Fusion proteins for inhibiting angiogenesis
Inventors
Wu, Pei-Tzu • SHIU, Jia-Hau • CHERUKURY, Madhu • Nguyen, Tan • ZEN, Kevin
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12152057-B2
Publication Date
2024-11-26
Expiration Date
Abstract
The present invention relates to a biologic that inhibits angiogenesis. In particular, the present invention relates to fusion proteins that inhibit the integrin activated pathway and one other angiogenic factor-activated pathway, the compositions of these fusion proteins, as well as methods for producing and using the same.
Core Innovation
The invention relates to angiogenesis-inhibiting fusion biologics that target integrin activated pathways and simultaneously target an angiogenic factor pathway. The fusion biologics include an extracellular domain of a VEGF receptor comprising an Ig-like domain D2 of VEGFR1 and an Ig-like domain D3 of VEGFR2, and the fusion biologics are configured to include an Fc domain and an integrin binding peptide with binding selectivity for integrin αvβx and αvβ5 (x is 3, 5, or 6).
The integrin binding peptide comprises disintegrin with a mutated amino acid sequence of SEQ ID NO:1, where defined substitution positions within SEQ ID NO:1 are substituted with amino acid sequences of SEQ ID NO:26 or SEQ ID NO:28, with optional additional substitutions at positions 39 to 45 (SEQ ID NO:36) and positions 65 to 68 (SEQ ID NO:42). The fusion architecture is described as a VEGF-receptor extracellular domain with defined Ig-like domains together with an Fc-fused VEGF-receptor extracellular-domain component in a “VEGF trap” architecture and an integrin-activated-pathway targeting component.
The document further describes optional structural and formulation refinements for the fusion biologics, including insertion of a GS or G9 linker between the Fc domain and the integrin binding peptide, inclusion of an upstream signal peptide, and definition of a dimeric fusion protein. Broadly, the fusion biologics are described for inhibition of angiogenesis and are associated with applications including ocular neovascular diseases, inflammation/autoimmune, fibrosis, and cancer, with example performance data for Fusion Protein 1 including VEGF165 binding affinity, integrin αvβ3 competitive binding, and inhibition of HUVEC proliferation and tube formation.
Claims Coverage
The independent claim defines one fusion protein architecture with a specified N- to C-terminal order and a constrained set of mutations for an integrin-binding disintegrin peptide, while dependent claims refine linkage, expression-related features, molecular assembly, mutation completeness, and pharmaceutical composition formulation. The independent claim therefore includes three inventive features: a VEGF receptor extracellular domain portion, an Fc domain, and a disintegrin-based integrin-binding peptide having defined mutation substitutions and binding selectivity across integrin αvβx and αvβ5 (x = 3, 5, or 6).
VEGF receptor extracellular domain with VEGFR1 Ig-like domain D2 and VEGFR2 Ig-like domain D3
An extracellular domain of a VEGF receptor comprising an Ig-like domain D2 of a VEGFR1 having the amino acid sequence of SEQ ID NO: 8 and an Ig-like domain D3 of VEGFR2 having the amino acid sequence of SEQ ID NO: 9.
Fc domain in the N-terminus to C-terminus fusion architecture
An Fc domain positioned in the specified N- to C-terminus order between the VEGF receptor extracellular domain and the integrin binding peptide.
Integrin binding disintegrin peptide with binding selectivity for integrin αvβx and αvβ5 (x=3,5,6)
An integrin binding peptide comprising disintegrin having a binding selectivity for integrin αvβx and αvβ5, wherein the integrin binding peptide has a mutated amino acid sequence of SEQ ID NO:1 comprising a first mutation defined by substitution of the amino acid sequence at positions 46 to 53 of SEQ ID NO:1 with the amino acid sequence of SEQ ID NO:26 or SEQ ID NO:28, and at least one mutation selected from a second mutation substituting positions 39 to 45 with SEQ ID NO:36 and/or a third mutation substituting positions 65 to 68 with SEQ ID NO:42, wherein x is 3, 5, or 6.
Overall claim coverage is centered on an angiogenesis-inhibiting fusion protein defined by a VEGFR1 D2 and VEGFR2 D3 extracellular domain plus an Fc domain, fused to a disintegrin integrin-binding peptide with defined binding selectivity and a constrained set of SEQ ID NO:1 mutations at positions 46–53 and optionally at positions 39–45 and/or 65–68.
Stated Advantages
Documented Applications
No documented applications found
Interested in licensing this patent?