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Molecular Imaging of Radiolabeled Bispecific T-cell Engager 89Zr-AMG211 Targeting CEA-positive Tumors

Waaijer, S. J. H., Warnders, F-J., Stienen, S. K., Friedrich, M., Sternjak, A., Cheung, H-K., Terwisscha van Scheltinga, A. G. T., Schröder, C. P., de Vries, E. G. & Lub-de Hooge, M. N., 15-Oct-2018, In : Clinical Cancer Research. 24, 20, p. 4988-4996 9 p.

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  • Molecular Imaging of Radiolabeled Bispecific T-cell Engager 89Zr-AMG211 Targeting CEA-positive Tumors

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DOI

BACKGROUND: AMG 211, a bispecific T‑cell engager (BiTE) antibody construct, targets carcinoembryonic antigen (CEA) and the CD3 epsilon subunit of the human T‑cell receptor. AMG 211 was labeled with zirconium-89 (89Zr) or fluorescent dye to evaluate the tumor targeting properties.

EXPERIMENTAL DESIGN: 89Zr‑AMG211 was administered to mice bearing CEA‑positive xenograft tumors of LS174T colorectal adenocarcinoma or BT474 breast cancer cells, as well as CEA‑negative HL‑60 promyelocytic leukemia xenografts. Biodistribution studies with 2‑10 µg 89Zr‑AMG211 supplemented with unlabeled AMG 211 up to 500 µg protein dose were performed. A BiTE® that does not bind CEA, 89Zr‑Mec14, served as a negative control. 89Zr-AMG211 integrity was determined in tumor lysates ex vivo. Intratumoral distribution was studied with IRDye800CW‑AMG211. Moreover, 89Zr‑AMG211 was manufactured according to Good Manufacturing Practice (GMP) guidelines for clinical trial NCT02760199 Results: 89Zr‑AMG211 demonstrated dose-dependent tumor uptake at 6 hours. The highest tumor uptake was observed with 2 μg dose, and the lowest tumor uptake was observed with 500 μg dose. After 24 hours, higher uptake of 10 μg 89Zr‑AMG211 occurred in CEA‑positive xenografts, compared to CEA‑negative xenografts. Although the blood half‑life of 89Zr‑AMG211 was ~1 hour, tumor retention persisted for at least 24 hours. 89Zr‑Mec14 showed no tumor accumulation beyond background level. Ex vivo autoradiography revealed time-dependent disintegration of 89Zr‑AMG211. 800CW‑AMG211 was specifically localized in CEA‑expressing viable tumor tissue. GMP‑manufactured 89Zr‑AMG211 fulfilled release specifications.

CONCLUSIONS: 89Zr‑AMG211 showed dose‑dependent CEA‑specific tumor targeting and localization in viable tumor tissue. Our data enabled its use to clinically evaluate AMG 211 in vivo behavior.

Original languageEnglish
Pages (from-to)4988-4996
Number of pages9
JournalClinical Cancer Research
Volume24
Issue number20
Publication statusPublished - 15-Oct-2018

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