Aim:
Pretargeted radioimmunotherapy (PRIT) with the anti-CEA x anti-HSG bispecific antibody TF2, and 177Lu-labeled di-HSG-DOTA peptide IMP288, can delay growth of CEA-expressing colon cancer xenografts. A phase I study has shown the safety and feasibility of PRIT in colorectal cancer patients. The therapeutic efficacy of PRIT may be improved by using alpha-emitting radionuclides. The aim of this study was to compare the therapeutic efficacy of 213Bi and 177Lu for PRIT of CEA-expressing xenografts.
Material and methods:
The vitro binding characteristics (IC50, Kd, internalization) of 213Bi-IMP288 were compared with those of 177Lu-IMP288. Tumor targeting of 213Bi-IMP288 and 177Lu-IMP288 was studied in mice with s.c. LS174T that were pretargeted with TF2. Finally, the effect of 213Bi-IMP288 (6, 12, or 17 MBq) and 177Lu-IMP288 (MTD: 60 MBq) on tumor growth and survival was assessed. Toxicity was determined by monitoring body weight and by analyzing blood samples for haematological toxicity (haemoglobin, leucocytes, platelets).
Results:
Binding characteristics of 213Bi-IMP288 were similar to those of 177Lu-IMP288 (Kd = 0.8 nM). Tumor uptake was observed as early as 15 min post injection (9.2 ± 2.0 %ID/g) and the peptide cleared rapidly from the circulation. At 30 min post injection the blood level of 213Bi-IMP288 was 0.44 ± 0.28 %ID/g. Uptake of 213Bi-IMP288 in other normal tissues was very low, except for some uptake in the kidneys (1.8 ± 1.1 %ID/g). The biodistribution was comparable to that of 177Lu-IMP288. PRIT treated mice showed significant inhibition of tumor growth and prolonged survival. Mean doubling time of the tumor following treatment with PBS, 6 MBq 213Bi-IMP288, 12 MBq 213Bi-IMP288, 17 MBq 213Bi-IMP288, and 60 MBq 177Lu-IMP288 group was 3.3 ± 0.3, 6.5 ± 1.2, 11.1 ± 3.2, 37.1 ± 25.0, and 11.8 ± 9.3 days. Median survival for the PBS, 6 MBq, and 17 MBq 213Bi-IMP288 group was 22, 31, and 24 days, respectively. The 12 MBq 213Bi-IMP288 and 60 MBq 177Lu-IMP288 groups did not yet reach the median survival at day 35. No changes in haemoglobin, platelets, and leucocytes were observed.
Conclusion:
This study showed that PRIT with the alpha-emitting radionuclide is feasible and at least as effective as 177Lu-IMP288. Haematological toxicity and survival of mice treated with 12 MBq 213Bi-IMP288 and 60 MBq 177Lu-IMP288 were comparable. Future experiments should study the effect of multiple cycles of 213Bi- and 177Lu-IMP288 on tumor growth, survival, and haematological and renal toxicity.
HESKAMP Sandra;
HERNANDEZ Reinier;
MOLKENBOER-KUENEN J.D.M.;
ESSLER Markus;
BRUCHERTSEIFER Frank;
MORGENSTERN Alfred;
OYEN Wim;
SEIDL C.;
MCBRIDE William;
GOLDENBERG David;
BOERMAN Otto;
2015-11-06
SPRINGER
JRC96385
1619-7070,
https://publications.jrc.ec.europa.eu/repository/handle/JRC96385,
10.1007/s00259-015-3198-z,
