Abstract 5346: Preclinical evaluation of maximum tolerated dose (MTD) following single dose administration of 212Pb-RM2
Authors: Rold Tammy L. , Devanny Elisabeth A. , Okoye Nkemakonam C. , Quinn Thomas P. , Hoffman Timothy J. 
Published: September 2020

Abstract
Introduction: Lead-212 (Pb-212)-RM2 is under evaluation as a potential BB2r targeted alpha therapy (TAT) agent for the treatment of BB2r positive prostate cancers. The purpose of this study was to define maximum tolerated dose (MTD) levels for conducting initial therapeutic efficacy studies using human prostate cancer xenograft models and to identify targeted organs and tissues for assessing potential radiotoxicity effects.
Methods: The RM2 peptide (DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) was commercially synthesized and radiolabeled with Pb-212 eluted from a Ra-224/Pb-212 generator. Radiosynthesis was accomplished using an Eckert & Ziegler PharmTracer. HPLC QC confirming &gt;93% product purity was performed prior to and post administration of Pb-212 RM2. CF1 mice were administered a single intravenous bolus of either saline (non-treated controls / NTC), 50uCi, 100uCi, or 200uCi of 212Pb-RM2. Weekly complete blood counts (CBC), body weight (BW), and body condition score (BCS) were obtained up to 30 weeks post administration. Subsets of 3-5 mice/group were harvested at 30, 50, 70, 90 days, and 30 weeks for histopathology analysis and pooled serum analysis. An additional set of mice (n=3/group/time point) were administered saline (NTC), 50uCi or 200uCi of Pb-212 RM2 and tissues/serum were obtained at 2, 5, and 7 days to evaluate ALT, AST, BUN, lipase, amylase, and creatinine levels at early timepoints.
Results: We observed BW loss in all treatment groups compared to the NTC. We further observed that only the high dose (200uCi) treatment group experienced weight loss that was significantly (P=0.0168) below that of the NTC at 30 weeks. No animals were removed from the study due to BW loss. WBC counts were suppressed at Week1(100uCi and 200uCi groups) and fully recovered by Week 2. WBC counts for all treatment groups were not significantly different at 30 weeks. Platelet counts were slightly suppressed at Week1 (all groups) and fully recovered by Week 2. Week 30 platelet counts were consistent between all treatment groups. Significantly elevated amylase/lipase levels were observed (Day 2) in the 200uCi treatment group with recovery to normal by Day 5. Liver (ALT and AST) and kidney (BUN and creatinine) markers showed nominal changes between groups. Marked changes in pancreas and kidney histopathology were observed only at 30 weeks (100uCi and 200uCi group).
Conclusions: Based on BW, CBC, histopathology, and serum analysis, the 50uCi and 100uCi dose levels of Pb-212 RM2 appear to be well tolerated. The high dose Pb-212 RM2 group (200uCi) presented with initially elevated pancreatic enzymes (Day 2) and altered histopathology of the pancreas and kidney appearing only at 30 weeks post treatment. These data suggest that preclinical single dose administration of Pb-212 RM2 TAT at 100uCi or lower should be tolerable.
This work was supported by USVA IK6BX004856, USVA IO1BX001699, and NCI RO1CA222293.
Citation Format: Tammy L. Rold, Elisabeth A. Devanny, Nkemakonam C. Okoye, Thomas P. Quinn, Timothy J. Hoffman. Preclinical evaluation of maximum tolerated dose (MTD) following single dose administration of 212Pb-RM2 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5346.