Evaluating CD133 as a radiotheranostic target in small-cell lung cancer Journal Article
| Authors: | Sarrett, S. M.; Rodriguez, C.; Delaney, S.; Hosny, M. M.; Sebastiano, J.; Santos-Coquillat, A.; Keinänen, O. M.; Carter, L. M.; Lastwika, K. J.; Lampe, P. D.; Zeglis, B. M. |
| Article Title: | Evaluating CD133 as a radiotheranostic target in small-cell lung cancer |
| Abstract: | 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. © 2024 The Authors. Published by American Chemical Society. |
| Keywords: | controlled study; human cell; drug efficacy; nonhuman; positron emission tomography; mouse; animal; animals; mice; animal tissue; lung neoplasms; animal experiment; cohort analysis; in vivo study; in vitro study; tumor xenograft; cell line, tumor; diagnostic imaging; immunoreactivity; lung tumor; tumor cell line; positron-emission tomography; radiopharmaceutical agent; pet imaging; cd133 antigen; radioimmunotherapy; early detection of cancer; zirconium 89; small-cell lung cancer; small cell lung cancer; small cell lung carcinoma; pentetic acid; procedures; gel filtration; lutetium 177; ultracentrifugation; humans; human; female; article; deglycosylation; cd133; patient-derived xenograft; early cancer diagnosis; theranostic nanomedicine; orthotopic xenograft; metastatic xenograft |
| Journal Title: | Molecular Pharmaceutics |
| Volume: | 21 |
| Issue: | 3 |
| ISSN: | 1543-8384 |
| Publisher: | American Chemical Society |
| Date Published: | 2024-03-04 |
| Start Page: | 1402 |
| End Page: | 1413 |
| Language: | English |
| DOI: | 10.1021/acs.molpharmaceut.3c01063 |
| PUBMED: | 38331430 |
| PROVIDER: | scopus |
| PMCID: | PMC10915790 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Brian Zeglis -- Source: Scopus |
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