High-affinity anti-VEGF antibody KLHa505
Inventors
MURAKAMI, Yasufumi • MUKOUBATA, Shigeki • AKIYAMA, Hirotada • Konomi, Koji
Assignees
ORDER-MADE MEDICAL RESEARCH Inc • Santen Pharmaceutical Co Ltd
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Publication Number
US-11872271-B2
Publication Date
2024-01-16
Expiration Date
Abstract
An object of the present invention is to provide an antibody having significantly high affinity for VEGF compared to the prior art. The present invention provides a monoclonal antibody against VEGF, which binds to a vascular endothelial growth factor (VEGF) with a dissociation constant of 1×10−11 mol/L or less.
Core Innovation
The invention relates to a high-affinity anti-VEGF monoclonal antibody that binds to vascular endothelial growth factor (VEGF) and inhibits VEGF receptor binding. The antibody is exemplified by KLHa505/KLHb1501 and is characterized by a dissociation constant (KD) of ≤1×10−11 mol/L. Competitive inhibition of VEGF binding to VEGFR1 and/or VEGFR2 is emphasized, with high-affinity binding measured using BIAcore.
The document defines CDR sequence composition for the monoclonal antibody by specifying CDR-H1 comprising SEQ ID NO: 14, CDR-H2 comprising SEQ ID NO: 16, and CDR-H3 comprising SEQ ID NO: 18, together with CDR-L1 comprising SEQ ID NO: 20, CDR-L2 comprising Trp-Ala-Ser, and CDR-L3 comprising SEQ ID NO: 22. The antibody may be provided in chimeric, humanized, and canized forms, and may be used as full-length antibodies or antigen-binding fragments.
The document further discusses constant-region scope using human IgG1 constant regions and canine IgGB constant regions, including variants with cross-reactivity and defined in vivo efficacy. Functional effects described include coverage of VEGF binding sites across VEGF isoforms, including VEGF165, VEGF121, and VEGF165b, suppression of endothelial cell proliferation/angiogenesis, and inhibition of tumor growth in vivo.
Claims Coverage
The independent claim defines a VEGF-binding monoclonal antibody or antigen-binding fragment by six CDR sequence components using SEQ ID numbers. Dependent claim coverage further introduces quantitative affinity constraints, VEGF receptor binding inhibition, heavy/light chain sequence composition, therapeutic use outcomes, and enumerated cancer indications.
Vegf-binding monoclonal antibody defined by specific CDR sequences
A monoclonal antibody against VEGF, or an antigen-binding fragment thereof, that binds to VEGF, comprising CDR-H1 with the amino acid sequence of SEQ ID NO: 14, CDR-H2 with the amino acid sequence of SEQ ID NO: 16, and CDR-H3 with the amino acid sequence of SEQ ID NO: 18, together with CDR-L1 with the amino acid sequence of SEQ ID NO: 20, CDR-L2 comprising the amino acid sequence of Trp-Ala-Ser, and CDR-L3 with the amino acid sequence of SEQ ID NO: 22.
High-affinity VEGF binding with dissociation constant threshold
The monoclonal antibody or antigen-binding fragment is defined by binding to VEGF with a dissociation constant of 1×10−11 mol/L or less.
Inhibition of VEGF binding to VEGFR1 and/or VEGFR2
The monoclonal antibody or antigen-binding fragment inhibits VEGF binding to vascular endothelial growth factor receptor-1 (VEGFR1) and/or vascular endothelial growth factor receptor-2 (VEGFR2).
Antibody sequence specification using heavy-chain and light-chain SEQ IDs
A specified antibody or antigen-binding fragment is defined by heavy-chain and light-chain sequences corresponding to listed SEQ ID numbers.
Therapeutically effective amount inhibits angiogenesis or vascular hyperpermeability
A therapeutically effective amount inhibits angiogenesis or vascular hyperpermeability.
Cancer indication restricted to an enumerated set of cancer types
The method is applicable to cancer selected from a listed group of specific cancer types.
Overall, the claim set coverage centers on a VEGF-binding monoclonal antibody or antigen-binding fragment defined by specific CDR amino-acid sequences, further limited by a KD affinity threshold, inhibition of VEGFR1 and/or VEGFR2 binding, and additional heavy/light-chain SEQ ID sequence constraints. The provided dependent-claim excerpts also restrict intended therapeutic outcomes and limit indications to an enumerated group of cancer types.
Stated Advantages
High-affinity VEGF binding (KD ≤1×10−11 mol/L).
Competitive inhibition of VEGF binding to VEGFR1 and/or VEGFR2.
Suppression of endothelial cell proliferation/angiogenesis.
In vivo tumor growth inhibition.
Coverage of VEGF binding sites across VEGF isoforms including VEGF165, VEGF121, and VEGF165b.
Documented Applications
Therapeutic use for VEGF-mediated cancers.
Therapeutic use for VEGF-mediated eye diseases, including age-related macular degeneration and diabetic retinopathy.
Treatment of cancers selected from a listed group of specific cancer types: colorectal cancer, rectal cancer, breast cancer, non-small-cell lung cancer, non-Hodgkin's lymphoma, renal cell cancer, prostate cancer, liver cancer, pancreas cancer, soft tissue sarcoma, Kaposi's sarcoma, carcinoid tumor, head and neck cancer, melanoma, ovarian cancer, and mesothelioma.
In vivo tumor growth inhibition exemplified using an LS174T xenograft model.
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