PT - JOURNAL ARTICLE AU - Vaughn, Brett AU - Veach, Darren AU - Burnes Vargas, Daniela AU - Punzalan, Blesida AU - Zanzonico, Pat AU - Xu, Hong AU - Guo, Hong-fen AU - Yang, Guangbin AU - Ouerfelli, Ouathek AU - Cheung, Nai-Kong AU - Larson, Steven AU - Cheal, Sarah TI - <strong>Pretargeted radioimmunotherapy with 212Pb-DOTA-based haptens in nude mice bearing established human-colorectal xenografts</strong> DP - 2023 Jun 01 TA - Journal of Nuclear Medicine PG - P1294--P1294 VI - 64 IP - supplement 1 4099 - http://jnm.snmjournals.org/content/64/supplement_1/P1294.short 4100 - http://jnm.snmjournals.org/content/64/supplement_1/P1294.full SO - J Nucl Med2023 Jun 01; 64 AB - P1294 Introduction: 212Pb is a promising isotope for molecularly targeted alpha therapy (TAT). 212Pb, produced via 224Ra/212Pb generator, is a beta (β)-emitter (t1/2 = 10.6 h) that decays to 212Bi, which is an α-emitter (t1/2 = 1.06 h), i.e., 212Pb functions as an in vivo generator of 212Bi. A pretargeted radioimmunotherapy (PRIT) approach that utilizes anti-tumor antigen/anti-DOTA bispecific antibodies (BsAb) in combination with rapidly clearing low-molecular weight DOTA-radiohaptens (DOTA-PRIT) have been developed against a variety of human tumor types for high-therapeutic index (TI) treatment with β- or α-emitting radioisotopes. We have recently established efficient pre-targeting of a novel 203Pb-radiohapten. Herin, we establish therapeutic efficacy and toxicity of this radiohapten with 212Pb.Methods: TCMC (1,4,7,10-tetrakis (carbamoylmethyl)-1,4,7,10-tetraazacyclododecane) has been used successfully to form conjugates for labeling with 203Pb/212Pb [2] The 212Pb was obtained via 224Ra/212Pb generator (purchased through US Department of Energy, Oak Ridge National Laboratory). The in vivo clearance of [212Pb]Pb(TCMC)-Proteus DOTA was evaluated in non-tumored nude mice. Studies with [212Pb]Pb(TCMC)-Proteus DOTA were performed in a model DOTA-PRIT system (i.e., targeting subcutaneous GPA33-expressing SW1222 human colorectal cancer (CRC) xenografts in mice). For [212Pb]Pb(TCMC)-Proteus DOTA PRIT, goups (n = 4-5/group) of SW1222-tumor bearing mice (approximate starting tumor volumes: 33 mm3) were injected intravenously in the tail vein: 250 µg (1.19 nmol) of anti-GPA33/anti-DOTA BsAb huA33-huC825, followed 24 h later with 25 µg (2.76 nmol) of dendrimer-clearing agent, and after an additional 4 h, [212Pb]Pb(TCMC)-Proteus DOTA was administered (3.2, 5.2, 9.3 MBq and 1.0, 3.0, and 8.0 MBq for fractionated dose regimen). For fractionated dose, three groups (1.0, 3.0, and 8.0 MBq) received a second administration of antibody, clearing agent and activity (fractionated dose; total activity for each group 2.0, 6.0, and 16.0 MBq). Mice were sacrificed at 137 days and submitted for histopathological evaluation. Controls included no treatment and non-specific [212Pb]Pb(TCMC)-Proteus DOTA. Additionally, naive mice with no tumor were administered the fractionated dose regimen (1.0, 3.0, and 8.0 MBq). Results: [212Pb]Pb(TCMC)-Proteus DOTA apparent molar activity = 92.5 MBq/nmol. RadioHPLC confirmed that no free radiometal remained (&gt;99% radiochemical purity; major isomer tR = 9.8 min). The biological half-life is t1/2 = 11.3 min for [212Pb]Pb(TCMC)-Proteus DOTA. Assay of in vitro stability of [212Pb]TCMC-PEG4-LuDOTA in rat serum revealed no detectable degradation when incubated at 37 °C for 24 h. We conducted 212Pb-DOTA-PRIT therapy studies targeting GPA33 in groups (n = 4-5/group; average starting tumor size was 46.6 mm3 (no significant differences in control versus therapy groups), of nude mice bearing SW1222 tumors. Within 15-20 days post-treatment, tumor regression to below quantifiable volume (&lt;4.2 mm3) was observed in all mice treated with pretargeted 212Pb-TCMC-radiohapten. The median survival for treated mice is 16 d, 18 d, and 51 d, 80 d, 6 d and 73 d for no treatment, non-targeted 212Pb-TCMC-radiohapten, 3.5 MBq, 5.2 MBq, 16.0 MBq and 2.0 MBq respectively. For 9.3 MBq, median survival is undefined (i.e., &gt;137) with mean tumor size for surviving (4/5) treated mice at day are &lt;4.2 mm3. For mice administered 6.0 MBq, median survival is undefined (i.e., &gt;137) with mean tumor size for surviving (5/5) treated mice at day are &lt;4.2 mm3.Conclusions: Substantial tumor regression or complete responses and significantly prolonged survival was observed following administration of GPA33 (212Pb)Pb-(TCMC)-Proteus DOTA, but evidence of acute toxicity suggests (as weight loss with recovery after less than 38 days and transient myelosuppression at 7 and 14 days) that further refinement of dose levels is required.