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


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.


CONCLUSIONS
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.
Department of Radiation Biology, Norwegian Radium Hospital, Oslo, Norway. nasir.abbas@rr-research.no
Nasir
N
Abbas
Øyvind Sverre
ØS
Bruland
Ellen Mengshoel
EM
Brevik
Jostein
J
Dahle
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics* / Q000633:toxicity; D058846:Antibodies, Monoclonal, Murine-Derived / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D008187:Lutetium / Q000493:pharmacokinetics* / Q000633:toxicity; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism*; D009942:Organometallic Compounds / Q000493:pharmacokinetics* / Q000633:toxicity; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010976:Platelet Count; D011868:Radioisotopes / Q000493:pharmacokinetics* / Q000633:toxicity; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000069283:Rituximab; D014018:Tissue Distribution; D000068878:Trastuzumab; D016896:Treatment Outcome
D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D008187:Lutetium; D009942:Organometallic Compounds; D011868:Radioisotopes; D018719:Erb-b2 Receptor Tyrosine Kinases; D000069283:Rituximab; D000068878:Trastuzumab; C544340:thorium-227-DOTA-rituximab