Pancreatic Cancer pp 137-150

Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 177)

Antisense Therapeutics for Tumor Treatment: The TGF-beta2 Inhibitor AP 12009 in Clinical Development Against Malignant Tumors

  • Karl-Hermann Schlingensiepen
  • Birgit Fischer-Blass
  • Susanne Schmaus
  • Sylvia Ludwig

Abstract

Overexpression of the cytokine transforming growth factor-beta 2 (TGF-beta2) is a hallmark of various malignant tumors including pancreatic carcinoma, malignant glioma, metastasizing melanoma, and metastatic colorectal carcinoma. This is due to the pivotal role of TGF-beta2 as it regulates key mechanisms of tumor development, namely immunosuppression, metastasis, angiogenesis, and proliferation. The antisense technology is an innovative technique offering a targeted approach for the treatment of different highly aggressive tumors and other diseases. Antisense oligonucleotides are being developed to inhibit the production of disease-causing proteins at the molecular level. The immunotherapeutic approach with the phosphorothioate oligodeoxynucleotide AP 12009 for the treatment of malignant tumors is based on the specific inhibition of TGF-beta2.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Agrawal S, Temsamani J, Tang JY (1991) Pharmacokinetics, biodistribution, and stability of oligodeoxynucleotide phosphorothioates in mice. Proc Natl Acad Sci U S A 88:7595–7599PubMedCrossRefGoogle Scholar
  2. 2.
    Agrawal S, Temsamani J, Galbraith W, Tang J (1995) Pharmacokinetics of antisense oligonucleotides. Clin Pharmacokinet 28:7–16PubMedGoogle Scholar
  3. 3.
    Agrawal S, Jiang Z, Zhao Q, Shaw D, Cai Q, Roskey A, Channavajjala L, Saxinger C, Zhang R (1997) Mixed-backbone oligonucleotides as second generation antisense oligonucleotides: in vitro and in vivo studies. Proc Natl Acad Sci U S A 94:2620–2625PubMedCrossRefGoogle Scholar
  4. 4.
    Akhtar S, Agrawal S (1997) In vivo studies with antisense oligonucleotides. Trends Pharmacol Sci 18:12–18PubMedCrossRefGoogle Scholar
  5. 5.
    Akhurst RJ, Derynck R (2001) TGF-beta signaling in cancer—a double-edged sword. Trends Cell Biol 11:S44–51PubMedGoogle Scholar
  6. 6.
    Annes JP, Munger JS, Rifkin DB (2003) Making sense of latent TGFbeta activation. J Cell Sci 116:217–224PubMedCrossRefGoogle Scholar
  7. 7.
    Auerbach M, Wampler GL, Lokich JJ, Fryer D, Fryer JG, Ahlgren JD (1997) Treatment of advanced pancreatic carcinoma with a combination of protracted infusional 5-fluorouracil and weekly carboplatin: a Mid-Atlantic Oncology Program Study. Ann Oncol 8:439–444PubMedCrossRefGoogle Scholar
  8. 8.
    Blobe GC, Schiemann WP, Pepin MC, Beauchemin M, Moustakas A, Lodish HF, O‘Connor-McCourt MD (2001) Functional roles for the cytoplasmic domain of the type III transforming growth factor beta receptor in regulating transforming growth factor beta signaling. J Biol Chem 276:24627–24637PubMedCrossRefGoogle Scholar
  9. 9.
    Bobo RH, Laske DW, Akbasak A, Morrison PF, Dedrick RL, Oldfield EH (1994) Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci U S A 91:2076–2080PubMedCrossRefGoogle Scholar
  10. 10.
    Bodmer S, Strommer K, Frei K, Siepl C, de Tribolet N, Heid I, Fontana A (1989) Immunosuppression and transforming growth factor-beta in glioblastoma. Preferential production of transforming growth factor-beta 2. J Immunol 143:3222–3229PubMedGoogle Scholar
  11. 11.
    Bogdahn U, Oliushine VE, Parfenov VE, Kunst M, Mahapatra AK, Sastry KVR, Venkataramana KN, Jachimczak P, Hau P, Schlingensiepen KH (2006) Results of G004, a phase IIb study in recurrent glioblastoma patients with the TGF-b2 targeted compound AP 12009. J Clin Oncol, ASCO Annual Meeting Proceedings 24:1553Google Scholar
  12. 12.
    Braasch DA, Corey DR (2002) Novel antisense and peptide nucleic acid strategies for controlling gene expression. Biochemistry 41:4503–4510PubMedCrossRefGoogle Scholar
  13. 13.
    Brysch W, Schlingensiepen KH (1994) Design and application of antisense oligonucleotides in cell culture, in vivo, and as therapeutic agents. Cell Mol Neurobiol 14:557–568PubMedCrossRefGoogle Scholar
  14. 14.
    Burgess TL, Fisher EF, Ross SL, Bready JV, Qian YX, Bayewitch LA, Cohen AM, Herrera CJ, Hu SS, Kramer TB, et al. (1995) The antiproliferative activity of c-myb and c-myc antisense oligonucleotides in smooth muscle cells is caused by a nonantisense mechanism. Proc Natl Acad Sci U S A 92:4051–4055PubMedCrossRefGoogle Scholar
  15. 15.
    Cardenes HR, Chiorean EG, Dewitt J, Schmidt M, Loehrer P (2006) Locally advanced pancreatic cancer: current therapeutic approach. Oncologist 11:612–623PubMedCrossRefGoogle Scholar
  16. 16.
    Choudhury A, Moniaux N, Ulrich AB, Schmied BM, Standop J, Pour PM, Gendler SJ, Hollingsworth MA, Aubert JP, Batra SK (2004) MUC4 mucin expression in human pancreatic tumours is affected by organ environment: the possible role of TGFbeta2. Br J Cancer 90:657–664PubMedCrossRefGoogle Scholar
  17. 17.
    Coppelli FM, Grandis JR (2005) Oligonucleotides as anticancer agents: from the benchside to the clinic and beyond. Curr Pharm Des 11:2825–2840PubMedCrossRefGoogle Scholar
  18. 18.
    Crooke ST (1999) Molecular mechanisms of action of antisense drugs. Biochim Biophys Acta 1489:31–44PubMedGoogle Scholar
  19. 19.
    Crookston KP, Webb DJ, Wolf BB, Gonias SL (1994) Classification of alpha 2-macroglobulin-cytokine interactions based on affinity of noncovalent association in solution under apparent equilibrium conditions. J Biol Chem 269:1533–1540PubMedGoogle Scholar
  20. 20.
    Danielpour D, Sporn MB (1990) Differential inhibition of transforming growth factor beta 1 and beta 2 activity by alpha 2-macroglobulin. J Biol Chem 265:6973–6977PubMedGoogle Scholar
  21. 21.
    Dean NM, Bennett CF (2003) Antisense oligonucleotide-based therapeutics for cancer. Oncogene 22:9087–9096PubMedCrossRefGoogle Scholar
  22. 22.
    Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425:577–584PubMedCrossRefGoogle Scholar
  23. 23.
    Dumont N, Arteaga CL (2000) Transforming growth factor-beta and breast cancer: tumor promoting effects of transforming growth factor-beta. Breast Cancer Res 2:125–132PubMedCrossRefGoogle Scholar
  24. 24.
    Eckstein F (1983) Phosphorothioate analogues of nucleotides—tools for the investigation of biochemical processes. Angew Chem Int Ed Engl 22:423–506CrossRefGoogle Scholar
  25. 25.
    Frankel B, Longo SL, Ryken TC (1999) Human astrocytomas co-expressing Fas and Fas ligand also produce TGFbeta2 and Bcl-2. J Neurooncol 44:205–212PubMedCrossRefGoogle Scholar
  26. 26.
    Friess H, Yamanaka Y, Buchler M, Ebert M, Beger HG, Gold LI, Korc M (1993) Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology 105:1846–1856PubMedGoogle Scholar
  27. 27.
    Gardlik R, Palffy R, Hodosy J, Lukacs J, Turna J, Celec P (2005) Vectors and delivery systems in gene therapy. Med Sci Monit 11:RA110–RA121Google Scholar
  28. 28.
    Geary RS, Yu RZ, Levin AA (2001) Pharmacokinetics of phosphorothioate antisense oligodeoxynucleotides. Curr Opin Investig Drugs 2:562–573PubMedGoogle Scholar
  29. 29.
    Gorelik L, Flavell RA (2001) Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 7:1118–1122PubMedCrossRefGoogle Scholar
  30. 30.
    Hau P, Stockhammer G, Kunst M, Mahapatra AK, Sastry KVR, Parfenov V, Leshinsky V, Jachimczak P, Bogdahn U, Schlingensiepen K-H (2006) Results of G004, a phase IIb actively controlled clinical trial with the TGF-b2 targeted compound AP 12009 for recurrent anaplastic astrocytoma. J Clin Oncol, ASCO Annual Meeting Proceedings 24:1566Google Scholar
  31. 31.
    Henry SP, Bolte H, Auletta C, Kornbrust DJ (1997) Evaluation of the toxicity of ISIS 2302, a phosphorothioate oligonucleotide, in a four-week study in cynomolgus monkeys. Toxicology 120:145–155PubMedCrossRefGoogle Scholar
  32. 32.
    Jachimczak P, Bogdahn U, Schneider J, Behl C, Meixensberger J, Apfel R, Dorries R, Schlingensiepen KH, Brysch W (1993) The effect of transforming growth factor-beta 2-specific phosphorothioate-anti-sense oligodeoxynucleotides in reversing cellular immunosuppression in malignant glioma. J Neurosurg 78:944–951PubMedGoogle Scholar
  33. 33.
    Jachimczak P, Hessdorfer B, Fabel-Schulte K, Wismeth C, Brysch W, Schlingensiepen KH, Bauer A, Blesch A, Bogdahn U (1996) Transforming growth factor-beta-mediated autocrine growth regulation of gliomas as detected with phosphorothioate antisense oligonucleotides. Int J Cancer 65:332–337PubMedCrossRefGoogle Scholar
  34. 34.
    Janji B, Melchior C, Gouon V, Vallar L, Kieffer N (1999) Autocrine TGF-beta-regulated expression of adhesion receptors and integrin-linked kinase in HT-144 melanoma cells correlates with their metastatic phenotype. Int J Cancer 83:255–262PubMedCrossRefGoogle Scholar
  35. 35.
    Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun M (2005) Cancer statistics, 2005. CA Cancer J Clin 55:10–30PubMedGoogle Scholar
  36. 36.
    Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ (2006) Cancer statistics, 2006. CA Cancer J Clin 56:106–130PubMedGoogle Scholar
  37. 37.
    Kjellman C, Olofsson SP, Hansson O, Von Schantz T, Lindvall M, Nilsson I, Salford LG, Sjogren HO, Widegren B (2000) Expression of TGF-beta isoforms, TGF-beta receptors, and SMAD molecules at different stages of human glioma. Int J Cancer 89:251–258PubMedCrossRefGoogle Scholar
  38. 38.
    Krieg AM (2002) CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol 20:709–760PubMedCrossRefGoogle Scholar
  39. 39.
    Kurreck J (2003) Antisense technologies. Improvement through novel chemical modifications. Eur J Biochem 270:1628–1644PubMedCrossRefGoogle Scholar
  40. 40.
    Lahn M, Kloeker S, Berry BS (2005) TGF-beta inhibitors for the treatment of cancer. Expert Opin Investig Drugs 14:629–643PubMedCrossRefGoogle Scholar
  41. 41.
    Lee Y, Vassilakos A, Feng N, Jin H, Wang M, Xiong K, Wright J, Young A (2006) GTI-2501, an antisense agent targeting R1, the large subunit of human ribonucleotide reductase, shows potent anti-tumor activity against a variety of tumors. Int J Oncol 28:469–478PubMedGoogle Scholar
  42. 42.
    Levin AA (1999) A review of the issues in the pharmacokinetics and toxicology of phosphorothioate antisense oligonucleotides. Biochim Biophys Acta 1489:69–84PubMedGoogle Scholar
  43. 43.
    Levin AA, Monteith DK, Leeds JM, Nicklin PL, Geary RS, Butler M, Templin MV, Henry SP (1998) Toxicity of oligonucleotide therapeutic agents. In: Crooke ST (ed) Antisense research and application. Springer, Berlin Heidelberg New York, pp 169–215Google Scholar
  44. 44.
    Li D, Xie K, Wolff R, Abbruzzese JL (2004) Pancreatic cancer. Lancet 363:1049–1057PubMedCrossRefGoogle Scholar
  45. 45.
    Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA (2006) Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 24:99–146PubMedCrossRefGoogle Scholar
  46. 46.
    Lieberman DM, Laske DW, Morrison PF, Bankiewicz KS, Oldfield EH (1995) Convection-enhanced distribution of large molecules in gray matter during interstitial drug infusion. J Neurosurg 82:1021–1029PubMedCrossRefGoogle Scholar
  47. 47.
    Liu Q, Ling TY, Shieh HS, Johnson FE, Huang JS, Huang SS (2001) Identification of the high affinity binding site in transforming growth factor-beta involved in complex formation with alpha 2-macroglobulin. Implications regarding the molecular mechanisms of complex formation between alpha 2-macroglobulin and growth factors, cytokines, and hormones. J Biol Chem 276:46212–46218PubMedCrossRefGoogle Scholar
  48. 48.
    Lowenfels AB, Maisonneuve P (2006) Epidemiology and risk factors for pancreatic cancer. Best Pract Res Clin Gastroenterol 20:197–209PubMedCrossRefGoogle Scholar
  49. 49.
    Lysik MA, Wu-Pong S (2003) Innovations in oligonucleotide drug delivery. J Pharm Sci 92:1559–1573PubMedCrossRefGoogle Scholar
  50. 50.
    Mahato RI (2005) Biomaterials for delivery and targeting of proteins and nucleic acids. CRC Press, Boca RatonGoogle Scholar
  51. 51.
    Mahato RI, Ye Z, Guntaka RV (2005) Antisense and antigene oligonucleotides: structure, stability and delivery. In: Mahato RI (ed) Biomaterials for delivering and targeting of proteins and nucleic acids. CRC Press, Boca Raton, pp 569–600Google Scholar
  52. 52.
    Maxwell M, Galanopoulos T, Neville-Golden J, Antoniades HN (1992) Effect of the expression of transforming growth factor-beta 2 in primary human glioblastomas on immunosuppression and loss of immune surveillance. J Neurosurg 76:799–804PubMedGoogle Scholar
  53. 53.
    Miller PS, McParland KB, Jayaraman K, Ts‘o PO (1981) Biochemical and biological effects of nonionic nucleic acid methylphosphonates. Biochemistry 20:1874–1880PubMedCrossRefGoogle Scholar
  54. 54.
    Moore MJ, Goldstein D, Hamm J, Figer A, Hecht J, Gallinger S, Au H, Ding J, Christy-Bittel J, Parulekar W (2005) Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer. A phase III trial of the National Cancer Institute of Canada Clinical Trials Group [NCIC-CTG]. J Clin Oncol, 2005 ASCO Annual Meeting Proceedings 23:16SGoogle Scholar
  55. 55.
    Moustakas A, Pardali K, Gaal A, Heldin CH (2002) Mechanisms of TGF-beta signaling in regulation of cell growth and differentiation. Immunol Lett 82:85–91PubMedCrossRefGoogle Scholar
  56. 56.
    Murphy-Ullrich JE, Poczatek M (2000) Activation of latent TGF-beta by thrombospondin-1: mechanisms and physiology. Cytokine Growth Factor Rev 11:59–69PubMedCrossRefGoogle Scholar
  57. 57.
    Nygaard SJ, Haugland HK, Laerum OD, Lund-Johansen M, Bjerkvig R, Tysnes OB (1998) Dynamic determination of human glioma invasion in vitro. J Neurosurg 89:441–447PubMedGoogle Scholar
  58. 58.
    O‘Connor-McCourt MD, Wakefield LM (1987) Latent transforming growth factor-beta in serum. A specific complex with alpha 2-macroglobulin. J Biol Chem 262:14090–14099PubMedGoogle Scholar
  59. 59.
    Oeklue R, Hesketh R (2000) The latent transforming growth factor beta binding protein (LTBP) family. Biochem J 352:601–610CrossRefGoogle Scholar
  60. 60.
    Oft M, Heider KH, Beug H (1998) TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol 8:1243–1252PubMedCrossRefGoogle Scholar
  61. 61.
    Piek E, Heldin CH, Ten Dijke P (1999) Specificity, diversity, and regulation in TGF-beta superfamily signaling. FASEB J 13:2105–2124PubMedGoogle Scholar
  62. 62.
    Plank C, Mechtler K, Szoka FC Jr, Wagner E (1996) Activation of the complement system by synthetic DNA complexes: a potential barrier for intravenous gene delivery. Hum Gene Ther 7:1437–1446PubMedCrossRefGoogle Scholar
  63. 63.
    Roberts AB (1998) Molecular and cell biology of TGF-beta. Miner Electrolyte Metab 24:111–119PubMedCrossRefGoogle Scholar
  64. 64.
    Roehr B (1998) Fomivirsen approved for CMV retinitis. J Int Assoc Physicians AIDS Care 4:14–16PubMedGoogle Scholar
  65. 65.
    Schlingensiepen KH, Schlingensiepen R, Kunst M, Klinger I, Gerdes W, Seifert W, Brysch W (1993) Opposite functions of jun-B and c-jun in growth regulation and neuronal differentiation. Dev Genet 14:305–312PubMedCrossRefGoogle Scholar
  66. 66.
    Schlingensiepen KH, Schlingensiepen R, Steinbrecher A, Hau P, Bogdahn U, Fischer-Blass B, Jachimczak P (2006) Targeted tumor therapy with the TGF-b2 antisense compound AP 12009. Cytokine Growth Factor Rev 17:129–139PubMedCrossRefGoogle Scholar
  67. 67.
    Schlingensiepen R, Brysch W, Schlingensiepen KH (1997) Antisense: from technology to therapy: lab manual and textbook. Blackwell Science, BerlinGoogle Scholar
  68. 68.
    Schlingensiepen R, Goldbrunner M, Szyrach MN, Stauder G, Jachimczak P, Bogdahn U, Schulmeyer F, Hau P, Schlingensiepen KH (2005) Intracerebral and intrathecal infusion of the TGF-beta2-specific antisense phosphorothioate oligonucleotide AP 12009 in rabbits and primates: toxicology and safety. Oligonucleotides 15:94–104PubMedCrossRefGoogle Scholar
  69. 69.
    Shaw JP, Kent K, Bird J, Fishback J, Froehler B (1991) Modified deoxyoligonucleotides stable to exonuclease degradation in serum. Nucleic Acids Res 19:747–750PubMedCrossRefGoogle Scholar
  70. 70.
    Shen ZJ, Kim SK, Lee YS, Lee JW, Moon BJ (1999) Inhibition of transforming growth factor-beta 2 expression with phosphorothioate antisense oligonucleotides in U937 cells. Bioorg Med Chem Lett 9:13–18PubMedCrossRefGoogle Scholar
  71. 71.
    Siech M, Schlosser W, Beger HG (2001) Modern techniques for operation for chronic pancreatitis and pancreatic carcinoma and postoperative consequences. Pancreatology 1:1–8CrossRefGoogle Scholar
  72. 72.
    Stein CA, Tonkinson JL, Zhang LM, Yakubov L, Gervasoni J, Taub R, Rotenberg SA (1993) Dynamics of the internalization of phosphodiester oligodeoxynucleotides in HL60 cells. Biochemistry 32:4855–4861PubMedCrossRefGoogle Scholar
  73. 73.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996PubMedCrossRefGoogle Scholar
  74. 74.
    Sung RS, Qin L, Bromberg JS (2001) TNFalpha and IFNgamma induced by innate anti-adenoviral immune responses inhibit adenovirus-mediated transgene expression. Mol Ther 3:757–767PubMedCrossRefGoogle Scholar
  75. 75.
    Tari AM, Lopez-Berestein G (2001) Cellular uptake of antisense oligonucleotides. Curr Opin Investig Drugs 2:1450–1453PubMedGoogle Scholar
  76. 76.
    Theodosopoulos PV, Lamborn KR, Malec M, et al. (2001) Temozolomide in the treatment of recurrent malignant glioma. Proc ASCO, San FranciscoGoogle Scholar
  77. 77.
    Tidd DM, Warenius HM (1989) Partial protection of oncogene, anti-sense oligodeoxynucleotides against serum nuclease degradation using terminal methylphosphonate groups. Br J Cancer 60:343–350PubMedGoogle Scholar
  78. 78.
    Wakefield LM, Roberts AB (2002) TGF-beta signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev 12:22–29PubMedCrossRefGoogle Scholar
  79. 79.
    Weller M, Fontana A (1995) The failure of current immunotherapy for malignant glioma. Tumor-derived TGF-beta, T-cell apoptosis, and the immune privilege of the brain. Brain Res Brain Res Rev 21:128–151PubMedCrossRefGoogle Scholar
  80. 80.
    Wickstrom E (1986) Oligodeoxynucleotide stability in subcellular extracts and culture media. J Biochem Biophys Methods 13:97–102PubMedCrossRefGoogle Scholar
  81. 81.
    Yang Y, Wilson JM (1995) Clearance of adenovirus-infected hepatocytes by MHC class I-restricted CD4+ CTLs in vivo. J Immunol 155:2564–2570PubMedGoogle Scholar
  82. 82.
    Yaswen P, Stampfer MR, Ghosh K, Cohen JS (1993) Effects of sequence of thioated oligonucleotides on cultured human mammary epithelial cells. Antisense Res Dev 3:67–77PubMedGoogle Scholar
  83. 83.
    Yingling JM, Blanchard KL, Sawyer JS (2004) Development of TGF-beta signalling inhibitors for cancer therapy. Nat Rev Drug Discov 3:1011–1022PubMedCrossRefGoogle Scholar
  84. 84.
    Yung WK (2000) Temozolomide in malignant gliomas. Semin Oncol 27:27–34PubMedGoogle Scholar
  85. 85.
    Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, Brada M, Spence A, Hohl RJ, Shapiro W, Glantz M, Greenberg H, Selker RG, Vick NA, Rampling R, Friedman H, Phillips P, Bruner J, Yue N, Osoba D, Zaknoen S, Levin VA (2000) A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 83:588–593PubMedCrossRefGoogle Scholar
  86. 86.
    Zamecnik P, Aghajanian J, Zamecnik M, Goodchild J, Witman G (1994) Electron micrographic studies of transport of oligodeoxynucleotides across eukaryotic cell membranes. Proc Natl Acad Sci U S A 91:3156–3160PubMedCrossRefGoogle Scholar
  87. 87.
    Zamecnik PC, Stephenson ML (1978) Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Natl Acad Sci U S A 75:280–284PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • Karl-Hermann Schlingensiepen
    • 1
  • Birgit Fischer-Blass
    • 1
  • Susanne Schmaus
    • 1
  • Sylvia Ludwig
    • 1
  1. 1.Antisense Pharma GmbHRegensburgGermany

Personalised recommendations