Granted Patent
B2
US 12,698,347 · App. 18/483,308 · Granted Aug 4, 2026
Bi-specific fusion proteins
Inventors:
Ulrik Nielsen (Quincy, MA); Thomas Wickham (Groton, MA); Birgit Schoeberl (Cambridge, MA); Brian Harms (Roslindale, MA); Bryan Linggi (Richland, WA); Matthew Onsum (El Cerrito, CA); Byron DeLaBarre (Cambridge, MA); Shaun M. Lippow (San Francisco, CA)
Assignee:
Silver Creek Pharmaceuticals, Inc.
C07K16/46A61K45/06A61K47/66A61K47/6811A61K47/6891B82Y5/00C07K14/47C07K14/475C07K14/485C07K14/65C07K16/44C12N15/62A61K38/00C07K2317/31C07K2317/76C07K2319/00C07K2319/80
View Patent ↗
Loading inventors, assignments & file history…
Abstract
Bi-specific fusion proteins with therapeutic uses are provided, as well as pharmaceutical compositions comprising such fusion proteins, and methods for using such fusion proteins to repair or regenerate damaged or diseased tissue. The bi-specific fusion proteins generally comprise: (a) a targeting polypeptide domain that binds to a target molecule; and (b) an activator domain that detectably modulates tissue regeneration.
Claims (20)
1 . A method for accumulating an IGF-1 fusion protein in cardiac tissue of a subject having myocardial infarction, the method comprising:
administering an effective amount of the IGF-1 fusion protein to the subject having myocardial infarction,
wherein the IGF-1 fusion protein comprises:
(i) a human IGF-1 having at least 98.5% identity with SEQ ID NO: 3;
(ii) a variant of human serum albumin having at least 95% identity with SEQ ID NO: 12, and comprising substitution of the cysteine residue corresponding to C34 to serine or alanine, and/or substitution of the asparagine residue corresponding to N503 to glutamine of SEQ ID NO: 12; and
(iii) optionally a connector polypeptide,
wherein the administering of the effective amount of the IGF-1 fusion protein to the subject results in accumulation of the IGF-1 fusion protein in the cardiac tissue, and
wherein the administering of the effective amount of the IGF-1 fusion protein to the subject results in reduction of the severity of the myocardial infarction.
2 . The method of claim 1 , wherein the IGF-1 is at the amino terminus of the fusion protein.
3 . The method of claim 1 , wherein the connector polypeptide is from 2 amino acids to 20 amino acids long.
4 . The method of claim 1 , wherein the connector polypeptide is a flexible or a structured polypeptide.
5 . A method for accumulating an IGF-1 fusion protein in cardiac tissue of a subject having myocardial infarction, the method comprising:
administering an effective amount of the IGF-1 fusion protein to the subject having myocardial infarction,
wherein the IGF-1 fusion protein comprises:
(i) a human IGF-1 having at least 98.5% identity with SEQ ID NO: 3;
(ii) a fragment of a human serum albumin comprising least at least 95% identity with Domain I comprising the amino acid sequence of SEQ ID NO: 27, Domain II comprising the amino acid sequence of SEQ ID NO: 25 or Domain III having the amino acid sequence of SEQ ID NO: 28; and
(iii) optionally a connector polypeptide,
wherein the administering of the effective amount of the IGF-1 fusion protein to the subject results in accumulation of the fusion protein in the cardiac tissue, and
wherein the administering of the effective amount of the IGF-1 fusion protein to the subject results in reduction of the severity of the myocardial infarction.
6 . The method of claim 5 wherein the fragment of human serum albumin comprises the amino acid sequence of SEQ ID NO: 24 or the amino acid sequence of SEQ ID NO: 26.
Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Oct 31, 2023
From: NIELSEN, ULRIK; WICKHAM, THOMAS; SCHOEBERL, BIRGIT; HARMS, BRIAN; LINGGI, BRYAN; ONSUM, MATTHEW; DELABARRE, BYRON; LIPPOW, SHAUN M.
To: MERRIMACK PHARMACEUTICALS, INC.
Reel/Frame 065403/0263 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Oct 31, 2023
From: MERRIMACK PHARMACEUTICALS, INC.
To: SILVER CREEK PHARMACEUTICALS, INC.
Reel/Frame 065403/0332 →
Continuity (7)
References Cited (245)
US 5273966A
· Sknottner-Lundin et al.
· 1993
[cited by applicant]
US 5632986A
· Tait et al.
· 1997
[cited by applicant]
US 5679771A
· Ballard et al.
· 1997
[cited by applicant]
US 6387663B1
· Hall et al.
· 2002
[cited by applicant]
US 6541610B1
· Smith
· 2003
[cited by examiner]
US 6566098B1
· Chan et al.
· 2003
[cited by applicant]
US 7226907B1
· Zhou
· 2007
[cited by applicant]
US 7396918B2
· Glass et al.
· 2008
[cited by applicant]
US 7459541B2
· Hall et al.
· 2008
[cited by applicant]
US 7521211B2
· Glass
· 2009
[cited by applicant]
US 7531318B2
· Srivastava et al.
· 2009
[cited by applicant]
US 7576186B2
· Lum et al.
· 2009
[cited by applicant]
US 7612164B2
· Zhou
· 2009
[cited by applicant]
US 7786074B2
· Gourdie et al.
· 2010
[cited by applicant]
US 7837999B2
· Glass et al.
· 2010
[cited by applicant]
US 8067357B2
· Reutelingsperger et al.
· 2011
[cited by applicant]
US 8158581B2
· Glass et al.
· 2012
[cited by applicant]
US 8445434B2
· Glass et al.
· 2013
[cited by applicant]
US 8691771B2
· Nielsen et al.
· 2014
[cited by applicant]
US 8748380B2
· Plumridge et al.
· 2014
[cited by applicant]
US 9238080B2
· Nielsen et al.
· 2016
[cited by applicant]
US 9718892B2
· Nielsen et al.
· 2017
[cited by applicant]
US 9982060B2
· Nielsen et al.
· 2018
[cited by applicant]
US 20040213738A1
· Croll-Kalish et al.
· 2004
[cited by applicant]
US 20060018897A1
· Lee et al.
· 2006
[cited by applicant]
US 20070048282A1
· Rosen
· 2007
[cited by examiner]
US 20070054851A1
· Lin et al.
· 2007
[cited by applicant]
US 20080071063A1
· Allan et al.
· 2008
[cited by applicant]
US 20090068181A1
· Lee et al.
· 2009
[cited by applicant]
US 20090093407A1
· Hall et al.
· 2009
[cited by applicant]
US 20090214507A1
· Srivastava et al.
· 2009
[cited by applicant]
US 20100055115A1
· Lum et al.
· 2010
[cited by applicant]
US 20100197890A1
· McTavish
· 2010
[cited by applicant]
US 20110045007A1
· Schuurman et al.
· 2011
[cited by applicant]
US 20110059076A1
· McDonagh et al.
· 2011
[cited by applicant]
US 20120244163A1
· Schoeberl et al.
· 2012
[cited by applicant]
US 20140315817A1
· Schmidt et al.
· 2014
[cited by applicant]
AU 2008200706
· 2008
[cited by applicant]
AU 2015204540
· 2016
[cited by applicant]
CA 2286264
· 1998
[cited by applicant]
CA 2768621
· 2011
[cited by applicant]
CA 2902744
· 2014
[cited by applicant]
EP 854884
· 1998
[cited by applicant]
EP 1141015
· 2001
[cited by applicant]
EP 1436316
· 2004
[cited by applicant]
EP 2275446
· 2011
[cited by applicant]
EP 2900255
· 2014
[cited by applicant]
WO WO1992008495
· 1992
[cited by applicant]
WO WO1994028133
· 1994
[cited by applicant]
WO WO1995032003
· 1995
[cited by applicant]
WO WO1996033698
· 1996
[cited by applicant]
WO WO2000002587
· 2000
[cited by applicant]
WO WO2002017951
· 2002
[cited by applicant]
WO WO2005117973
· 2005
[cited by applicant]
WO WO2006003488
· 2006
[cited by applicant]
WO WO2006004910
· 2006
[cited by applicant]
WO WO2006076525
· 2006
[cited by applicant]
WO WO2006079120
· 2006
[cited by applicant]
WO WO2006091209
· 2006
[cited by applicant]
WO WO2006128125
· 2006
[cited by applicant]
WO WO2007021494
· 2007
[cited by applicant]
WO WO2007044887
· 2007
[cited by applicant]
WO WO2007095338
· 2007
[cited by applicant]
WO WO2008063424
· 2008
[cited by applicant]
WO WO2008089567
· 2008
[cited by applicant]
WO WO2008091209
· 2008
[cited by applicant]
WO WO2008096158
· 2008
[cited by applicant]
WO WO2008151005
· 2008
[cited by applicant]
WO WO2008155134
· 2008
[cited by applicant]
WO WO2009030720
· 2009
[cited by applicant]
WO WO2009126920
· 2009
[cited by applicant]
WO WO2009126920A2
· 2009
[cited by examiner]
WO WO2010059315
· 2010
[cited by applicant]
WO WO2011011071
· 2011
[cited by applicant]
WO WO2011146902
· 2011
[cited by applicant]
WO WO2012078153
· 2012
[cited by applicant]
WO WO2013075066
· 2012
[cited by applicant]
WO WO2013086785
· 2013
[cited by applicant]
Osborn et al., Eur. J. Pharmacol. (2002), 456(1-3), pp. 149-158.
[cited by examiner]
Kineman et al (2018) J. Mol. Endocrinol. 61(1):T187-T198.
[cited by examiner]
Bork. Powers and Pitfalls in Sequence Analysis: The 70% Hurdle. Genome Research, 2000, 10:398-400 (Year: 2000).
[cited by examiner]
Greenspan et al. 1999. Defining epitopes: It's not as easy as it seems; Nature Biotechnology, 17:936-937 (Year: 1999).
[cited by examiner]
Bowie et al. Deciphering the Message in Protein Sequences: Tolerance to Amino Acid Substitutions. Science, 1990, 247:1306-1310 (Year: 1990).
[cited by examiner]
Burgess et al. Possible Dissociation of the Heparin-binding and Mitogenic Activities of Heparin-binding (Acidic Fibroblast) Growth Factor-1 from Its Receptor-binding Activities by Site-directed Mutagenesis of a Single L…
[cited by examiner]
Lazar et al. Transforming Growth Factor alpha: Mutation of Aspartic Acid 47 and Leucine 48 Results in Different Biological Activities. Mol. Cell. Biol., 8:1247-1252, 1988 (Year: 1988).
[cited by examiner]
Botusan et al (2018), https://journals.plos.org/plosone/article/?id=10.1371/journal.pone.0193084.
[cited by examiner]
Adderson, E., et al., “Molecular analysis of polyreactive monoclonal antibodies from rheumatic carditis: human anti-N-acetylglucosamine/anti-myosin antibody V region genes,” J Immunol., 161(4):2020-2031, (Aug. 15, 1998).
[cited by applicant]
Andrades, et al., “Engineering, expression, and renaturation of a collagen-targeted human bFGF fusion protein,” Growth Factors, 18:261-275, (Aug. 1999).
[cited by applicant]
Askari, et al., “Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy,” Mechanisms of Disease, 362: 697-703, (Aug. 30, 2003).
[cited by applicant]
Bai et al., “Tracking long-term survival of intramyocardially delivered human adipose tissue-derived stem cells using bioluminescence imaging,” Molecular Imaging and Biology, 13 pages (2010).
[cited by applicant]
Barbas, S., et al., “Human autoantibody recognition of DNA,” Proc Natl Acad Sci U S A, 92(7):2529-2533, (Mar. 28, 1995).
[cited by applicant]
Bauwens, C., et al., “Geometric control of cardiomyogenic induction in human pluripotent stem cells”, Tissue Eng., Part A, (Apr. 25, 2011).
[cited by applicant]
Bayne, Marvin et al., “The Roles of Tyrosines 24,31, and 60 in the High Affinity Binding of Insulin-like Growth Factor-I to the Type 1 Insulin-like Growth Factor Receptor”, The Journal of Biological Chemistry, vol. 265,…
[cited by applicant]
Bersell, et al., “Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury,” Cell, 138:257-270, (Jul. 24, 2009).
[cited by applicant]
Black, S., “In vivo models of myocardial ischemia and reperfusion injury: application to drug discovery and evaluation,” J. Pharmacol. Toxicol. Methods 43(2):153-167, (Mar.-Apr. 2000).
[cited by applicant]
Bock-Marquette, et al., “Thymosin B4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair,” Nature, 432:466-472, (Nov. 25, 2004).
[cited by applicant]
Buerke, et al., “Cardioprotective effect of insulin-like growth factor I in myocardial ischemia followed by reperfusion,” Proc. Natl. Acad. Sci. USA, 92: 8031-8035, (Aug. 1995).
[cited by applicant]
Bujak, 2007, Cardiovascular Research, vol. 74, Issue 2, pp. 184-195.
[cited by applicant]
Burchfield, et al., “Interleukin-10 from transplanted bone marrow mononuclear cells contributes to cardiac protection after myocardial infarction,” Circulation Research, 15 pages, (Mar. 23, 2011).
[cited by applicant]
Burchfield, et al., “Role of paracrine factors in stem and progenitor cell mediated cardiac repair and tissue fibrosis,” Fibrogenesis and Tissue Repair, 1(4):1-11, (2008).
[cited by applicant]
Burchfield, et al., “The cytoprotective effects of tumor necrosis factor are conveyed through tumor necrosis factor receptor-associated factor 2 in the heart,” Circulation Heart Failure, 16 pages, (Jan. 2010).
[cited by applicant]
Burrill, Devin et al., “Targeted erythropoietin selectively stimulates red blood cell expansion in vivo”, Proceedings of the National Academy of Sciences of the United States of America (PNAS), vol. 113, No. 19, pp. 524…
[cited by applicant]
Chen, et al. “Effects of receptor binding on plasma half-life of bifunctional transferrin fusion proteins,”Molecular Pharmaceutics 8: 457-65 (2011).
[cited by applicant]
Chen, et al., “Localization of monoclonal antibody TNT-1 in experimental kidney infarction of the mouse,” FASEB J., 4(12):3033-3039, (Sep. 1, 1990).
[cited by applicant]
Chimenti, et al., “Myocardial infarction: animal models,” Methods. Mol. Med., 98:217-226, (2004).
[cited by applicant]
Christman, et al., “Enhanced neovasculature formation in ischemic myocardium following delivery of pleiotrophin plasmid in a biopolymer,”Biomaterials, 26:1139-1144 (2005).
[cited by applicant]
Cironi, Pablo et al., “Enhancement of Cell Type Specificity by Quantitative Modulation of Chimeric Ligand”, The Journal of Biological Chemistry, vol. 283, No. 13, pp. 8460-8476, Mar. 28, 2008.
[cited by applicant]
Davis, “Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction,” Proc. Natl. Acad. Sci USA, 103(21):8155-8160, (May 23, 2006).
[cited by applicant]
Davletov, A. & Sudhof, T., “A single C2 domain from synaptotagmin I is sufficient for high affinity Ca2+/phospholipid binding,” J. Biol. Chem., 268(35):26386-2690, (Dec. 15, 1993).
[cited by applicant]
Doldan-Martelli et al., “A Mathematical Model for the Rational Design of Chimeric Ligands in Selective Drug Therapies,” CPT: Pharmacometrics & Systems Pharmacology (2013), 2, e26, Feb. 13, 2013.
[cited by applicant]
Dorn II, M.D., “Periostin and myocardial repair, regeneration, and recovery,” The New England Journal of Medicine, 357(15):1552-1554, (Oct. 11, 2007).
[cited by applicant]
Dubaquie, Y. et al. “Total Alanine-Scanning Mutagenesis of Insulin-Like Growth Factor I (IGF-I) Identifies Differential Binding Epitopes for IGFBP-1 and IGFBP-3”, Biochemistry, 1999, 38, 6386-6396.
[cited by applicant]
Dumont, et al., “Cardiomyocyte Death Induced by Myocardial Ischemia and Reperfusion: Measurement With Recombinant Human Annexin-V in a Mouse Model ,” Circulation 102(13):1564-1568, (Sep. 26, 2000).
[cited by applicant]
Engel, et al., “FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction,” PNAS, 103(42):15546-15551, (Oct. 17, 2006).
[cited by applicant]
Epa, V.C. et al., “Model for the Complex between the insulin-like growth factor 1 and its receptors: towards designing antagonists for the IGF-1 receptor”, Protein Engineering, Design & Selection, vol. 19, No. 8, pp. 37…
[cited by applicant]
Francis, G.L., et al., “Novel recombinant fusion protein analogues of insulin-like growth factor (IGF)-I indicate the relative importance of IGF-binding protein and receptor binding for enhanced biological potency”, Jou…
[cited by applicant]
GenBank: BAA78418.1, vascular endothelial growth factor isoform VEGF165 [
[cited by applicant]
George, et al., “Typhostin AG-556 reduces myocardial infarct size and improves cardiac performance in the rat,” Experimental and Molecular Pathology, 74:314-318 (2003).
[cited by applicant]
Gnecchi, et al., “Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement,” The FASEB Journal, 20:661-669, (Apr. 2006).
[cited by applicant]
Gnecchi, et al., “Paracrine mechanisms in adult stem cell signaling and therapy,” Adult Stem Cells and Paracrine Effects, 1204-1219, (Nov. 2008).
[cited by applicant]
Greenberg, et al., “Chapter 7. Mouse models of ischemic angiogenesis and ischemia-reperfusion injury,” Methods Enzymol., 444:159-174, (2008).
[cited by applicant]
Gripenberg, et al., “A Solid Phase Enzyme-linked Immunosorbent Assay (ELISA) for the Demonstration of Antibodies against Denatured, Single-stranded DNA in Patient Sera,” Scand. J. Immunol., 7(2):151-157, (Feb. 1978).
[cited by applicant]
Han, et al., “Refolding of a recombinant collagen-targeted TGF-B2 fusion protein expressed in
[cited by applicant]
Hashino, K., et al., “A 31-kDa Recombinant Fibronectin Cell-Binding Domain Fragment: Its Binding to Receptor, Cell Adhesive Activity, and Fusion Proteins,” J. Biochem., 119(4):604-609, (Apr. 4, 1996).
[cited by applicant]
Hausenloy et al., “Cardioprotective growth factors,” Cardiovascular Research, 83: 179-194, (2009).
[cited by applicant]
Hefta, et al., “Measuring Affinity Using Biosensors”, in “Antibody engineering: a Practical Approach”, pp. 99-116, Oxford University Press, 1996, Edited by McCafferty et al., (Hames B.D.eds).
[cited by applicant]
Henson, 2006, Cellular Signaling, vol. 18, pp. 2089-2097.
[cited by applicant]
Hinkel et al., “Thymosin B4 is an essential paracrine factor of embryonic endothelial progenitor cell-mediated cardioprotection,” Circulation, 2232-2240 (Apr. 29, 2008).
[cited by applicant]
Hoberg, E., et al., “Monoclonal antibodies specific for human cardiac myosin: selection, characterization and experimental myocardial infarct imaging,” Eur Heart J., 9(3):328-236, (Mar. 1988).
[cited by applicant]
Hofstra, et al., “Visualisation of cell death in vivo in patients with acute myocardial infarction,” The Lancet, 356(9225):209-212, (2000).
[cited by applicant]
Hsieh et al., “Local controlled intramyocardial delivery of plateet-derived growth factor improves postinfarction ventricular function without pulmonary toxicity,” Circulation, 637-644, (Aug. 15, 2006).
[cited by applicant]
Hu et al., Stromal cell-derived factor-1a confers protection against myocardial ischemia/reperfusion injury, Molecular Cardiology, 654-663, (Aug. 7, 2007).
[cited by applicant]
Ieda, et al., “Cardiac fibroblasts regulate myocardial proliferation through B1 integrin signaling,” Developmental Cell, 16: 233-244 (Feb. 17, 2009).
[cited by applicant]
Igarashi, K., et al., “Specific binding of a synthetic peptide derived from an antibody complementarity determining region to phosphatidylserine,” J Biochem., 117(2):452-457, (Feb. 1995).
[cited by applicant]
Ishikawa, et al., “Production of biologically active epidermal growth factor fusion protein with high collagen affinity,” J. Biochem., 129(4): 627-633 (2001).
[cited by applicant]
Jeon, et al., “Long-term and zero-order release of basic fibroblast growth factor from heparin-conjugated poly(L-lactide-co-glycolide) nanospheres and fibrin gel,” Biomaterials, 27:1598-1607 (2006).
[cited by applicant]
Kanashiro-Takeuchi, et al., “Cardioprotective effects of growth hormone-releasing hormone agonist after myocardial infarction,” PNAS, 107(6):2604-2609, (Feb. 9, 2010).
[cited by applicant]
Kardami, et al., “Fibroblast growth factor-2 and cardioprotection,” Heart Fail Rev., 12:267-277 (2007).
[cited by applicant]
Kawase Y. et al. “Construction and characterization of a fusion protein with epidermal growth factor and the cell-binding domain of fibronectin” FEBS letters, 298(2-3): 126-128, 1992.
[cited by applicant]
Kenis et al., “Annexin A5: shifting from a diagnostic towards a therapeutic realm”, Cellular Molecular Life Sciences, vol. 64, pp. 2859-2862, ePub Sep. 17, 2007.
[cited by applicant]
Kenis, H., et al., “Annexin A5 uptake in ischemic myocardium: demonstration of reversible phosphatidylserine externalization and feasibility of radionuclide imaging” J. Nucl Med., 51(2):259-67, (Feb. 2010).
[cited by applicant]
Kenis, H., et al., “Cell surface-expressed phosphatidylserine and annexin A5 open a novel portal of cell entry,” J Biol Chem., 279(50):52623-52629, Epub Sep. 20, 2004, (Dec. 10, 2004).
[cited by applicant]
Khaw, B., et al., “Monoclonal antibody to cardiac myosin: imaging of experimental myocardial infarction,” Hybridoma, 3(1):11-23, (1984).
[cited by applicant]
King et al., “Production and characterization of recombinant insulin-like growth factor-I (IGF-I) and potent analogues of IGF-I, with Gly or Arg substituted for Glu3, following their expression in
[cited by applicant]
Klopsch, et al., “Intracardiac injection of erythropoietin induces stem cell recruitment and improves cardiac functions in a rat myocardial infarction model,” J. Cell. Mol. Med. 13(4): 664-679, (2009).
[cited by applicant]
Ko, Y., et al., “Gene delivery into ischemic myocardium by double-targeted lipoplexes with anti-myosin antibody and TAT peptide,” Gene Ther., 16(1):52-9. Epub Aug. 14, 2008, (Jan. 2009).
[cited by applicant]
Kobayashi, et al., “Effect of atrial natriuretic peptide on ischemia-reperfusion injury in a porcine total hepatic vascular exclusion model,” World J. Gastroenterol., 13(25):3487-3492, (Jul. 7, 2007).
[cited by applicant]
Kuhn, et al., “Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair,” Nature Medicine, 13(8):962-969, (Aug. 2007).
[cited by applicant]
Kuramochi, “Cardiac Endothelial Cells Regulate Reactive Oxygen Species-induced Cardiomyocyte Apoptosis through Neuregulin-1_/erbB4 Signaling,” J. Biol. Chem., 279(49): 51141-51147, (2004).
[cited by applicant]
Laajoki, L. et al. Solution Structure and Backbone Dynamics of Long-[ARG3] Insulin-like Growth Factor-I; Journal of Biological Chemistry, vol. 275, No. 14, pp. 10009-10015, Apr. 7, 2000.
[cited by applicant]
Laroche-Traineau, J., et al., “A human monoclonal antibody obtained from EBV-transformed B cells with specificity for myosin,” Br J Haematol., 91(4):951-962, (Dec. 1995).
[cited by applicant]
Laroche-Traineau, J., et al., “Analysis of the V genes coding for a monospecific human antibody to myosin and functional expression of single chain Fv fragments,” FEBS Lett., 460(1):86-92, (Oct. 22, 1999).
[cited by applicant]
Laroche-Traineau, J., et al., “Three-step purification of bacterially expressed human single-chain Fv antibodies for clinical applications,” J Chromatogr B Biomed Sci Appl., 737(1-2):107-117, (Jan. 14, 2000).
[cited by applicant]
Liang, W., et al., “ATP-containing immunoliposomes specific for cardiac myosin,” Curr Drug Deliv., 1(1):1-7, (Jan. 2004).
[cited by applicant]
Liu, et al., “Neuregulin-1/erbB-activation improves cardiac function and survival in models of ischemic, dilated, and viral cardiomyopathy,” Journal of the American College of Cardiology, 48(7):1438-1447, (Oct. 3, 2006).
[cited by applicant]
Loddick, S. et al., “Displacement of insulin-like growth factors from their binding proteins as a potential treatment for stroke”, PNAS, vol. 95, pp. 1894-1898, Feb. 1998.
[cited by applicant]
Lorts, et al., “Genetic manipulation of periostin expression in the heart does not affect myocyte content, cell cycle activity, or cardiac repair,” UltraRapid Communication, e1-e7, (Jan. 2, 2009).
[cited by applicant]
Marshall, K.W. & Marks, J.D. “Engineering and characterization of a novel fusion protein incorporating B7.2 and an anti-ErbB-2 single-chain antibody fragment for the activation of Jurkat T cells,” Journal of Immunothera…
[cited by applicant]
Mihardja, et al., “Targeted in vivo extracellular matrix formation promotes neovascularization in a rodent model of myocardial infarction,” PLoS One, 5(4):e10384 (8 pages), (Apr. 2010).
[cited by applicant]
Mira, et al., “Inhibition of cytosolic phospholipase A2 by annexin V in differentiated permeabilized HL-60 cells. Evidence of crucial importance of domain I type II Ca2+-binding site in the mechanism of inhibition,” J. …
[cited by applicant]
Miranda, et al., “Endothelium-dependent and -independent hepatic artery vasodilatation is not impaired in a canine model of liver ischemia-reperfusion injury,” Braz. J. Med. Biol. Res., 40(6):857-865, (Jun. 2007).
[cited by applicant]
Murray and Brown, “Measurement of association constants in ELISA. Reactions between solid-phase antibody and fluid-phase biotinylated antigen,” J. Immunol. Methods., 127(1):25-28 (Feb. 20, 1990).
[cited by applicant]
Nedelman, M., et al., “Rapid infarct imaging with a technetium-99m-labeled antimyosin recombinant single-chain Fv: evaluation in a canine model of acute myocardial infarction,” J Nucl Med., 34(2):234-241, (Feb. 1993).
[cited by applicant]
Nelson, P., et al. “Characterization of anti-myosin monoclonal antibodies,” Hybridoma (Larchmt), 24(6):314-318, (Dec. 2005).
[cited by applicant]
Nimni, “Polypeptide growth factors: targeted delivery systems,” Biomaterials, 18(18):1201-1225, (1997).
[cited by applicant]
Nishi, et al., “Collagen-binding growth factors: Production and characterization of functional fusion proteins having a collagen-binding domain,” Proc. Natl. Acad. Sci. USA, 95:7018-7023, (Jun. 1998).
[cited by applicant]
Novo Nordisk Pharmatech A/S “How Insulin and IGF-1 Bind to the receptors” retrieved from http://novonordiskpharmatech.com/how-insulin0and-igf-1-bind-to-their-receptors/ ; retrieved Dec. 16, 2016.
[cited by applicant]
O' Sullivan et al., “Potent Long-Term Cardioprotective Effects of Single Low-Dose Insulin-Like Growth Factor-1 Treatment Postmyocardial Infarction”, American Heart Association—Circulation: Cardiovascular Interventions, …
[cited by applicant]
Pak, K., et al., “An instant kit method for labeling antimyosin Fab' with technetium-99m: evaluation in an experimental myocardial infarct model,” J. Nucl Med., 33(1):144-149, (Jan. 1992).
[cited by applicant]
Peter, K., et al., “Construction and functional evaluation of a single-chain antibody fusion protein with fibrin targeting and thrombin inhibition after activation by factor Xa,” Circulation, 101(10):1158-1164, (Mar. 14…
[cited by applicant]
Pietronave, et al., “Agonist monoclonal antibodies against HGF receptor protect cardiac muscle cells from apoptosis,” Am J Physiol Heart circ Physiol, 298:H1155-H1165, (2010).
[cited by applicant]
Prior, et al. “Cytotoxic Activity of a Recombinant Fusion Protein between Insulin-like Growth Factor I and Pseudomonas Exotoxin,” Cancer, 174-180 (1991).
[cited by applicant]
Rosenthal, et al., “Growth factor enhancement of cardiac regeneration,” Cell Transplantation, 15(1):S41-S45, (2006).
[cited by applicant]
Saxena, et al., “Stromal cell-derived factor-la is cardioprotective after mocardial infarction,” Molecular Cardiology, 2224-2231, (2008).
[cited by applicant]
Schutters, K. & Reutelingsperger, C.P.M. “Phosphatidylserine targeting for diagnosis and treatment of human diseases,” Apoptosis: an International Journal on Programmed Cell Death. 15:1072-82, (2010).
[cited by applicant]
Scott, R.C. et al. “Targeted Delivery of Antibody Conjugated Liposomal Drug Carriers to Rat Myocardial Infarction,” Biotechnology, 96:795-802, (2007).
[cited by applicant]
Scott, et al. “Aiming for the heart: targeted delivery of drugs to diseased cardiac tissue,” Expert Opinion on Drug Delivery, 5:459-70, (2008).
[cited by applicant]
Scott, et al., “Targeting VEGF-encapsulated immunoliposomes to MI heart improves vascularity and cardiac function”, The FASEB Journal: Research Communication, vol. 23, pp. 3361-3367, (Oct. 2009).
[cited by applicant]
Segers, et al., “Protein therapeutics for cardiac regeneration after myocradial infarction,” J. of Cardiovasc. Trans. Res., 9 pages, (Jul. 7, 2010).
[cited by applicant]
Shan, et al., “Overexpression of TRPC3 increases apoptosis but not necrosis in response to ischemia-reperfusion in adult mouse cardiomyocytes,” Am. J. Physiol. Cell. Physiol., 294(3):833-841, (Mar. 2008).
[cited by applicant]
Shin, S.U. & Morrison, S.L., “Expression and characterization of an antibody binding specificity joined to insulin-like growth factor 1: potential applications for cellular targeting,” Proceedings of the National Academ…
[cited by applicant]
Shin, et al. “Functional properties of antibody insulin-like growth factor fusion proteins,” The Journal of Biological Chemistry, 269: 4979-8,5 (1994).
[cited by applicant]
Simeonova, P., et al., “Identification of human ventricular myosin heavy chain fragments with monoclonal antibody 2F4 in human sera after myocardial necrosis,” Clin Chim Acta., 201(3):207-221, (Sep. 30, 1991).
[cited by applicant]
Stamm et al., Human ortholog to mouse gene imap38 encoding an ER-localized G-protein belongs to the gene family clustered on chromosome 7q32-36, Gene vol. 282: 159-167, 2003.
[cited by applicant]
Stokes, et al., “A simple, rapid ELISA method for the detection of DNA antibodies,” J. Clin. Pathol., 35(5):566-573, (May 1982).
[cited by applicant]
Stowe, et al., Engineering Growth Factors for Cardiomyocyte Survival and Regeneration Following Ischemic Injury. American Heart Association Basic Cardiovascular Science [online Jul. 15, 2014 [retrieved Dec. 5, 2016].
[cited by applicant]
Suleiman, et al., “Apoptosis and the cardiac action of insulin-like growth factor I,” Pharmacology and Therapeutics, 114:278-294, (2007).
[cited by applicant]
Sutton, R., et al., “Structure of the first C2 domain of synaptotagmin I: a novel Ca2+/phospholipid-binding fold,” Cell, 80(6):929-938, (Mar. 24, 1995).
[cited by applicant]
Tomas, F.M. et al., “IGF-I variants which bind poorly to IGF-binding proteins show more potent and prolonged hypoglycemic action that native IGF-I in pigs and marmoset monkeys”, Journal of Endocrinology (1997), 155, 377…
[cited by applicant]
Tuan et al., “Engineering, expression and renaturation of targeted TGF-beta fusion proteins”; Connect Tissue Res. 1996; 34(1):1-9.
[cited by applicant]
Ueda, et al., “A potential cardioprotective role of hepatocyte growth factor in myocardial infarction in rats,” Cardiovascular Research, 51:41-50, (2001).
[cited by applicant]
Umeda, M., et al., “Effective production of monoclonal antibodies against phosphatidylserine: stereo-specific recognition of phosphatidylserine by monoclonal antibody,” J Immunol., 143(7):2273-2279, (Oct. 1, 1989).
[cited by applicant]
Ungethum, et al., “Engineered annexin A5 variants have impaired cell entry for molecular imaging of apoptosis using pretargeting strategies,” J Biol Chem., 286(3):1903-10. Epub Nov. 15, 2010, (Jan. 21, 2011).
[cited by applicant]
Urbanek K et al., “Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure,” Proc. Natl. Acad. Sci. USA, 102(24):8692-8697, (Jun. 14, 2005).
[cited by applicant]
Wang, et al., “Degradable PLGA scaffolds with basic fibroblast growth factor,” Texas Heart Institute Journal, 89-97, (2009).
[cited by applicant]
Wassaf, et al., “High-throughput affinity ranking of antibodies using surface plasmon resonance microarrays,” Anal. Biochem., 351(2):241-253, (Apr. 15, 2006).
[cited by applicant]
Winter, et al. “A new bioassay for the immunocytokine L19-IL2 for simultaneous analysis of both functional moieties,” Journal of Pharmaceutical and Biomedical Analysis, 54:81-6 (2011).
[cited by applicant]
Yang L. et al., “Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population”, Nature. May 22, 2008, 453(7194):524-8. Epub Apr. 23, 2008.
[cited by applicant]
Yeghiazarians, et al., “Injection of bone marrow cell extract into infarcted hearts results in functional improvement comparable to intact cell therapy,” The American Society of Gene Therapy, 17(7):1250-1256, (Jul. 2009…
[cited by applicant]
Zaruba, et al., “Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction,” Cell Stem Cell, 4:313-323, (Apr. 3, 2009).
[cited by applicant]
Zbinden, et al., “Interanimal variability in preexisting collaterals is a major factor determining outcome in experimental angiogenesis trials,” Am. J. Physiol. Heart Circ. Physiol., 292(4): H1891-H1897, (Apr. 2007).
[cited by applicant]
Zentilin, et al., “Cardiomyocyte VEGFR-1 activation by VEGF-B induces compensatory hypertrophy and preserves cardiac function after myocardial infarction,” The FASEB Journal, 24:1467-1478, (May 2010).
[cited by applicant]
Zhang et al., “Collagen-Targeting Vascular Endothelial Growth Factor Improves Cardiac Performance After Myocardial Infarction”, Circulation, vol. 119, No. (13), pp. 1776-1784, epub Mar. 23, 2009.
[cited by applicant]
Zhao, et al., “Neuregulins promote survival and growth of cardiac myocytes,” The Journal of Biological Chemistry, 273(17):0261-10269, (Apr. 24, 1998).
[cited by applicant]
Zhao, Ming, et al., 99m Tc-Labeled C2A Domain of Synaptotagmin I as a Target-Specific Molecular Probe for Noninvasive Imaging of Acute Myocardial Infarction, The Journal of Nuclear Medicine, vol. 47, No. 8, Aug. 2006, p…
[cited by applicant]
Zhao, et al., “Recruitment of endogenous stem cells for tissue repair,” Macromolecular Bioscience, 8:836-842, (2008).
[cited by applicant]
Ziegler m. et al., “The bispecific SDF1-GPVI fusion protein preserves myocardial function after transient ischemia in mice” Circulation Feb. 7, 2012; 125(5): 685-96. Doi: 10.1161/Circulation.111.070508.Epub Jan. 5, 2012.
[cited by applicant]
International Search Report based on PCT/2011/037459, mailed Aug. 30, 2011.
[cited by applicant]
Forsberg et al., “Separation and characterization of modified variants of recombinant human insulin-like growth factor I derived from a fusion protein secreted from
[cited by applicant]
Gadgil et al., “Affinity purification of DNA-binding proteins”, J Biochem Biophys Methods, vol. 49 (1-3), pp. 607-624, Oct. 30, 2001.
[cited by applicant]
Park et al., “Crystal structure of single-domain VL of an anti-DNA binding antibody 3D8 scFv and its active site revealed by complex structures of a small molecule and metals.”, Proteins, vol. 71, No. 4, pp. 2091-2096, …
[cited by applicant]
Rivadeneyra-Espinoza et al., “Cell-penetrating anti-native DNA antibodies trigger apoptosis through both the neglect and programmed pathways.”, J Autoimmun., vol. 26, No. 1, pp. 52-56, Feb. 2006.
[cited by applicant]