Skip to main content

Advertisement

SpringerLink
Log in

In vitro evaluation of the astatinated chimeric monoclonal antibody U36, a potential candidate for treatment of head and neck squamous cell carcinoma

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

The purpose of this study was to analyse the properties of the astatinated chimeric MAb (cMAb) U36 as a conjugate to selectively target and eradicate head and neck squamous cell carcinoma (HNSCC).

Methods

cMAb U36 was labelled with 211At via the linker N-succinimidyl 4-(trimethylstannyl)benzoate (SPMB). The quality of the conjugate was extensively evaluated for binding and internalisation capacity, and compared with 125I-SPMB-cMAb U36. The cellular toxicity of the astatinated conjugate was assessed in two types of in vitro growth assay and compared with 131I-labelled cMAb U36 (directly labelled).

Results

Comparisons between 211At-cMAb U36 and 125I-cMAb U36 demonstrated an optimal functional capacity of the labelled products. Immunoreactivity and affinity assays showed high immunoreactive fractions (>93%), and an affinity in good agreement between the astatinated and iodinated antibodies. For both conjugates, specific binding to HNSCC cells could be demonstrated, as well as some internalisation. Retention of the astatinated conjugate was just slightly lower than for the iodinated conjugate and still reasonable for therapeutic use (31±2% vs 42.6±1.0% at 22 h), demonstrating no adverse effects from astatination of the antibody. Studies on cellular toxicity demonstrated a dose-dependent and antigen-specific cellular toxicity for 211At-cMAb U36, with about 10% cell survival at 50 decays per cell. The 131I-labelled conjugate was not as efficient, with a surviving cell fraction of about 50% at 55 decays per cell.

Conclusion

These results indicate that 211At-cMAb U36 might be a promising future candidate for eradicating HNSCC micrometastases in vivo.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Hoffman HT, Karnell LH, Funk GF, Robinson RA, Menck HR. The National Cancer Data Base report on cancer of the head and neck. Arch Otolaryngol Head Neck Surg 1998;124:951–62

    Article  CAS  PubMed  Google Scholar 

  2. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001;2:533–43

    Article  CAS  PubMed  Google Scholar 

  3. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001;94:153–6

    Article  CAS  PubMed  Google Scholar 

  4. Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002. CA Cancer J Clin 2002;52:23–47

    Article  PubMed  Google Scholar 

  5. Alvi A, Johnson JT. Development of distant metastasis after treatment of advanced-stage head and neck cancer. Head Neck 1997;19:500–5

    Article  CAS  PubMed  Google Scholar 

  6. Carlsson J, Forssell Aronsson E, Hietala SO, Stigbrand T, Tennvall J. Tumour therapy with radionuclides: assessment of progress and problems. Radiother Oncol 2003;66:107–17

    Article  CAS  PubMed  Google Scholar 

  7. Heider KH, Kuthan H, Stehle G, Munzert G. CD44v6: a target for antibody-based cancer therapy. Cancer Immunol Immunother 2004;53:567–79

    Article  CAS  PubMed  Google Scholar 

  8. Terpe HJ, Storkel S, Zimmer U, Anquez V, Fischer C, Pantel K, et al. Expression of CD44 isoforms in renal cell tumors. Positive correlation to tumor differentiation. Am J Pathol 1996;148:453–63

    CAS  PubMed  Google Scholar 

  9. Gunthert U, Hofmann M, Rudy W, Reber S, Zoller M, Haussmann I, et al. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell 1991;65:13–24

    Article  CAS  PubMed  Google Scholar 

  10. Heider KH, Sproll M, Susani S, Patzelt E, Beaumier P, Ostermann E, et al. Characterization of a high-affinity monoclonal antibody specific for CD44v6 as candidate for immunotherapy of squamous cell carcinomas. Cancer Immunol Immunother 1996;43:245–53

    Article  CAS  PubMed  Google Scholar 

  11. de Bree R, Roos JC, Plaizier MA, Quak JJ, van Kamp GJ, den Hollander W, et al. Selection of monoclonal antibody E48 IgG or U36 IgG for adjuvant radioimmunotherapy in head and neck cancer patients. Br J Cancer 1997;75:1049–60

    Article  PubMed Central  PubMed  Google Scholar 

  12. de Bree R, Roos JC, Quak JJ, den Hollander W, Snow GB, van Dongen GA. Radioimmunoscintigraphy and biodistribution of technetium-99 m-labeled monoclonal antibody U36 in patients with head and neck cancer. Clin Cancer Res 1995;1:591–8

    PubMed  Google Scholar 

  13. Colnot DR, Ossenkoppele GJ, Roos JC, Quak JJ, de Bree R, Borjesson PK, et al. Reinfusion of unprocessed, granulocyte colony-stimulating factor-stimulated whole blood allows dose escalation of 186Re-labeled chimeric monoclonal antibody U36 radioimmunotherapy in a phase I dose escalation study. Clin Cancer Res 2002;8:3401–6

    CAS  PubMed  Google Scholar 

  14. Colnot DR, Quak JJ, Roos JC, van Lingen A, Wilhelm AJ, van Kamp GJ, et al. Phase I therapy study of 186Re-labeled chimeric monoclonal antibody U36 in patients with squamous cell carcinoma of the head and neck. J Nucl Med 2000;41:1999–2010

    CAS  PubMed  Google Scholar 

  15. Colnot DR, Nieuwenhuis EJC, Kuik DJ, Leemans CR, Dijkstra J, Snow GB, et al. Clinical significance of micrometastatic cells detected by E48 (ly-6D) reverse transcriptase-polymerase chain reaction in bone marrow of head and neck cancer patients. Clin Cancer Res 2004;10:7827–33

    Article  CAS  PubMed  Google Scholar 

  16. Breitz HB. How far have we come with solid (nonhematologic) tumor radioimmunotherapy? J Nucl Med 2000;41:2011–4

    CAS  PubMed  Google Scholar 

  17. Zalutsky MR, Vaidyanathan G. Astatine-211-labeled radiotherapeutics: an emerging approach to targeted alpha-particle radiotherapy. Curr Pharm Des 2000;6:1433–55

    Article  CAS  PubMed  Google Scholar 

  18. Andersson H, Elgqvist J, Horvath G, Hultborn R, Jacobsson L, Jensen H, et al. Astatine-211-labeled antibodies for treatment of disseminated ovarian cancer: an overview of results in an ovarian tumor model. Clin Cancer Res 2003;9:3914S–21S

    CAS  PubMed  Google Scholar 

  19. Hadley SW, Wilbur DS, Gray MA, Atcher RW. Astatine-211 labeling of an antimelanoma antibody and its Fab fragment using N-succinimidyl p-astatobenzoate: comparisons in vivo with the p-[125I]iodobenzoyl conjugate. Bioconjug Chem 1991;2:171–9

    Article  CAS  PubMed  Google Scholar 

  20. Brakenhoff RH, van Gog FB, Looney JE, van Walsum M, Snow GB, van Dongen GA. Construction and characterization of the chimeric monoclonal antibody E48 for therapy of head and neck cancer. Cancer Immunol Immunother 1995;40:191–200

    Article  CAS  PubMed  Google Scholar 

  21. Schrijvers AH, Quak JJ, Uyterlinde AM, van Walsum M, Meijer CJ, Snow GB, et al. MAb U36, a novel monoclonal antibody successful in immunotargeting of squamous cell carcinoma of the head and neck. Cancer Res 1993;53:4383–90

    CAS  PubMed  Google Scholar 

  22. Sjöström A, Tolmachev V, Lebeda O, Koziorowski J, Carlsson J, Lundqvist H. Direct astatination of a tumour-binding protein, human epidermal growth factor, using nido-carborane as a prosthetic group. J Radioanal Nucl Chem 2003;256:191–7

    Article  Google Scholar 

  23. Koziorowski J, Henssen C, Weinreich R. A new convenient route to radioiodinated N-succinimidyl 3- and 4-iodobenzoate, two reagents for radioiodination of proteins. Appl Radiat Isotopes 1998;49:955–9

    Article  CAS  Google Scholar 

  24. van Gog FB, Visser GW, Stroomer JW, Roos JC, Snow GB, van Dongen GA. High dose rhenium-186-labeling of monoclonal antibodies for clinical application: pitfalls and solutions. Cancer 1997;80:2360–70

    Article  PubMed  Google Scholar 

  25. Demartis S, Tarli L, Borsi L, Zardi L, Neri D. Selective targeting of tumour neovasculature by a radiohalogenated human antibody fragment specific for the ED-B domain of fibronectin. Eur J Nucl Med 2001;28:534–9

    Article  CAS  PubMed  Google Scholar 

  26. Palm S, Andersson H, Back T, Claesson I, Delle U, Hultborn R, et al. In vitro effects of free 211At, 211At-albumin and 211At-monoclonal antibody compared to external photon irradiation on two human cancer cell lines. Anticancer Res 2000;20:1005–12

    CAS  PubMed  Google Scholar 

  27. Johansson L, Nilsson K, Carlsson J, Larsson B, Jakobsson P. Radiation effects on cultured human lymphoid cells. Analysis using the growth extrapolation method. Acta Radiol Oncol 1981;20:51–9

    Article  CAS  PubMed  Google Scholar 

  28. Behr TM, Behe M, Stabin MG, Wehrmann E, Apostolidis C, Molinet R, et al. High-linear energy transfer (LET) alpha versus low-LET beta emitters in radioimmunotherapy of solid tumors: therapeutic efficacy and dose-limiting toxicity of 213Bi- versus 90Y-labeled CO17-1A Fab’ fragments in a human colonic cancer model. Cancer Res 1999;59:2635–43

    CAS  PubMed  Google Scholar 

  29. Supiot S, Faivre-Chauvet A, Couturier O, Heymann MF, Robillard N, Kraeber-Bodere F, et al. Comparison of the biologic effects of MA5 and B–B4 monoclonal antibody labeled with iodine-131 and bismuth-213 on multiple myeloma. Cancer 2002;94:1202–9

    Article  CAS  PubMed  Google Scholar 

  30. Andersson H, Palm S, Lindegren S, Back T, Jacobsson L, Leser G, et al. Comparison of the therapeutic efficacy of 211At- and 131I-labelled monoclonal antibody MOv18 in nude mice with intraperitoneal growth of human ovarian cancer. Anticancer Res 2001;21:409–12

    CAS  PubMed  Google Scholar 

  31. Nestor M, Persson M, Cheng J, Tolmachev V, van Dongen G, Anniko M, et al. Biodistribution of the chimeric monoclonal antibody U36 radioiodinated with a closo-dodecaborate-containing linker. Comparison with other radioiodination methods. Bioconjug Chem 2003;14:805–10

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank Dr. Anna Orlova for synthesis of N-succinimidyl 4-(trimethylstannyl)benzoate. This work was supported by Akademiska Sjukhuset, Uppsala, Sweden (project number AFN901), Cancerfonden, Sweden (project numbers 3978-B03-07XBB and 4712-B02-01XAC), and European Union FP6, LSHC-CT-2003-5032, STROMA. This publication reflects only the authors’ views. The European Commission is not liable for any use that may be made of the information contained.

Author information

Authors and Affiliations

  1. Unit of Otolaryngology and Head & Neck Surgery, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden

    M. Nestor & M. Anniko

  2. Unit of Urology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden

    M. Persson

  3. Unit of Biomedical Radiation Science, Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala, Sweden

    M. Persson, H. Lundqvist & V. Tolmachev

  4. Department of Otolaryngology/Head and Neck Surgery, Vrije Universiteit Medical Center, Amsterdam, The Netherlands

    G. A. M. S. van Dongen

  5. PET and Cyclotron Unit, Department of Clinical Physiology and Nuclear Medicine, Righshospitalet, Copenhagen, Denmark

    H. J. Jensen

Authors
  1. M. Nestor
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Persson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G. A. M. S. van Dongen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H. J. Jensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H. Lundqvist
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Anniko
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. V. Tolmachev
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Nestor.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nestor, M., Persson, M., van Dongen, G.A.M.S. et al. In vitro evaluation of the astatinated chimeric monoclonal antibody U36, a potential candidate for treatment of head and neck squamous cell carcinoma. Eur J Nucl Med Mol Imaging 32, 1296–1304 (2005). https://doi.org/10.1007/s00259-005-1848-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-005-1848-2

Keywords

Search

Navigation