism for a therapeutic polypeptide or protein payload. Dependent refinements in the provided excerpt further narrow the targeting peptide to SEQ ID NO: 5 exactly and narrow the therapeutic agent categories and delivery or format options, but additional independent claim coverage is not explicitly provided in the partial claim list.
Stated Advantages
Provides CXCR4-specific binding of the targeting peptide.
Promotes internalization of the therapeutic agent in a cell expressing CXCR4.
Enables delivery of therapeutic polypeptide or protein agents using CXCR4-targeted conjugates.
Documented Applications
Cancer treatment involving CXCR4+ tumors, with preferred colorectal cancer and pancreatic cancer as explicitly discussed use cases.
Treatment of HIV infection-associated disease using CXCR4-targeted conjugates with antiretroviral agent payload categories described in the document.
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