Evaluating CD133 as a Radiotheranostic Target in Small-Cell Lung Cancer

• DOI: 10.1021/acs.molpharmaceut.3c01063
• Publication Date: 2024-02-09T01:10:41Z
• Authors: Samantha M. Sarrett; Cindy Rodriguez; Samantha Delaney; Meena M. Hosny; Joni Sebastiano; Ana Santos-Coquillat; Outi M. Keinänen; Lukas M. Carter; Kristin J. Lastwika; Paul D. Lampe; Brian M. Zeglis
• Keywords: Metastatic xenograft; Orthotopicxenograft; PET imaging; Pharmacy; Cd133; Radioimmunotherapy; Cancers; Patient-derivedxenograft; Small-cell lung cancer; General medicine, internal medicine and other clinical medicine

Despite decades of work, small-cell lung cancer (SCLC) remains a frustratingly recalcitrant disease. Both diagnosis and treatment are challenges: low-dose computed tomography (the approved method used for lung cancer screening) is unable to reliably detect early SCLC, and the malignancy's 5 year survival rate stands at a paltry 7%. Clearly, the development of novel diagnostic and therapeutic tools for SCLC is an urgent, unmet need. CD133 is a transmembrane protein that is expressed at low levels in normal tissue but is overexpressed by a variety of tumors, including SCLC. We previously explored CD133 as a biomarker for a novel autoantibody-to-immunopositron emission tomography (PET) strategy for the diagnosis of SCLC, work that first suggested the promise of the antigen as a radiotheranostic target in the disease. Herein, we report the in vivo validation of a pair of CD133-targeted radioimmunoconjugates for the PET imaging and radioimmunotherapy of SCLC. To this end, [89Zr]Zr-DFO-αCD133 was first interrogated in a trio of advanced murine models of SCLC─i.e., orthotopic, metastatic, and patient-derived xenografts─with the PET probe consistently producing high activity concentrations (>%ID/g) in tumor lesions combined with low uptake in healthy tissues. Subsequently, a variant of αCD133 labeled with the β-emitting radiometal 177Lu─[177Lu]Lu-DTPA-A″-CHX-αCD133─was synthesized and evaluated in a longitudinal therapy study in a subcutaneous xenograft model of SCLC, ultimately revealing that treatment with a dose of 9.6 MBq of the radioimmunoconjugate produced a significant increase in median survival compared to a control cohort. Taken together, these data establish CD133 as a viable target for the nuclear imaging and radiopharmaceutical therapy of SCLC.