RT Journal Article
SR Electronic
T1 Alpha- versus beta-emitting radionuclides for pretargeted radioimmunotherapy of CEA-expressing human colon cancer xenografts
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP jnumed.116.187021
DO 10.2967/jnumed.116.187021
A1 Heskamp, Sandra
A1 Hernandez, Reinier
A1 Molkenboer-Kuenen, Janneke D.M.
A1 Essler, Markus
A1 Bruchertseifer, Frank
A1 Morgenstern, Alfred
A1 Steenbergen, Erik
A1 Cai, Weibo
A1 Seidl, Christof
A1 McBride, William
A1 Goldenberg, David
A1 Boerman, Otto
YR 2017
UL http://jnm.snmjournals.org/content/early/2017/02/22/jnumed.116.187021.abstract
AB Rational: Pretargeted radionuclide therapy (PRIT) with the beta-emitting radionuclide 177Lu is an attractive approach to treat CEA-expressing tumors. The therapeutic efficacy of PRIT could be improved by using alpha-emitting radionuclides such as 213Bi. Herein, we report and compare the tumor targeting properties and therapeutic efficacy of 213Bi and 177Lu for PRIT of CEA-expressing xenografts, using the bispecific antibody TF2 (anti-CEA x anti-HSG) and the di-HSG-DOTA peptide IMP288. Methods: The in vitro binding characteristics of 213Bi-IMP288 were compared with those of 177Lu-IMP288. Tumor targeting of 213Bi-IMP288 and 177Lu-IMP288 was studied in mice bearing subcutaneous (s.c.) LS174T tumors that were pretargeted with the bispecific antibody TF2. Finally, the effect of 213Bi-IMP288 (6, 12, or 17 MBq) and 177Lu-IMP288 (60 MBq) on tumor growth and survival was assessed. Toxicity was determined by monitoring body weight, analyzing blood samples for haematological and renal toxicity (haemoglobin, leucocytes, platelets, creatinine), and by immunohistochemical analysis of the kidneys. Results: The in vitro binding characteristics of 213Bi-IMP288 (Kd = 0.45 ± 0.20 nM) to TF-2 pretargeted LS174T cells were similar to those of 177Lu-IMP288 (Kd = 0.53 ± 0.12 nM). In vivo accumulation of 213Bi-IMP288 in LS174T tumors was observed as early as 15 min post injection (9.2 ± 2.0 %ID/g). 213Bi-IMP288 cleared rapidly from the circulation; at 30 min post injection the blood levels were 0.44 ± 0.28 %ID/g. Uptake in normal tissues was very low, except for the kidneys where uptake was 1.8 ± 1.1 %ID/g, at 30 min p.i. The biodistribution of 213Bi-IMP288 was comparable to that of 177Lu-IMP288. Mice treated with a single dose of 213Bi-IMP288 or 177Lu-IMP288 showed significant inhibition of tumor growth. Median survival for the PBS, 6 MBq 213Bi-IMP288, 12 MBq 213Bi-IMP288, and 60 MBq 177Lu-IMP288 treated groups was 22, 31, 45, and 42 days, respectively. Mice receiving 17 MBq 213Bi-IMP288 showed significant weight loss, resulting in a median survival of only 24 days. No changes in haemoglobin, platelets, and leucocytes were observed in the treatment groups. However, immunohistochemical analysis of the kidneys of mice treated with 17 or 12 MBq 213Bi-IMP288 showed signs of tubular damage, indicating nephrotoxicity. Conclusion: This study showed, for the first time, that PRIT with TF2 and 213Bi-IMP288 is feasible and comparable to 177Lu-IMP288 in terms of effectiveness. However, at the higher doses, kidney toxicity was observed. Future studies are warranted to determine the optimal dosing schedule to improve the therapeutic efficacy while reducing renal toxicity.