Functional characterization of a VEGF-A-targeting Anticalin, prototype of a novel therapeutic human protein class

Angiogenesis

Volumn 19, Issue 1, 2016, Pages 79-94

  Gille, Hendrik ^a,d   Hülsmeyer, Martin ^a   Trentmann, Stefan ^a   Matschiner, Gabriele ^a   Christian, Hans Jürgen ^a   Meyer, Todd ^c   Amirkhosravi, Ali ^c   Audoly, Laurent P ^a   Hohlbaum, Andreas M ^a   Skerra, Arne ^b  

^a Pieris Pharmaceuticals GmbH   (Germany)

^b TECHNICAL UNIVERSITY OF MUNICH   (Germany)

^c FLORIDA HOSPITAL   (United States)

^d Silence Therapeutics GmbH   (Germany)

Author keywords

Angiogenesis; Cancer; Lipocalin; Protein engineering; Protein scaffold

Indexed keywords

ANGIOGENESIS INHIBITOR; ANTICALIN; BEVACIZUMAB; RANIBIZUMAB; UNCLASSIFIED DRUG; VASCULOTROPIN A; ANTIGEN ANTIBODY COMPLEX; FC RECEPTOR; FC RECEPTOR IIA; LIPOCALIN; MACROGOL DERIVATIVE; MITOGENIC AGENT;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ARTICLE; BINDING AFFINITY; BLOOD VESSEL PERMEABILITY; CELL PROLIFERATION; CONCENTRATION RESPONSE; CONTROLLED STUDY; CROSS REACTION; DRUG BINDING; DRUG EFFICACY; DRUG HALF LIFE; DRUG SAFETY; DRUG SPECIFICITY; ENDOTHELIUM CELL; FEMALE; HUMAN; HUMAN CELL; IC50; IN VIVO STUDY; MITOSIS; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN CROSS LINKING; PROTEIN TARGETING; SIGNAL TRANSDUCTION; THROMBOCYTE AGGREGATION; THROMBOSIS; TUMOR GROWTH; TUMOR VOLUME; ANIMAL; ANTAGONISTS AND INHIBITORS; ANTIGEN ANTIBODY COMPLEX; BLOOD RETINA BARRIER; CAPILLARY PERMEABILITY; CHEMISTRY; DRUG EFFECTS; HALF LIFE TIME; METABOLISM; MOLECULARLY TARGETED THERAPY; NEOPLASMS; NUDE MOUSE; PATHOLOGY; PROTEIN ENGINEERING; RABBIT; SURFACE PLASMON RESONANCE; TRANSGENIC MOUSE; UMBILICAL VEIN ENDOTHELIAL CELL;

ANIMALS; ANTIGEN-ANTIBODY COMPLEX; BEVACIZUMAB; BLOOD-RETINAL BARRIER; CAPILLARY PERMEABILITY; CELL PROLIFERATION; FEMALE; HALF-LIFE; HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS; HUMANS; LIPOCALINS; MICE, NUDE; MICE, TRANSGENIC; MITOGENS; MOLECULAR TARGETED THERAPY; NEOPLASMS; POLYETHYLENE GLYCOLS; PROTEIN ENGINEERING; RABBITS; RECEPTORS, IGG; SIGNAL TRANSDUCTION; SURFACE PLASMON RESONANCE; THROMBOSIS; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

EID: 84952983457     PISSN: 09696970     EISSN: 15737209     Source Type: Journal    
DOI: 10.1007/s10456-015-9490-5     Document Type: Article

References (60)

1. Nelson AL, Dhimolea E, Reichert JM (2010) Development trends for human monoclonal antibody therapeutics. Nat Rev Drug Discov 9:767–774
2. Reichert JM (2014) Antibodies to watch in 2014. mAbs 6:5–14
3. Skerra A (2007) Alternative non-antibody scaffolds for molecular recognition. Curr Opin Biotechnol 18:295–304
4. Richter A, Eggenstein E, Skerra A (2014) Anticalins: exploiting a non-Ig scaffold with hypervariable loops for the engineering of binding proteins. FEBS Lett 588:213–218
5. Åkerström B, Borregaard N, Flower DR, Salier J-S (2006) Lipocalins. Landes Bioscience, Georgetown
6. Skerra A (2000) Lipocalins as a scaffold. Biochim Biophys Acta 1482:337–350
7. Schiefner A, Skerra A (2015) The menagerie of human lipocalins: a natural protein scaffold for molecular recognition of physiological compounds. Acc Chem Res 48:976–985
8. Newcomer ME, Jones TA, Aqvist J, Sundelin J, Eriksson U, Rask L, Peterson PA (1984) The three-dimensional structure of retinol-binding protein. EMBO J 3:1451–1454
9. Goetz DH, Holmes MA, Borregaard N, Bluhm ME, Raymond KN, Strong RK (2002) The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol Cell 10:1033–1043
10. Fluckinger M, Haas H, Merschak P, Glasgow BJ, Redl B (2004) Human tear lipocalin exhibits antimicrobial activity by scavenging microbial siderophores. Antimicrob Agents Chemother 48:3367–3372
11. Flo TH, Smith KD, Sato S, Rodriguez DJ, Holmes MA, Strong RK, Akira S, Aderem A (2004) Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432:917–921
12. Beste G, Schmidt FS, Stibora T, Skerra A (1999) Small antibody-like proteins with prescribed ligand specificities derived from the lipocalin fold. Proc Natl Acad Sci USA 96:1898–1903
13. Schönfeld D, Matschiner G, Chatwell L, Trentmann S, Gille H, Hülsmeyer M, Brown N, Kaye PM, Schlehuber S, Hohlbaum AM, Skerra A (2009) An engineered lipocalin specific for CTLA-4 reveals a combining site with structural and conformational features similar to antibodies. Proc Natl Acad Sci USA 106:8198–8203
14. Gebauer M, Schiefner A, Matschiner G, Skerra A (2013) Combinatorial design of an Anticalin directed against the extra-domain B for the specific targeting of oncofetal fibronectin. J Mol Biol 425:780–802
15. Redl B (2000) Human tear lipocalin. Biochim Biophys Acta 1482:241–248
16. Breustedt DA, Korndörfer IP, Redl B, Skerra A (2005) The 1.8-Å crystal structure of human tear lipocalin reveals an extended branched cavity with capacity for multiple ligands. J Biol Chem 280:484–493
17. Breustedt DA, Chatwell L, Skerra A (2009) A new crystal form of human tear lipocalin reveals high flexibility in the loop region and induced fit in the ligand cavity. Acta Crystallogr D Biol Crystallogr 65:1118–1125
18. Olwill SA, Joffroy C, Gille H, Vigna E, Matschiner G, Allersdorfer A, Lunde BM, Jaworski J, Burrows JF, Chiriaco C, Christian HJ, Hülsmeyer M, Trentmann S, Jensen K, Hohlbaum AM, Audoly L (2013) A highly potent and specific MET therapeutic protein antagonist with both ligand-dependent and ligand-independent activity. Mol Cancer Ther 12:2459–2471
19. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676
20. Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362:841–844
21. Shojaei F, Ferrara N (2007) Antiangiogenesis to treat cancer and intraocular neovascular disorders. Lab Invest 87:227–230
22. Ferrara N, Hillan KJ, Gerber HP, Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3:391–400
23. Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S (2008) Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA 300:2277–2285
24. Scappaticci FA, Skillings JR, Holden SN, Gerber HP, Miller K, Kabbinavar F, Bergsland E, Ngai J, Holmgren E, Wang J, Hurwitz H (2007) Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst 99:1232–1239
25. Rudge JS, Holash J, Hylton D, Russell M, Jiang S, Leidich R, Papadopoulos N, Pyles EA, Torri A, Wiegand SJ, Thurston G, Stahl N, Yancopoulos GD (2007) VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade. Proc Natl Acad Sci USA 104:18363–18370
26. Gerber HP, Wu X, Yu L, Wiesmann C, Liang XH, Lee CV, Fuh G, Olsson C, Damico L, Xie D, Meng YG, Gutierrez J, Corpuz R, Li B, Hall L, Rangell L, Ferrando R, Lowman H, Peale F, Ferrara N (2007) Mice expressing a humanized form of VEGF-A may provide insights into the safety and efficacy of anti-VEGF antibodies. Proc Natl Acad Sci USA 104:3478–3483
27. Meyer T, Robles-Carrillo L, Robson T, Langer F, Desai H, Davila M, Amaya M, Francis JL, Amirkhosravi A (2009) Bevacizumab immune complexes activate platelets and induce thrombosis in FCGR2A transgenic mice. J Thromb Haemost 7:171–181
28. Christinger HW, Muller YA, Berleau LT, Keyt BA, Cunningham BC, Ferrara N, de Vos AM (1996) Crystallization of the receptor binding domain of vascular endothelial growth factor. Proteins 26:353–357
29. Skerra A (2001) ‘Anticalins’: a new class of engineered ligand-binding proteins with antibody-like properties. J Biotechnol 74:257–275
30. Gille H, Kowalski J, Li B, LeCouter J, Moffat B, Zioncheck TF, Pelletier N, Ferrara N (2001) Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). A reassessment using novel receptor-specific vascular endothelial growth factor mutants. J Biol Chem 276:3222–3230
31. Miyamoto K, Khosrof S, Bursell SE, Moromizato Y, Aiello LP, Ogura Y, Adamis AP (2000) Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1). Am J Pathol 156:1733–1739
32. Tolentino MJ, Miller JW, Gragoudas ES, Jakobiec FA, Flynn E, Chatzistefanou K, Ferrara N, Adamis AP (1996) Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology 103:1820–1828
33. Narayanan R, Kuppermann BD, Jones C, Kirkpatrick P (2006) Ranibizumab. Nat Rev Drug Discov 5:815–816
34. Bakri SJ, Snyder MR, Reid JM, Pulido JS, Ezzat MK, Singh RJ (2007) Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology 114:2179–2182
35. Roberts MJ, Bentley MD, Harris JM (2002) Chemistry for peptide and protein PEGylation. Adv Drug Deliv Rev 54:459–476
36. Kubetzko S, Sarkar CA, Plückthun A (2005) Protein PEGylation decreases observed target association rates via a dual blocking mechanism. Mol Pharmacol 68:1439–1454
37. Dvorak HF, Brown LF, Detmar M, Dvorak AM (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146:1029–1039
38. Mordenti J, Thomsen K, Licko V, Chen H, Meng YG, Ferrara N (1999) Efficacy and concentration-response of murine anti-VEGF monoclonal antibody in tumor-bearing mice and extrapolation to humans. Toxicol Pathol 27:14–21
39. Muller YA, Chen Y, Christinger HW, Li B, Cunningham BC, Lowman HB, de Vos AM (1998) 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 6:1153–1167
40. McKenzie SE, Taylor SM, Malladi P, Yuhan H, Cassel DL, Chien P, Schwartz E, Schreiber AD, Surrey S, Reilly MP (1999) The role of the human Fc receptor FcγRIIA in the immune clearance of platelets: a transgenic mouse model. J Immunol 162:4311–4318
41. Stahl A, Stumpp MT, Schlegel A, Ekawardhani S, Lehrling C, Martin G, Gulotti-Georgieva M, Villemagne D, Forrer P, Agostini HT, Binz HK (2013) Highly potent VEGF-A-antagonistic DARPins as anti-angiogenic agents for topical and intravitreal applications. Angiogenesis 16:101–111
42. 125I-labeled full-length and Fab antibodies in rhesus monkeys following intravitreal administration. Toxicol Pathol 27:536–544
43. Mross K, Richly H, Fischer R, Scharr D, Buchert M, Stern A, Gille H, Audoly LP, Scheulen ME (2013) First-in-human phase I study of PRS-050 (Angiocal), an Anticalin targeting and antagonizing VEGF-A, in patients with advanced solid tumors. PLoS One 8:e83232
44. EPAR (2006) Avastin: EPAR—Scientific Discussion. European Medicines Agency; http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000582/WC500029262.pdf
45. Gerber HP, Kowalski J, Sherman D, Eberhard DA, Ferrara N (2000) Complete inhibition of rhabdomyosarcoma xenograft growth and neovascularization requires blockade of both tumor and host vascular endothelial growth factor. Cancer Res 60:6253–6258
46. Liang WC, Wu X, Peale FV, Lee CV, Meng YG, Gutierrez J, Fu L, Malik AK, Gerber HP, Ferrara N, Fuh G (2006) Cross-species vascular endothelial growth factor (VEGF)-blocking antibodies completely inhibit the growth of human tumor xenografts and measure the contribution of stromal VEGF. J Biol Chem 281:951–961
47. Yu L, Wu X, Cheng Z, Lee CV, LeCouter J, Campa C, Fuh G, Lowman H, Ferrara N (2008) Interaction between bevacizumab and murine VEGF-A: a reassessment. Invest Ophthalmol Vis Sci 49:522–527
48. Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25:581–611
49. Akeson A, Herman A, Wiginton D, Greenberg J (2010) Endothelial cell activation in a VEGF-A gradient: relevance to cell fate decisions. Microvasc Res 80:65–74
50. Finley SD, Engel-Stefanini MO, Imoukhuede PI, Popel AS (2011) Pharmacokinetics and pharmacodynamics of VEGF-neutralizing antibodies. BMC Syst Biol 5:193
51. Santora LC, Kaymakcalan Z, Sakorafas P, Krull IS, Grant K (2001) Characterization of noncovalent complexes of recombinant human monoclonal antibody and antigen using cation exchange, size exclusion chromatography, and BIAcore. Anal Biochem 299:119–129
52. Leal T, Robins HI (2010) Bevacizumab induced reversible thrombocytopenia in a patient with recurrent high-grade glioma: a case report. Cancer Chemother Pharmacol 65:399–401
53. Kumar J, Bhargava M, Aggarwal S (2012) Bevacizumab-induced reversible thrombocytopenia in a patient with adenocarcinoma of colon: rare adverse effect of bevacizumab. Case Rep Oncol Med 2012:695430
54. Van Walle I, Gansemans Y, Parren PW, Stas P, Lasters I (2007) Immunogenicity screening in protein drug development. Expert Opin Biol Ther 7:405–418
55. Breustedt DA, Schönfeld DL, Skerra A (2006) Comparative ligand-binding analysis of ten human lipocalins. Biochim Biophys Acta 1764:161–173
56. Schlehuber S, Beste G, Skerra A (2000) A novel type of receptor protein, based on the lipocalin scaffold, with specificity for digoxigenin. J Mol Biol 297:1105–1120
57. Kim HJ, Eichinger A, Skerra A (2009) High-affinity recognition of lanthanide(III) chelate complexes by a reprogrammed human lipocalin 2. J Am Chem Soc 131:3565–3576
58. Skerra A (1994) Use of the tetracycline promoter for the tightly regulated production of a murine antibody fragment in Escherichia coli. Gene 151:131–135
59. Miles AA, Miles EM (1952) Vascular reactions to histamine, histamine-liberator and leukotaxine in the skin of guinea-pigs. J Physiol 118:228–257
60. Simpson-Herren L, Lloyd HH (1970) Kinetic parameters and growth curves for experimental tumor systems. Cancer Chemother Rep 54:143–174