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Preclinical Evaluation of PTK7-Targeted Radionuclide Therapy
Kim Lindland1,2,3, Sara Westrøm3, Srdan M Dragovic3
1Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
Abstract:
Protein tyrosine kinase 7 (PTK7), a receptor found in tumor-initiating cells, is expressed in various malignancies, including ovarian cancer. Whereas PTK7 has been explored as a target for antibody-drug conjugates, this study is the first to investigate its potential for targeted radionuclide therapy. We developed a murine monoclonal IgG1 antibody (mOI-1) using hybridoma technology and generated a chimeric version (chOI-1) with human IgG1 constant regions. A cell-based screening approach using a library of 6,100 cell surface proteins identified PTK7 as the target, confirmed by flow cytometry and surface plasmon resonance analyses. IHC showed strong PTK7 expression in ovarian cancer tissues, and in vitro studies demonstrated specific binding and internalization of OI-1 in the ovarian cancer cell line SKOV-3-luc. Biodistribution studies using 177Lu-DOTA-mOI-1 injected intravenously in xenograft mice with subcutaneous SKOV-3-luc revealed high tumor uptake and retention. Therapeutic efficacy was assessed by intraperitoneal treatment with 212Pb-TCMC-chOI-1 in an intraperitoneal xenograft model, showing significant tumor growth inhibition compared with nonradioactive controls. This study provides the first investigation of a PTK7-targeting antibody (OI-1) as an antibody-radionuclide conjugate (212Pb-labeled) in a preclinical model of intraperitoneal ovarian cancer. These results support further investigation of OI-1 as a candidate for targeted radionuclide therapy in PTK7-expressing cancers.
Insights
This study introduces a novel targeted radionuclide therapy for ovarian cancer using an antibody targeting Protein Tyrosine Kinase 7 (PTK7). The developed antibody-radionuclide conjugate demonstrated significant tumor growth inhibition in preclinical models.
Area of Science:
- Oncology
- Radiochemistry
- Immunotherapy
Background:
- Protein tyrosine kinase 7 (PTK7) is a receptor expressed in tumor-initiating cells and various malignancies, including ovarian cancer.
- PTK7 has been investigated for antibody-drug conjugates, but its potential for targeted radionuclide therapy remains unexplored.
Purpose of the Study:
- To investigate the potential of a PTK7-targeting antibody (OI-1) for targeted radionuclide therapy in ovarian cancer.
- To develop and evaluate antibody-radionuclide conjugates (ARCs) based on the OI-1 antibody.
Main Methods:
- Development of a murine monoclonal antibody (mOI-1) against PTK7 using hybridoma technology, followed by chimeric version (chOI-1) generation.
- Cell-based screening, flow cytometry, and surface plasmon resonance to confirm PTK7 as the target.
- In vitro and in vivo studies using ovarian cancer cell lines and xenograft mouse models with radiolabeled OI-1 (177Lu-DOTA-mOI-1 and 212Pb-TCMC-chOI-1).
Main Results:
- PTK7 expression was confirmed in ovarian cancer tissues, and OI-1 showed specific binding and internalization in SKOV-3-luc cells.
- Biodistribution studies with 177Lu-DOTA-mOI-1 revealed high tumor uptake and retention in xenograft mice.
- Therapeutic efficacy studies with 212Pb-TCMC-chOI-1 demonstrated significant inhibition of intraperitoneal ovarian tumor growth.
Conclusions:
- The OI-1 antibody is a promising candidate for developing targeted radionuclide therapies against PTK7-expressing cancers.
- This study provides the first preclinical evidence for a PTK7-targeting antibody-radionuclide conjugate in ovarian cancer models.
- Further investigation of OI-1 based ARCs is warranted for clinical translation in ovarian and other PTK7-positive malignancies.
