3508 Background: SPECT imaging with 111In-DTPA-trastuzumab has recently identified new tumor lesions, undetected with conventional staging, in 13/15 patients with HER2++ breast cancers (Perik et al., J Clin Oncol 2006). The aim of this study was to develop an immunoPET label, suitable for clinical use, which would allow excellent detection of HER2 positive tumor lesions and quantification of HER2 expression levels in vivo. Methods: Trastuzumab has essentially been radiolabeled as described by Verel et al. (J Nucl Med 2003). Radiochemical purity (rcp) and stability were determined by SEC-HPLC, immunoreactivity with a Lindmo assay. Biodistribution was performed in nude mice bearing HER2 positive (SKOV3) or HER2 negative (GLC4) xenografts. Five animals per group were co-injected with 111In-ITC-DTPA-trastuzumab and 89Zr-trastuzumab, imaged on a microPET (Focus 220) and sacrificed 144 hours post injection. Results: The immunoreactive fraction of 89Zr-trastuzumab was 0.96, labeling efficiency > 90% and rcp > 95%. 89Zr-trastuzumab was stable for 7 days in buffer at 4 °C and in human serum at 37 °C. MicroPET imaging showed excellent tumor uptake and could easily detect metastases with a size approximating the spatial resolution of the microPET scanner. 89Zr- and 111In-ITC-DTPA-trastuzumab showed similar biodistribution. Highest uptake was found in HER2 positive tumors at 144 hours post injection (40% ID/g tissue for 89Zr-trastuzumab and 47% ID/g for 111In-ITC-DTPA-trastuzumab) compared to 8% ID/g tissue in HER2 negative control tumors. Liver uptake was low (8–12% ID/g tissue). Preliminary results in HER2 positive breast cancer patients show excellent tumor tracer uptake and a resolution unapproachable by 111In-DTPA-trastuzumab. Conclusions: 89Zr-trastuzumab is stable, shows excellent and specific tumor uptake and is suitable for clinical use. Minimal aspecific tracer uptake in the liver allows detection of abdominal metastases. No significant financial relationships to disclose.
BACKGROUND AND PURPOSE The TNF‐related apoptosis inducing ligand (TRAIL) induces apoptosis through activation of the death receptors, TRAIL‐R1 and TRAIL‐R2. Recombinant human (rh) TRAIL and the TRAIL‐R1 directed monoclonal antibody mapatumumab are currently clinically evaluated as anticancer agents. The objective of this study was to develop radiopharmaceuticals targeting the TRAIL‐R1, suitable for clinical use to help understand and predict clinical efficacy in patients. EXPERIMENTAL APPROACH rhTRAIL was radioiodinated with 125I, and conjugated mapatumumab was radiolabelled with 111In. The radiopharmaceuticals were characterized, their in vitro stability and death receptor targeting capacities were determined and in vivo biodistribution was studied in nude mice bearing human tumour xenografts with different expression of TRAIL‐R1. KEY RESULTS Labelling efficiencies, radiochemical purity, stability and binding properties were optimized for the radioimmunoconjugates. In vivo biodistribution showed rapid renal clearance of [125I]rhTRAIL, with highest kidney activity at 15 min and almost no detectable activity after 4 h. Activity rapidly decreased in almost all organs, except for the xenografts. Radiolabelled mapatumumab showed blood clearance between 24 and 168 h and a reduced decrease in radioactivity in the high receptor expression xenograft. CONCLUSIONS AND IMPLICATIONS rhTRAIL and mapatumumab can be efficiently radiolabelled. The new radiopharmaceuticals can be used clinically to study pharmacokinetics, biodistribution and tumour targeting, which could support evaluation of the native targeted agents in phase I/II trials.
e14521 Background: Mapatumumab is a fully human agonistic monoclonal antibody (mAb) to the tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1). Mapatumumab combined with gemcitabine and cisplatin increased cytotoxicity in preclinical models and was safe in a phase 1 study. To study its biodistribution, 111Indium (111In) labeled mapatumumab was developed for γ-camera imaging and tested in mice. Subsequently, 111In-mapatumumab scintigraphy was performed in patients (pts). Methods: Mapatumumab was labeled with 111In. Labeling efficiency, radiochemical purity, stability and binding properties were determined in vitro. Biodistribution was studied at multiple time points in nude mice bearing human xenografts (SKBR3 or SW948). Tissue activity was expressed as % injected dose/gram tissue (%ID/g). In a feasibility study, gemcitabine 1250 mg/m2 IV on days 1 and 8, cisplatin 80 mg/m2 IV and mapatumumab 20 mg/kg on day 1 was administered to advanced solid tumor pts every 21 days. In cycles 1 and 3, pts underwent γ-camera imaging directly, and at day 1, 3, and 6 after 150 MBq 111In-mapatumumab IV (planar and single-photon emission computed tomography (SPECT)). Results: Labeling efficiency was 92.0% and radiochemical purity 96.0%. 111In-mapatumumab was stable in serum for 1 week at 37°C and specific TRAIL-R1 binding was maintained after labeling. In mice, high uptake was seen in liver (8.14 ± 0.75 %ID/g), kidneys (16.30 ± 1.75 %ID/g), spleen (7.25 ± 2.64 %ID/g) and bone (5.68 ± 1.31 %ID/g), with a maximum 24–72 hours (h) after tracer injection. Maximum uptake in the xenografts was observed after 72 h (7.55 ± 3.54 %ID/g for SKBR3 and 6.21 ± 2.03 %ID/g for SW948). Five pts have been enrolled in the ongoing clinical study. Known tumor lesions (by CT-scan) showed variable tracer uptake in 3 pts, while within pts not all known tumor lesions were positive on SPECT. Conclusions: Mapatumumab can be efficiently radiolabeled for clinical use. Preliminary results show that mapatumumab scintigraphy identifies some but not all tumor lesions in pts. This is the first demonstration that mAb targeting a TRAIL-R distributes to tumor tissues in patients and could potentially guide mapatumumab therapy. [Table: see text]
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