First-in-Man Evaluation of ¹²⁴I-PGN650: A PET Tracer for Detecting Phosphatidylserine as a Biomarker of the Solid Tumor Microenvironment

Abstract

Purpose:PGN650 is a F(ab′)2 antibody fragment that targets phosphatidylserine (PS), a marker normally absent that becomes exposed on tumor cells and tumor vasculature in response to oxidative stress and increases in response to therapy. PGN650 was labeled with 124I to create a positron emission tomography (PET) agent as an in vivo biomarker for tumor microenvironment and response to therapy. In this phase 0 study, we evaluated the pharmacokinetics, safety, radiation dosimetry, and tumor targeting of this tracer in a cohort of patients with cancer.Methods:Eleven patients with known solid tumors received approximately 140 MBq (3.8 mCi) 124I-PGN650 intravenously and underwent positron emission tomography–computed tomography (PET/CT) approximately 1 hour, 3 hours, and either 24 hours or 48 hours later to establish tracer kinetics for the purpose of calculating radiation dosimetry (from integration of the organ time-activity curves and OLINDA/EXM using the adult male and female models).Results:Known tumor foci demonstrated mildly increased uptake, with the highest activity at the latest imaging time. There were no unexpected adverse events. The liver was the organ receiving the highest radiation dose (0.77 mGy/MBq); the effective dose was 0.41 mSv/MBq.Conclusion:Although 124I-PGN650 is safe for human PET imaging, the tumor targeting with this agent in patients was less than previously observed in animal studies.

Rational design of caspase-responsive smart molecular probe for positron emission tomography imaging of drug-induced apoptosis

“…Direct imaging biomarkers include the active caspase-3 and plasma membrane depolarization. The activation of caspase-3 commits the cell to programmed cell death (apoptosis) 3, 4, while the plasma membrane depolarization 6, 7 occurs downstream of caspase-3 or is exposed as a result of membrane rupture during necrosis. Several diverse imaging techniques have been used to detect the biomarkers so as to measure and monitor the response of different types of malignant tumors to chemotherapy, radiotherapy, or hormonal therapy 3-10.…”

Radiochemistry, Production Processes, Labeling Methods, and ImmunoPET Imaging Pharmaceuticals of Iodine-124

“…Pharmacokinetics, tumor uptake, and radiation dosimetry in cancer patients were assessed. Apart from the tumor, the liver was found to receive a high radiation dose [ 256 ]. Annexin-V, a calcium-dependent protein that binds with high specificity to phosphatidylserine exposed during apoptosis, was labeled with 124 I for use as a potential PET probe.…”

Antibody targeting of phosphatidylserine for the detection and immunotherapy of cancer

“… 110 , 111 Based on the results from the preclinical imaging studies, a Phase 0 clinical study was conducted using 124 I-labeled PGN650 as a PET imaging agent to monitor safety, pharmacokinetics, radiation dosimetry, and tumor targeting. 113 Patients with solid tumors received ~140 MBq (3.8 mCi) 124 I-PGN650 intravenously and underwent PET/CT ~1, 3, and either 24 or 48 hours later to establish tracer kinetics. The safety of 124 I-PGN650 was established for human PET imaging; however, the tumor targeting in these patients was less than previously observed in animal studies.…”

“…The safety of 124 I-PGN650 was established for human PET imaging; however, the tumor targeting in these patients was less than previously observed in animal studies. An example of whole-body PET imaging of a patient’s tumor is shown in a recent publication, 113 which demonstrates the retention of the probe in the tumor and correlates with the targeting of 18 F-deoxyglucose, a marker for high cellular metabolism.…”