Granted Patent
B2
US 12,600,769 · App. 18/165,845 · Granted Apr 14, 2026
Stable and soluble antibodies inhibiting VEGF
Assignee:
Novartis AG
C07K16/22C07K1/00C07K7/06C07K2317/24C07K2317/54C07K2317/55C07K2317/56C07K2317/565C07K2317/567C07K2317/622C07K2317/73C07K2317/92
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Abstract
The present invention relates to soluble and stable anti-VEGF imunobinders comprising CDRs from rabbit monoclonal antibodies. Said antibodies are designed for the diagnosis and/or treatment of VEGF-mediated disorders. The hybridomas, nucleic acids, vectors and host cells for expression of the recombinant antibodies of the invention, methods for isolating them and the use of said antibodies in medicine are also disclosed.
Claims (12)
1 . A method of treating a VEGF-mediated disease in a subject, comprising administering to the subject in need thereof a humanized antibody or antigen-binding fragment thereof, the humanized antibody comprising a variable heavy chain (VH), and a variable light chain (VL), wherein: the VH comprises CDRH1, CDRH2 and CDRH3 sequences of SEQ ID NO: 8, SEQ ID NO: 20 and SEQ ID NO: 32, respectively, and the VL comprises CDRL1, CDRL2, and CDRL3 sequences of SEQ ID NO: 43, SEQ ID NO: 55 and SEQ ID NO: 66, respectively, wherein the antibody or antigen-binding fragment thereof binds human VEGF 165 with an affinity (K d ) of ≤1×10 −9 M, and wherein the VEGF-mediated disease is age-related macular degeneration (AMD).
2 . The method of claim 1 , wherein the fragment is an scFv, a Fab fragment, a Fab′ fragment, or a F(ab′)2 fragment.
3 . The method of claim 1 , wherein the fragment is an scFv.
4 . The method of claim 1 , wherein the humanized antibody or antigen-binding fragment comprises a heavy chain variable region having at least 95% sequence identity to the sequence of SEQ ID NO: 164.
5 . The method of claim 4 , wherein the humanized antibody or antigen-binding fragment comprises a heavy chain variable region having the sequence of SEQ ID NO: 164.
6 . The method of claim 1 , wherein the humanized antibody or antigen-binding fragment comprises a light chain variable region having at least 95% sequence identity to the sequence of SEQ ID NO: 87.
7 . The method of claim 6 , wherein the humanized antibody or antigen-binding fragment comprises a light chain variable region having the sequence of SEQ ID NO: 87.
8 . The method of claim 1 , wherein the fragment is an scFv and wherein the heavy chain variable region and the light chain variable region are linked by the sequence of SEQ ID NO: 181.
9 . The method of claim 1 , wherein the humanized antibody or antigen-binding fragment comprises a heavy chain variable region having at least 90% sequence identity to the sequence of SEQ ID NO: 164.
10 . The method of claim 1 , wherein the humanized antibody or antigen-binding fragment comprises a light chain variable region having at least 90% sequence identity to the sequence of SEQ ID NO: 87.
11 . The method of claim 1 , wherein the humanized antibody or antigen-binding fragment thereof is formulated for intraocular administration.
12 . The method of claim 3 , wherein the antigen-binding fragment is administered and formulated for intraocular administration.
Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Nov 17, 2025
From: BORRAS, LEONARDO; URECH, DAVID; GUNDE, TEA
To: ESBATECH, AN ALCON BIOMEDICAL RESEARCH UNIT LLC
Reel/Frame 072926/0001 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jan 26, 2024
From: ESBATECH, A NOVARTIS COMPANY LLC
To: NOVARTIS AG
Reel/Frame 066375/0338 →
Continuity (10)
Division
13000423
Provisional Application
61155041
· Feb 24, 2009
Provisional Application
61075692
· Jun 25, 2008
Provisional Application
61075697
· Jun 25, 2008
Provisional Application
61133212
· Jun 25, 2008
References Cited (243)
US 4376110A
· David et al.
· 1983
[cited by applicant]
US 4881175A
· Ladner
· 1989
[cited by applicant]
US 4946778A
· Ladner et al.
· 1990
[cited by applicant]
US 5013653A
· Huston et al.
· 1991
[cited by applicant]
US 5091513A
· Huston et al.
· 1992
[cited by applicant]
US 5132405A
· Huston et al.
· 1992
[cited by applicant]
US 5225539A
· Winter
· 1993
[cited by applicant]
US 5226539A
· Cheng
· 1993
[cited by applicant]
US 5258498A
· Huston et al.
· 1993
[cited by applicant]
US 5260203A
· Ladner et al.
· 1993
[cited by applicant]
US 5455030A
· Ladner et al.
· 1995
[cited by applicant]
US 5476786A
· Huston et al.
· 1995
[cited by applicant]
US 5482858A
· Huston et al.
· 1996
[cited by applicant]
US 5530101A
· Queen et al.
· 1996
[cited by applicant]
US 5585089A
· Queen et al.
· 1996
[cited by applicant]
US 5693761A
· Queen et al.
· 1997
[cited by applicant]
US 5693762A
· Queen et al.
· 1997
[cited by applicant]
US 5730977A
· Ooka et al.
· 1998
[cited by applicant]
US 5859205A
· Adair et al.
· 1999
[cited by applicant]
US 6180370B1
· Queen et al.
· 2001
[cited by applicant]
US 6342219B1
· Thorpe et al.
· 2002
[cited by applicant]
US 6342221B1
· Thorpe et al.
· 2002
[cited by applicant]
US 6407213B1
· Carter et al.
· 2002
[cited by applicant]
US 6416758B1
· Thorpe et al.
· 2002
[cited by applicant]
US 6524583B1
· Thorpe et al.
· 2003
[cited by applicant]
US 6548640B1
· Winter
· 2003
[cited by applicant]
US 6576941B1
· Lee et al.
· 2003
[cited by applicant]
US 6632927B2
· Adair et al.
· 2003
[cited by applicant]
US 6639055B1
· Carter et al.
· 2003
[cited by applicant]
US 6676941B2
· Thorpe et al.
· 2004
[cited by applicant]
US 6703020B1
· Thorpe et al.
· 2004
[cited by applicant]
US 6815540B1
· Pluckthun et al.
· 2004
[cited by applicant]
US 6887468B1
· Thorpe et al.
· 2005
[cited by applicant]
US 6982321B2
· Winter
· 2006
[cited by applicant]
US 6986890B1
· Shitara et al.
· 2006
[cited by applicant]
US 7022500B1
· Queen et al.
· 2006
[cited by applicant]
US 7052693B2
· Shitara et al.
· 2006
[cited by applicant]
US 7056509B2
· Thorpe et al.
· 2006
[cited by applicant]
US 7227004B2
· Kim
· 2007
[cited by applicant]
US 7241877B2
· Adair et al.
· 2007
[cited by applicant]
US 7244615B2
· Adair et al.
· 2007
[cited by applicant]
US 7244832B2
· Adair et al.
· 2007
[cited by applicant]
US 7262050B2
· Adair et al.
· 2007
[cited by applicant]
US 7375193B2
· Baca et al.
· 2008
[cited by applicant]
US 7482005B2
· Kim
· 2009
[cited by applicant]
US 7803371B2
· Ke et al.
· 2010
[cited by applicant]
US 8293235B2
· Borras et al.
· 2012
[cited by applicant]
US 8349322B2
· Borras et al.
· 2013
[cited by applicant]
US 8673310B2
· Borras et al.
· 2014
[cited by applicant]
US 8937162B2
· Borras et al.
· 2015
[cited by applicant]
US 9090684B2
· Borras
· 2015
[cited by examiner]
US 9422366B2
· Borras et al.
· 2016
[cited by applicant]
US 9593161B2
· Borras et al.
· 2017
[cited by applicant]
US 9873737B2
· Borras et al.
· 2018
[cited by applicant]
US 20030023046A1
· Ferrara et al.
· 2003
[cited by applicant]
US 20050033031A1
· Couto
· 2005
[cited by applicant]
US 20050048578A1
· Zhang
· 2005
[cited by applicant]
US 20060099204A1
· Couto et al.
· 2006
[cited by applicant]
US 20060280747A1
· Fuh et al.
· 2006
[cited by applicant]
US 20070020267A1
· Fuh et al.
· 2007
[cited by applicant]
US 20070190058A1
· Shams
· 2007
[cited by applicant]
US 20080112952A1
· Finger
· 2008
[cited by applicant]
US 20080226629A1
· Baca et al.
· 2008
[cited by applicant]
US 20080248033A1
· Ferrara et al.
· 2008
[cited by applicant]
US 20090081232A1
· Kim
· 2009
[cited by applicant]
US 20110117091A1
· Borras et al.
· 2011
[cited by applicant]
US 20110135644A1
· Hulmann-Cottier et al.
· 2011
[cited by applicant]
US 20110152505A1
· Urech et al.
· 2011
[cited by applicant]
US 20120014958A1
· Borras et al.
· 2012
[cited by applicant]
US 20140004114A1
· Borras et al.
· 2014
[cited by applicant]
US 20150274820A1
· Borras et al.
· 2015
[cited by applicant]
US 20180072802A1
· Borras et al.
· 2018
[cited by applicant]
US 20180127493A1
· Borras et al.
· 2018
[cited by applicant]
US 20180371074A1
· Borras et al.
· 2018
[cited by applicant]
US 20200172608A1
· Borras et al.
· 2020
[cited by applicant]
US 20200190179A1
· Sigg et al.
· 2020
[cited by applicant]
US 20200270336A1
· Zhang et al.
· 2020
[cited by applicant]
US 20210017266A1
· Racine et al.
· 2021
[cited by applicant]
CN 1445242A
· 2003
[cited by applicant]
EP 1179541B1
· 2004
[cited by applicant]
EP 0817648B1
· 2004
[cited by applicant]
EP 1627643A2
· 2006
[cited by applicant]
EP 1238986B1
· 2008
[cited by applicant]
EP 1975181B1
· 2011
[cited by applicant]
EP 3216803A1
· 2017
[cited by applicant]
EP 3722310A1
· 2020
[cited by applicant]
WO 8906692A1
· 1989
[cited by applicant]
WO 9101753A1
· 1991
[cited by applicant]
WO 9845331A2
· 1998
[cited by applicant]
WO 0130393A2
· 2001
[cited by applicant]
WO 0148017A1
· 2001
[cited by applicant]
WO 03080672A1
· 2003
[cited by applicant]
WO 03097697A2
· 2003
[cited by applicant]
WO 2004016740A2
· 2004
[cited by applicant]
WO 2005000900A1
· 2005
[cited by applicant]
WO 2005012359A2
· 2005
[cited by applicant]
WO 2005016950A1
· 2005
[cited by applicant]
WO 2005054273A2
· 2005
[cited by applicant]
WO 2006012688A1
· 2006
[cited by applicant]
WO 2006047325A1
· 2006
[cited by applicant]
WO 2006050491A2
· 2006
[cited by applicant]
WO 2007019620A1
· 2007
[cited by applicant]
WO 2007089445A2
· 2007
[cited by applicant]
WO 2007140534A1
· 2007
[cited by applicant]
WO 2008006235A2
· 2008
[cited by applicant]
WO 2008063932A2
· 2008
[cited by applicant]
WO 2008110348A1
· 2008
[cited by applicant]
WO 2008149147A2
· 2008
[cited by applicant]
WO 2008149148A2
· 2008
[cited by applicant]
WO 2009000098A2
· 2008
[cited by applicant]
WO 2009000099A2
· 2008
[cited by applicant]
WO 2009155724A2
· 2009
[cited by applicant]
WO 2009155725A1
· 2009
[cited by applicant]
WO 2009155726A2
· 2009
[cited by applicant]
Adamis, et al., Inhibition of Vascular Endothelial Growth Factor Prevents Retinal Ischemia\p=m-\Associated Iris Neovascularization in a Nonhuman Primate, Arch Ophthalmol., 1996, 66-71, 114.
[cited by applicant]
Aiello, et al., Vascular Endothelial Growth Factor in Ocular Fluid of Patients With Diabetic Retinopathy and Other Retinal Disorders, N Engl J Med, Dec. 1, 1994, 480-487, 331.
[cited by applicant]
Alfthan, et al., Properties of a single-chain antibody containing different linker peptides, Protein Engineering, 1995, 725-731, 8(7).
[cited by applicant]
Allen, Ligand-Targeted Therapeutics in Anticancer Therapy, Nature Reviews Cancer, Oct. 2002, 750-763, 2.
[cited by applicant]
Asano, et al., An Anti-Human VEGF Monoclonal Antibody, MV833, That Exhibits Potent Anti-Tumor Activity In Vivo, Hybridoma, 1998, 185-190, 17(2).
[cited by applicant]
Banyay, et al., Three-Dimensional Imaging of In Situ Specimens with Low-Dose Electron Tomography to Analyze Protein Conformation, ASSAY and Drug Development Technologies, 2004, 561-567, 2(5).
[cited by applicant]
Berkman, et al., Expression of the Vascular Permeability Factor/Vascular Endothelial Growth Factor Gene in Central Nervous System Neoplasms, J Clin Invest, 1993, 153-159, 91.
[cited by applicant]
Bird, et al., Single-Chain Antigen-Binding Proteins, Science, Oct. 21, 1988, 423-426, 242.
[cited by applicant]
Borgstrom, et al., Complete Inhibition of Angiogenesis and Growth of Microtumors by Anti-Vascular Endothelial Growth Factor Neutralizing Antibody: Novel Concepts of Angiostatic Therapy from Intravital Videomicroscopy, C…
[cited by applicant]
Boulton, et al., VEGF localisation in diabetic retinopathy, British Journal of Ophthalmology, 1998, 561-568, 82(5).
[cited by applicant]
Brennan, et al., Preparation of Bispecific Antibodies by Chemical Recombination of Monoclonal Immunoglobulin G1 Fragments, Science, Jul. 5, 1985, 81-83, 229.
[cited by applicant]
Brown, et al., Expression of Vascular Permeability Factor (Vascular Endothelial Growth Factor) and Its Receptors in Adenocarcinomas of the Gastrointestinal Tract, Cancer Research, Oct. 1, 1993, 4727-4735, 53.
[cited by applicant]
Brown, et al., Expression of Vascular Permeability Factor (Vascular Endothelial Growth Factor) and Its Receptors in Breast Cancer, Human Pathology, 1995, 86-91, 26.
[cited by applicant]
Brummell, et al., Probing the Combining Site of an Anti-Carbohydrate Antibody by Saturation-Mutagenesis: Role of the Heavy-Chain CDR3 Residues, Biochemistry, 1993, 1180-1187, 32(4).
[cited by applicant]
Burks, et al., In vitro scanning saturation mutagenesis of an antibody binding pocket, Proc. Natl. Acad. Sci. USA, Jan. 1997, 412-417, 94.
[cited by applicant]
Choi, et al., Recombinant chimeric OKT3 scFv IgM antibodies mediate immune suppression while reducing T cell activation in vitro, Eur J Immunol, 2001, 94-106, 31.
[cited by applicant]
Cilley, et al., Bevacizumab in the treatment of colorectal cancer, Expert Opinion on Biological Therapy, May 3, 2007, 739-749, 7(5).
[cited by applicant]
Clinical Trial NCT01304693, Feb. 25, 2011, available at https://www.clinicaltrials.gov/ct2/show/NCT01304693.
[cited by applicant]
Clinical Trial NCT01796964, Feb. 22, 2013, available at https://www.clinicaltrials.gov/ct2/show/NCT01796964.
[cited by applicant]
Clinical Trial NCT01849692, May 8, 2013, available at https://www.clinicaltrials.gov/ct2/show/NCT01849692.
[cited by applicant]
Clinical Trial NCT02307682, Feb. 11, 2020, available at https://www.clinicaltrials.gov/ct2/show/NCT04264819.
[cited by applicant]
Clinical Trial NCT02434328, Feb. 11, 2020, available at https://www.clinicaltrials.gov/ct2/show/NCT02434328.
[cited by applicant]
Clinical Trial NCT02507388, Jul. 23, 2015, available at https://www.clinicaltrials.gov/ct2/show/NCT02507388.
[cited by applicant]
Clinical Trial NCT03386474, Dec. 29, 2017, available at https://www.clinicaltrials.gov/ct2/show/NCT03386474.
[cited by applicant]
Clinical Trial NCT03481634, Mar. 29, 2018, available at https://www.clinicaltrials.gov/ct2/show/NCT03481634.
[cited by applicant]
Clinical Trial NCT03481660, Mar. 29, 2018, available at https://www.clinicaltrials.gov/ct2/show/NCT03481660.
[cited by applicant]
Clinical Trial NCT03710564, Oct. 18, 2018, available at https://www.clinicaltrials.gov/ct2/show/NCT03710564.
[cited by applicant]
Clinical Trial NCT03802630, Jan. 14, 2019, available at https://www.clinicaltrials.gov/ct2/show/NCT03802630.
[cited by applicant]
Clinical Trial NCT03810313, Jan. 18, 2019, available at https://www.clinicaltrials.gov/ct2/show/NCT03810313.
[cited by applicant]
Clinical Trial NCT03917472, Apr. 17, 2019, available at https://www.clinicaltrials.gov/ct2/show/NCT03917472.
[cited by applicant]
Clinical Trial NCT03930641, Apr. 29, 2019, available at https://www.clinicaltrials.gov/ct2/show/NCT03930641.
[cited by applicant]
Clinical Trial NCT03954626, May 17, 2019, available at https://www.clinicaltrials.gov/ct2/show/NCT03954626.
[cited by applicant]
Clinical Trial NCT04005352, Jul. 2, 2019, available at https://www.clinicaltrials.gov/ct2/show/NCT04005352.
[cited by applicant]
Clinical Trial NCT04047472, Aug. 6, 2019, available at https://www.clinicaltrials.gov/ct2/show/NCT04047472.
[cited by applicant]
Clinical Trial NCT04058067, Aug. 15, 2019, available at https://www.clinicaltrials.gov/ct2/show/NCT04058067.
[cited by applicant]
Clinical Trial NCT04079231, Sep. 6, 2019, available at https://www.clinicaltrials.gov/ct2/show/NCT04079231.
[cited by applicant]
Clinical Trial NCT04239027, Jan. 23, 2020, available at https://www.clinicaltrials.gov/ct2/show/NCT04239027.
[cited by applicant]
Clinical Trial NCT04264819, Feb. 11, 2020, available at https://www.clinicaltrials.gov/ct2/show/NCT04264819.
[cited by applicant]
Clinical Trial NCT04278417, Feb. 20, 2020. available at https://www.clinicaltrials.gov/ct2/show/NCT04278417.
[cited by applicant]
Clinical Trial NCT04287348, Feb. 27, 2020, available at https://www.clinicaltrials.gov/ct2/show/NCT04287348.
[cited by applicant]
Clinical Trial NCT04543331, Sep. 10, 2020, available at https://www.clinicaltrials.gov/ct2/show/NCT04543331.
[cited by applicant]
Clinical Trial NCT04597632, Oct. 22, 2020, available at https://www.clinicaltrials.gov/ct2/show/NCT04597632.
[cited by applicant]
Clinical Trial NCT04662944, Dec. 10, 2020, available at https://www.clinicaltrials.gov/ct2/show/NCT04662944.
[cited by applicant]
Clinical Trial NCT04679935, Dec. 22, 2020, available at https://www.clinicaltrials.gov/ct2/show/NCT04679935.
[cited by applicant]
Clinical Trial NCT05112835, Nov. 9, 2021, available at https://www.clinicaltrials.gov/ct2/show/NCT05112835.
[cited by applicant]
Cornette, et al., Hydrophobicity Scales and Computational Techniques for Detecting Amphipathic Structures in Proteins, J. Mol. Biol., 1987, 659-685, 195.
[cited by applicant]
De Pascalis, et al., Grafting of “Abbreviated” Complementarity-Determining Regions Containing Specifity-Determining Residues Essential for Ligand Contact to Engineer a Less Immunogenic Humanized Monoclonal Antibody, The…
[cited by applicant]
De Vries, et al., The fms-Like Tyrosine Kinase, a Receptor for Vascular Endothelial Growth Factor, Science, Feb. 21, 1992, 989-991, 255.
[cited by applicant]
Dugel, et al., Hawk and Harrier: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration, Ophthalmology, Jan. 2020, 72-84, 127(1).
[cited by applicant]
Dumoulin, et al., Single-domain antibody fragments with high conformational stability, Protein Science, 2002, 500-515, 11.
[cited by applicant]
Dvorak, et al., Vascular Permeability FactorNascular Endothelial Growth Factor, Microvascular Hyperpermeability, and Angiogenesis, American Journal of Pathology, May 1995, 1029-1039, 146(5).
[cited by applicant]
Eng, et al., Ranibizumab in neovascular age-related macular degeneration, Clinical Interventions in Aging, 2006, 451-466, 1(4).
[cited by applicant]
Ferrara, et al., The Biology of Vascular Endothelial Growth Factor, Endocrine Reviews, Feb. 1997, 4-25, 18 (1).
[cited by applicant]
Fogarty et al., Learning from angiogenesis trial failures: disappointment collides with optimism. (Research), The Scientist, Mar. 18, 2002, 33, vol. 16 Issue 6.
[cited by applicant]
Folkman, et al., Angiogenesis, The Journal of Biological Chemistry, Jun. 5, 1992, 10931-10934, 267(16).
[cited by applicant]
Foote, et al., Antibody Framework Residues Affecting the Conformation of the Hypervariable Loops, J. Mol. Biol., 1992, 487-499, 224.
[cited by applicant]
Fuh, et al., Structure-Function Studies of Two Synthetic Anti-vascular Endothelial Growth Factor Fabs and Comparison with the AvastinTM Fab., The Journal of Biological Chemistry, Mar. 10, 2006, 6625-6631, 281(10).
[cited by applicant]
Glennie, et al., Preparation and Performance of bispecific F(ab′ gamma)2 antibody containing thioether-linked Fab′ gamma fragments, The Journal of Immunology, Oct. 1, 1987, 2367-2375, 139.
[cited by applicant]
Hamers-Casterman, et al., Naturally occurring antibodies devoid of light chains, Nature, Jun. 3, 1993, 446-448, 363.
[cited by applicant]
Holliger, et al., “Diabodies”: Small bivalent and bispecific antibody fragments, Proc. Natl. Acad. Sci. USA, Jul. 1993, 6444-6448, 90.
[cited by applicant]
Honegger, et al., Yet Another Numbering Scheme for Immunoglobulin Variable Domains: An Automatic Modeling and Analysis Tool, Journal of Molecular Biology, 2001, 657-670, 309.
[cited by applicant]
Horak, et al., Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer, The Lancet, Nov. 7, 1992, 1120-1124, 340.
[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, 1991, 1806-1814, 5.
[cited by applicant]
Hu, et al., Minibody: A Novel Engineered Anti-Carcinoembryonic Antigen Antibody Fragment (Single-Chain Fv-CH3) Which Exhibits Rapid, High-Level Targeting of Xenografts, Cancer Research, Jul. 1, 1996, 3055-3061, 56.
[cited by applicant]
Huston, et al., Protein engineering of antibody binding sited: recovery of specific activity in an anti-digoxin single-chain Fv analogue produced in
[cited by applicant]
Jones, et al., Replacing the complementarity determining regions in a human antibody with those from a mouse, Nature, May 29, 1986, 522-525, 321.
[cited by applicant]
Karpovsky, et al., Production of Target-Specific Effector Cells Using Hetero-Cross-Linked Aggrehates Containing Anti-Target Cell and Anti-Fcy Receptor Antibodies, Journal of Experimental Medicine, Dec. 1984, 1686-1701, …
[cited by applicant]
Kim, et al., Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo, Nature, Apr. 29, 1993, 841-844, 362.
[cited by applicant]
Kipriyanov, et al., Bispecific Tandem Diabody for Tumor Therapy with Improved Antigen Binding and Pharmacokinetics, J. Mol. Biol., 1999, 41-56, 293.
[cited by applicant]
Klagsbrun, Regulators of Angiogenesis, Annu Rev Physiol, 1991, 217-239, 53.
[cited by applicant]
Kobayashi, et al., Tryptophan H33 plays an important role in pyrimidine (6-4) pyrimidone photoproduct binding by a high-affinity antibody, Protein Engineering, 1999, 879-884, 12(10).
[cited by applicant]
Kohno, et al., Neutralizing Effects of an Anti-Vascular Endothelial Growth Factor Antibody on Tooth Movement, Angle Orthodontist, 2005, 797-804, 75(5).
[cited by applicant]
Leung, et al., Vascular Endothelial Growth Factor Is a Secreted Angiogenic Mitogen, Science, Dec. 8, 1989, 1306-1309, 246.
[cited by applicant]
Liang, et al., Cross-species vascular endothelial growth factor (VEGF)-blocking antibodies completely inhibit the growth of human tumor xenografts and measure the contribution of stromal VEGF, The Journal of Biological …
[cited by applicant]
Liu, et al., Heteroantibody duplexes target cells for lysis by cytotoxic T lymphocytes, Proc. Natl. Acad. Sci. USA, Dec. 1985, 8648-8652, 82.
[cited by applicant]
Lopez, et al., Transdifferentiated Retinal Pigment Epithelial Cells Are Immunoreactive for Vascular Endothelial Growth Factor in Surgically Excised Age-Related Macular Degeneration- Related Choroidal Neovascular Membran…
[cited by applicant]
MacCallum, et al., Antibody-antigen Interactions: Contact Analysis and Binding Site Topography, Journal of Molecular Biology, 1996, 732-745, 262.
[cited by applicant]
MacChiarini, et al., Relation of neovascularisation to metastasis of non-small-cell lung cancer, The Lancet, Jul. 18, 1992, 145-146, 340.
[cited by applicant]
Mattern, et al., Association of vascular endothelial growth factor expression with intratumoral micro vessel density and tumour cell proliferation in human epidermoid lung carcinoma, British Journal of Cancer, 1996, 931…
[cited by applicant]
Matthews, et al., A receptor tyrosine kinase cDNA isolated from a population of enriched primitive hematopoietic cells and exhibiting close genetic linkage to c-kit, Proc. Natl. Acad. Sci. USA, Oct. 1991, 9026-9030, 88.
[cited by applicant]
Melnyk, et al., Vascular Endothelial Growth Factor Promotes Tumor Dissemination by a Mechanism Distinct from Its Effect on Primary Tumor Growth, Cancer Research, Feb. 15, 1996, 921-924, 56.
[cited by applicant]
Moore, et al., Kinetics and Thermodynamics of Dimer Formation and Dissociation for a Recombinant Humanized Monoclonal Antibody to Vascular Endothelial Growth Factor, Biochemistry, 1999, 13960-13967, 38.
[cited by applicant]
Muller, et al., VEGF and the Fab fragment of a humanized neutralizing antibody: crystal structure of the complex at 2.4 Å resolution and mutational analysis of the interface, Structure, Sep. 15, 1998, 1153-1167, 6(9).
[cited by applicant]
Myers, et al., Optimal alignments in linear space, Cabios, 1988, 11-17, 4(1).
[cited by applicant]
NCBI Reference Sequence: NP 003367.4, Vascular endothelial growth factor A isoform b [
[cited by applicant]
Needleman, et al., A General Method Applicable to the Search for Similarities in the Amino Acid Sequence of Two Proteins, Journal of Molecular Biology, 1970, 443-453, 48.
[cited by applicant]
Pastan, et al., Overview: Immunotoxins in cancer therapy, Current Opinion in Investigational Drugs, 2002, 1089-1091, 3(7).
[cited by applicant]
Paulus, Preparation and Biomedical Applications of Bispecific Antibodies, Behring Institute Mitteilungen, 1985, 118-132, 78.
[cited by applicant]
Payne, Progress in immunoconjugate cancer therapeutics, Cancer Cell, Mar. 2003, 207-212, 3.
[cited by applicant]
Popkov, et al., Human/mouse cross-reactive anti-VEGF receptor 2 recombinant antibodies selected from an immune b9 allotype rabbit antibody library, Journal of Immunological Methods, 2004, 149-164, 288.
[cited by applicant]
Queen, et al., A humanized antibody that binds to the interleukin 2 receptor, Proc. Natl. Acad. Sci. USA, Dec. 1989, 10029-10033, 86.
[cited by applicant]
Rader, et al., The Rabbit Antibody Repertoire as a Novel Source for the Generation of Therapeutic Human Antibodies, The Journal of Biological Chemistry, May 5, 2000, 13668-13678, 275(18).
[cited by applicant]
Ran, et al., Generation of new rabbit monoclonal antibody RAM-1 against human VEGF-C, Proc Amer Assoc Cancer Res, May 1, 2005, 911, 46.
[cited by applicant]
Riechmann, et al., Reshaping human antibodies for therapy, Nature, Mar. 24, 1988, 323-327, 332.
[cited by applicant]
Roitt, et al., Antibodies and cell receptors for them, Immunology, 2000, 97-109, chapter 6.
[cited by applicant]
Roovers, et al., In vitro characterisation of a monovalent and bivalent form of a fully human anti Ep-CAM phage antibody, Cancer Immunol Immunother, 2001, 51-59, 50.
[cited by applicant]
Rose, et al., Hydrophobicity of Amino Acid Residues in Globular Proteins, Science, Aug. 30, 1985, 834-838, 229.
[cited by applicant]
Rossi, et al., A Comparative Study Between a Novel Category of Immunoreagents and the Corresponding Mouse Monoclonal Antibodies, Am J Clin Pathol, 2005, 295-302, 124.
[cited by applicant]
Rudikoff, et al., Single amino acid substitution altering antigen-binding specificity, PNAS, Mar. 1982, 1979-1983, 79.
[cited by applicant]
Saito, et al., Drug delivery strategy utilizing conjugation via reversible disulfide linkages: role and site of cellular reducing activities, Advanced Drug Delivery Reviews, 2003, 199-215, 55.
[cited by applicant]
Shibuya, et al., Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (fit) closely related to the fms family, Oncogene, 1990, 519-524, 5.
[cited by applicant]
Singh, et al., Modeling and predicting clinical efficacy for drugs targeting the tumor milieu, Nature Biotechnology, Jul. 2012, 648-657, 30(7).
[cited by applicant]
Skerra, et al., Assembly of a Functional Immunoglobulin F, Fragment in
[cited by applicant]
Sone, et al., Neutralization of Vascular Endothelial Growth Factor Prevents Collagen-Induced Arthritis and Ameliorates Established Disease in Mice, Biochemical and Biophysical Research Communications, 2001, 562-568, 281.
[cited by applicant]
Steinberger, et al., Generation and Characterization of a Recombinant Human CCR5-specific Antibody, The Journal of Biological Chemistry, Nov. 17, 2000, 36073-36078, 275(46).
[cited by applicant]
Tamura, et al., Structural Correlates of an Anticarcinoma Antibody: Identification of Specificity-Determining Residues (SDRs) and Development of a Minimally Immunogenic Antibody Variant by Retention of SDRs Only, The Jo…
[cited by applicant]
Teplyakov, et al., Antibody modeling assessment II. Structures and models, Proteins, 2014, 1563-1582, 82.
[cited by applicant]
Terman, et al., Identification of a new endothelial cell growth factor receptor tyrosine kinase, Oncogene, 1991, 1677-1683, 6.
[cited by applicant]
Terman, et al., Identification of the KDR Tyrosine Kinase as a Receptor for Vascular Endothelial Cell Growth Factor, Biochemical and Biophysical Research Communications, Sep. 30, 1992, 1579-1586, 187(3).
[cited by applicant]
Thorpe, et al., The Preparation and Cytotoxic Properties of Antibody-Toxin Conjugates, Immunological Reviews, 1982, 119-158, 62.
[cited by applicant]
Trail, et al., Monoclonal antibody drug immunoconjugates for targeted treatment of cancer, Cancer Immunol Immunother, 2003, 328-337, 52.
[cited by applicant]
Vajdos, et al., Comprehensive Functional Maps of the Antigen-binding Site of an Anti-ErbB2 Antibody Obtained with Shotgun Scanning Mutagenesis, Journal of Molecular Biology, 2002, 415-428, 320.
[cited by applicant]
Mlches-Moure, et al., Comparison of rabbit monoclonal and mouse monoclonal antibodies in immunohistochemistry in canine tissues, J Vet Diagn Invest, 2005, 346-350, 17.
[cited by applicant]
Wang, et al., The effect of antibody against vascular endothelial growth factor on tumor growth and metastasis, J Cancer Res Clin Oncol, 1998, 615-620, 124.
[cited by applicant]
Warren, et al., Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis, The Journal of Clinical Investigation, Apr. 1995, 1789-1797, 95(4).
[cited by applicant]
Weidner, et al., Tumor Angiogenesis and Metastasis—Correlation in Invasive Breast Carcinoma, The New England Journal of Medicine, Jan. 3, 1991, 1-6, 324(1).
[cited by applicant]
Wu, et al., Humanization of a Murine Monoclonal Antibody by Simultaneous Optimization of Framework and CDR Residues, Journal of Molecular Biology, 1999, 151-162, 294.
[cited by applicant]
Yannuzzi, et al., Brolucizumab: evidence to date in the treatment of neovascular age-related macular degeneration, Clinical Ophthalmology, 2019, 1323-1329, 13.
[cited by applicant]
Yu, et al., Interaction between Bevacizumab and Murine VEGF-A: A Reassessment, Investigative Ophthalmology & Visual Science, Feb. 2008, 522-527, 49(2).
[cited by applicant]
Zhang et al., EPI0030, a humanized anti-VEGF rabbit monoclonal antibody, exhibits potent activity in preclinical models, 2009 AACR Annual Meeting, Apr. 19, 2009, 1 page, Denver Colorado.
[cited by applicant]
International Search Report and Written Opinion for International Application No. PCT/CH09/00220 dated Feb. 8, 2010.
[cited by applicant]
Zhang et al., “Abstract #1235: EPI0030, a humanized anti-VEGF rabbit monoclonal antibody, exhibits potent activity in preclinical models.” Proc Am Assoc Cancer Res; vol. 50, p. 296, Apr. 22, 2009.
[cited by applicant]