ATL-101(Cornell University)

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.

Prostate-specific membrane antigen (PSMA)-targeted PET has shown strong potential for localizing metastatic prostate cancer, as we have shown with [⁸⁹Zr]Zr-huJ591 immuno-PET.Here, we report the case of a 51-yr-old woman diagnosed 8.5 years ago with grade II oligodendroglioma (1p/19q co-deleted, IDH mutant) who was referred for [⁸⁹Zr]Zr-huJ591 PET two days after MRI performed with i.v. injected gadopentetate dimeglumine (Magnevist; Bayer HealthCare Pharmaceuticals, Wayne, NJ) revealed concern for disease progression despite multiple prior treatments including surgery and chemoradiation, most recently with IDH inhibitor AG-120 (NCT02074839).[⁸⁹Zr]Zr-huJ591 PET offers quant. visualization of PSMA expression in neovasculature, prospective dosimetry for huJ591-based radioimmunotherapy supported by serial imaging over multiple days, and assessment of response to radiolabeled J591 and other anti-angiogenic agents.Cold antibody huJ591 (23.5 mg) was injected i.v. over five minutes followed by 182.04 MBq/1.5 mg of [⁸⁹Zr]Zr-huJ591 injected i.v. over one minute.In view of the persistent and/or continuously rising lesional tracer accumulation in this patient, longer post-injection imaging periods are indicated in future studies, particularly for optimized dosimetric calculations