Development of radiolabeled mapatumumab and imaging in solid tumor patients who are treated with gemcitabine, cisplatin, and mapatumumab

Abstract

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]