Alpha- versus beta-emitting radionuclides for pretargeted radioimmunotherapy of CEA-expressing human colon cancer xenografts

Abstract

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.