Tumor-Targeting Ability of Novel Anti-Prostate-Specific Membrane Antigen Antibodies

Hsin-Hua Hsieh; Wei-Ying Kuo; Jia-Jia Lin; Hong-Sen Chen; Hung-Ju Hsu; Chun-Yi Wu

doi:10.1021/acsomega.2c04230

Tumor-Targeting Ability of Novel Anti-Prostate-Specific Membrane Antigen Antibodies

ACS Omega. 2022 Aug 23;7(35):31529-31537. doi: 10.1021/acsomega.2c04230. eCollection 2022 Sep 6.

Authors

Hsin-Hua Hsieh¹, Wei-Ying Kuo², Jia-Jia Lin³, Hong-Sen Chen², Hung-Ju Hsu², Chun-Yi Wu¹

Affiliations

¹ Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei Branch, Taipei 112, Taiwan.
² Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
³ Department of Nuclear Medicine, New Taipei Municipal TuCheng Hospital (Built and Operated by Chang Gung Medical Foundation), New Taipei City 236, Taiwan.

Abstract

Patients with prostate-specific membrane antigen (PSMA)-positive tumors can benefit from PSMA-targeted therapy; thus, we have constructed a phage-displayed synthetic antibody library for the production of novel PSMA antibodies with superior PSMA-targeting ability, favoring clinical management. The binding affinities of anti-PSMA antibodies were verified by an enzyme-linked immunosorbent assay (ELISA). Several in vitro and in vivo experiments, including cellular uptake, internalization, and cytotoxicity studies, micro single photon emission computed tomography (microSPECT)/CT, and biodistribution studies, were performed to select the most promising antibody among six different antibodies. The results showed the target affinities of our antibodies in the ELISA assays (7A, 8C, 8E, and 11A) were comparable to the existing antibodies (J591). The half-maximal effective concentrations of 7A, 8C, 8E, 11A, and J591 were 2.95, 6.64, 5.50, 2.08, and 4.79, respectively. The radiochemical yield of ¹¹¹In-labeled antibodies ranged from 30% to 50% with high radiochemical purity (>90%). In the cellular uptake studies, the accumulated radioactivity of ¹¹¹In-J591, ¹¹¹In-7A, and ¹¹¹In-11A increased over time. The internalized percentage of ¹¹¹In-11A was the highest (32.14% ± 2.06%) at 48 h after incubation, whereas that of ¹¹¹In-J591 peaked at 22.43% ± 4.38% at 24 h and dropped to 13.52% ± 3.03% at 48 h postincubation. Twenty-four hours after injection, radioactivity accumulation appeared in the LNCaP xenografts of the mice injected with ¹¹¹In-11A, ¹¹¹In-8E, ¹¹¹In-7A, and ¹¹¹In-J591 but not in the xenografts of the ¹¹¹In-8C-injected group. Marked liver uptake was noticed in all groups except the ¹¹¹In-11A-injected group. Moreover, the killing effect of ¹⁷⁷Lu-11A was superior to that of ¹⁷⁷Lu-J591 at low concentrations. In conclusion, we successfully demonstrated that 11A IgG owned the most optimal biological characteristics among several new anti-PSMA antibodies and it can be an excellent PSMA-targeting component for the clinical use.