Development of a theranostic convergence bioradiopharmaceutical for immuno-PET based radioimmunotherapy of L1CAM in cholangiocarcinoma model

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 radioimmunotherapy 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-triazacyclono-nane-1,4,7-triacetic acid (NOTA) chelator and labeled with ⁶⁴Cu or ¹⁷⁷Lu and evaluated the immuno-PET or SPECT/CT imaging and biodistribution with ⁶⁴Cu-/¹⁷⁷Lu-cA10-A3 in various cholangiocarcinoma xenograft models. Therapeutic efficacy and response monitoring were performed by ¹⁷⁷Lu-cA10-A3 and ¹⁸F-FDG-PET, respectively, and immunohistochemistry was done by TUNEL and Ki-67. Results: Radiolabeled cA10-A3 antibodies specifically recognized L1CAM in vitro, clearly visualized cholangiocarcinoma tumors in immuno-PET and SPECT/CT imaging, and differentiated the L1CAM expression level in cholangiocarcinoma xenograft models. ¹⁷⁷Lu-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 ¹⁷⁷Lu-cA10-A3 treatment increased TUNEL-positive and decreased Ki-67-positive cells, compared with saline, cA10-A3, or ¹⁷⁷Lu-isotype. Conclusions: Anti-L1CAM immuno-PET imaging using ⁶⁴Cu-cA10-A3 could be translated into the clinic for characterizing the pharmacokinetics and selecting appropriate patients for radioimmunotherapy. Radioimmunotherapy using ¹⁷⁷Lu-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.