Synthesis and application of a novel cysteine-based DTPA-NCS for targeted radioimmunotherapy

Abstract: Introduction: For the development of safe and effective protein-based radiolabeled complexes such as radioimmunotherapy (RIT), the selection of the radionuclides and the chelating agents used for the radiolabeling of tumor-targeting molecules is a critical factor. We aim to synthesize a novel bifunctional chelating agent containing the isothiocyanate group for easy conjugation with antibodies having the characteristics of high stable chelation with therapeutic radionuclides. Methods: We have synthesized the DTPA analogue retaining L-cysteine as a core ligand of the thiol group. The chelating power of cysteine-based DTPA-NCS (cys-DTPA-NCS) was compared with that of commercial ρ-SCN-Bn-DTPA. In an application, the cetuximab was radioimmunoconjugated with 177Lu using cys-DTPA-NCS. The affinity was tested in a cell line overexpressing EGFR. A therapy study was conducted in nude mice with subcutaneous HT-29 xenografts. Results: The cys-DTPA-NCS presents an excellent ability to chelate as compared to the ρ-SCN-Bn-DTPA. For mean ratio chemical labeling yields of 95%, the result was 0.97. 177Lu-cys-DTPA-NCS-cetuximab was prepared under ambient condition with a high radiolabeling yield and the radiochemical purity was sustained for at least 6days. The IC50 value of the 177Lu-labeled cetuximab was 10nM (95% confidence). The stability and therapeutic efficacy of the candidate radiopharmaceutical were verified. Conclusion: The new DTPA derivative, cys-DTPA-NCS, is a good bifunctional chelating agent that can be used for protein-based radiopharmaceutical using lanthanides such as 177Lu and 90Y. The prepared 177Lu-cys-DTPA-NCS-cetuximab can be used for the diagnosis and treatment of human colorectal tumor. [Copyright &y& Elsevier]