Fusion proteins for inhibiting angiogenesis
Inventors
Wu, Pei-Tzu • SHIU, Jia-Hau • CHERUKURY, Madhu • Nguyen, Tan • ZEN, Kevin
Assignees
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Publication Number
US-11192927-B2
Publication Date
2021-12-07
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 patent describes fusion proteins designed for anti-angiogenesis by combining an integrin-binding component with an Fc-linked angiogenic-factor-binding component. In the independent formulation, the fusion protein is arranged from N-terminus to C-terminus as an extracellular domain of a VEGF receptor comprising VEGFR1 Ig-like domain D2 and VEGFR2 Ig-like domain D3, followed by an Fc domain, and then an integrin binding peptide selected from specified sequences (SEQ ID NO: 12, 13, and 14).
The integrin-binding portion is configured as an integrin binding peptide, including specific peptide amino acid sequences (SEQ ID NO: 12, 13, and 14) and corresponding alternative or specific overall fusion-protein sequence definitions in dependent coverage (SEQ ID NO: 15-18 and related sequence identifiers). The angiogenic-factor-binding portion is defined by VEGF receptor extracellular domains with amino acid sequences corresponding to SEQ ID NO: 8, SEQ ID NO: 9, or other VEGF receptor sequence identifiers used in narrower claim sets.
The patent further describes pharmaceutical compositions that include the fusion proteins and therapeutic methods for angiogenesis-related diseases. Documented embodiments include anti-angiogenesis activity characterized by binding to VEGF165 and integrin-related competitive binding, and demonstrate inhibition of VEGF-dependent endothelial cell functions together with inhibition of endothelial tube formation and in vivo reduction in lesion outcomes in models involving VEGF-induced retinal leakage and laser-induced choroidal neovascularization.
Claims Coverage
The independent claim set includes two independent claims, with each claim defining a fusion protein architecture composed of a VEGF receptor extracellular domain, an Fc domain, and an integrin binding peptide. Across the independent claims, the coverage is organized around two main inventive feature groups: the defined domain/order architecture and the selection of specific integrin-binding and VEGF-receptor sequence identities.
Domain-ordered VEGF receptor extracellular domain plus Fc plus selected integrin binding peptide
A fusion protein comprising, from N-terminus to C-terminus in the following order: an extracellular domain of a Vascular Endothelial Growth Factor (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 a VEGFR2 having the amino acid sequence of SEQ ID NO: 9; a Fc domain; and an integrin binding peptide having the amino acid sequence selected from a group consisting of SEQ ID NO: 12, 13, and 14.
Integrin binding peptide plus VEGF receptor extracellular domain plus Fc domain
A fusion protein comprising: an integrin binding peptide comprising the amino acid sequence of SEQ ID NO:13; an extracellular domain of a Vascular Endothelial Growth Factor (VEGF) receptor comprising the amino acid sequence of SEQ ID NO: 10; and a Fc domain.
Overall claim coverage centers on fusion proteins that combine VEGF receptor extracellular domains with an Fc domain and an integrin binding peptide, with specific sequence identities and architectures defined by the two independent claims. Dependent claims further refine the fusion-protein sequences and include pharmaceutical composition framing and therapeutic method use for vascular leakage and related lesion reduction.
Stated Advantages
Inhibition of VEGF-dependent HUVEC proliferation.
Inhibition of integrin alphavbeta3/alpha5beta1-mediated adhesion.
Inhibition of endothelial tube formation.
Demonstrated in vivo efficacy, including reduction in VEGF-induced retinal leakage and reduction in lesion size in laser-induced choroidal neovascularization.
Documented Applications
Treatment of vascular leakage in a subject by administering the fusion protein.
Treatment of retinal vascular leakage in a subject by administering the fusion protein.
Reducing lesion size caused by laser-induced choroidal neovascularization (CNV) in a subject by administering the fusion protein.
Anti-angiogenesis activity documented via binding and inhibition of VEGF-dependent endothelial functions in models described in the document, including VEGF-induced retinal leakage and laser-induced choroidal neovascularization lesion reduction.
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