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

Recently, promising results of antitumor activity were observed in patients with metastatic castration resistant prostate cancer treated with [177Lu]Lu-PSMA. Radionuclide therapy efficacy may even be improved by using the alpha emitter Ac-225. Higher efficacy is claimed due to high LET energies specifically towards PSMA positive cells, causing more double strand breaks. The aim of this study is to manufacture [225Ac]Ac-PSMA-I&T according to good manufacturing practice guidelines for the translation of [225Ac]Ac-PSMA-I&T into the clinic for phase 1 dose escalation study. For labeling and optimization, quencher addition during labeling is investigated. Quality control of [225Ac]Ac-PSMA-I&T is based on measurement of Fr-221 (218KeV), which forms an equilibrium with Ac-225 in ~6T½ of Fr-221 (4.8min). Radio-(I)TLC methods are utilized for identification of the different chemical forms, gamma-counter for concentration determination, and radiochemical yield by HPGe-detector. Radiochemical purity is determined by HPLC analyzes. Final patient dose is prepared and diluted with equal ratio quencher as during labeling with an activity of 8-12MBq(±5%), pH>5.5, 100μg(±20%)PSMA-I&T, radiochemical yield >95%, radiochemical purity >90% (up to 3h after filtration), endotoxin levels of <5EU/mL, osmolarity of 2100 mOsmol and produced according to current guidelines. The start of phase I dose escalation study is planned in the near future.

HOOIJMAN Eline;  CHALISKAN Yoslem;  LING S W;  KARYGAHIL Figen;  SEGBERS Marcel;  BRUCHERTSEIFER Frank;  MORGENSTERN Alfred;  SEIMBILLE Yann;  KOOLEN Stijn;  BRABANDER Tessa;  DE BLOIS Erik; 

2021-05-27

MDPI

JRC124591

1999-4923 (online),   

https://publications.jrc.ec.europa.eu/repository/handle/JRC124591,   

10.3390/pharmaceutics13050715 (online),