Antibody inhibiting binding of VEGF to NRP1
Inventors
MURAKAMI, Yasufumi • Satofuka, Hiroyuki • MUKOUBATA, Shigeki • AKIYAMA, Hirotada • Kurose, Tatsuji • AKAO, Sae
Assignees
ORDER-MADE MEDICAL RESEARCH Inc • Santen Pharmaceutical Co Ltd
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Publication Number
US-11008387-B2
Publication Date
2021-05-18
Expiration Date
Abstract
An object of the present invention is to provide an antibody against VEGF that inhibits binding of a vascular endothelial growth factor (VEGF) to neuropilin-1 (NRP1). The present invention provides an antibody against VEGF that inhibits binding of VEGF to NRP1.
Core Innovation
The disclosed invention relates to an antigen-binding fragment or an antibody against VEGF that inhibits binding of VEGF to neuropilin-1 (NRP1). The binding is defined by specific antibody CDR amino acid sequences, including CDR-H1 comprising the amino acid sequence of SEQ ID NO: 14, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 16, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 18, together with CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20, CDR-L2 comprising the amino acid sequence of Glu-Gly-Asn, and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22.
The antigen-binding fragment is a single-chain antibody or a double-chain antibody. The document describes additional antibody scope, including recombinant forms and immunoglobulin formats such as scFv, Fab, and dabody, and recombinant monoclonal antibodies including chimeric human IgG1 and caninized IgGB.
The invention is further supported by an anti-VEGF antibody example that inhibits VEGF binding to NRP1 and further inhibits VEGF binding to VEGFR2 and/or VEGFR1. The antibody is characterized by binding to VEGF exon 1–5 while still inhibiting VEGF–NRP1 interaction, and by cross-species binding reported for a canine IgGB chimeric antibody.
The document asserts functional inhibition and in vivo efficacy for the described anti-VEGF antibody. In vitro results include inhibition of VEGF-driven HUVEC proliferation, and in vivo results include suppression of tumor growth in xenograft models and reduced CNV area in a mouse laser-induced choroidal neovascularization (wet-AMD) model.
Claims Coverage
The partial content provides two independent claims. Each independent claim is directed to an anti-VEGF binding molecule defined primarily by specific CDR sequence requirements that inhibit VEGF binding to neuropilin-1 (NRP1), with one claim limited to particular antigen-binding fragment formats and the other directed to an antibody or antigen-binding fragment thereof.
CDR-defined VEGF binding fragment blocking VEGF–NRP1 interaction
An antigen binding fragment against VEGF that inhibits binding of VEGF to neuropilin-1 (NRP1), wherein the antibody comprises CDR-H1 comprising the amino acid sequence of SEQ ID NO: 14, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 16, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 18; and CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20, CDR-L2 comprising the amino acid sequence of Glu-Gly-Asn, and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22, wherein the antigen-binding fragment is a single-chain antibody or a double-chain antibody.
CDR-defined VEGF antibody blocking VEGF–NRP1 interaction
An antibody, or an antigen binding fragment thereof, against VEGF that inhibits binding of VEGF to neuropilin-1 (NRP1), wherein the antibody comprises CDR-H1 comprising the amino acid sequence of SEQ ID NO: 14, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 16, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 18; and CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20, CDR-L2 comprising the amino acid sequence of Glu-Gly-Asn, and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22.
Across the independent claims, the core coverage is an anti-VEGF antigen-binding fragment or antibody defined by specific CDR amino acid sequences that inhibit VEGF binding to neuropilin-1 (NRP1), with one claim additionally requiring the antigen-binding fragment be a single-chain antibody or a double-chain antibody.
Stated Advantages
Inhibits VEGF binding to neuropilin-1 (NRP1).
Inhibits VEGF-driven HUVEC proliferation (in vitro).
Suppresses tumor growth in xenograft models (in vivo).
Suppresses choroidal neovascularization in a wet-AMD model by reducing CNV area.
Still inhibits VEGF–NRP1 interaction while binding VEGF exons 1–5 (as described).
Provides cross-species binding and in vivo tumor suppression in both human cancer cell line xenografts and canine cancer cell line models.
Documented Applications
Treatment or prevention of VEGF-mediated eye diseases with aberrant angiogenesis, including age-related macular degeneration and other listed ocular conditions described in the partial content.
Treatment/prevention uses for cancer and VEGF-mediated eye diseases, including diabetic retinopathy, diabetic macular edema, neovascular glaucoma, retinal vein occlusion, retinopathy of prematurity, choroidal neovascularization associated with pathological myopia, pterygium, rubeosis, pannus, and Stevens-Johnson syndrome, as listed in the partial content.
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