Tumor Biology

, Volume 33, Issue 3, pp 601–606 | Cite as

Pretargeted radioimmunotherapy (pRAIT) in medullary thyroid cancer (MTC)

  • Françoise Kraeber-Bodéré
  • Pierre-Yves Salaun
  • Catherine Ansquer
  • Delphine Drui
  • Eric Mirallié
  • Alain Faivre-Chauvet
  • Jacques Barbet
  • David M. Goldenberg
  • Jean-François Chatal
Research Article


Prognosis of medullary thyroid carcinoma (MTC) varies from long- to short-term survival, based on prognostic factors, such as serum calcitonin doubling time (Ct DT). Pretargeted radioimmunotherapy (pRAIT) is a novel targeted radionuclide therapy, using a bispecific monoclonal antibody (BsMAb) and a radiolabeled bivalent hapten, designed to improve the therapeutic index and to deliver increased tumor-absorbed doses to relatively radioresistant solid tumors. Pretargeting has demonstrated a more favorable therapeutic index and clinical efficacy than directly labeled anti-carcinoembryonic antigen (CEA) MAb in preclinical MTC models. Moreover, two phase I/II clinical trials assessing anti-CEA × anti-DTPA-indium BsMAb (murine F6x734 and chimeric hMN14x734) with 131I-di-DTPA-indium showed encouraging therapeutic results in progressive, metastatic, MTC patients, with an improved survival in intermediate- and high-risk (pre-pRAIT Ct DT, <2 years) patients, as compared to contemporaneous untreated patients (median overall survival, 110 months vs 61 months; P < 0.030). pRAIT efficacy has been recently confirmed in a prospective multicenter phase II study assessing hMN14x734 and 131I-di-DTPA-indium in rapidly progressive MTC patients. New pRAIT compounds are now available with fully humanized, recombinant, trivalent BsMAb (anti-CEA TF2) and histamine–succinyl–glutamine (HSG) peptides. The HSG peptide allows easy and stable labeling with different radiometals, such as 177Lu or 90Y beta-emitters having favorable physical features for pRAIT or 68Ga and 18F positron-emitters, allowing the development of a highly sensitive and specific immuno-positron emission tomography method in MTC or other CEA-positive tumors.


Pretargeted radioimmunotherapy Medullary thyroid cancer Calcitonin Bispecific antibody Immuno-PET 


Conflicts of interest



  1. 1.
    Hundahl SA, Fleming ID, Fremgen AM, et al. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985–1995. Cancer. 1998;83:2638–48.PubMedCrossRefGoogle Scholar
  2. 2.
    Schlumberger M, Carlomagno F, Baudin E, et al. New therapeutic approaches to treat medullary thyroid carcinoma. Nat Clin Pract Endocrinol Metab. 2008;4:22–32.PubMedCrossRefGoogle Scholar
  3. 3.
    Tubiana M, Milhaud G, Coutris G, Lacour J, Parmentier C, Bok B. Medullary carcinoma and thyrocalcitonin. Br Med J. 1968;4:87–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Machens A, Schneyer U, Holzhausen HJ, Dralle H. Prospects of remission in medullary thyroid carcinoma according to basal calcitonin level. J Clin Endocrinol Metab. 2005;90:2029–34.PubMedCrossRefGoogle Scholar
  5. 5.
    Fialkowski E, DeBenedetti M, Moley J. Long-term outcome of reoperations for medullary thyroid carcinoma. World J Surg. 2008;32:754–65.PubMedCrossRefGoogle Scholar
  6. 6.
    Bergholm U, Bergström R, Ekbom A. Long-term follow-up of patients with medullary thyroid carcinoma of the thyroid. Cancer. 1997;79:132–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Juweid M, Sharkey RM, Behr T, et al. Radioimmunotherapy of medullary thyroid cancer with 131I-labeled anti-CEA antibodies. J Nucl Med. 1996;37:905–11.PubMedGoogle Scholar
  8. 8.
    Juweid ME, Hajjar G, Swayne LC, et al. Phase I/II trial of (131)I-MN-14F(ab)2 anti-carcinoembryonic antigen monoclonal antibody in the treatment of patients with metastatic medullary thyroid carcinoma. Cancer. 1999;85:1828–42.PubMedCrossRefGoogle Scholar
  9. 9.
    Juweid ME, Hajjar G, Stein R, et al. Initial experience with high-dose radioimmunotherapy of metastatic medullary thyroid cancer using 131I-MN-14F(ab)2 anti-carcinoembryonic antigen MAb and AHSCR. J Nucl Med. 2000;41:93–103.PubMedGoogle Scholar
  10. 10.
    Goldenberg DM, Sharkey RM, Paganelli G, et al. Antibody pretargeting advances cancer radioimmunodetection and radioimmunotherapy. J Clin Oncol. 2006;24:823–34.PubMedCrossRefGoogle Scholar
  11. 11.
    Modigliani E, Cohen R, Campos JM, et al. Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. Clin Endocrinol. 1998;48:265–73.CrossRefGoogle Scholar
  12. 12.
    Miccoli P, Minuto MN, Ugolini C, et al. Clinically unpredictable prognostic factors in the outcome of medullary thyroid cancer. Endocr Relat Cancer. 2007;14:1099–105.PubMedCrossRefGoogle Scholar
  13. 13.
    Kebebew E, Ituarte PH, Siperstein AE, Duh QY, Clark OH. Medullary thyroid carcinoma. Clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer. 2000;88:1139–48.PubMedCrossRefGoogle Scholar
  14. 14.
    Byar DP, Green SB, Dor P, et al. A prognostic index for thyroid carcinoma. A study of the E.O.R.T.C. Thyroid Cancer Cooperative Group. Eur J Cancer. 1979;15:1033–41.PubMedCrossRefGoogle Scholar
  15. 15.
    Elisei R, Cosci B, Romei C, et al. Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study. J Clin Endocrinol Metab. 2008;93:682–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Ito Y, Yoshida H, Tomoda C. Expression of cdc25B and cdc25A in medullary thyroid carcinoma: cdc25B expression level predicts a poor prognosis. Cancer Lett. 2005;229:291–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Tisell LE, Oden A, Muth A, et al. The Ki67 index a prognostic marker in medullary thyroid carcinoma. Br J Cancer. 2003;89:2093–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Barbet J, Campion L, Kraeber-Bodéré F, et al. Prognostic impact of serum calcitonin and carcinoembryonic antigen doubling-times in patients with medullary thyroid carcinoma. J Clin Endocrinol Metab. 2005;90:6077–84.PubMedCrossRefGoogle Scholar
  19. 19.
    Mirallié E, Vuillez JP, Bardet S, et al. High frequency of bone/bone marrow involvement in advanced medullary thyroid cancer. J Clin Endocrinol Metab. 2005;90:779–88.PubMedCrossRefGoogle Scholar
  20. 20.
    Oudoux A, Salaun PY, Bournaud C, et al. Sensitivity and prognostic value of positron emission tomography with F-18-fluorodeoxyglucose and sensitivity of immunoscintigraphy in patients with medullary thyroid carcinoma treated with anticarcinoembryonic antigen-targeted radioimmunotherapy. J Clin Endocrinol Metab. 2007;92:4590–7.PubMedCrossRefGoogle Scholar
  21. 21.
    American Thyroid Association Guidelines Task Force, Kloos RT, Eng C, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19:565–612.PubMedCrossRefGoogle Scholar
  22. 22.
    Luster M, Karges W, Zeich K, et al. Clinical value of 18-fluorine-fluorodihydroxyphenylalanine positron emission tomography/computed tomography in the follow-up of medullary thyroid carcinoma. Thyroid. 2010;20:527–33.PubMedCrossRefGoogle Scholar
  23. 23.
    Karacay H, Sharkey RM, McBride WJ, et al. Optimization of hapten-peptide labeling for pretargeted immunoPET of bispecific antibody using generator-produced 68Ga. J Nucl Med. 2011;52:555–9.PubMedCrossRefGoogle Scholar
  24. 24.
    McBride WJ, Sharkey RM, Karacay H, et al. A novel method of 18F radiolabeling for PET. J Nucl Med. 2009;50:991–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Schoffelen R, Sharkey RM, Goldenberg DM, et al. Pretargeted immuno-positron emission tomography imaging of carcinoembryonic antigen-expressing tumors with a bispecific antibody and a 68Ga- and 18F-labeled hapten peptide in mice with human tumor xenografts. Mol Cancer Ther. 2010;9:1019–27.PubMedCrossRefGoogle Scholar
  26. 26.
    McBride WJ, Zanzonico P, Sharkey RM, et al. Bispecific antibody pretargeting PET (immunoPET) with an 124I-labeled hapten-peptide. J Nucl Med. 2006;47:1678–88.PubMedGoogle Scholar
  27. 27.
    Hosono M, Hosono M, Kraeber-Bodéré F, et al. Biodistribution and dosimetry study in medullary thyroid cancer xenograft using bispecific antibody and iodine-125-labeled bivalent hapten. J Nucl Med. 1998;39:1608–13.PubMedGoogle Scholar
  28. 28.
    Kraeber-Bodéré F, Faivre-Chauvet A, Sai-Maurel C, et al. Comparative toxicity and efficacy of one- and two-step (bipecific antibody and bivalent hapten) radioimmunotherapy in CEA-producing medullary thyroid cancer. J Nucl Med. 1999;40:198–204.PubMedGoogle Scholar
  29. 29.
    Kraeber-Bodere F, Bardet S, Hoefnagel CA, et al. Radioimmunotherapy in medullary thyroid cancer using bispecific antibody and iodine 131-labeled bivalent hapten: preliminary results of a phase I/II clinical trial. Clin Cancer Res. 1999;5:3190–8.Google Scholar
  30. 30.
    Kraeber-Bodere F, Faivre-Chauvet A, Ferrer L, et al. Pharmacokinetics and dosimetry studies for optimisation of carcinoembryonic antigen × anti-hapten bispecific antibody mediated pretargeting of iodine-131-labeled hapten in a phase I radioimmunotherapy trial. Clin Cancer Res. 2003;9:3973–81.Google Scholar
  31. 31.
    Kraeber-Bodere F, Rousseau C, Bodet-Milin C, et al. Targeting, toxicity and efficacy of 2-step, pretargeted radioimmunotherapy using a chimeric bispecific antibody and 131-I-labeled bivalent hapten in a phase I optimisation clinical trial. J Nucl Med. 2006;47:247–55.PubMedGoogle Scholar
  32. 32.
    Chatal JF, Campion L, Kraeber-Bodéré F, et al. Survival improvement in patients with medullary thyroid carcinoma who undergo pretargeted anti-carcinoembryonic-antigen radioimmunotherapy: a collaborative study with the French Endocrine Tumor Group. J Clin Oncol. 2006;24:1705–11.PubMedCrossRefGoogle Scholar
  33. 33.
    Salaun PY, Bournaud C, Bardet S, et al. Pretargeted radioimmunotherapy (pRAIT) in progressive metastatic medullary thyroid cancer (MTC): results of a phase II trial. Annual Congress of Society of Nuclear Medicine, San Antonio. 2011.Google Scholar
  34. 34.
    Kraeber-Bodéré F, Saï-Maurel C, Campion L, et al. Enhanced antitumor activity of combined pretargeted radioimmunotherapy and paclitaxel in medullary thyroid cancer xenograft. Mol Cancer Ther. 2002;1:267–74.PubMedGoogle Scholar
  35. 35.
    Kraeber-Bodéré F, Bodet-Milin C, Niaudet C, et al. Comparative toxicity and efficacy of combined radioimmunotherapy and antiangiogenic therapy in carcinoembryonic antigen-expressing medullary thyroid cancer xenograft. J Nucl Med. 2010;51:624–31.PubMedCrossRefGoogle Scholar
  36. 36.
    Salaun PY, Bodet-Milin C, Frampas E, et al. Toxicity and efficacy of combined radioimmunotherapy and bevacizumab in a mouse model of medullary thyroid carcinoma. Cancer. 2010;116:1053–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Iten F, Müller B, Schindler C, et al. Response to [90Ytrium-DOTA]-TOC treatment is associated with long-term survival benefit in metastasized medullary thyroid cancer: a phase II clinical trial. Clin Cancer Res. 2007;13:6696–702.PubMedCrossRefGoogle Scholar
  38. 38.
    Gross DJ, Munter G, Bitan M, et al. The role of imatinib mesylate (Glivec) for treatment of patients with malignant endocrine tumors positive for c-kit or PDGF-R. Endocr Relat Cancer. 2006;13:535–40.PubMedCrossRefGoogle Scholar
  39. 39.
    de Groot JWB, Zonnenberg BA, Quarles van Ufford-Mannesse P, et al. A phase II trial of imatinib therapy for metastatic medullary thyroid carcinoma. J Clin Endocrinol Metab. 2007;92:3466–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Frank-Raue K, Fabel M, Delorme S, et al. Efficacy of imatinib mesylate in advanced medullary thyroid carcinoma. Eur J Endocrinol. 2007;157:215–20.PubMedCrossRefGoogle Scholar
  41. 41.
    Schlumberger MJ, Elisei R, Bastholt L, et al. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J Clin Oncol. 2009;27:3794–801.PubMedCrossRefGoogle Scholar
  42. 42.
    Lam ET, Ringel MD, Kloos RT, et al. Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J Clin Oncol. 2010;28:2323–30.PubMedCrossRefGoogle Scholar
  43. 43.
    Wells Jr SA, Gosnell JE, Gagel RF, et al. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol. 2010;28:767–72.PubMedCrossRefGoogle Scholar
  44. 44.
    Wells SA, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30:134–41.PubMedCrossRefGoogle Scholar
  45. 45.
    Goldenberg DM, Rossi EA, Sharkey RM, et al. Multifunctional antibodies by the Dock-and-Lock method for improved cancer imaging and therapy by pretargeting. J Nucl Med. 2008;49:158–63.PubMedCrossRefGoogle Scholar
  46. 46.
    Rossi EA, Goldenberg DM, Cardillo TM, et al. Stably tethered multifunctional structures of defined composition made by the dock and lock method for use in cancer targeting. Proc Natl Acad Sci U S A. 2006;103:6841–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Schoffelen R, van der Graaf WT, Franssen G, et al. Pretargeted 177Lu radioimmunotherapy of carcinoembryonic antigen-expressing human colonic tumors in mice. J Nucl Med. 2010;51:1780–7.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2012

Authors and Affiliations

  • Françoise Kraeber-Bodéré
    • 1
    • 2
    • 8
  • Pierre-Yves Salaun
    • 3
  • Catherine Ansquer
    • 1
    • 2
  • Delphine Drui
    • 4
  • Eric Mirallié
    • 5
  • Alain Faivre-Chauvet
    • 1
    • 2
  • Jacques Barbet
    • 2
    • 6
  • David M. Goldenberg
    • 7
  • Jean-François Chatal
    • 6
  1. 1.Nuclear Medicine DepartmentUniversity Hospital, ICO René GauducheauNantesFrance
  2. 2.Cancer Research CenterUniversity of Nantes, InsermNantesFrance
  3. 3.Nuclear Medicine DepartmentUniversity HospitalBrestFrance
  4. 4.Endocrinology DepartmentUniversity HospitalNantesFrance
  5. 5.Surgery DepartmentUniversity HospitalNantesFrance
  6. 6.Arronax CyclotronUniversity of NantesNantesFrance
  7. 7.Garden State Cancer CentreCenter for Molecular Medicine and ImmunologyMorris PlainsUSA
  8. 8.Nuclear Medicine DepartmentHôtel Dieu University HospitalNantesFrance

Personalised recommendations