Preclinical 203/212Pb-DOTA-Based Pretargeted Radioimmunotherapy in Nude Mice Bearing Established Human Colorectal Cancer Xenografts.
Academic Article
Overview
abstract
The 203Pb (half-life [t1/2], 51.9 h) and 212Pb (t1/2 = 10.6 h) theranostic pair shows great potential for radiopharmaceutical therapy. We have developed a highly versatile pretargeted radioimmunotherapy (PRIT) platform that utilizes antitumor antigen/anti-DOTA bispecific antibodies (BsAbs) in combination with rapidly clearing, low-molecular-weight DOTA-radiohaptens (DOTA-PRIT). In this study, we tested the hypothesis that high-therapeutic index (TI) targeting of 212Pb (an in vivo generator of α-emitting progeny, specifically 212Bi (t1/2 = 1.01 h) and 212Po (t1/2 = 0.3 µs), and its imaging surrogate, 203Pb (γ-emitter, 279 keV), would be feasible with anti-glycoprotein A33 (GPA33) DOTA-PRIT for treatment of human colorectal cancer (CRC). Methods: For efficient and stable chelation of lead and high-affinity recognition by BsAbs, we synthesized a TCMC-based radiohapten precursor named TCMC-Proteus (TCMC-Pr). We prepared [212Pb]Pb-TCMC-Pr and confirmed its stability in vitro and recognition by BsAbs. Using the 203Pb analog, we conducted serial biodistribution and SPECT/CT imaging studies with a 3-step GPA33 DOTA-PRIT approach and extrapolated dosimetry for 212Pb. We then established anti-GPA33 212Pb-DOTA-PRIT in mouse xenografts of human CRC (GPA33-expressing SW1222). Results: TCMC-Pr was successfully radiolabeled with 203Pb/212Pb and verified stable in serum, and specific BsAb binding was confirmed. For GPA33-pretargeted [203Pb]Pb-TCMC-Pr, the blood, SW1222 tumor, and kidney uptakes at 24 h after injection were 0.27 ± 0.14 %IA/g, 8.04 ± 2.94 %IA/g, and 0.88 ± 0.14 %IA/g, respectively. 212Pb doses to tumor, blood, and kidneys were 12,723 mGy/MBq, 313 mGy/MBq (TI, 40.6), and 1,075 mGy/MBq (TI, 11.8), respectively. During 212Pb-DOTA-PRIT therapy studies, we established efficacy and identified a double-cycle treatment regimen (938 kBq + 938 kBq separated by 48 h; total, 1.88 MBq) that led to prolonged survival including 3 of 5 histologic cures at the study endpoint of 137 d. Mice in this treatment group exhibited normal bone marrows and moderate tubulointerstitial lesions, with overall preserved renal function. Conclusion: We have developed a safe, curative GPA33-targeted 212Pb-DOTA-PRIT treatment in a preclinical model of human CRC. This research underscores the potential of 203/212Pb-DOTA-PRIT in managing CRC and provides a road map for its modular application to other human tumor target antigens compatible with DOTA-PRIT.
