Antigen targeting and anti-tumor activity of a novel anti-CD146 212 Pb internalizing alpha-radioimmunoconjugate against malignant peritoneal mesothelioma.

Autor: Lindland K; Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0316, Oslo, Norway. lindland@oncoinvent.com.; Department of Radiation Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, 0379, Oslo, Norway. lindland@oncoinvent.com.; Oncoinvent ASA, 0484, Oslo, Norway. lindland@oncoinvent.com., Malenge MM; Oncoinvent ASA, 0484, Oslo, Norway., Li RG; Oncoinvent ASA, 0484, Oslo, Norway., Wouters R; Oncoinvent ASA, 0484, Oslo, Norway.; Laboratory of Tumour Immunology and Immunotherapy, Department of Oncology, Leuven Cancer Institute, KU Leuven, 3000, Leuven, Belgium., Bønsdorff TB; Oncoinvent ASA, 0484, Oslo, Norway., Juzeniene A; Department of Radiation Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, 0379, Oslo, Norway.; Department of Physics, University of Oslo, Oslo, Norway., Dragovic SM; Oncoinvent ASA, 0484, Oslo, Norway.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Oct 29; Vol. 14 (1), pp. 25941. Date of Electronic Publication: 2024 Oct 29.
DOI: 10.1038/s41598-024-76778-z
Abstrakt: Malignant mesothelioma, a highly aggressive cancer that primarily affects the serosal membranes, has limited therapeutic options, particularly for cavitary tumors, such as peritoneal and pleural malignant mesothelioma. Intracavitary administration of a radioimmunoconjugate to locally target mesothelioma cancer cells has been proposed as a treatment. CD146, upregulated in mesothelioma but not in healthy tissues, is a promising therapeutic target. This study characterized CD146 expression and binding/internalization kinetics of the CD146-targeting antibody OI-3 coupled with 212 Pb ( 212 Pb-TCMC-OI-3) in human mesothelioma cells. Flow cytometry showed that both chimeric (chOI-3) and murine (mOI-3) antibodies rapidly bound and internalized within 1-6 h in MSTO-211H cells. 212 Pb-TCMC-chOI-3 exhibited 3.1- to 13.7-fold and 3.1- to 8.5-fold increased internalized 212 Pb and 212 Bi atoms per cell at 2 and 24 h, respectively, compared to isotype control, underscoring enhanced internalization efficiency. Intraperitoneal administration of 212 Pb-TCMC-mOI-3 to mice with intraperitoneal MSTO-211H xenografts improved median survival by a ratio of 1.3 compared to non-binding 212 Pb-TCMC-mIgG1. The ability of 212 Pb-TCMC-mOI-3 to target and inhibit the growth of intraperitoneal mesothelioma xenografts supports targeted radionuclide therapy's efficacy for metastatic peritoneal mesothelioma. This study highlights the potential of localized CD146-targeted radioimmunotherapy for malignant mesothelioma, offering a new avenue for improving patient outcomes.
(© 2024. The Author(s).)
Databáze: MEDLINE
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