Fusion protein comprising a ligand binding domain of VEGF and PDGF
Inventors
ZEN, Kevin • Wu, Pei-Tzu • Her, Jeng-Horng • Chen, Huang-Tsu • Leou, Jiun-Shyang • HSU, Ching-Hsuan
Assignees
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Publication Number
US-11299531-B2
Publication Date
2022-04-12
Expiration Date
Abstract
Fusion proteins containing a PDGF binding portion, a VEGF binding portion, and an Fc antibody region are described. Also described are nucleic acids encoding the fusion proteins, compositions comprising the fusion proteins, and methods of using the fusion proteins for treating or preventing clinical conditions characterized by abnormal angiogenesis, such as vascular permeability, edema or inflammation.
Core Innovation
The invention relates to a fusion protein that combines VEGFR1 Ig-like domain D2 and VEGFR2 Ig-like domain D3 as a first peptide, together with an Fc region of an antibody consisting of CH2 and CH3 regions of IgG1, and with a second peptide comprising Ig-like domains D1 to D3 of PDGFRβ. The fusion protein includes a linker peptide and is arranged from N-terminus to C-terminus in an order selected from (a)-(b)-(d)-(c) or (c)-(b)-(d)-(a).
The fusion protein is capable of binding to VEGF and PDGF and inhibiting the activity of VEGF and the activity of PDGF. The disclosure also defines the fusion protein by specific amino-acid sequence identities relative to SEQ ID references and by selecting specific linker peptide sequences from named SEQ ID numbers.
The described disclosure also provides nucleic acids encoding the fusion protein, expression vectors, host cells for producing the fusion protein, and pharmaceutical formulations and administration concepts. The document further frames the biological purpose as inhibiting VEGF-dependent and PDGF-dependent activities and includes characterization and efficacy assessments directed to abnormal angiogenesis and ocular neovascular conditions.
Claims Coverage
The patent contains two independent claims. The independent claim set defines a dual-binding VEGF/PDGF fusion protein with specified Ig-like domain architecture and Fc multimerization, and a second independent claim defines the fusion protein by selected amino-acid sequence options.
Ig-like domain fusion architecture for VEGF/PDGF binding and inhibition
A fusion protein consisting of a first peptide comprising an Ig-like domain D2 of a VEGFR1 and an Ig-like domain D3 of a VEGFR2, an Fc region of an antibody consisting of a CH2 and a CH3 region of IgG1, a second peptide consisting of Ig-like domains D1 to D3 of a PDGFRβ, and a linker peptide, wherein the fusion protein is arranged from N-terminus to C-terminus in an order selected from (a)-(b)-(d)-(c) or (c)-(b)-(d)-(a), and wherein the fusion protein is capable of binding to a VEGF and a PDGF and inhibiting the activity of the VEGF and the activity of the PDGF.
Selected fusion protein amino-acid sequences
A fusion protein consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 38, SEQ ID NO: 40, amino acids 20-766 of SEQ ID NO: 42, amino acids 21-769 of SEQ ID NO: 44 and amino acids 20-768 of SEQ ID NO: 50.
Across the independent claims, the inventive subject matter is a VEGF/PDGF dual-binding Ig-like domain fusion protein with an IgG1 Fc (CH2/CH3) and a defined domain order, and an alternative set of definitions of the fusion protein by specific SEQ ID sequence selections and amino-acid ranges.
Stated Advantages
Capable of binding to VEGF and PDGF.
Inhibits the activity of VEGF and PDGF.
Documented Applications
Treatment of ocular neovascular disorders, including choroidal neovascularization (CNV), wet age-related macular degeneration, geographic atrophy, and diabetic retinopathy.
Inhibition of abnormal angiogenesis and related conditions including ocular neovascularization, vascular permeability, edema, and inflammation.
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