Development of a Theranostic Convergence Bioradiopharmaceutical for Immuno-PET Based Radioimmunotherapy of L1CAM in Cholangiocarcinoma

초록

Purpose: Cholangiocarcinoma is a malignancy of bile duct with a poor prognosis. Conventional chemotherapy and radiotherapy are generally ineffective, and surgical resection is the only curative treatment for cholangiocarcinoma. L1-cell adhesion molecule (L1CAM) has been known as a novel prognostic marker and therapeutic target for cholangiocarcinoma. This study aimed to evaluate the feasibility of immuno-PET imaging-based radio-immunotherapy using radiolabeled anti-L1CAM antibody in cholangiocarcinoma xenograft model. Experimental Design: We prepared a theranostic convergence bioradiopharmaceutical using chimeric anti-L1CAM antibody (cA10-A3) conjugated with 1,4,7-triazacyclononane-1,4,7-triacetic acid ( NOTA) chelator and labeled with Cu-64 or Lu-177 and evaluated the immuno-PET or SPECT/CT imaging and biodistribution with Cu-64-/(177)LucA10-A3 in various cholangiocarcinoma xenograft models. Therapeutic efficacy and response monitoring were performed by Lu-177-cA10-A3 and F-18-FDG-PET, respectively, and immunohistochemistry was done by TUNEL and Ki-67. Results: Radiolabeled cA10-A3 antibodies specifically recognized L1CAM in vitro, clearly visualized cholangio-carcinoma tumors in immuno-PET and SPECT/CT imaging, and differentiated the L1CAM expression level in cholangiocarcinoma xenograft models. Lu-177-cA10-A3 (12.95 MBq/100 mg) showed statistically significant reduction in tumor volumes (P < 0.05) and decreased glucose metabolism (P < 0.01). IHC analysis revealed Lu-177-cA10-A3 treatment increased TUNEL-positive and decreased Ki-67-positive cells, compared with saline, cA10-A3, or Lu-177-isotype. Conclusions: Anti-L1CAM immuno-PET imaging using Cu-64-cA10-A3 could be translated into the clinic for characterizing the pharmacokinetics and selecting appropriate patients for radioimmunotherapy. Radioimmunotherapy using Lu-177-cA10-A3 may provide survival benefit in L1CAM-expressing cholangiocarcinoma tumor. Theranostic convergence bioradiopharmaceutical strategy would be applied as imaging biomarker-based personalized medicine in L1CAM-expressing patients with cholangiocarcinoma.

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