Therapeutic nanoconjugates and uses thereof
Inventors
Villaverde Corrales, Antonio Pedro • Vázquez Gómez, Esther • Unzueta Elorza, Ugutz • Mangues Bafalluy, Ramón • CÉSPEDES NAVARRO, María Virtudes • CASANOVA RIGAT, ISOLDA
Assignees
Universitat Autonoma de Barcelona UAB • Fundacio Institut de Recerca de lHospital de La Santa Creu i Sant Pau • Centro de Investigacion Biomedica en Red CIBER
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Publication Number
US-12202866-B2
Publication Date
2025-01-21
Expiration Date
Abstract
The present invention relates to nanostructured conjugates, more specifically to nanostructured fusion proteins suitable for the selective delivery of their conjugated therapeutic agents to specific cell and tissue types. It also relates to nanoparticles comprising such nanostructured proteins and the therapeutic uses thereof.
Core Innovation
The invention relates to nanostructured fusion proteins for selective delivery of therapeutic payloads. A fusion protein includes a polycationic peptide selected from SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, together with an intervening polypeptide region conjugated to at least three chemotherapy agents and a polyhistidine region.
The intervening polypeptide is selected from SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, cystatin B, cystatin C, cystatin D, cystatin M, and variants having one or more mutations selected from G4W, G4R, V48D, V48L, G50S, K71N, S72G, L73P, L82R and T83S with respect to the numbering in SEQ ID NO: 40. The polyhistidine region is used as a positively charged amino-acid-rich region, and the intervening polypeptide region carries chemotherapy agents.
Multiple copies of the fusion proteins form self-assembling nanostructures sized in the range of 10-100 nm. The resulting constructs are configured for targeted therapeutic use for cancer, with reported cytotoxicity differences and tumor biodistribution dependent on CXCR4 targeting.
Claims Coverage
The independent claim covers a fusion protein defined by three linked components: a specified polycationic peptide, an intervening polypeptide conjugated to at least three chemotherapy agents, and a polyhistidine region. Dependent claims further refine polyhistidine length, terminal orientation and optional linkers, chemotherapy-agent type and specific agent identity, and nanoparticle diameter range.
Polycationic peptide selection
A fusion protein comprising a polycationic peptide wherein the polycationic peptide comprises a sequence selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8.
Intervening polypeptide conjugated to chemotherapy agents
An intervening polypeptide region conjugated to at least three chemotherapy agents, wherein the intervening polypeptide is selected from the group consisting of SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO:40, cystatin B, cystatin C, cystatin D, cystatin M, and a variant having one or more mutations selected from the group consisting of a G4W, a G4R, a V48D, a V48L, a G50S, a K71N, a S72G, a L73P, a L82R and a T83S mutation with respect to the numbering in SEQ ID NO: 40.
Polyhistidine region
A polyhistidine region.
Polyhistidine length constraint
The polyhistidine region contains between 2 and 10 contiguous histidine residues.
Terminal orientation and optional linker sequences
A polycationic peptide is at either the N-terminus or C-terminus and the polyhistidine region is at the opposite terminus, with optional peptide linkers using a first peptide linker that comprises SEQ ID NO: 33 or SEQ ID NO: 34.
Chemotherapy agent class limitation
The chemotherapy agent is an antimetabolite that is a pyrimidine analogue or an oligomeric form of a pyrimidine analogue.
Floxuridine chemotherapy agent limitation
The pyrimidine analogue is floxuridine.
Nanoparticle diameter range
The nanoparticle has a diameter between 10 and 100 nm.
Overall, the claim set centers on a fusion protein built from a specified polycationic peptide, an intervening polypeptide conjugated to at least three chemotherapy agents, and a polyhistidine region, with refinements for polyhistidine length, terminal orientation/linkers, chemotherapy-agent identity, and a specified nanoparticle diameter range.
Stated Advantages
Higher cytotoxicity versus free oligo-FdU, with CXCR4-dependent internalization.
Targeted tumor biodistribution.
Increased DNA double-strand breaks and apoptosis in tumor tissue.
Metastasis prevention and metastasis regression.
Limited toxicity/biodistribution to normal tissues.
Documented Applications
Therapeutic use for cancer, including effects in mouse CRC models involving metastasis prevention/regression.
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