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Anti-L1CAM radioimmunotherapy is more effective with the radiolanthanide terbium-161 compared to lutetium-177 in an ovarian cancer model

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

The L1 cell adhesion molecule (L1CAM) is considered a valuable target for therapeutic intervention in different types of cancer. Recent studies have shown that anti-L1CAM radioimmunotherapy (RIT) with 67Cu- and 177Lu-labelled internalising monoclonal antibody (mAb) chCE7 was effective in the treatment of human ovarian cancer xenografts. In this study, we directly compared the therapeutic efficacy of anti-L1CAM RIT against human ovarian cancer under equitoxic conditions with the radiolanthanide 177Lu and the potential alternative 161Tb in an ovarian cancer therapy model.

Methods

Tb was produced by neutron bombardment of enriched 160Gd targets. 161Tb and 177Lu were used for radiolabelling of DOTA-conjugated antibodies. The in vivo behaviour of the radioimmunoconjugates (RICs) was assessed in IGROV1 tumour-bearing nude mice using biodistribution experiments and SPECT/CT imaging. After ascertaining the maximal tolerated doses (MTD) the therapeutic impact of 50 % MTD of 177Lu- and 161Tb-DOTA-chCE7 was evaluated in groups of ten mice by monitoring the tumour size of subcutaneous IGROV1 tumours.

Results

The average number of DOTA ligands per antibody was 2.5 and maximum specific activities of 600 MBq/mg were achieved under identical radiolabelling conditions. RICs were stable in human plasma for at least 48 h. 177Lu- and 161Tb-DOTA-chCE7 showed high tumour uptake (37.8–39.0 %IA/g, 144 h p.i.) with low levels in off-target organs. SPECT/CT images confirmed the biodistribution data. 161Tb-labelled chCE7 revealed a higher radiotoxicity in nude mice (MTD: 10 MBq) than the 177Lu-labelled counterpart (MTD: 12 MBq). In a comparative therapy study with equitoxic doses, tumour growth inhibition was better by 82.6 % for the 161Tb-DOTA-chCE7 than the 177Lu-DOTA-chCE7 RIT.

Conclusions

Our study is the first to show that anti-L1CAM 161Tb RIT is more effective compared to 177Lu RIT in ovarian cancer xenografts. These results suggest that 161Tb is a promising candidate for future clinical applications in combination with internalising antibodies.

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References

  1. Yap TA, Carden CP, Kaye SB. Beyond chemotherapy: targeted therapies in ovarian cancer. Nat Rev Cancer. 2009;9:167–81.

    Article  CAS  PubMed  Google Scholar 

  2. Bukowski RM, Ozols RF, Markman M. The management of recurrent ovarian cancer. Semin Oncol. 2007;34:S1–15.

    Article  CAS  PubMed  Google Scholar 

  3. Hirte HW. Profile of erlotinib and its potential in the treatment of advanced ovarian carcinoma. Onco Targets Ther. 2013;6:427–35.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Schilder RJ, Sill MW, Lee RB, Shaw TJ, Senterman MK, Klein-Szanto AJ, et al. Phase ii evaluation of imatinib mesylate in the treatment of recurrent or persistent epithelial ovarian or primary peritoneal carcinoma: a gynecologic oncology group study. J Clin Oncol. 2008;26:3418–25.

    Article  CAS  PubMed  Google Scholar 

  5. Raveh S, Gavert N, Ben-Ze’ev A. L1 cell adhesion molecule (L1CAM) in invasive tumors. Cancer Lett. 2009;282:137–45.

    Article  CAS  PubMed  Google Scholar 

  6. Weidle UH, Eggle D, Klostermann S. L1-CAM as a target for treatment of cancer with monoclonal antibodies. Anticancer Res. 2009;29:4919–31.

    CAS  PubMed  Google Scholar 

  7. Kiefel H, Bondong S, Hazin J, Ridinger J, Schirmer U, Riedle S, et al. L1CAM a major driver for tumor cell invasion and motility. Cell Adhes Migr. 2012;6:374–84.

    Article  Google Scholar 

  8. Gavert N, Ben-Shmuel A, Raveh S, Ben-Ze’ev A. L1-CAM in cancerous tissues. Expert Opin Biol Ther. 2008;8:1749–57.

    Article  CAS  PubMed  Google Scholar 

  9. Novak-Hofer I. The L1 cell adhesion molecule as a target for radioimmunotherapy. Cancer Biother Radiopharm. 2007;22:175–84.

    Article  CAS  PubMed  Google Scholar 

  10. Boo YJ, Park JM, Kim J, Chae YS, Min BW, Um JW, et al. L1 expression as a marker for poor prognosis, tumor progression, and short survival in patients with colorectal cancer. Ann Surg Oncol. 2007;14:1703–11.

    Article  PubMed  Google Scholar 

  11. Fogel M, Gutwein P, Mechtersheimer S, Riedle S, Stoeck A, Smirnov A, et al. L1 expression as a predictor of progression and survival in patients with uterine and ovarian carcinomas. Lancet. 2003;362:869–75.

    Article  CAS  PubMed  Google Scholar 

  12. Kaifi JT, Reichelt U, Quaas A, Schurr PG, Wachowiak R, Yekebas EF, et al. L1 is associated with micrometastatic spread and poor outcome in colorectal cancer. Mod Pathol. 2007;20:1183–90.

    Article  CAS  PubMed  Google Scholar 

  13. Huszar M, Moldenhauer G, Gschwend V, Ben-Arie A, Altevogt P, Fogel M. Expression profile analysis in multiple human tumors identifies L1 (CD171) as a molecular marker for differential diagnosis and targeted therapy. Hum Pathol. 2006;37:1000–8.

    Article  CAS  PubMed  Google Scholar 

  14. Arlt MJE, Novak-Hofer I, Gast D, Gschwend V, Moldenhauer G, Grünberg J, et al. Efficient inhibition of intra-peritoneal tumor growth and dissemination of human ovarian carcinoma cells in nude mice by anti-L1-cell adhesion molecule monoclonal antibody treatment. Cancer Res. 2006;66:936–43.

    Article  CAS  PubMed  Google Scholar 

  15. Fischer E, Grünberg J, Cohrs S, Hohn A, Waldner-Knogler K, Jeger S, et al. L1-CAM-targeted antibody therapy and 177Lu-radioimmunotherapy of disseminated ovarian cancer. Int J Cancer. 2012;130:2715–21.

    Article  CAS  PubMed  Google Scholar 

  16. Knogler K, Grünberg J, Zimmermann K, Cohrs S, Honer M, Ametamey S, et al. Copper-67 radioimmunotherapy and growth inhibition by anti-L1-cell adhesion molecule monoclonal antibodies in a therapy model of ovarian cancer metastasis. Clin Cancer Res. 2007;13:603–11.

    Article  CAS  PubMed  Google Scholar 

  17. Wolterink S, Moldenhauer G, Fogel M, Kiefel H, Pfeifer M, Luttgau S, et al. Therapeutic antibodies to human L1CAM: functional characterization and application in a mouse model for ovarian carcinoma. Cancer Res. 2010;70:2504–15.

    Article  CAS  PubMed  Google Scholar 

  18. Friedli A, Fischer E, Novak-Hofer I, Cohrs S, Ballmer-Hofer K, Schubiger PA, et al. The soluble form of the cancer-associated L1 cell adhesion molecule is a pro-angiogenic factor. Int J Biochem Cell Biol. 2009;41:1572–80.

    Article  CAS  PubMed  Google Scholar 

  19. Novak-Hofer I, Amstutz HP, Morgenthaler JJ, Schubiger PA. Internalization and degradation of monoclonal-antibody chCE7 by human neuroblastoma-cells. Int J Cancer. 1994;57:427–32.

    Article  CAS  PubMed  Google Scholar 

  20. Lehenberger S, Barkhausen C, Cohrs S, Fischer E, Grünberg J, Hohn A, et al. The low-energy beta(-) and electron emitter Tb-161 as an alternative to Lu-177 for targeted radionuclide therapy. Nucl Med Biol. 2011;38:917–24.

    Article  CAS  PubMed  Google Scholar 

  21. Grünberg J, Novak-Hofer I, Honer M, Zimmermann K, Knogler K, Bläuenstein P, et al. In vivo evaluation of Lu-177- and Cu-67/64-labelled recombinant fragments of antibody chCE7 for radioimmunotherapy and PET imaging of L1-CAM-positive tumors. Clin Cancer Res. 2005;11:5112–20.

    Article  PubMed  Google Scholar 

  22. Lindmo T, Boven E, Cuttitta F, Fedorko J, Bunn PA. Determination of the immunoreactive fraction of radiolabeled monoclonal-antibodies by linear extrapolation to binding at infinite antigen excess. J Immunol Methods. 1984;72:77–89.

    Article  CAS  PubMed  Google Scholar 

  23. Foltz CJ, Ullman-Cullere M. Guidelines for assessing the health and condition of mice. Lab Anim. 1999;28:28–32.

    Google Scholar 

  24. Shannon RD. Revised effective ionic-radii and systematic studies of interatomic distances in halides and chalcogenides. Acta Crystallogr A. 1976;32:751–67.

    Article  Google Scholar 

  25. Viola-Villegas N, Doyle RP. The coordination chemistry of 1,4,7,10-tetraazacyclododecane-n, n′, n″, n′″-tetraacetic acid (h(4)DOTA): structural overview and analyses on structure-stability relationships. Coord Chem Rev. 2009;253:1906–25.

    Article  CAS  Google Scholar 

  26. Corneillie TM, Whetstone PA, Fisher AJ, Meares CF. A rare earth-DOTA-binding antibody: probe properties and binding affinity across the lanthanide series. J Am Chem Soc. 2003;125:3436–7.

    Article  CAS  PubMed  Google Scholar 

  27. Reddy N, Ong GL, Behr TM, Sharkey RM, Goldenberg DM, Mattes MJ. Rapid blood clearance of mouse IgG2a and human IgG1 in many nude and nu/+mouse strains is due to low IgG2a serum concentrations. Cancer Immunol Immunother. 1998;46:25–33.

    Article  CAS  PubMed  Google Scholar 

  28. van Gog FB, Brakenhoff RH, Snow GB, van Dongen G. Rapid elimination of mouse/human chimeric monoclonal antibodies in nude mice. Cancer Immunol Immunother. 1997;44:103–11.

    Article  PubMed  Google Scholar 

  29. Brouwers AH, van Eerd JE, Oosterwijk E, Oyen WJ, Corstens FH, Boerman OC. Preparation, characterization and application of I-131, Re-186, Y-90 and Lu-177-labeled cG250 for radioimmunotherapy of renal cell carcinoma. J Nucl Med. 2002;43:268P–9.

    Google Scholar 

  30. Kassis AI. The amazing world of Auger electrons. Int J Radiat Biol. 2004;80:789–803.

    Article  CAS  PubMed  Google Scholar 

  31. Pouget JP, Santoro L, Raymond L, Chouin N, Bardies M, Bascoul-Mollevi C, et al. Cell membrane is a more sensitive target than cytoplasm to dense ionization produced by Auger electrons. Radiat Res. 2008;170:192–200.

    Article  CAS  PubMed  Google Scholar 

  32. Behr TM, Behe M, Lohr M, Sgouros G, Angerstein C, Wehrmann E, et al. Therapeutic advantages of Auger electron- over beta-emitting radiometals or radioiodine when conjugated to internalizing antibodies. Eur J Nucl Med. 2000;27:753–65.

    Article  CAS  PubMed  Google Scholar 

  33. Paillas S, Boudousq V, Piron B, Kersual N, Bardies M, Chouin N, et al. Apoptosis and p53 are not involved in the anti-tumor efficacy of I-125-labeled monoclonal antibodies targeting the cell membrane. Nucl Med Biol. 2013;40:471–80.

    Article  CAS  PubMed  Google Scholar 

  34. Boswell CA, Brechbiel MW. Auger electrons: lethal, low energy, and coming soon to a tumor cell nucleus near you. J Nucl Med. 2005;46:1946–7.

    PubMed  Google Scholar 

  35. Kassis AI. Molecular and cellular radiobiological effects of Auger emitting radionuclides. Radiat Prot Dosim. 2011;143:241–7.

    Article  CAS  Google Scholar 

  36. Buchegger F, Perillo-Adamer F, Dupertuis YM, Delaloye AB. Auger radiation targeted into DNA: a therapy perspective. Eur J Nucl Med Mol Imaging. 2006;33:1352–63.

    Article  PubMed  Google Scholar 

  37. Chen P, Wang J, Hope K, Jin LQ, Dick J, Camron R, et al. Nuclear localizing sequences promote nuclear translocation and enhance the radiotoxicity of the anti-CD33 monoclonal antibody hum195 labeled with In-111 in human myeloid leukemia cells. J Nucl Med. 2006;47:827–36.

    CAS  PubMed  Google Scholar 

  38. Costantini DL, Chan C, Cai ZL, Vallis KA, Reilly RM. In-111-labeled trastuzumab (herceptin) modified with nuclear localization sequences (nls): an Auger electron-emitting radiotherapeutic agent for her2/neu-amplified breast cancer. J Nucl Med. 2007;48:1357–68.

    Article  CAS  PubMed  Google Scholar 

  39. Guo YJ, Parry JJ, Laforest R, Rogers BE, Anderson CJ. The role of p53 in combination radioimmunotherapy with Cu-64-DOTA-cetuximab and cisplatin in a mouse model of colorectal cancer. J Nucl Med. 2013;54:1621–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Boyd M, Ross SC, Dorrens J, Fullerton NE, Tan KW, Zalutsky MR, et al. Radiation-induced biologic bystander effect elicited in vitro by targeted radiopharmaceuticals labeled with alpha-, beta-, and Auger electron-emitting radionuclides. J Nucl Med. 2006;47:1007–15.

    CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Swiss Cancer Research Foundation (Project No. KFS-2546-02-2010) to Jürgen Grünberg

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Authors and Affiliations

  1. Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232, Villigen, Switzerland

    Jürgen Grünberg, Dennis Lindenblatt, Susan Cohrs, Eliane Fischer & Roger Schibli

  2. Laboratory of Radiochemistry and Environmental Chemistry, Paul Scherrer Institute, Villigen, Switzerland

    Holger Dorrer & Andreas Türler

  3. ITG Isotope Technologies Garching GmbH, Garching, Germany

    Konstantin Zhernosekov

  4. Institut Laue-Langevin, Grenoble, France

    Ulli Köster

  5. Department of Chemistry and Biochemistry, University of Bern, Berne, Switzerland

    Andreas Türler

  6. Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland

    Roger Schibli

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  1. Jürgen Grünberg
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Correspondence to Roger Schibli.

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Grünberg, J., Lindenblatt, D., Dorrer, H. et al. Anti-L1CAM radioimmunotherapy is more effective with the radiolanthanide terbium-161 compared to lutetium-177 in an ovarian cancer model. Eur J Nucl Med Mol Imaging 41, 1907–1915 (2014). https://doi.org/10.1007/s00259-014-2798-3

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  • DOI: https://doi.org/10.1007/s00259-014-2798-3

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