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

Volumn 8, Issue 12, 2013, Pages

  Mross, Klaus ^a   Richly, Heike ^b   Fischer, Richard ^c   Scharr, Dirk ^a   Büchert, Martin ^c   Stern, Angelika ^d   Gille, Hendrik ^e   Audoly, Laurent P ^e   Scheulen, Max E ^b  

^a UNIVERSITY OF FREIBURG   (Germany)

^b UNIVERSITY HOSPITAL ESSEN   (Germany)

^c UNIVERSITY OF FREIBURG   (Germany)

^d Stern Consult   (Switzerland)

^e Pieris Pharmaceuticals GmbH   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ANGIOCAL; BILIRUBIN; GAMMA GLUTAMYLTRANSFERASE; GELATINASE A; PRS 050; UNCLASSIFIED DRUG; URIC ACID; VASCULOTROPIN A; VASCULOTROPIN INHIBITOR; ANGIOCAL PROTEIN; ANGIOGENESIS INHIBITOR; LIPOCALIN; LIPOCALIN 1; MMP2 PROTEIN, HUMAN; VEGFA PROTEIN, HUMAN;

ABDOMINAL PAIN; ADULT; ADVANCED CANCER; AGED; AREA UNDER THE CURVE; ARTICLE; BACKACHE; BILIRUBIN BLOOD LEVEL; BODY WEIGHT DISORDER; CANCER PAIN; CANCER SURGERY; CHILL; CLINICAL ARTICLE; COLORECTAL CARCINOMA; CONSTIPATION; DECREASED APPETITE; DOSE RESPONSE; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG DOSE ESCALATION; DRUG EXPOSURE; DRUG HALF LIFE; DRUG PROTEIN BINDING; DRUG SAFETY; DRUG TOLERABILITY; DYSPEPSIA; DYSPNEA; FATIGUE; FEMALE; FEVER; FLATULENCE; GAMMA GLUTAMYL TRANSFERASE BLOOD LEVEL; HUMAN; HYPERTENSION; HYPOTENSION; LIVER CELL CARCINOMA; MALE; MAXIMUM PLASMA CONCENTRATION; MELANOMA; NAUSEA; NEUROENDOCRINE TUMOR; OPEN STUDY; PANCREAS CARCINOMA; PERIPHERAL EDEMA; PHARMACODYNAMICS; PHASE 1 CLINICAL TRIAL; PLASMA CONCENTRATION-TIME CURVE; RECOMMENDED DRUG DOSE; REPEATED DRUG DOSE; RIGOR; SINGLE DRUG DOSE; SMALL INTESTINE PERFORATION; SOLID TUMOR; SYSTEMIC THERAPY; UNSPECIFIED SIDE EFFECT; URIC ACID BLOOD LEVEL; WEIGHT REDUCTION; ANTAGONISTS AND INHIBITORS; BLOOD; CLINICAL TRIAL; MIDDLE AGED; NEOPLASMS; TIME;

ADULT; AGED; ANGIOGENESIS INHIBITORS; DOSE-RESPONSE RELATIONSHIP, DRUG; FEMALE; HUMANS; LIPOCALIN 1; LIPOCALINS; MATRIX METALLOPROTEINASE 2; MIDDLE AGED; NEOPLASMS; TIME FACTORS; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

EID: 84892633112     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0083232     Document Type: Article

References (61)

1. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86: 353-364. doi: 10.1016/S0092-8674(00)80108-7. PubMed: 8756718.
2. Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25: 581-611. doi:10.1210/er.2003-0027. PubMed: 15294883.
3. Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23: 1011-1027. PubMed: 15585754.
4. Holmes DI, Zachary I (2005) The vascular endothelial growth factor (VEGF) family: angiogenic factors in health and disease. Genome Biol 6: 209. doi:10.1186/gb-2005-6-2-209. PubMed: 15693956.
5. Rahimi N (2006) VEGFR-1 and VEGFR-2: two non-identical twins with a unique physiognomy. Front Biosci 11: 818-829. PubMed: 16146773.
6. Kim KJ, Li B, Winer J, Armanini M, Gillett N et al. (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362: 841-844. doi:10.1038/362841a0. PubMed: 7683111.
7. Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A (1994) Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367: 576-579. doi:10.1038/367576a0. PubMed: 8107827.
8. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S et al. (2009) Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 10: 25-34. doi:10.1016/S1470-2045(08) 70285-7. PubMed: 19095497.
9. Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH et al. (2006) Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368: 1329-1338. doi:10.1016/S0140-6736(06)69446-4. PubMed: 17046465.
10. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM et al. (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356: 115-124. doi:10.1056/NEJMoa065044. PubMed: 17215529.
11. Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA et al. (2008) Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 26: 5422-5428. doi:10.1200/JCO.2008.16.9847. PubMed: 18936475.
12. Mross K, Drevs J, Müller M, Medinger M, Marmé D et al. (2005) Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours. Eur J Cancer 41: 1291-1299. doi:10.1016/j.ejca.2005.03.005. PubMed: 15939265.
13. Mross K, Frost A, Scheulen ME, Krauss J, Strumberg D et al. (2011) Phase I study of telatinib (BAY 57-9352): analysis of safety, pharmacokinetics, tumor efficacy, and biomarkers in patients with colorectal cancer. Vasc Cell 3: 16. doi:10.1186/2045-824X-3-16. PubMed: 21801343.
14. Schlehuber S, Skerra A (2005) Lipocalins in drug discovery: from natural ligand-binding proteins to anticalins. Drug Discov Today 10: 23-33. doi:10.1016/S1359-6446(04)03294-5. PubMed: 15676296.
15. Breustedt DA, Schönfeld DL, Skerra A (2006) Comparative ligand-binding analysis of ten human lipocalins. Biochim Biophys Acta 1764: 161-173. doi:10.1016/j.bbapap.2005.12.006. PubMed: 16461020.
16. Dartt DA (2011) Tear lipocalin: structure and function. Ocul Surf 9: 126-138. doi:10.1016/S1542-0124(11)70022-2. PubMed: 21791187.
17. Skerra A (2000) Lipocalins as a scaffold. Biochim Biophys Acta 1482: 337-350. doi:10.1016/S0167-4838(00)00145-X. PubMed: 11058774.
18. Schönfeld D, Matschiner G, Chatwell L, Trentmann S, Gille H et al. (2009) An engineered lipocalin specific for CTLA-4 reveals a combining site with structural and conformational features similar to antibodies. Proc Natl Acad Sci U S A 106: 8198-8203. doi:10.1073/pnas.0813399106. PubMed: 19416843.
19. Gebauer M, Skerra A (2012) Anticalins small engineered binding proteins based on the lipocalin scaffold. Methods Enzymol 503: 157-188. doi:10.1016/B978-0-12-396962-0.00007-0. PubMed: 22230569.
20. Skerra A (2007) Anticalins as alternative binding proteins for therapeutic use. Curr Opin Mol Ther 9: 336-344. PubMed: 17694446.
21. Breustedt DA, Korndörfer IP, Redl B, Skerra A (2005) The 1.8-A crystal structure of human tear lipocalin reveals an extended branched cavity with capacity for multiple ligands. J Biol Chem 280: 484-493. PubMed: 15489503.
22. Olwill SA, Joffroy C, Gille H, Vigna E, Matschiner G et al. (2013) A highly potent and specific MET therapeutic protein antagonist with both ligand-dependent and ligand-independent activity. Mol Cancer Ther 12: 2459-2471. doi:10.1158/1535-7163.MCT-13-0318. PubMed: 24002935.
23. Gille H, Huelsmeyer M, Christian HJ, Matschiner G, Trentmann S et al. (; April 12-162008) Discovery and characterization of a novel Anticalin with potent in vivo antagonistic activity towards VEGF-A [Poster #4077]. Presented at the American Association for Cancer Research (AACR) Annual Meeting; April 12-16, 2008.
24. Mirjolet JF, Sourzat B, Tizon X, Bichat F, Hohlbaum AM et al. (2009) The VEGF antagonist PRS-050 decreases vascular permeability in tumors and inhibits tumor growth: an analysis using dynamic contrast-enhanced magnetic resonance imaging [Poster #2318]. Presented at the American Association for Cancer Research (AACR) Annual Meeting; April 18-22, 2009.
25. Gille H, Christian HJ, Huelsmeyer M, Meyer T, Amirkhosravi A et al. (2011) Nonclinical pharmacokinetics and safety of Angiocal, the first VEGF-A-specific alternative scaffold protein entering clinical development for cancer [Poster #3632]. Presented at the American Association for Cancer Research (AACR) Annual Meeting; April 2-6, 2011.
26. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS et al. (2000) New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92: 205-216. doi:10.1093/jnci/92.3.205. PubMed: 10655437.
27. Scheffler K (2003) On the transient phase of balanced SSFP sequences. Magn Reson Med 49: 781-783. doi:10.1002/mrm.10421. PubMed: 12652552.
28. Tofts PS (1997) Modeling tracer kinetics in dynamic Gd-DTPA MR imaging. J Magn Reson Imaging 7: 91-101. doi:10.1002/jmri.1880070113. PubMed: 9039598.
29. Heinzerling JH, Huerta S (2006) Bowel perforation from bevacizumab for the treatment of metastatic colon cancer: incidence, etiology, and management. Curr Surg 63: 334-337. doi:10.1016/j.cursur.2006.06.002. PubMed: 16971205.
30. Mordenti J, Thomsen K, Licko V, Chen H, Meng YG (1999) Efficacy and concentration-response of murine anti-VEGF monoclonal antibody in tumor-bearing mice and extrapolation to humans. Toxicol Pathol 27: 14-21. doi:10.1177/ 019262339902700104. PubMed: 10367667.
31. Song X, Long SR, Barber B, Kassed CA, Healey M et al. (2012) Systematic review on infusion reactions associated with chemotherapies and monoclonal antibodies for metastatic colorectal cancer. Curr Clin Pharmacol 7: 56-65. doi: 10.2174/157488412799218806. PubMed: 22299770.
32. Launay-Vacher V, Deray G (2009) Hypertension and proteinuria: a class-effect of antiangiogenic therapies. Anticancer Drugs 20: 81-82. doi:10.1097/CAD.0b013e3283161012. PubMed: 19343005.
33. Rini BI, Cohen DP, Lu DR, Chen I, Hariharan S et al. (2011) Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 103: 763-773. doi:10.1093/jnci/ djr128. PubMed: 21527770.
34. Robinson ES, Khankin EV, Karumanchi SA, Humphreys BD (2010) Hypertension induced by vascular endothelial growth factor signaling pathway inhibition: mechanisms and potential use as a biomarker. Semin Nephrol 30: 591-601. doi:10.1016/j.semnephrol.2010.09.007. PubMed: 21146124.
35. Roodhart JM, Langenberg MH, Witteveen E, Voest EE (2008) The molecular basis of class side effects due to treatment with inhibitors of the VEGF/VEGFR pathway. Curr Clin Pharmacol 3: 132-143. doi: 10.2174/157488408784293705. PubMed: 18690886.
36. George S, Reichardt P, Lechner T, Li S, Cohen DP et al. (2012) Hypertension as a potential biomarker of efficacy in patients with gastrointestinal stromal tumor treated with sunitinib. Ann Oncol 23: 3180-3187. doi:10.1093/annonc/mds179. PubMed: 22858558.
37. Österlund P, Soveri LM, Isoniemi H, Poussa T, Alanko T et al. (2011) Hypertension and overall survival in metastatic colorectal cancer patients treated with bevacizumab-containing chemotherapy. Br J Cancer 104: 599-604. doi:10.1038/bjc.2011.2. PubMed: 21304526.
38. Tahover E, Uziely B, Salah A, Temper M, Peretz T et al. (2013) Hypertension as a predictive biomarker in bevacizumab treatment for colorectal cancer patients. Med Oncol 30: 327. doi:10.1007/s12032-012-0327-4. PubMed: 23254964.
39. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ et al. (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349: 427-434. doi:10.1056/NEJMoa021491. PubMed: 12890841.
40. Patel TV, Morgan JA, Demetri GD, George S, Maki RG et al. (2008) A preeclampsia-like syndrome characterized by reversible hypertension and proteinuria induced by the multitargeted kinase inhibitors sunitinib and sorafenib. J Natl Cancer Inst 100: 282-284. doi:10.1093/jnci/djm311. PubMed: 18270341.
41. He H, Venema VJ, Gu X, Venema RC, Marrero MB et al. (1999) Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c-Src. J Biol Chem 274: 25130-25135. doi:10.1074/jbc.274.35.25130. PubMed: 10455194.
42. Shen BQ, Lee DY, Zioncheck TF (1999) Vascular endothelial growth factor governs endothelial nitric-oxide synthase expression via a KDR/Flk-1 receptor and a protein kinase C signaling pathway. J Biol Chem 274: 33057-33063. doi:10.1074/jbc.274.46.33057. PubMed: 10551875.
43. Wei W, Jin H, Chen ZW, Zioncheck TF, Yim AP et al. (2004) Vascular endothelial growth factor-induced nitric oxide- and PGI2-dependent relaxation in human internal mammary arteries: a comparative study with KDR and Flt-1 selective mutants. J Cardiovasc Pharmacol 44: 615-621. doi:10.1097/00005344- 200411000-00016. PubMed: 15505501.
44. Drevs J, Zirrgiebel U, Schmidt-Gersbach CI, Mross K, Medinger M et al. (2005) Soluble markers for the assessment of biological activity with PTK787/ZK 222584 (PTK/ZK), a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor in patients with advanced colorectal cancer from two phase I trials. Ann Oncol 16: 558-565. doi: 10.1093/annonc/mdi118. PubMed: 15705616.
45. Mross K, Fasol U, Frost A, Benkelmann R, Kuhlmann J et al. (2009) DCE-MRI assessment of the effect of vandetanib on tumor vasculature in patients with advanced colorectal cancer and liver metastases: a randomized phase I study. J Angiogenes Res 1: 5. doi: 10.1186/2040-2384-1-5. PubMed: 19946413.
46. Mross K, Frost A, Steinbild S, Hedbom S, Büchert M et al. (2012) A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin Cancer Res 18: 2658-2667. doi: 10.1158/1078-0432.CCR-11-1900. PubMed: 22421192.
47. Jones SF, Spigel DR, Yardley DA, Thompson DF, Burris HA III (2011) A phase I trial of vatalanib (PTK/ZK) in combination with bevacizumab in patients with refractory and/or advanced malignancies. Clin Adv Hematol Oncol 9: 845-852. PubMed: 22252616.
48. Langenberg MH, Witteveen PO, Roodhart J, Lolkema MP, Verheul HM et al. (2011) Phase I evaluation of telatinib, a VEGF receptor tyrosine kinase inhibitor, in combination with bevacizumab in subjects with advanced solid tumors. Ann Oncol 22: 2508-2515. doi:10.1093/annonc/mdq767. PubMed: 21378200.
49. Hu J, Chen C, Su Y, Du J, Qian X et al. (2012) Vascular endothelial growth factor promotes the expression of cyclooxygenase 2 and matrix metalloproteinases in Lewis lung carcinoma cells. Exp Ther Med 4: 1045-1050. PubMed: 23226772.
50. Rooprai HK, Rucklidge GJ, Panou C, Pilkington GJ (2000) The effects of exogenous growth factors on matrix metalloproteinase secretion by human brain tumour cells. Br J Cancer 82: 52-55. doi:10.1054/bjoc.1999.0876. PubMed: 10638966.
51. Hua H, Li M, Luo T, Yin Y, Jiang Y (2011) Matrix metalloproteinases in tumorigenesis: an evolving paradigm. Cell Mol Life Sci 68: 3853-3868. doi:10.1007/s00018-011-0763-x. PubMed: 21744247.
52. Bergers G, Brekken R, McMahon G, Vu TH, Itoh T et al. (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2: 737-744. doi:10.1038/35036374. PubMed: 11025665.
53. Collen A, Hanemaaijer R, Lupu F, Quax PH, van Lent N et al. (2003) Membrane-type matrix metalloproteinase-mediated angiogenesis in a fibrin-collagen matrix. Blood 101: 1810-1817. doi:10.1182/blood-2002-05-1593. PubMed: 12393408.
54. Gupta GP, Nguyen DX, Chiang AC, Bos PD, Kim JY et al. (2007) Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446: 765-770. doi:10.1038/nature05760. PubMed: 17429393.
55. Itoh T, Tanioka M, Yoshida H, Yoshioka T, Nishimoto H et al. (1998) Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res 58: 1048-1051. PubMed: 9500469.
56. Belotti D, Paganoni P, Manenti L, Garofalo A, Marchini S et al. (2003) Matrix metalloproteinases (MMP9 and MMP2) induce the release of vascular endothelial growth factor (VEGF) by ovarian carcinoma cells: implications for ascites formation. Cancer Res 63: 5224-5229. PubMed: 14500349.
57. Dean RA, Butler GS, Hamma-Kourbali Y, Delbé J, Brigstock DR et al. (2007) Identification of candidate angiogenic inhibitors processed by matrix metalloproteinase 2 (MMP-2) in cell-based proteomic screens: disruption of vascular endothelial growth factor (VEGF)/heparin affin regulatory peptide (pleiotrophin) and VEGF/Connective tissue growth factor angiogenic inhibitory complexes by MMP-2 proteolysis. Mol Cell Biol 27: 8454-8465. doi:10.1128/MCB.00821-07. PubMed: 17908800.
58. 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. doi:10.1001/jama.2008.656. PubMed: 19017914.
59. Rudge JS, Holash J, Hylton D, Russell M, Jiang S et al. (2007) VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade. Proc Natl Acad Sci U S A 104: 18363-18370. doi:10.1073/pnas.0708865104. PubMed: 18000042.
60. Gerber HP, Wu X, Yu L, Wiesmann C, Liang XH et al. (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 U S A 104: 3478-3483. doi:10.1073/pnas.0611492104. PubMed: 17360669.
61. Meyer T, Robles-Carrillo L, Robson T, Langer F, Desai H et al. (2009) Bevacizumab immune complexes activate platelets and induce thrombosis in FCGR2A transgenic mice. J Thromb Haemost 7: 171-181. doi:10.1111/j.1538-7836.2008. 03212.x. PubMed: 18983497.