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

Abstract

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 177 Luradiolabeled TE-1132 to exhibit high radioactivity up to 520 MBq/nmol. In mice bearing BxPC3 tumors, immuno-SPECT/CT imaging of [ 111 In]In-TE-1132 and the biodistribution of [ 177 Lu]Lu-TE-1132 showed selective tumor accumulation. Single and multiple doses of [ 177 Lu]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.

Diagnostic and Therapeutic Radiopharmaceuticals: A “Hot” Topic

“…Treatment with an antibody targeting carbo­hydrate antigen 19-9 conjugated to DOTA chelating 177 Lu was found to be effective in suppressing tumor growth and prolonging survival of mice bearing BxPC3 tumor xenografts. In addition to therapeutic applications, TE-1132 also demonstrated good potential for diagnosis, as 111 In-TE-1132 immuno-SPECT/CT imaging in a xenograft model could reveal the location and size of tumors and detect distant metastases …”

“…In addition to therapeutic applications, TE-1132 also demonstrated good potential for diagnosis, as 111 In-TE-1132 immuno-SPECT/CT imaging in a xenograft model could reveal the location and size of tumors and detect distant metastases. 26 The manuscript submitted by Zha et al reports the synthesis and evaluation of radiolabeled (Lu-177 and Ga-68) heterobivalent ligands targeting both prostate-specific membrane antigen (PSMA) and bone remodeling. Prostate cancer tends to metastasize to bone, so hetero-bivalent ligands to target both PSMA and bone remodeling were designed to increase tumor uptake in order to achieve a higher detection sensitivity and/or treatment efficacy.…”