Sara Westrøm

Preclinical Evaluation of PTK7-Targeted Radionuclide Therapy

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.

Radon-220 diffusion from 224Ra-labeled calcium carbonate microparticles: Some implications for radiotherapeutic use

Alpha-particle emitting radionuclides continue to be the subject of medical research because of their high energy and short range of action that facilitate effective cancer therapies. Radium-224 (224Ra) is one such candidate that has been considered for use in combating micrometastatic disease. In our prior studies, a suspension of224Ra-labeled calcium carbonate (CaCO3) microparticles was designed as a local therapy for disseminated cancers in the peritoneal cavity. The progenies of224Ra, of which radon-220 (220Rn) is the first, together contribute three of the four alpha particles in the decay chain. The proximity of the progenies to the delivery site at the time of decay of the224Ra-CaCO3microparticles can impact its therapeutic efficacy. In this study, we show that the diffusion of220Rn was reduced in labeled CaCO3suspensions as compared with cationic224Ra solutions, both in air and liquid volumes. Furthermore, free-floating lead-212 (212Pb), which is generated from released220Rn, had the potential to be re-adsorbed onto CaCO3microparticles. Under conditions mimicking anin vivoenvironment, more than 70% of the212Pb was adsorbed onto the CaCO3at microparticle concentrations above 1 mg/mL. Further, the diffusion of220Rn seemed to occur whether the microparticles were labeled by the surface adsorption of224Ra or if the224Ra was incorporated into the bulk of the microparticles. The therapeutic benefit of differently labeled224Ra-CaCO3microparticles after intraperitoneal administration was similar when examined in mice bearing intraperitoneal ovarian cancer xenografts. In conclusion, both the release of220Rn and re-adsorption of212Pb are features that have implications for the radiotherapeutic use of224Ra-labeled CaCO3microparticles. The release of220Rn through diffusion may extend the effective range of alpha-particle dose deposition, and the re-adsorption of the longer lived212Pb onto the CaCO3microparticles may enhance the retention of this nuclide in the peritoneal cavity.