Development of 90Y-DOTA-nimotuzumab Fab fragment for radioimmunotherapy

  • Luis M. Alonso Martínez
  • Abmel Xiques Castillo
  • Victoria N. Calzada Falcón
  • Marylaine Pérez-Malo Cruz
  • René Leyva Montaña
  • Minely Zamora Barrabí
  • Ignacio Hernández González
  • Mariela León Pérez
  • Alejandro Arbesú Valdivia
Article
First Online:
Received:

Abstract

Yttrium-90-(90Y) labeled monoclonal antibodies prepared with a chelating agent, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), have been used for radioimmunotherapy of cancer. In the present work, the Fab fragment of anti-EGFR monoclonal antibody nimotuzumab was prepared with high purity, integrity and biological activity. The Fab fragment with high specific recognition of EGFR in NCI-H125 human lung adenocarcinoma cells was derivatized with DOTA-NHS applying a simple procedure. DOTA-nimotuzumab Fab fragment was successfully radiolabeled with 90Y with high radiochemical yield. The in vitro stability of labeled product was optimal over 24 h in buffered solution at 37 °C. Biodistribution and pharmacokinetic studies correctly evaluated the in vivo non-tumor uptake, dosage regimen and excretion pathway in normal Wistar rats.

Keywords

90Y Radioimmunotherapy Nimotuzumab Fab fragment DOTA Radiopharmaceutical development 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

The authors would like to thank the Center of Molecular Immunology for their kind support. Funding of this work was partially provided by the International Atomic Energy Agency through the co-ordinated research project on “Development of Generator Technologies for Therapeutic Radionuclides: 90Y and 188Re”.

References

  1. 1.
    Boonstra J, Rijken P, Humbel B (1995) Cell Biol Int 19:413–430CrossRefGoogle Scholar
  2. 2.
    Mateo C, Moreno E, Amour K, Lombardero J, Harris W, Perez R (1997) Immunotechnology 3:71–81CrossRefGoogle Scholar
  3. 3.
    Crombet T, Casaco A, Iznaga N (2003) Drugs future 28:847–853CrossRefGoogle Scholar
  4. 4.
    Casaco A (2004) Proc Am Soc Clin Oncol 22 Abstract no. 2530Google Scholar
  5. 5.
    Beckford D, Xiques A, Leyva R, Perez-Malo M, Casanova E, Zamora M (2007) Nucleus 41:3–8Google Scholar
  6. 6.
    Ondarse D, Leyva R, Zamora M, Ducat L, Hernández I, Alonso LM (2011) Nucleus 49:26–32Google Scholar
  7. 7.
    Beran M, Beckford D, Forsterova M, Laznickova A, Laznicek M, Melichar F, Leyva R, Barta P (2009) J Label Compd Radiopharm 52:S511Google Scholar
  8. 8.
    Beckford D, Eigner S, Beran M, Henke KE, Laznickova A, Laznicek M, Melichar F, Chinol M (2011) Cancer Biother Radiopharm 26:287–297CrossRefGoogle Scholar
  9. 9.
    Beckford D, Eigner S, Henke KE, Lebeda O, Melichar F, Beran M (2012) Nucl Med Biol 39:3–13CrossRefGoogle Scholar
  10. 10.
    Calzada V, Zhang X, Fernández M, Díaz A, Iznaga N, Deutscher SL, Balter H, Quinn TP, Cabral PA (2012) Curr Radiopharm 5:318–324CrossRefGoogle Scholar
  11. 11.
    Grünberg J, Novak I, Honer M (2005) Clin Cancer Res 11:5112–5120CrossRefGoogle Scholar
  12. 12.
    Parham P (1983) J Immunol 131:2895–2902Google Scholar
  13. 13.
    Laemmli UK (1970) Nature 227:680–685CrossRefGoogle Scholar
  14. 14.
    Lewis MR, Raubitschek A, Shively JE (1994) Bioconjug Chem 5:565–576CrossRefGoogle Scholar
  15. 15.
    Xiques A, Isaac K, Casanova E, Beckford D, Leyva R, Montero A, Olive E (2009) Radiochim Acta 97:739Google Scholar
  16. 16.
    Sakahara H, Endo K, Nakashima T, Koizumi M, Ohta H, Torizuka K, Furukawa T, Ohmomo Y, Okada K, Yoshida O, Nishi S (1985) J Nucl Med 26:750–755Google Scholar
  17. 17.
    Tikhomirov I, Garrido G, Rabasa A, Perez R (2009) Ann Oncol 20:III32–III35Google Scholar
  18. 18.
    Salomon DS, Brandt R, Ciardiello F, Normanno N (1995) Crit Rev Oncol Hematol 19:83–232CrossRefGoogle Scholar
  19. 19.
    Parham P (1986) In: Wier DM (ed) Handbook of experimental immunology: immunochemistry. Blackwell Scientific, LondonGoogle Scholar
  20. 20.
    Parham P (1983) J Immunol 131:2895–2902Google Scholar
  21. 21.
    Behr TM, Sharkey RM, Sgouros G (1997) Cancer 80:2591–2610CrossRefGoogle Scholar
  22. 22.
    Zimmermann K, Gianollini S, Schubiger PA, Novak-Hofer I (1999) Nucl Med Biol 26:943–950CrossRefGoogle Scholar
  23. 23.
    Kim I, Kobayashi H, Yoo TM (2002) Nucl Med Biol 29:795–801CrossRefGoogle Scholar
  24. 24.
    Behr TM, Sharkey RM, Juweid ME, Blumenthal RD, Dunn RM, Griffiths GL, Bair HJ, Wolf FG, Becker WS, Goldenberg DM (1995) Cancer Res 55:3825–3834Google Scholar
  25. 25.
    Chapman AP (2002) Adv Drug Deliv Rev 54:531–545CrossRefGoogle Scholar
  26. 26.
    Meibohm B (2006) Pharmacokinetics and pharmacodynamics of biotech drugs. Wiley, GermanyCrossRefGoogle Scholar
  27. 27.
    Iznaga N, Morales A, Duconge J, Caballero I, Fernández E, Gomez JA (1998) Nucl Med Biol 25:17–23CrossRefGoogle Scholar
  28. 28.
    Beckford D, Eigner S, Eigner KH, Leyva R, Melichar F, Beran M (2013) Results Cancer Res 194:301–317CrossRefGoogle Scholar
  29. 29.
    Covell DG, Barbet J, Holton OD (1986) Cancer Res 46:3969–3978Google Scholar

Copyright information

© Akadémiai Kiadó, Budapest, Hungary 2014

Authors and Affiliations

  • Luis M. Alonso Martínez
    • 1
  • Abmel Xiques Castillo
    • 1
    • 2
  • Victoria N. Calzada Falcón
    • 3
  • Marylaine Pérez-Malo Cruz
    • 1
  • René Leyva Montaña
    • 1
  • Minely Zamora Barrabí
    • 4
  • Ignacio Hernández González
    • 5
  • Mariela León Pérez
    • 5
  • Alejandro Arbesú Valdivia
    • 4
  1. 1.Deparment of RadiopharmacyCenter of IsotopesGuanabacoaCuba
  2. 2.Jubilant DraxImageKirklandCanada
  3. 3.Centro de Investigaciones NuclearesUniversidad de la RepúblicaMontevideoUruguay
  4. 4.Deparment of Quality ControlCenter of IsotopesGuanabacoaCuba
  5. 5.Deparment of DevelopmentCenter of IsotopesGuanabacoaCuba

Personalised recommendations