NANETS2022 15th Annual Multidisciplinary NET Medical Symposium NANETS 2022 Basic Science (16 abstracts)
[212Pb]PSC-PEG2-TOC Therapy for NET Leads to Complete Responses in Mice Bearing SSTR2 Positive Tumors - Comparison to [177Lu]DOTATATE in a Preclinical Model
Michael K. Schultz 1,2 , Dijie Liu 2 , Mengshi Li 2 , Brianna S. Cagle 2 , Zhiming Dai 2 , Dongyoul Lee 2 , Kelly Orcutt 2 , Edwin Sagastume 2 , Nicholas J. Baumhover 2 , Ivy Vance 2 , Amos Hedt 2 , Yusuf Menda 1 & Frances L. Johnson 2
1Department of Radiology, University of Iowa; 2Viewpoint Molecular Targeting, Inc.
Background: Peptide-based targeted alpha-particle radiotherapy has emerged as a promising approach to cancer treatment. 203Pb/212Pb is the only elementally identical isotope pair for this application. Tyr3-Octreotide (TOC) peptide ligands targeting SSTR2 have been widely investigated preclinically and clinically. [177Lu]DOTATATE was approved by the US FDA to treat patients with gastroenteropancreatic neuroendocrine tumors. However, the objective response rate (18%) reported in the Phase III trial leaves significant room for improvement. In this study, we modified TOC with a Pb specific chelator (PSC) and PEG2 linker and evaluated the in vivo biodistribution profiles and efficacy of [203/212Pb]PSC-PEG2-TOC in preclinical mouse model in comparison with [177Lu]DOTATATE.
Methods: PSC-PEG2-TOC was radiolabeled with 203Pb and 212Pb by published methods1, 2. [177Lu]DOTATATE was synthesized and radiolabeled using published methods3. Biodistributions were conducted in female athymic nu/nu mice bearing AR42J tumor xenografts following intravenous injection of 74 kBq of 203Pb-labeled PSC-PEG2-TOC at 1, 3, 6 and 24 h post-injection (pi). Single or fractionated doses of [212Pb]PSC-PEG2-TOC (total activity at 4.44 MBq) were administered to mice bearing AR42J tumors for efficacy evaluation. Administered fractionated doses of [177Lu]DOTATATE were based on previous literature. Tumor volume, body weight, complete blood count, and serum chemistry were monitored.
Results: PSC-PEG2-TOC labeled efficiently with 203Pb at high specific activity (50-100 MBq/nmol). 24-h radiochemical purity and maintained near quantitative levels in excipients. In vivo biodistribution studies demonstrated high tumor uptake and rapid renal clearance for [203Pb]PSC-PEG2-TOC. The administration of 4 fractionated doses of [212Pb]PSC-PEG2-TOC produced 100% complete tumor responses at 100 days post therapy initiation and was well-tolerated compared to [177Lu]DOTATATE, which produced improved PFS (28.5 days), but no complete responses.
Conclusions: These data demonstrate that [203/212Pb]PSC-PEG2-TOC has the potential to produce a higher rate of objective tumor responses than beta-particle emitting therapeutics for NETs.
Abstract ID 21938
Volume 89
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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