Vascular endothelial growth factor antagonists
Inventors
Bottaro, Donald P. • Cecchi, Fabiola
Assignees
US Department of Health and Human Services
Publication Number
US-11434268-B2
Publication Date
2022-09-06
Expiration Date
2033-04-26
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Abstract
The present invention provides variant VEGF polypeptides which have been altered in their C-terminal heparin binding region to lower their heparin binding affinity. These variants have been found to act as receptor antagonists for VEGF receptors and antagonize angiogenesis. These variants are useful to treat diseases characterized by pathological angiogenesis.
Core Innovation
The invention provides variant vascular endothelial growth factor (VEGF) polypeptides which have been altered in their C-terminal heparin binding domain. These variants have one or more amino acid substitutions designed to reduce or repel binding affinity to heparin and heparan sulfate proteoglycans compared to native VEGF, while substantially maintaining affinity for VEGF receptors VEGFR-1 (FLT-1) and VEGFR-2 (KDR/FLK-1). These variants act as receptor antagonists, specifically antagonizing KDR signal activation and angiogenesis, useful for treating diseases characterized by pathological angiogenesis.
The problem addressed arises from the critical role of VEGF signaling in pathological angiogenesis in diseases like cancer and neovascular ophthalmic diseases. Although existing VEGF antagonists like neutralizing antibodies and ATP binding antagonists have been developed, they present limitations such as high production costs or off-target toxicities. There is a need for receptor antagonists that effectively inhibit VEGF receptor activation, including activation independent of VEGF binding, and that can be produced cost-effectively, for instance using less expensive expression systems.
The invention demonstrates that modification of specific arginine residues in the heparin binding domain, replacing them with acidic (negatively charged) amino acids, reduces heparin binding but retains receptor binding affinity, resulting in competitive antagonism of VEGF signaling. This is a surprising discovery given that previous alanine substitutions at these sites did not inhibit VEGF activity. The variants inhibit angiogenesis and tumor growth in vitro and in vivo, suggesting a novel antagonist development strategy through receptor occupancy and charge-based repulsion of heparan sulfate proteoglycans.
Claims Coverage
The claims include two main independent claims covering variant VEGF polypeptides characterized by specific amino acid substitutions and their use in methods of inhibiting VEGF-mediated angiogenesis.
VEGF variant polypeptides with acidic substitutions at key positions
The inventive feature covers vascular endothelial growth factor (VEGF) variant polypeptides that have substitutions of arginine residues with acidic amino acids (glutamic acid or aspartic acid) at positions 149, 150, and 185 of SEQ ID NO:25 or at positions 123, 124, and 159 of SEQ ID NO:26. The variants retain substantial sequence identity with the native polypeptides and possess the ability to antagonize VEGF-mediated angiogenesis.
Method of inhibiting VEGF-mediated angiogenesis using VEGF variant polypeptides
Methods comprising administering a pharmaceutically effective amount of the VEGF variant polypeptides described above to a patient in need thereof to inhibit VEGF-mediated angiogenesis.
The claims focus on VEGF variants with specific acidic residue substitutions at crucial heparin binding positions that enable antagonism of VEGF-mediated angiogenesis and methods of using these variants therapeutically to inhibit pathological angiogenesis.
Stated Advantages
The variant VEGF polypeptides provide potent receptor antagonism by maintaining receptor affinity while disrupting heparin binding, offering an effective general strategy for antagonizing VEGF signaling.
They offer a potential for lower production costs compared to existing antibody-based VEGF antagonists, enabling manufacturing in less expensive systems such as Pichia pastoris.
The antagonists are highly selective for VEGF receptors, reducing off-target effects often seen with ATP binding site antagonists.
Documented Applications
Treatment of diseases characterized by pathological angiogenesis, including cancer and ocular diseases such as macular degeneration and diabetic retinopathy.
Use in inhibiting tumor growth and metastasis via antagonism of VEGF signaling.
Potential use in molecular imaging as agents targeting VEGF receptors for diagnosis and evaluation of pathological angiogenesis.
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