Fusion proteins having a toxin and cancer marker, nanoparticles, and uses related thereto
Inventors
Yang, Lily • Guo, Xiangxue • Mao, Hui • Chen, Wei
Assignees
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Publication Number
US-12458603-B2
Publication Date
2025-11-04
Expiration Date
Abstract
This disclosure relates to nanoparticles coated with fusion proteins comprising a domain that binds a cancer marker and a domain comprising a toxic polypeptide. In certain embodiments, the targeted cancer marker is urokinase plasminogen activator receptor (uPAR) insulin-like growth factor 1 receptor (IGF1R), EGFR, HER2, and/or other member of the ErbB family of receptors. In certain embodiments, the molecule that binds a cancer marker is an amino terminal fragment of uPA or variant capable of binding uPAR and/or IGF1 or variant capable of binding IGF1R. In certain embodiments, the toxic polypeptide is a bacterial exotoxin.
Core Innovation
The invention relates to a nanoparticle platform where the nanoparticle is coated with a fusion peptide comprising a first domain and a second domain of a toxin, and the nanoparticle is further coated with a molecule that binds insulin-like growth factor 1 receptor. The platform presents dual targeting elements, including an anti-EGFR single-chain antibody domain and an insulin-like growth factor 1 receptor binding molecule, and the fusion peptide comprises the amino acid sequence of SEQ ID NO:5.
The platform further includes fusion proteins or peptides in which the toxin domain is fused to target-binding domains, with target-ligand options including ATF-uPA, ScFvEGFR, and IGF1. The toxin domain is described as a bacterial exotoxin, including Pseudomonas exotoxin (PE38/PE38KDEL), and the nanoparticle can be used as a cancer-theranostic construct.
Nanoparticle cores are described as iron oxide/gold/silver/iron-oxide and quantum dots, with polymer coatings and conjugation chemistries described for assembling the multi-component surface. The described theranostic use includes cancer treatment and optional imaging via NIR/MRI, including NIR optical imaging and MRI/3D-MRI theranostics.
Documented uses include treating cancer by administering a nanoparticle that comprises a chemotherapy agent, where the cancer treatment is associated with the targeting fusion peptide and the IGF1R-binding coating. Example data are described as showing reduced systemic toxicity and enhanced antitumor activity for dual-targeted uPAR plus IGF1R PE38 nanoparticle conjugates versus single-targeted or controls, using orthotopic breast PDX tumor models.
Claims Coverage
The provided independent claims are clm-00001, clm-00008, and clm-00010. Each independent claim focuses on a key aspect: the coated nanoparticle construction, the cancer-treatment method by administering a chemotherapy-agent nanoparticle with the specified dual-targeting surface, and the nucleic acid sequence encoding the specified fusion protein amino acid sequence, SEQ ID NO:5.
Dual-targeted nanoparticle with anti-EGFR-toxin fusion peptide and IGF-1R binding coating
A nanoparticle coated with a fusion peptide comprising a first domain having a single-chain anti-EGFR antibody sequence and the second domain of a toxin, wherein the nanoparticle is further coated with a molecule that binds insulin-like growth factor 1 receptor; and wherein the fusion peptide comprises the amino acid sequence of SEQ ID NO:5.
Cancer treatment by administering chemotherapy-agent nanoparticle with anti-EGFR-toxin fusion peptide and IGF-1R binding coating
A method of treating cancer comprising administering an effective amount of a nanoparticle comprising a chemotherapy agent to a subject in need thereof, wherein the nanoparticle is coated with a fusion peptide comprising a first domain having a single-chain anti-EGFR antibody sequence and the second domain of a toxin, and wherein the nanoparticle is further coated with a molecule that binds insulin-like growth factor 1 receptor; wherein the fusion peptide comprises the amino acid sequence of SEQ ID NO:5.
Nucleic acid encoding the specified anti-EGFR-toxin fusion protein
A nucleic acid sequence comprising a sequence encoding the fusion protein having the amino acid sequence of SEQ ID NO:5.
Across the independent claims, the inventive concept is captured by a nanoparticle with a toxin fusion peptide that includes a single-chain anti-EGFR antibody domain and an additional coating that binds insulin-like growth factor 1 receptor, use of such a nanoparticle in cancer treatment when it comprises a chemotherapy agent, and a nucleic acid sequence encoding the specified SEQ ID NO:5 fusion protein.
Stated Advantages
Reduced systemic toxicity is described in the example data.
Enhanced antitumor activity is described in the example data for dual-targeted constructs versus single-targeted or controls.
Documented Applications
Cancer treatment by administering a nanoparticle comprising a chemotherapy agent to a subject in need thereof.
Optional imaging including NIR optical imaging and MRI/3D-MRI theranostics as part of the cancer-theranostic construct.
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