Interrogating the theranostic capacity of a MUC16-targeted antibody for ovarian cancer Journal Article
| Authors: | Mack, K. N.; Samuels, Z. V.; Carter, L. M.; Viray, T. D.; Mandleywala, K.; Brooks, C. L.; Hollingsworth, M. A.; Radhakrishnan, P.; Lewis, J. S. |
| Article Title: | Interrogating the theranostic capacity of a MUC16-targeted antibody for ovarian cancer |
| Abstract: | Aberrantly expressed glycans on mucins such as mucin-16 (MUC16) are implicated in the biology that promotes ovarian cancer (OC) malignancy. Here, we investigated the theranostic potential of a humanized antibody, huAR9.6, targeting fully glycosylated and hypoglycosylated MUC16 isoforms. Methods: In vitro and in vivo targeting of the diagnostic radiotracer [89Zr]Zr-DFO-huAR9.6 was investigated via binding experiments, immuno-PET imaging, and biodistribution studies on OC mouse models. Ovarian xenografts were used to determine the safety and efficacy of the therapeutic version, [177Lu]Lu-CHX-A99- DTPA-huAR9.6. Results: In vivo uptake of [89Zr]Zr-DFO-huAR9.6 supported in vitro-determined expression levels: high uptake in OVCAR3 and OVCAR4 tumors, low uptake in OVCAR5 tumors, and no uptake in OVCAR8 tumors. Accordingly, [177Lu]Lu-CHX-A99-DTPAhuAR9.6 displayed strong antitumor effects in the OVCAR3 model and improved overall survival in the OVCAR3 and OVCAR5 models in comparison to the saline control. Hematologic toxicity was transient in both models. Conclusion: PET imaging of OC xenografts showed that [89Zr]Zr-DFO-huAR9.6 delineated MUC16 expression levels, which correlated with in vitro results. Additionally, we showed that [177Lu]Lu-CHX-A99-DTPA-huAR9.6 displayed strong antitumor effects in highly MUC16-expressing tumors. These findings demonstrate great potential for 89Zr- and 177Lu-labeled huAR9.6 as theranostic tools for the diagnosis and treatment of OC. © 2024 by the Society of Nuclear Medicine andMolecular Imaging. |
| Keywords: | controlled study; shoulder; unclassified drug; drug efficacy; drug safety; nonhuman; positron emission tomography; ovarian cancer; ovarian neoplasms; mouse; animal; animals; mice; apoptosis; ovary cancer; gene expression; tumor volume; blood toxicity; animal experiment; animal model; membrane proteins; body weight; in vivo study; antineoplastic activity; in vitro study; tumor xenograft; cell line, tumor; diagnostic imaging; food; drug distribution; tissue distribution; infant; ovary tumor; membrane protein; tumor cell line; glycosylation; radiopharmaceutical agent; pet imaging; ca 125 antigen; ca-125 antigen; water; cancer classification; antigen binding; radioimmunotherapy; ex vivo study; zirconium 89; personalized medicine; radiochemistry; mucin; muc16; pentetic acid; radiochemical purity; lutetium 177; muc16 protein, human; mucin 16; humans; human; female; article; precision medicine; positron emission tomography-computed tomography; theranostic nanomedicine; radiation dose response; muc16 gene; huar9.6; chx a'' dtpa huar9.6 lu 177; dfo huar9.6 zr 89; hypoglycosylation |
| Journal Title: | Journal of Nuclear Medicine |
| Volume: | 65 |
| Issue: | 4 |
| ISSN: | 0161-5505 |
| Publisher: | Society of Nuclear Medicine |
| Date Published: | 2024-04-01 |
| Start Page: | 580 |
| End Page: | 585 |
| Language: | English |
| DOI: | 10.2967/jnumed.123.266524 |
| PUBMED: | 38485271 |
| PROVIDER: | scopus |
| PMCID: | PMC10995531 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- MSK corresponding author is Jason Lewis -- Source: Scopus |
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