Preclinical evaluation of 227Th-labeled and 177Lu-labeled trastuzumab in mice with HER-2-positive ovarian cancer xenografts

Nucl Med Commun. 2012 Aug;33(8):838-47. doi: 10.1097/MNM.0b013e328354df7c.


Objective: The aim of the present study was to compare the biodistribution, normal tissue toxicity, and therapeutic effect of two low-dose rate radioimmunoconjugates (RICs) in mice with HER2-expressing ovarian cancer xenografts: the α-particle-emitting (227)Th-trastuzumab and the β-particle-emitting (177)Lu-trastuzumab.

Materials and methods: Trastuzumab (Herceptin), conjugated to DOTA and radiolabeled with (227)Th or (177)Lu, was injected intravenously into mice bearing SKOV-3 xenografts. The biodistribution was determined at different time points after injection. The organs were collected and measured for radioactivity content using a gamma spectrometer. Inhibition of tumor growth was measured after a single injection of (227)Th-trastuzumab, (227)Th-rituximab, (177)Lu-trastuzumab, trastuzumab alone, and NaCl. The toxicity of (227)Th-trastuzumab and (177)Lu-trastuzumab was evaluated by measurement of body weight, determination of blood cell counts, analysis of clinical chemistry parameters, and histological examination of tissue specimens.

Results: The absorbed radiation dose to the tumor was 4 Gy after administration of 400 kBq/kg (227)Th-trastuzumab and 72 MBq/kg (177)Lu-trastuzumab. A significantly better antitumor effect of (227)Th-trastuzumab (8 and 30 days' growth delay for 400 and 600 kBq/kg, respectively) was observed as compared with untreated control, trastuzumab alone, 600 kBq/kg (227)Th-rituximab (nonspecific targeting), and 72 MBq/kg (177)Lu-trastuzumab. Mean survival of mice after treatment with (227)Th-trastuzumab (107 ± 9 and 129 ± 12 days for 400 and 600 kBq/kg (227)Th-trastuzumab, respectively) was significantly improved compared with control (88 ± 11 days) and other RICs (85 ± 8 and 66 ± 6 days for 72 MBq/kg (177)Lu-trastuzumab and 600 kBq/kg (227)Th-rituximab, respectively) (P<0.05, Kaplan-Meier). Treatment-related toxicity was not observed in any group except for a transient decrease in white blood cells between 3 and 9 weeks after treatment with 400 and 600 kBq/kg (227)Th-trastuzumab.

Conclusion: The α-particle-emitting RIC (227)Th-trastuzumab effectively delayed tumor growth and prolonged survival of mice compared with β-emitting (177)Lu-trastuzumab administered at the same absorbed radiation dose to tumor. This new therapeutic approach warrants further studies aiming at clinical testing in patients with micrometastatic ovarian cancer.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacokinetics*
  • Antibodies, Monoclonal, Humanized / toxicity
  • Antibodies, Monoclonal, Murine-Derived / pharmacokinetics*
  • Antibodies, Monoclonal, Murine-Derived / toxicity
  • Female
  • Lutetium / pharmacokinetics*
  • Lutetium / toxicity
  • Mice
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / metabolism*
  • Organometallic Compounds / pharmacokinetics*
  • Organometallic Compounds / toxicity
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / metabolism*
  • Platelet Count
  • Radioisotopes / pharmacokinetics*
  • Radioisotopes / toxicity
  • Receptor, ErbB-2 / metabolism
  • Rituximab
  • Tissue Distribution
  • Trastuzumab
  • Treatment Outcome


  • Antibodies, Monoclonal, Humanized
  • Antibodies, Monoclonal, Murine-Derived
  • Organometallic Compounds
  • Radioisotopes
  • thorium-227-DOTA-rituximab
  • Rituximab
  • Lutetium
  • Receptor, ErbB-2
  • Trastuzumab