Site-specific Conjugation of 6 DOTA Chelators to a CA19-9-targeting scFv-Fc Antibody for Imaging and Therapy

• Published in: Journal of medicinal chemistry Vol. 66; no. 15; pp. 10604 - 10616
• Main Authors: Chen, Li-An, Yu, Yueh-Hsiang, Tian, Wei-Ting, Lin, Wei-Chen, Grauffel, Cédric, Wu, Chun-Yi, Chen, Chuan-Lin, Lim, Carmay, Chu, Hsing-Mao, Chang, Tse-Wen, Peng, Chi-Jiun
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10.08.2023
• Subjects: Animals; CA-19-9 Antigen; Cell Line, Tumor; Chelating Agents; Immunoconjugates; Lutetium; Mice; Pancreatic Neoplasms; Pancreatic Neoplasms - diagnostic imaging; Pancreatic Neoplasms - drug therapy; Radiopharmaceuticals - pharmacokinetics; Tissue Distribution
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c00753

Antibodies conjugated with diagnostic/therapeutic radionuclides are attractive options for inoperable cancers lacking accurate imaging methods and effective therapeutics, such as pancreatic cancer. Hence, we have produced an antibody radionuclide conjugate termed TE-1132 comprising a α-CA19-9 scFv-Fc that is site-specifically conjugated at each C-terminus to 3 DOTA chelators via a cysteine-containing peptide linker. The smaller scFv-Fc size facilitates diffusivity within solid tumors, whereas the chelator-to-antibody ratio of six enabled 177Lu-radiolabeled TE-1132 to exhibit high radioactivity up to 520 MBq/nmol. In mice bearing BxPC3 tumors, immuno-SPECT/CT imaging of [111In]­In-TE-1132 and the biodistribution of [177Lu]­Lu-TE-1132 showed selective tumor accumulation. Single and multiple doses of [177Lu]­Lu-TE-1132 effectively inhibited the BxPC3 tumor growth and prolonged the survival of mice with no irreversible body weight loss or hematopoietic damage. The adequate pharmacokinetic parameters, prominent tumor accumulation, and efficacy with good safety in mice encourage the further investigation of theranostic TE-1132 for treating pancreatic cancer.