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(12) United States Patent (10) Patent No.: US 9,078,860 B2 Szkudlinski Et Al

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(12) United States Patent (10) Patent No.: US 9,078,860 B2 Szkudlinski Et Al US00907886OB2 (12) United States Patent (10) Patent No.: US 9,078,860 B2 Szkudlinski et al. (45) Date of Patent: Jul. 14, 2015 (54) VEGF ANALOGS 6,020,473 A 2/2000 Keytet al. 6,057,428 A * 5/2000 Keytet al. ..................... 530.399 (71) Applicant: Trophogen Inc., Rockville, MD (US) 2: R R388 Rita etal (72) Inventors: Mariusz W. Szkudlinski, Rockville, g: R 839; Snowski et al. MD (US); Bruce D. Weintraub, 6,291,740 B1 9, 2001 Bremel et al. Rockville, MD (US) 6,361,992 B1 3/2002 Szkudlinski et al. 6,475,796 B1 1 1/2002 Pollitt et al. (73) Assignee: Trophogen, Inc., Rockville, MD (US) 3. R 1 838, (his et al. 7.005.505 B 2.2006 Keytet al. (*) Notice: Subject to any disclaimer, the term of this 2001, 0046521 A1 11, 2001 E. al. patent is extended or adjusted under 35 2003/0064922 A1 4/2003 Nissen et al. U.S.C. 154(b) by 0 days. 2004/0265972 A1 12/2004 Weintraub et al. 2005.0054036 A1 3/2005 Bates et al. 21) Appl. No.: 14/312,446 (21) App 9 FOREIGN PATENT DOCUMENTS (22) Filed: Jun. 23, 2014 JP 1998-511557 11, 1998 O O JP 2000-507456 6, 2000 (65) Prior Publication Data JP 2001-5.17075 10, 2001 JP 2003-5 17275 5, 2003 US 2014/0308264 A1 Oct. 16, 2014 WO 90.08832 8, 1990 WO 97.08313 3, 1997 Related U.S. Application Data WO 98,07832 2, 1998 WO OOf 17360 3, 2000 (62) Division of application No. 12/089,296, filed as WO OO,25805 5, 2000 application No. PCT/US2006/039181 on Oct. 6, 2006, WO 2005/042575 5, 2005 now Pat. No. 8,759,285. WO 2005, O724.17 8, 2005 (60) Provisional application No. 60/808,106, filed on May OTHER PUBLICATIONS 25, 2006, provisional application No. 60/723,917, Keytet al., “Identification of vascular endothelial growth factor deter filed on Oct. 6, 2005. minants for binding KDR and FLT-1 receptors. Generation of recep tor-selective VEGF variants by site-directed mutagenesis,” Journal of (51) Int. Cl. Biological Chemistry, 271 (10):5638-5646 (1998). A6 IK38/8 (2006.01) Siemeister et al., “An antagonistic vascular endothelial growth factor A6 IK38/6 (2006.01) (VEGF) variant inhibits VEGF-stimulated receptor A6 IK38/17 (2006.01) autophosphorylation and proliferation of human endothelial cells.” C07K I4/475 (2006.01) Proc. Natl Acad Sci USA, 95(8): 4625-4629 (1998). C07K I4/52 (2006.01) Lietal. “Receptor-selective Variants of Human Vascular Endothelial A6 IK 45/06 (2006.01) Growth Factor.” Journal of Biological Chemistry, 275 (38): 29823-8 A61 K38/00 (2006.015 (1998). (52) U.S. Cl. * cited by examiner CPC ............. A61K 38/1866 (2013.01); A61K 45/06 (2013.01); C07K 14/475 (2013.01); C07K Primary Examiner — Christine J Saoud 14/52 (2013.01); A61 K38/00 (2013.01) Assistant Examiner — Jon M Lockard (58) Field of Classification Search (74) Attorney, Agent, or Firm — Morgan Lewis & Bockius None LLP See application file for complete search history. (57) ABSTRACT (56) References Cited Modified VEGF proteins that inhibit VEGF-mediated activa U.S. PATENT DOCUMENTS tion or proliferation of endothelial cells are disclosed. The analogs may be used to inhibit VEGF-mediated activation of 4.902,505 A 2/1990 Pardridge et al. endothelial cells in angiogenesis-associated diseases Such as 5,008,050 A 4, 1991 Cullis et al. 5,017,566 A 5, 1991 Bodor cancer, inflammatory diseases, eye diseases, and skin disor 5,380,531 A 1/1995 Chakrabarti et al. ders. 5,604,198 A 2f1997 Poduslo et al. 5,612,034 A 3/1997 Pouletty et al. 22 Claims, 6 Drawing Sheets U.S. Patent Jul. 14, 2015 Sheet 1 of 6 US 9,078,860 B2 Figure 1A Binding of VEGF mutants&WT to imobilized KOR-FC 2500 e 83K 2000 WT 1500 5 1000 500 O 10-6 10-6 10-4 10-3 10-2 10-1 100 VEGF(ug/ml) Figure 1B HUVEC-2 Cell Proliferation Assay-Glo 225 Wt 200 o 83K 175 s S 150 O 125 SS 100 75 HTTTo TTTIn-Tim-Trim-Trim-rrttem-rm 0 10-13 10-12 10-11 10-10 10-0 0-0 0- 0-8 VEGF (M) U.S. Patent Jul. 14, 2015 Sheet 2 of 6 US 9,078,860 B2 Figure 2A Yeast VEGF Mutants Binding Assay 125 e Y-VEGF A3H 100 E44R 75 O O HTTTwo-TTTTwo-rrnu-TTTTTTm-rrm-Trium 0 1013 10-12 10-11 101 100 10 10-7 10-8 VEGF (M) Figure 2B HUVEC-2 Cell Proliferation Assay-Glo 225 Wt 200 o E44R 175 150 125 100 - 0 10-13 10-1210-11 10-10 0-0 0-0 0-7 10-8 VEGF (M) U.S. Patent Jul. 14, 2015 Sheet 3 of 6 US 9,078,860 B2 Figure 3A Yeast VEGF Mutants Binding Assay 125 e Y-VEGF A3 100 a EE72/73RR 75 SO 25 0 1-S 1012 101 10-10 10 0 107 10 VEGF (M) Figure 3B HUVEC-2 Cell Proliferation Assay-Glo 225 Wt 200 o EE7273/RR 175 150 125 10-G =c 75 -trator TTTTTTTTTTTTTTTTTTo-Trp-rate 0 10-13 10-12 101110-10 10-0 10-s 10-7 10-8 VEGF (M) U.S. Patent Jul. 14, 2015 Sheet 5 of 6 US 9,078,860 B2 G?un61-I ?onu?suoo?seeA6u?pu?gHQXÁessW 0000Z (INdo) punoq-93A-l U.S. Patent Jul. 14, 2015 Sheet 6 of 6 US 9,078,860 B2 eunfil-l9 ?sea?10.nu?suooNCIX6u?pu?ºKessy 0000Z 0000|| (Wido) punoq-93A-l US 9,078,860 B2 1. 2 VEGF ANALOGS KDR is the predominant receptor in angiogenic signaling, whereas Flt-1 is associated with the regulation of blood vessel CROSS-REFERENCE TO RELATED morphogenesis and Flt-4 regulates lymphangiogenesis. APPLICATIONS These receptors are expressed almost exclusively on endot helial cells, with a few exceptions such as the expression of This application claims the benefit of U.S. Provisional Flt-1 in monocytes where it mediates chemotaxis (Barleon et Application No. 60/723,917, filed Oct. 6, 2005, and U.S. al., 1996, Blood. 87: 3336-3343). Provisional Application No. 60/808,106, filed May 25, 2006, VEGF receptors are closely related to Fms, Kit and PDGF which are herein incorporated by reference in their entireties. receptors. They consist of seven extracellular immunoglobu 10 lin (Ig)-like domains, a transmembrane (TM) domain, a regu SEQUENCE LISTING SUBMISSION VIA latory juxtamembrane domain, an intracellular tyrosine EFS-WEB kinase domain interrupted by a short peptide, the kinase insert domain, followed by a sequence carrying several tyrosine A computer readable text file, entitled “056815-5005-01 residues involved in recruiting downstream signaling mol SequenceListing..txt created on or about Jun. 20, 2014, with 15 ecules. Mutation analysis of the extracellular domains of a file size of about 146 kb contains the sequence listing for this Flt-1 and KDR show that the second and third Ig-like domains application and is hereby incorporated by reference in its constitute the high-affinity ligand-binding domain for VEGF entirety. with the first and fourth Ig domains apparently regulating ligand binding and receptor dimerization, respectively FIELD OF INVENTION (Davis-Smyth et al., 1998, J. Biol. Chem. 273: 3216-3222: Fuh et al., 1998, J. Biol. Chem. 273: 11197-11204; and Shin This application relates to the design and use of vascular kai et al., 1998, J. Biol. Chem. 273:31283-31288). Receptor endothelial growth factor (VEGF) analogs as VEGF receptor tyrosine kinases are activated upon ligand-mediated receptor antagonists to inhibitor reduce angiogenesis for the treatment dimerization (Hubbard, 1991, Prog. Biophys. Mol. Biol. 71: of conditions and diseases associated with angiogenesis. The 25 343-358: Jiang and Hunter, 1999, Curr. Biol. 9: R568-R571; application also discloses VEGF analogs that exhibit and Lemmon and Schlessinger, 1998, Methods Mol. Biol. 84: increased receptor binding affinity to native receptors such as 49-71). Signal specificity of VEGF receptors is further modu KDR. lated upon recruitment of coreceptors, such as neuropilins, heparin Sulfate, integrins or cadherins. BACKGROUND OF INVENTION 30 VEGF molecules interact with one or more tyrosine kinase receptors during angiogenesis. For instance, VEGF-A acts Vascular endothelial growth factors (VEGFs) regulate predominantly through KDR and Flt-1. VEGF-C and blood and lymphatic vessel development. They are predomi VEGF-D similarly are specific ligands for KDR and nantly produced by endothelial, hematopoietic and stromal VEGFR3. PIGF and VEGF-B are believed to bind only to cells in response to hypoxia and stimulation with growth 35 Flt-1. Viral VEGF-E variants activate KDR, VEGF-F variants factors such as transforming growth factors, interleukins and interact with either VEGFR3 or KDR. platelet-derived growth factor. In addition to the two classical receptors, there are several In mammals, VEGFs are encoded by a family of genes and membrane or soluble receptors modulating VEGF bioactivity include VEGF-A, VEGF-B, VEGF-C, VEGF-D and Placenta and angiogenesis. For instance, neuropilin-1 and neuropilin-2 like Growth Factor (PIGF). Highly related proteins include 40 interact with both KDR and Flt-1, respectively, stimulating orf virus-encoded VEGF-like proteins referred to as VEGF-E signaling of those receptors. Isoforms of VEGF-A, VEGF-B, and a series of snake venoms referred to as VEGF-F. VEGFs PlGF-2 have been shown to bind to neuropilin-1 (Soker et al., and VEGF-related proteins are members of the Platelet 1998, Cell.92: 735-745; Makinen et al., 1999, J.
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