Granted Patent
B2
US 12,514,905 · App. 18/640,840 · Granted Jan 6, 2026
Methods and compositions for treatment of angiogenic disorders using anti-VEGF agents
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Abstract
Provided are methods and compositions for treatment of angiogenic disorders using anti-VEGF agents. The anti-VEGF agents comprise VEGF binding domains and have the ability to bind vitreous. Provided are exemplary embodiments of Fc-IgG fusion proteins with VEGF binding domains with strong heparin-binding characteristics, strong inhibition of VEGF mitogenic activity, and improved pharmacokinetics, namely longer half-lives of the anti-VEGF agents and consequently less frequent dosing.
Claims (3)
1 . An anti-Vascular Endothelial Growth Factor (anti-VEGF) agent comprising amino acid residues 27-456 of SEQ ID NO: 13.
2 . A pharmaceutical composition comprising a therapeutically effective amount of the anti-VEGF agent of claim 1 and a pharmaceutically acceptable excipient.
3 . A polynucleotide encoding the anti-VEGF agent of claim 1 .
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jul 12, 2024
From: FERRARA, NAPOLEONE
To: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
Reel/Frame 067977/0070 →
Continuity (4)
Continuation
18053311
· Nov 7, 2022
Continuation
16962529
Provisional Application
62622382
· Jan 26, 2018
References Cited (311)
US 5595760A
· Cherif-Cheikh
· 1997
[cited by applicant]
US 5672659A
· Shalaby et al.
· 1997
[cited by applicant]
US 5712380A
· Kendall et al.
· 1998
[cited by applicant]
US 5861484A
· Kendall et al.
· 1999
[cited by applicant]
US 5952199A
· Davis-Smyth et al.
· 1999
[cited by applicant]
US 5959760A
· Yamada et al.
· 1999
[cited by applicant]
US 6270993B1
· Shibuya et al.
· 2001
[cited by applicant]
US 6383486B1
· Davis-Smyth et al.
· 2002
[cited by applicant]
US 6833349B2
· Xia et al.
· 2004
[cited by applicant]
US 7070959B1
· Papadopoulos et al.
· 2006
[cited by applicant]
US 7071159B2
· Kendall et al.
· 2006
[cited by applicant]
US 7087411B2
· Daly et al.
· 2006
[cited by applicant]
US 7141607B1
· Si et al.
· 2006
[cited by applicant]
US 7279159B2
· Daly et al.
· 2007
[cited by applicant]
US 7303746B2
· Wiegand et al.
· 2007
[cited by applicant]
US 7303747B2
· Wiegand et al.
· 2007
[cited by applicant]
US 7303748B2
· Wiegand et al.
· 2007
[cited by applicant]
US 7306799B2
· Wiegand et al.
· 2007
[cited by applicant]
US 7354578B2
· Kandel et al.
· 2008
[cited by applicant]
US 7354579B2
· Holash et al.
· 2008
[cited by applicant]
US 7354580B2
· Cedarbaum
· 2008
[cited by applicant]
US 7354581B2
· Cedarbaum et al.
· 2008
[cited by applicant]
US 7354582B2
· Yung et al.
· 2008
[cited by applicant]
US 7374757B2
· Papadopoulos et al.
· 2008
[cited by applicant]
US 7374758B2
· Papadopoulos et al.
· 2008
[cited by applicant]
US 7396664B2
· Daly et al.
· 2008
[cited by applicant]
US 7399612B2
· Daly et al.
· 2008
[cited by applicant]
US 7449182B2
· Cedarbaum et al.
· 2008
[cited by applicant]
US 7479272B2
· Cedarbaum
· 2009
[cited by applicant]
US 7479273B2
· Cedarbaum
· 2009
[cited by applicant]
US 7479274B2
· Cedarbaum
· 2009
[cited by applicant]
US 7479275B2
· Cedarbaum
· 2009
[cited by applicant]
US 7482001B2
· Cedarbaum
· 2009
[cited by applicant]
US 7482002B2
· Cedarbaum
· 2009
[cited by applicant]
US 7521049B2
· Wiegand et al.
· 2009
[cited by applicant]
US 7531172B2
· Stahl et al.
· 2009
[cited by applicant]
US 7531173B2
· Wiegand et al.
· 2009
[cited by applicant]
US 7582726B2
· Chen et al.
· 2009
[cited by applicant]
US 7608261B2
· Furfine et al.
· 2009
[cited by applicant]
US 7635474B2
· Daly et al.
· 2009
[cited by applicant]
US 7704500B2
· Papadopoulos et al.
· 2010
[cited by applicant]
US 7807164B2
· Furfine et al.
· 2010
[cited by applicant]
US 7972598B2
· Daly et al.
· 2011
[cited by applicant]
US 8034375B2
· Desai et al.
· 2011
[cited by applicant]
US 8034772B2
· Kendall et al.
· 2011
[cited by applicant]
US 8048418B2
· Noguera-Troise et al.
· 2011
[cited by applicant]
US 8084234B2
· Papadopoulos et al.
· 2011
[cited by applicant]
US 8092803B2
· Furfine et al.
· 2012
[cited by applicant]
US 8110546B2
· Dix et al.
· 2012
[cited by applicant]
US 8273353B2
· Davis-Smyth et al.
· 2012
[cited by applicant]
US 8324169B2
· Quinn
· 2012
[cited by applicant]
US 8350010B2
· Chuntharapai et al.
· 2013
[cited by applicant]
US 8404638B2
· Dix et al.
· 2013
[cited by applicant]
US 8481046B2
· Furfine et al.
· 2013
[cited by applicant]
US 8647842B2
· Papadopoulos et al.
· 2014
[cited by applicant]
US 8710004B2
· Dix et al.
· 2014
[cited by applicant]
US 8735394B2
· Desai et al.
· 2014
[cited by applicant]
US 8802107B2
· Furfine et al.
· 2014
[cited by applicant]
US 8921316B2
· Dix et al.
· 2014
[cited by applicant]
US 9056102B2
· Quinn
· 2015
[cited by applicant]
US 9139644B2
· Papadopoulos et al.
· 2015
[cited by applicant]
US 9254338B2
· Yancopoulos
· 2016
[cited by applicant]
US 9273113B2
· Davis-Smyth et al.
· 2016
[cited by applicant]
US 9284369B2
· Ferrara et al.
· 2016
[cited by applicant]
US 9340594B2
· Furfine et al.
· 2016
[cited by applicant]
US 9416167B2
· Dix et al.
· 2016
[cited by applicant]
US 9441029B2
· Stefano et al.
· 2016
[cited by applicant]
US 9511140B2
· Dix et al.
· 2016
[cited by applicant]
US 9561288B2
· Desai et al.
· 2017
[cited by applicant]
US 9580489B2
· Furfine et al.
· 2017
[cited by applicant]
US 9636400B2
· Dix et al.
· 2017
[cited by applicant]
US 9637534B2
· Pechan et al.
· 2017
[cited by applicant]
US 9657084B2
· Ke et al.
· 2017
[cited by applicant]
US 9669069B2
· Yancopoulos
· 2017
[cited by applicant]
US 9708386B2
· Papadopoulos et al.
· 2017
[cited by applicant]
US 9777261B2
· Kim et al.
· 2017
[cited by applicant]
US 9856462B2
· Kim et al.
· 2018
[cited by applicant]
US 9914763B2
· Furfine et al.
· 2018
[cited by applicant]
US 9931330B2
· Zarnitsyn et al.
· 2018
[cited by applicant]
US 20030017977A1
· Xia et al.
· 2003
[cited by applicant]
US 20070010442A1
· Kendall et al.
· 2007
[cited by applicant]
US 20080292628A1
· Hui
· 2008
[cited by applicant]
US 20130101557A1
· Yun
· 2013
[cited by applicant]
US 20130195984A1
· Desai et al.
· 2013
[cited by applicant]
US 20150175675A1
· Kitajewski et al.
· 2015
[cited by applicant]
US 20160297854A1
· Ghosh et al.
· 2016
[cited by applicant]
US 20170232199A1
· Fiedler
· 2017
[cited by applicant]
US 20180015181A1
· Desai et al.
· 2018
[cited by applicant]
US 20180326126A1
· Fiedler
· 2018
[cited by applicant]
US 20190201385A1
· Beeharry et al.
· 2019
[cited by applicant]
US 20190240208A1
· Zarnitsyn et al.
· 2019
[cited by applicant]
US 20230136080A1
· Ferrara
· 2023
[cited by applicant]
CN 1793179A
· 2006
[cited by applicant]
CN 101205252A
· 2008
[cited by applicant]
CN 101575379A
· 2009
[cited by applicant]
CO 2017004596A2
· 2017
[cited by applicant]
CO 2017007693A2
· 2017
[cited by applicant]
CO 15200429
· 2020
[cited by applicant]
EP 1183353B1
· 2005
[cited by applicant]
EP 1261317B1
· 2007
[cited by applicant]
EP 1962895A2
· 2008
[cited by applicant]
EP 1544299B1
· 2008
[cited by applicant]
EP 2364691B1
· 2013
[cited by applicant]
EP 1938799B1
· 2013
[cited by applicant]
EP 2663325A1
· 2013
[cited by applicant]
EP 2097078B1
· 2014
[cited by applicant]
EP 2099489B1
· 2014
[cited by applicant]
EP 1989231B1
· 2015
[cited by applicant]
EP 1861116B1
· 2015
[cited by applicant]
EP 2944306A1
· 2015
[cited by applicant]
EP 2203479B1
· 2016
[cited by applicant]
EP 2481405B1
· 2016
[cited by applicant]
EP 2916827A4
· 2016
[cited by applicant]
EP 3108885A1
· 2016
[cited by applicant]
EP 3143044A1
· 2017
[cited by applicant]
EP 2586459B1
· 2017
[cited by applicant]
EP 3195874A1
· 2017
[cited by applicant]
EP 3222285A1
· 2017
[cited by applicant]
EP 3224278A1
· 2017
[cited by applicant]
EP 2601214B1
· 2017
[cited by applicant]
EP 3327032A1
· 2018
[cited by applicant]
EP 3224278A4
· 2018
[cited by applicant]
EP 3377151A1
· 2018
[cited by applicant]
EP 3412288A1
· 2018
[cited by applicant]
EP 3215158B1
· 2019
[cited by applicant]
EP 3492495A1
· 2019
[cited by applicant]
EP 3194974B1
· 2019
[cited by applicant]
KR 20160013516A
· 2016
[cited by applicant]
WO WO0075319A1
· 2000
[cited by applicant]
WO WO2007149334A2
· 2007
[cited by applicant]
WO WO2012097019A1
· 2012
[cited by applicant]
WO WO2012159548A1
· 2012
[cited by applicant]
WO WO2013082511A1
· 2013
[cited by applicant]
WO WO2013106765A1
· 2013
[cited by applicant]
WO WO2015000181A1
· 2015
[cited by applicant]
WO WO2015109898A1
· 2015
[cited by applicant]
WO WO2015140638A1
· 2015
[cited by applicant]
WO WO2017001990A1
· 2017
[cited by applicant]
WO WO2018224614A1
· 2018
[cited by applicant]
WO WO2019004799A1
· 2019
[cited by applicant]
WO WO2019055902A1
· 2019
[cited by applicant]
WO WO2019062642A1
· 2019
[cited by applicant]
WO WO2019099921A2
· 2019
[cited by applicant]
WO WO2019147944A1
· 2019
[cited by applicant]
WO WO2019154776A1
· 2019
[cited by applicant]
WO WO2021108255A1
· 2021
[cited by applicant]
Drumm et al, Genetic Variation and Clinical Heterogeneity in Cystic Fibrosis, Annu. Rev. Pathol. Mech. Dis., 2012, 7, pp. 267-282 (Year: 2012).
[cited by examiner]
Yampolsky et al, The Exchangeability of Amino Acids in Proteins, Genetics, 2005, 170, pp. 1459-1472. (Year: 2005).
[cited by examiner]
Aiello et al.: Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc. Natl. Acad. Sci. USA 92:10457-10461 (1995)…
[cited by applicant]
Alitalo et al.: Lymphangiogenesis in development and human disease. Nature. 438:946-953 (2005).
[cited by applicant]
Apte et al.: VEGF in Signaling and Disease: Beyond Discovery and Development. Cell. 176:1248-1264 (2019).
[cited by applicant]
Bachmann et al.: The role of antibody concentration and avidity in antiviral protection. Science. 276-2024-2027 (1997).
[cited by applicant]
Barleon et al.: Mapping of the sites for ligand binding and receptor dimerization at the extracellular domain of the vascular endothelial growth factor receptor FLT-1. Journal of Biological Chemistry. 272:10382-10388 (1…
[cited by applicant]
Bhattacharya et al., Impact of Genetic Variation on Three Dimensional Structure and Function of Proteins. PLoS One 12(3):e0171355 (Mar. 15, 2017).
[cited by applicant]
Bogdanovich et al.: Human IgG1 antibodies suppress angiogenesis in a target-independent manner. Signal Transduct Target Ther. 1 (2016).
[cited by applicant]
Brozzo et al.: Thermodynamic and structural description of allosterically regulated VEGFR-2 dimerization. Blood. 119:1781-1788 (2012).
[cited by applicant]
Campa et al.: Effects of an anti-VEGF-A Monoclonal antibody on laser-induced choroidal neovascularization in mice: optimizing methods to quantify vascular changes. Invest Ophthalmol Vis Sci. 49:1178-1183 (2008).
[cited by applicant]
Capon et al.: Designing CD4 immunoadhesins for AIDS therapy. Nature. 337:525-531 (1989).
[cited by applicant]
Chakrabarti et al.: Studies to Prevent Degradation of Recombinant Fc-Fusion Protein Expressed in Mammalian Cell Line and Protein Characterization. International Journal of Molecular Sciences. 17(6):1-22 (2016).
[cited by applicant]
Chamow et al.: Immunoadhesins: principles and applications. Trends In Biotechnology. 14:52-60 (1996).
[cited by applicant]
Chamow et al.: Therapeutic Fc-Fusion Proteins. Landes Bioscience. 6(4):810-811 (2014).
[cited by applicant]
Chen et al.: Erythropoietin deficiency decreases vascular stability in mice. J Clin Invest. 118:526-533 (2008).
[cited by applicant]
Chen et al.: Selection and Analysis of an Optimized Anti-VEGF Antibody: Crystal Structure of an Affinity-matured Fab in Complex With Antigen. Journal of Molecular Biology 293(4):865-881 (1999).
[cited by applicant]
Chen et al.: Suppression of retinal neovascularization by erythropoietin siRNA in a mouse model of proliferative retinopathy. Invest Ophtalmol Vis Sci. 50:1329-1335 (2009).
[cited by applicant]
Christinger et al.: The Crystal Structure of Placental Growth Factor in Complex with Domain 2 of Vascular Endothelial Growth Factor Receptor-1. J Biol Chem. 279:10382-10388 (2004).
[cited by applicant]
Davis-Smyth et al.: The second immunoglobulin-like domain of the VEGF tyrosine kinase receptor Flt-1 determines ligand binding and may initiate a signal transduction cascade. The EMBO Journal. 15(18):4919-4927 (1996).
[cited by applicant]
De Vries et al.: The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science. 255:989-991 (1992).
[cited by applicant]
Dvorak et al.: Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels. Journal of Experimental Medicine. 174:1275-1278 (1991).
[cited by applicant]
Ellison et al.: The nucleotide sequence of a human immunoglobulin Cy1 gene. Nucleic Acids Research. 10(13): 4071-4079 (1982).
[cited by applicant]
EP20891865.6 Extended European Search Report dated Jul. 27, 2023.
[cited by applicant]
European Patent Application No. 19744016.7 Extended European Search Report dated Oct. 21, 2021.
[cited by applicant]
Fenton et al. Rheostat positions: A new classification of protein positions relevant to pharmacogenomics. Medicinal Chemistry Research. 29:1133-1146 (2020).
[cited by applicant]
Ferrara et al.: Ten years of anti-vascular endothelial growth factor therapy. Nat Rev Drug Discov. 15:385-403 (2016).
[cited by applicant]
Ferrara et al.: The biology of VEGF and its receptors. Nature Med. 9:669-676 (2003).
[cited by applicant]
Ferrara et al.: Vascular endothelial growth factor is essential for corpus luteum angiogenesis, Nature Medicine, vol. 4, No. 3, pp. 336-340, Mar. 1998.
[cited by applicant]
Ferrara N.: Binding to the extracellular matrix and proteolytic processing: two key mechanisms regulating vascular endothelial growth factor action. Mol Biol Cell. 21:687-690 (2010).
[cited by applicant]
Ferrara N.: VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer. 2:759-803 (2002).
[cited by applicant]
Folkman et al.: Angiogenic factors. Science. 235:442-447 (1987).
[cited by applicant]
Freund et al.: Aflibercept: a review of its use in the treatment of choroidal neovascularization due to age-related macular degeneration. Clinical Ophthalmology. 9:2355-2371 (2015).
[cited by applicant]
Gait et al.: Oligonucleotide Synthesis, a Practical Approach: Oxford Press. pp. 217 Abstract (1984).
[cited by applicant]
Gardiner et al.: Inhibition of tumor necrosis factor-alpha improves physiological angiogenesis and reduces pathological neovascularization in ischemic retinopathy. Am J Pathol. 166:637-644 (2005).
[cited by applicant]
Gerber et al.: Complete inhibition of rhabdomysocarcoma xenograft growth and neovascularization requires blockade of both tumor and host vascular endothelial growth factor. Cancer Res. 60:6253-6258 (2000).
[cited by applicant]
Gerber et al.: Mice expressing a humanized form of VEGF-A may provide insights into safety and efficacy of anti-VEGF antibodies. Proc Natl Acad Sci U.S.A. 104:3478-3483 (2007).
[cited by applicant]
Gerber et al.: VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochrondral bone formation. Nature Med. 5:623-628 (1999).
[cited by applicant]
Gerber et al.: VEGF is required for growth and survival in neonatal mice. Development. 126:1149-1159 (1999).
[cited by applicant]
Gerhardt et al.: VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol. 161:1163-1177 (2003).
[cited by applicant]
Ghosh et al.: Long-acting protein drugs for the treatment of ocular diseases. nature communications. 8(Article No. 14837):1-10 (2017).
[cited by applicant]
Harding et al.: Adeno-Associated Virus Serotype 6 (AAV-6) Vector Mediated Gene Transfer of Soluble VEGF Receptors for the Treatment of Glioblastoma Multiforme. Molecular Therapy. Elsevier Inc. 9:405-406 (2004) Abstract.
[cited by applicant]
Heier, Jeffrey S et al. Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial. Lancet 390(10089):50-61 (2017).
[cited by applicant]
Herley et al.: Characterization of the VEGF Binding Site on the Flt-1 Receptor, Biochemical and Biophysical Research Communications, 262, pp. 731-738, 1999.
[cited by applicant]
Holash et al.: VEGF-Trap: A VEGF blocker with potent antitumor effects. PNAS. 99(17):11393-11398 (2002).
[cited by applicant]
Holz et al.: Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration. Br J Ophthalmol. 99:220-226 (2015).
[cited by applicant]
Houck et al.: Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J-Biol-Chem 267:26031-26037 (1992).
[cited by applicant]
Houck et al.: The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Molecular Endocrinology. 5:1806-1814 (1991).
[cited by applicant]
Joukov et al.: A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGRF-2) receptor tyrosine kinases. EMBO-J. 15(2):290-298 (1996).
[cited by applicant]
Kendall et al.: Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc. Natl. Acad. Sci. USA. 90:10705-10709 (1993).
[cited by applicant]
Kim et al.: Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma. Proc Natl Acad Sci U.S.A. 99:11399-11404 (2002).
[cited by applicant]
Klagsbrun et al.: Regulators of angiogenesis. Annu Rev Physiol. 53:217-239 (1991).
[cited by applicant]
Kwak et al.: VEGF is major stimulator in model of choroidal neovascularization. Invest Ophthalmol Vis Sci. 41:3158-3164 (2000).
[cited by applicant]
Lambert et al.: Laser-induced choroidal neovascularization model to study age-related macular degeneration in imce. Nat Protoc. 8:2197-2211 (2013).
[cited by applicant]
Lange et al. Intravitreal injection of the heparin analog 5-amino-2-naphthalenesulfonate reduces retinal neovascularization in mice. Exp Eye Res. 85:323-327 (2007).
[cited by applicant]
Lee et al. Novel Glycosylated VEGF Decoy Receptor Fusion Protein, VEGF-Grab, Efficiently Suppresses Tumor Angiogenesis and Progression. Mol Cancer Ther; 14(2) Feb. 2015. E-publication Dec. 22, 2014.
[cited by applicant]
Lee et al.: Novel Glycosylated VEGF Decoy Receptor Fusion Protein, VEGF-Grab, Efficiently Suppresses Tumor Angiogenesis and Progression. Mol. Cancer Ther. 14(2)470-479 (2015).
[cited by applicant]
Li et al.: A fusion Fragment from Flt-1 and KDR, acted as VEGF decoy receptor and exhibited anti-tumor function. Biotechnol Lett. 32:1609-1613 (2010).
[cited by applicant]
Lissbrant et al.: Neutralizing VEGF bioactivity with a soluble chimeric VEGF-receptor protein flt(1-3)lgG inhibits testosterone-stimulated prostate growth in castrated mice. Prostate. 58:57-65 (2004).
[cited by applicant]
Ma et al.: Identification of the ligand-binding domain of human vascular-endothelial-growth-factor receptor Flt-I, Biotechnol. Appl. Biochem. 34:199-204 (2001).
[cited by applicant]
Maguire et al.: Comparison of Age-related Macular Degeneration Treatments Trials Research. Ophthalmology. 123:1751-1761 (2016).
[cited by applicant]
Malyala et al.: Endotoxin limits in formulations for preclinical research. J Pharm Sci. 97:2041-2044 (2008).
[cited by applicant]
Markovic-Mueller et al.: Structure of the Full-length VEGFR-1 Extracellular Domain in Complex with VEGF-A. Structure. 25:341-352 (2017).
[cited by applicant]
Miller et al.: Vascular endothelial growth factor a in intraocular vascular disease. Ophthalmology. 120:106-114 (2013).
[cited by applicant]
Morin et al.: Neurodevelopmental Outcomes Following Bevacizumab Injections for Retinopathy of Prematurity. Pediatrics. 137 (2016).
[cited by applicant]
Nguyen et al.: Combercept (KH-902) for the treatment of neovascular age-related macular degeneration. Expert Rev Clin Pharmacol. 8:541-548 (2015).
[cited by applicant]
Olsson et al.: VEGF receptor signalling—in control of vascular function. Nat Rev Mol Cell Biol. 7:359-371 (2006).
[cited by applicant]
Paetzel et al.: Signal Peptidases. Chem. Rev. 102:4549-4579 (2002).
[cited by applicant]
Park et al.: Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J-Biol-Chem. 269:25646-25654 (1994).
[cited by applicant]
Park et al.: The Fourth Immunoglobulin-like Loop in the Extracellular Domain of FLT-1, a VEGF Receptor, Includes a Major Heparin-Binding Site, Biochemical and Biophysical Research Communications. 264:730-734 (1999).
[cited by applicant]
Park et al. The vascular endothelial growth factor isoforms (VEGF): Differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Molecular Biology of the Cell. …
[cited by applicant]
PCT/US2019/015160 International Preliminary Report on Patentability dated Jul. 28, 2020.
[cited by applicant]
PCT/US2019/015160 International Search Report and Written Opinion dated Apr. 10, 2019.
[cited by applicant]
PCT/US2020/061519 International Search Report and Written Opinion mailed Feb. 12, 2021.
[cited by applicant]
Pechan et al.: Novel anti-VEGF chimeric molecules delivered by AAV vectors in inhibition of retinal neovascularization. Gene Ther. 16(1):10-16 (2009).
[cited by applicant]
Plate et al.: Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature. 359:845-848 (1992).
[cited by applicant]
Presta et al.: Humanization of an Anti-Vascular Endothelial Growth Factor Monoclonal Antibody for the Therapy of Solid Tumors and Other Disorders. Cancer Res. 57:4593-4599 (1997).
[cited by applicant]
Qu-Hong et al.: Ultrastructural localization of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) to the abluminal plasma membrane and vesiculovacuolar organelles of tumor microvascular endothel…
[cited by applicant]
Rakoczy et al.: Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trial. Lancet. 386:2395-2403 (2015).
[cited by applicant]
Ratanji et al.: Immunogenicity of therapeutic proteins: influence of aggregation. J Immunotoxicol. 11:99-109 (2014).
[cited by applicant]
Regula et al.: Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases. EMBO Mol Med. 8:1265-1288 (2016).
[cited by applicant]
Roberts CJ: Therapeutic protein aggregation: mechanisms, design, and control. Trends Biotechnol. 32:372-380 (2014).
[cited by applicant]
Rodrigues et al.: Functional Characterization of Abicipar-Pegol, an Anti-VEGF DARP in Therapeutic That Potently Inhibits Angiogenesis and Vascular Permeability. Invest Ophthalmol Vis Sci. 59:5836-5846 (2018).
[cited by applicant]
Ruhrberg et al.: Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev. 16:2684-2698 (2002).
[cited by applicant]
Saishin et al.: VEGF-TRAP(R1R2) suppresses choroidal neovascularization and VEGF-induced breakdown of the blood-retinal barrier. J Cell Physiol. 195:241-248 (2003).
[cited by applicant]
Sankar et al.: Anti-vascular endothelial growth factor (VEGF) drugs for treatment of retinopathy of prematurity. Cochrane Database Syst Rev. 1:CD009734 (2018).
[cited by applicant]
Sarrazin et al.: Heparan sulfate proteoglycans. Cold Spring Harb Perspect Biol. 3(7):a004952 (2011).
[cited by applicant]
Shibuya M.: VEGFR and type-V RTK activation and signaling. Cold Spring Harb Perspect Biol. 5:a009092 (2013).
[cited by applicant]
Silva et al.: Tyrosine kinase blocking collagen IV-derived peptide suppresses ocular neovascularization and vascular leakage. Sci Transl Med. 9(373):1-23 (2017).
[cited by applicant]
Singapore Patent Application No. SG11202007130R Written Opinion dated Mar. 1, 2022.
[cited by applicant]
Smith et al.: Essential role of growth hormone in ischemia-induced retinal neovascularization. Science. 276:1706-1709 (1997).
[cited by applicant]
Smith et al.: Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor. Nature Medicine. 5:1390-1395 (1999).
[cited by applicant]
Tan et al.: A small peptide derived from Flt-1 (VEGFR-1) functions as an angiogenic inhibitor. FEBS Letters. 494:150-156 (2001).
[cited by applicant]
Terman et al.: Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem-Biophys-Resj-Commun. 187:1579-1586 (1992).
[cited by applicant]
Tischer et al.: The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. Journal of Biological Chemistry. 266:11947-11954 (1991).
[cited by applicant]
U.S. Appl. No. 16/962,529 Office Action dated Jan. 18, 2022.
[cited by applicant]
U.S. Appl. No. 16/962,529 Restriction Requirement dated Nov. 5, 2021.
[cited by applicant]
U.S. Appl. No. 17/522,318 Office Action dated Jan. 20, 2022.
[cited by applicant]
U.S. Appl. No. 17/522,422 Final Office Action dated Jul. 27, 2022.
[cited by applicant]
U.S. Appl. No. 17/522,422 Office Action dated Mar. 29, 2022.
[cited by applicant]
U.S. Appl. No. 17/526,929 Office Action dated Jan. 21, 2022.
[cited by applicant]
Von Heijne.: A new method for predicting signal sequence cleavage sites. Nucleic Acids Research 14(11):4683-4690 (1986).
[cited by applicant]
Vorum et al.: Real world evidence of use of anti-VEGF therapy in Denmark. Curr Med Res Opin. 1-32 (2016).
[cited by applicant]
Wang et al.: IgG Fc engineering to modulate antibody effector functions. Protein Cell 9:63-73 (2018).
[cited by applicant]
Wiesmann et al.: Crystal structure at 1.7 A resolution of VEGF in complex with domain 2 of the Flt-1 receptor. Cell. 91:695-704 (1997).
[cited by applicant]
Woodard et al.: Heparan Sulfate Binding Promotes Accumulation of Intravitreally Delivered Adeno-associated Viral Vectors at the Retina for Enhanced Transduction by Weakly Invluences Tropism. J Virol. 90:9878-9888 (2016).
[cited by applicant]
Xiao et al.: Fully automated, deep learning segmentation of oxygen-induced retinopathy images. JCI Insight. 2 (2017).
[cited by applicant]
Xin et al.: Evidence for Pro-angiogenic Functions of VEGF-Ax. Cell. 167:275-284 e6 (2016).
[cited by applicant]
Xin et al.: Heparin-binding VEGFR1 variants as long-acting VEGF inhibitors for treatment of intraocular neovascular disorders. PNAS. 118(21):e191252118 (2021).
[cited by applicant]
Yang et al.: Comparison of binding characteristics and in vitro activities of three inhibitors of vascular endothelial growth factor a. Mol Pharm. 11:3421-3430 (2014).
[cited by applicant]
Yang et al.: Comparison of biosensor platforms in the evaluation of high affinity antibody-antigen binding kinetics. Anal Biochem. 508:78-96 (2016).
[cited by applicant]
Yu et al.: Direct identification of a major autophosphorylation site on vascular endothelial growth factor receptor Flt-1 that mediates phosphatidylinositol 3′-kinase binding. Biochem. J. 358:465-472 (2001).
[cited by applicant]
Yu et al.: Interaction between Bevacizumab and Murine VEGF-A: A Reassessment. Invest Ophthalmol Vis Sci. 49:522-527 (2008).
[cited by applicant]
Yu et al.: Soluble Vascular Endothelial Growth Factor Decoy Receptor FP3 Exerts Potent Antiangiogenic Effects. 20(5):938-947 (2012) www.moleculartherapy.org.
[cited by applicant]
Zheng et al.: Contribution of vascular endothelial growth factor in the neovascularization process during the pathogenesis of herpetic stromal keratitis. J Virol. 75:9828-9835 (2001).
[cited by applicant]
CN Serial No. 201980013682.0 Office Action dated Sep. 2, 2022.
[cited by applicant]
IL310376 Israel Patent Application Office Action dated Jul. 22, 2024.
[cited by applicant]
JP Serial No. 2020-540442 Office Action dated Jan. 26, 2024.
[cited by applicant]
JP Serial No. 2022-529850 Office Action dated May 22, 2024.
[cited by applicant]
NZ766484 Office Action dated Feb. 3, 2025.
[cited by applicant]
U.S. Appl. No. 17/813,889 Non-Final Office Action dated Dec. 23, 2024.
[cited by applicant]
U.S. Appl. No. 17/830,298 Office Action dated Nov. 21, 2024.
[cited by applicant]
CN Serial No. 2022111886171 Office Action dated May 23, 2025.
[cited by applicant]
Drumm, Mitchell L., et al. Genetic variation and clinical heterogeneity in cystic fibrosis. Annual Review of Pathology: Mechanisms of Disease 7.1: 267-282. (2012).
[cited by applicant]
EA202392042 Office Action dated Feb. 17, 2025, and an English translation.
[cited by applicant]
EA202392042 Office Action dated Jun. 9, 2025, and an English translation.
[cited by applicant]
EP24210269.7 Extended European Search Report dated Mar. 24, 2025.
[cited by applicant]
KR20207023765 Notice of Allowance dated Jan. 16, 2025, and an English translation.
[cited by applicant]
U.S. Appl. No. 17/813,889 Final Office Action dated Jun. 13, 2025.
[cited by applicant]
U.S. Appl. No. 17/830,298 Office Action dated Jun. 3, 2025.
[cited by applicant]
U.S. Appl. No. 18/640,840 Non-Final Office Action dated Apr. 30, 2025.
[cited by applicant]
Yampolsky, Lev, et al., The Exchangeability of Amino Acids in Proteins. Genetics 170(4):1459-1472 (2005).
[cited by applicant]