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

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 patent describes CXCR4-targeted conjugates that use a poliphemusin-derived T22 peptide. The targeting peptide comprises the sequence RRWCYRKCYKGYCYRKCR (SEQ ID NO: 5), or a peptide with at least one conservative amino acid substitution in that sequence, and specifically binds to CXCR4. The conjugate promotes internalization of an attached therapeutic agent in a cell expressing CXCR4.

The therapeutic agent is selected from polynucleotides and small organic molecules. Receptor-mediated internalization is used to deliver attached molecules, and endosomal escape can optionally be supported. The system is designed to provide specificity through CXCR4 binding and subsequent internalization.

The disclosure additionally describes coupling of the targeting peptide to delivery systems such as nanoparticles, lipid-based carriers including liposomes and micelles, viral nanotransporters including viruses and virus-like particles, protein cages, and nanotransporters such as ferritin cages. The patent also describes linkers or spacers and expression constructs comprising polynucleotides, vectors, and host cells, with therapeutic payloads that can include genes such as tumor suppressor genes, suicide genes, and immune-activating polynucleotides.

The background and examples are presented in the context of overcoming limitations of prior-art CXCR4 ligands and translocation fusions. The patent provides use in disease settings including cancer and HIV-associated disease, and it focuses particularly on colorectal and pancreatic cancer indications. Internalization and CXCR4-dependent behavior are demonstrated using peptide-conjugated imaging or labeling constructs and in vivo biodistribution toward CXCR4+ colorectal tumor xenografts and peritoneal metastases or lymph nodes.

Claims Coverage

The independent claim is directed to a CXCR4-targeted conjugate with two inventive features: a targeting peptide selected from the specified T22 sequence or conservative variants, and a therapeutic agent selected from polynucleotides or small organic molecules, where CXCR4 binding promotes internalization in CXCR4-expressing cells.

Across the independent claim, the inventive core is pairing a CXCR4-binding poliphemusin-derived T22 peptide with a therapeutic agent selected from polynucleotides or small organic molecules, such that CXCR4-specific binding promotes internalization of the therapeutic agent in CXCR4-expressing cells.

Stated Advantages

Documented Applications

No documented applications found