Development of [225Ac]Ac-PSMA-I&T for Targeted Alpha Therapy According to GMP Guidelines for Treatment of mCRPC

Abstract

Recently, promising results of the antitumor effects were observed in patients with metastatic castration-resistant prostate cancer treated with 177Lu-labeled PSMA-ligands. Radionuclide therapy efficacy may even be improved by using the alpha emitter Ac-225. Higher efficacy is claimed due to high linear energy transfer specifically towards PSMA positive cells, causing more double-strand breaks. This study aims to manufacture [225Ac]Ac-PSMA-I&T according to good manufacturing practice guidelines for the translation of [225Ac]Ac-PSMA-I&T into a clinical phase 1 dose escalation study. Quencher addition during labeling was investigated. Quality control of [225Ac]Ac-PSMA-I&T was based on measurement of Fr-221 (218 keV), in equilibrium with Ac-225 in approximately six half-lives of Fr-221 (T½ = 4.8 min). Radio-(i)TLC methods were utilized for identification of the different radiochemical forms, gamma counter for concentration determination, and HPGe-detector for the detection of the radiochemical yield. Radiochemical purity was determined by HPLC. The final patient dose was prepared and diluted with an optimized concentration of quenchers as during labeling, with an activity of 8–12 MBq (±5%), pH > 5.5, 100 ± 20 μg/dose, PSMA-I&T, radiochemical yield >95%, radiochemical purity >90% (up to 3 h), endotoxin levels of <5 EU/mL, osmolarity of 2100 mOsmol, and is produced according to current guidelines. The start of the phase I dose escalation study is planned in the near future.

In vitro dose effect relationships of actinium-225- and lutetium-177-labeled PSMA-I&T

“…The labeling of PSMA-I&T with actinium-225 has been described previously [ 20 ]. Briefly, PSMA-I&T (Huayi Isotopes Co. via ATT Scintomics) was labeled with actinium-225 (JRC, Karlsruhe, Germany) with a molar activity of 0.225 MBq/nmol.…”

“…Briefly, PSMA-I&T (Huayi Isotopes Co. via ATT Scintomics) was labeled with actinium-225 (JRC, Karlsruhe, Germany) with a molar activity of 0.225 MBq/nmol. To prevent radiolysis, quenchers ascorbate (1 M) and ethanol (6%), were used [ 20 ]. Quality control was performed by assessing radiochemical yield (RCY) by instant thin-layer chromatography and radiochemical purity (RCP) by high-pressure liquid chromatography.…”

“…To make sure the measured radioactivity of francium-221 directly corresponds to the amount of activity of actinium-225, there was at least 30 min between the preparation of the samples and the measurements (during quality control and all experiments), so that an equilibrium had formed between francium-221 and actinium-225 [ 20 ].…”

The determination of the radiochemical purity of Actinium-225 radiopharmaceuticals: a conundrum

“…This fundamental characterization is usually accomplished by applying techniques for structure determination to macroscopic amounts of the authentic sample synthesized using a stable isotope of the radionuclide incorporated into the radiopharmaceutical. Then, the chromatographic profile of the authentic sample can be compared with the profile of the corresponding radiopharmaceutical both collected using High-Performance Liquid Chromatography (HPLC) and/or Instant Thin-layer Chromatography (ITLC) under the same experimental conditions for cross validation (Thakral et al 2021 ; Hooijman et al 2021 ). When there exists a close matching between these two chromatographic profiles, it is reasonable to assume that the radiopharmaceutical has the same chemical identity of the authentic sample.…”

Radiolabeled PSMA Inhibitors

“…For example, 225 Ac can play a pivotal role in targeted alpha therapy (TAT) of prostate cancer [ 48 , 51 , 78 , 209 , 210 , 211 , 212 , 213 , 214 , 215 ], but additional preclinical studies and prospective clinical trials need to be performed to secure its safety and efficacy [ 216 , 217 , 218 , 219 , 220 , 221 ]. The importance of 225 Ac-labeled radiopharmaceuticals is affirmed by efforts to establish GMP-compliant procedures for production and quality control [ 222 , 223 , 224 , 225 , 226 ]. Regulatory aspects on the supply of radionuclides for routine clinical application represent a hurdle that needs to be considered for the translation of new radiopharmaceuticals [ 227 , 228 ].…”