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Pretargeted Radioimmunotherapy Based on the Inverse Electron Demand Diels-Alder Reaction

Pretargeted Radioimmunotherapy Based on the Inverse Electron Demand Diels-Alder Reaction

Published on: January 29, 2019

Preclinical ^203/212Pb-DOTA-Based Pretargeted Radioimmunotherapy in Nude Mice Bearing Established Human Colorectal

Brett A Vaughn^1,2, Darren R Veach^3,4, Daniela Burnes Vargas^1,2

¹Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, New York.

Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine

|February 12, 2026

Abstract:

The ²⁰³Pb (half-life [t_1/2], 51.9 h) and ²¹²Pb (t_1/2 = 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 (t_1/2 = 1.01 h) and ²¹²Po (t_1/2 = 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.

Insights

This study developed a novel pretargeted radioimmunotherapy (PRIT) using lead-212 (²¹²Pb) for colorectal cancer (CRC). The ²¹²Pb-DOTA-PRIT treatment demonstrated safety and efficacy in preclinical models, offering a potential new therapy for CRC.

Area of Science:

Nuclear Medicine
Oncology
Radiopharmaceutical Therapy

Background:

The ²⁰³Pb/²¹²Pb theranostic pair holds promise for radiopharmaceutical therapy.
Pretargeted radioimmunotherapy (PRIT) using bispecific antibodies (BsAbs) and DOTA-radiohaptens offers a versatile platform.
²¹²Pb acts as an in vivo generator of alpha-emitting progeny, ideal for targeted cancer therapy.

Purpose of the Study:

To evaluate the efficacy of anti-glycoprotein A33 (GPA33) DOTA-PRIT using ²⁰³Pb for imaging and ²¹²Pb for therapy in human colorectal cancer (CRC).
To test the hypothesis that high-therapeutic index (TI) targeting with ²⁰³Pb/²¹²Pb-DOTA-PRIT is feasible for CRC treatment.

Main Methods:

Synthesis of a novel TCMC-based radiohapten precursor, TCMC-Proteus (TCMC-Pr), for stable lead chelation.
Radiolabeling of TCMC-Pr with ²⁰³Pb and ²¹²Pb, followed by in vitro stability and BsAb binding confirmation.
Biodistribution, SPECT/CT imaging with ²⁰³Pb-DOTA-PRIT, dosimetry extrapolation for ²¹²Pb, and therapeutic efficacy studies in mouse xenografts of human CRC.

Main Results:

TCMC-Pr was successfully radiolabeled with ²⁰³Pb/²¹²Pb and demonstrated stability in serum with specific BsAb binding.
²⁰³Pb-DOTA-PRIT showed favorable biodistribution in GPA33-expressing tumors with low uptake in healthy organs.
²¹²Pb-DOTA-PRIT achieved significant tumor dose (12,723 mGy/MBq) with acceptable TI values for tumor, blood, and kidneys, leading to prolonged survival and histologic cures in mice.

Conclusions:

A safe and curative GPA33-targeted ²¹²Pb-DOTA-PRIT treatment was developed for preclinical human CRC models.
^203/212Pb-DOTA-PRIT shows significant potential for CRC management.
The modular DOTA-PRIT platform can be adapted for other tumor-associated antigens.

Read full analysis

Keywords:

212Pb colorectal cancer glycoprotein A33 pretargeted radioimmunotherapy targeted α-therapy

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