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ImmunoPET for assessing the differential uptake of a CD146-specific monoclonal antibody in lung cancer

Haiyan Sun, Christopher G England, Reinier Hernandez, Stephen A Graves, Rebecca L Majewski, Anyanee Kamkaew, Dawei Jiang, Todd E Barnhart, Yunan Yang, Weibo Cai
European Journal of Nuclear Medicine and Molecular Imaging 2016, 43 (12): 2169-2179

PURPOSE: Overexpression of CD146 in solid tumors has been linked to disease progression, invasion, and metastasis. We describe the generation of a (64)Cu-labeled CD146-specific antibody and its use for quantitative immunoPET imaging of CD146 expression in six lung cancer models.

METHODS: The anti-CD146 antibody (YY146) was conjugated to 1,4,7-triazacyclononane-triacetic acid (NOTA) and radiolabeled with (64)Cu. CD146 expression was evaluated in six human lung cancer cell lines (A549, NCI-H358, NCI-H522, HCC4006, H23, and NCI-H460) by flow cytometry and quantitative western blot studies. The biodistribution and tumor uptake of (64)Cu-NOTA-YY146 was assessed by sequential PET imaging in athymic nude mice bearing subcutaneous lung cancer xenografts. The correlation between CD146 expression and tumor uptake of (64)Cu-NOTA-YY146 was evaluated by graphical software while ex vivo biodistribution and immunohistochemistry studies were performed to validate the accuracy of PET data and spatial expression of CD146.

RESULTS: Flow cytometry and western blot studies showed similar findings with H460 and H23 cells showing high levels of expression of CD146. Small differences in CD146 expression levels were found among A549, H4006, H522, and H358 cells. Tumor uptake of (64)Cu-NOTA-YY146 was highest in CD146-expressing H460 and H23 tumors, peaking at 20.1 ± 2.86 and 11.6 ± 2.34 %ID/g at 48 h after injection (n = 4). Tumor uptake was lowest in the H522 model (4.1 ± 0.98 %ID/g at 48 h after injection; n = 4), while H4006, A549 and H358 exhibited similar uptake of (64)Cu-NOTA-YY146. A positive correlation was found between tumor uptake of (64)Cu-NOTA-YY146 (%ID/g) and relative CD146 expression (r (2) = 0.98, p < 0.01). Ex vivo biodistribution confirmed the accuracy of the PET data.

CONCLUSION: The strong correlation between tumor uptake of (64)Cu-NOTA-YY146 and CD146 expression demonstrates the potential use of this radiotracer for imaging tumors that elicit varying levels of CD146. In the future, this tool may promote enhanced monitoring of therapeutic response and improved patient stratification.


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