Abstract 5049: Pb-203 image guided Pb-212 receptor targeted alpha particle therapy for cancer - a powerful emerging paradigm
Authors: Schultz Michael King , Menda Yusuf , Liu Dijie , Li Mengshi , Johnson Frances , Cagle Brianna , Baumhover Nicholas , Vance Ivy 
Published: April 2023

Objective: Pb-203 and Pb-212 have emerged as a promising elementally-matched theranostic pair for imaging-guided alpha-particle radiotherapy for cancer. A somatostatin receptor 2 (SSTR2)-targeted peptide coupled with novel Pb specific chelator (PSC) has been developed (PSC-PEG2-TOC). Here, preclinical in vitro and in vivo evaluation of 203Pb/212Pb-labeled PSC-PEG2-TOC was conducted including head to head therapy of SSTR2+ tumors in mice vs standard of care beta particle therapy and first in humans clinical imaging of SSTR2+ tumors.

Method: [203Pb]PSC-PEG2-TOC and [212Pb]PSC-PEG2-TOC was prepared by published methods. Radiochemical stability of [203Pb]PSC-PEG2-TOC, [212Pb]PSC-PEG2-TOC and [212Bi]PSC-PEG2-TOC in human serum was determined. Binding affinity of [203Pb]PSC-PEG2-TOC was determined by binding assays in AR42J cells. In vivo SSTR2-mediated tumor targeting of [203Pb]PSC-PEG2-TOC was determined by SPECT imaging in athymic nude mice bearing AR42J xenografts. In vivo biodistribution of [212Pb]PSC-PEG2-TOC in normal organs and potential redistribution of 212Bi daughter were determined in CD-1 Elite mice. Clinical imaging was conducted under appropriate regulations to determine the biodistribution of the agent in patients bearing SSTR2+ tumors as determined by gold standard 68Ga-DOTATOC PET imaging.

Results: Rapid incorporation of 203Pb and 212Pb in PSC-PEG2-TOC was observed after reactions at temperatures as low as 4°C within 15 min. Greater than 95% radiochemical stability was observed for both [203Pb]PSC-PEG2-TOC and [212Pb]PSC-PEG2-TOC after incubation in human serum for up to 55 hours. Stable decay product [212Bi]PSC-PEG2-TOC with minimal free 212Bi was observed. Agents demonstrated superior binding affinity to SSTR2 with Kd=0.59 nM. In in vivo studies, rapid tumor uptake and renal clearance of [203Pb]PSC-PEG2-TOC were observed in athymic nude mice bearing AR42J xenografts. In the biodistribution study, nearly identical biodistribution profiles of [212Pb]PSC-PEG2-TOC and progeny [212Bi]PSC-PEG2-TOC were found. No redistribution of 212Bi activity was identified, indicating that 212Bi remained co-localized with parent [212Pb]PSC-PEG2-TOC in vivo. Therapeutic studies in this same mouse model resulted in 100% complete responses for both a single dose 4.4 MBq administration of [212Pb]PSC-PEG2-TOC or a fractionated regimen of 4 × 1.1 MBq. First in humans clinical imaging showed PK properties that included rapid tumor accumulation and retention at over 20 h post administration, coupled with fast renal clearance of residual agent.

Conclusion: [203Pb]PSC-PEG2-TOC and [212Pb]PSC-PEG2-TOC have promising potential for image-guide alpha-particle therapy for SSTR2 positive tumors. Agents have received a Fastrack designation by the US FDA and a safe to proceed for a Phase 1 trial.

Citation Format: Michael King Schultz, Yusuf Menda, Dijie Liu, Mengshi Li, Frances Johnson, Brianna Cagle, Nicholas Baumhover, Ivy Vance. Pb-203 image guided Pb-212 receptor targeted alpha particle therapy for cancer - a powerful emerging paradigm. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5049.