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

  • Sci Rep. 2024 Oct 29;14(1):25941. doi: 10.1038/s41598-024-76778-z.
Kim Lindland  1  2  3 ,  Marion Masitsa Malenge  4 ,  Ruth Gong Li  4 ,  Roxanne Wouters  4  5 ,  Tina Bjørnlund Bønsdorff  4 ,  Asta Juzeniene  6  7 ,  Srdan M Dragovic  4
Affiliations
  • 1. Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0316, Oslo, Norway. [email protected].
  • 2. Department of Radiation Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, 0379, Oslo, Norway. [email protected].
  • 3. Oncoinvent ASA, 0484, Oslo, Norway. [email protected].
  • 4. Oncoinvent ASA, 0484, Oslo, Norway.
  • 5. Laboratory of Tumour Immunology and Immunotherapy, Department of Oncology, Leuven Cancer Institute, KU Leuven, 3000, Leuven, Belgium.
  • 6. Department of Radiation Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, 0379, Oslo, Norway.
  • 7. Department of Physics, University of Oslo, Oslo, Norway.
PMID: 39472474 DOI: 10.1038/s41598-024-76778-z
Abstract

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 212Pb (212Pb-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. 212Pb-TCMC-chOI-3 exhibited 3.1- to 13.7-fold and 3.1- to 8.5-fold increased internalized 212Pb and 212Bi atoms per cell at 2 and 24 h, respectively, compared to isotype control, underscoring enhanced internalization efficiency. Intraperitoneal administration of 212Pb-TCMC-mOI-3 to mice with intraperitoneal MSTO-211H xenografts improved median survival by a ratio of 1.3 compared to non-binding 212Pb-TCMC-mIgG1. The ability of 212Pb-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.

Keywords
212Pb; CD146 antigen; Internalization; Malignant peritoneal mesothelioma xenograft model; Radioimmunoconjugate; Targeted alpha therapy.
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