Targeting tumor-specific epitope for imaging and therapy for mesothelioma

Abstract: Malignant mesothelioma is a devastating disease without effective therapy. Among the three major subtypes, epithelioid, sarcomatoid, and mixed (biphasic), the sarcomatoid subtype is the most difficult-to-treat. Alpha emitting radionuclide in the form of radioimmunotherapy (RIT) has shown promising results in several cancers due to high potency in tumor killing and low toxicity to neighboring organs/tissues. We aim to develop and evaluate a 203Pb/212Pb isotope pair based SPECT imaging and targeted alpha therapy as precision therapeutic tools for mesothelioma. We propose to target a tumor selective CD46 epitope that we found recently to be highly expressed in all three major subtypes of mesothelioma. This differentiates CD46 from mesothelin that is expressed mainly in the epithelioid but not the sarcomatous subtype. We will build our work on a novel human monoclonal antibody that we discovered that binds to the tumor selective epitope. The antibody has been manufactured under cGMP. An antibody-drug conjugate based on this antibody has entered clinical studies for prostate cancer and multiple myeloma and has shown an excellent safety profile in clinical trials. We have generated preliminary data that are directly relevant to this proposal: (1) We found that this antibody is internalized rapidly by both epithelioid and sacromatous mesothelioma cell lines. (2) We labeled the antibody with 89Zr and showed that it specifically detects by PET mesothelioma in xenograft models. (3) We developed a robust and reproducible 212Pb radiolabeling process that is scalable for clinical use, facilitating translation. We hypothesize that targeting CD46 using our clinical stage human monoclonal antibody for SPECT imaging and alpha particle therapy will lead to the development of new treatments against mesothelioma especially for the biphasic and sarcomatous subtypes, addressing a dire clinical need. We will evaluate 203Pb-labeled antibody for SPECT imaging and study the 212Pb-labeled antibody in both mesothelioma cell-line and patient-derived xenograft models to determine dosing scheme, therapeutic efficacy and tolerability. The proposed study has a high potential of translation to the clinic and differentiates by targeting a new tumor selective epitope with rapid internalization and increased subtype coverage. If successfully carried out, our work will lead to future clinical trials where 203Pb-based SPECT is used for patient selection and dosimetry and 212Pb-based RIT is used to treat mesothelioma patients across subtypes.