Preclinical safety studies of 213BI labeled PA12 for targeted alpha therapy of cancer

Full text: The urokinase plasminogen activator (uPA) system is involved in cancer growth and metastasis. The plasminogen activator inhibitor type 2 (PAI2) and uPA can form a stable complex, which is bound to the cell surface uPA receptor (uPAR). We labeled PAI2 with 213Bi to form the alpha conjugate. This conjugate targets uPA/uPAR and has been found to have promising therapeutic properties for breast, prostate and pancreatic cancer. This paper reports studies of the acute and delayed toxicity in mice; the effect of lysine renal protection; pharmacokinetics; a comparison of CHX-A-DTPA and cDTPA chelators, and in vivo 213Bi-PAI2 stability by Ca-DTPA challenge. Pharmacokinetics of 213Bi-PAI2 in nude mice demonstrated that the kidneys were the critical organs for retention of Bismuth in the chelate complex. The CHX-A-DTPA and cDTPA immunoconjugates were found to have similar percent I D/kg in the kidney, with no significant retention of Bi evident in other organs such as liver, heart, lung, and spleen. Ca-DTPA chelators significantly reduced the renal 213Bi accumulation at 15 minutes, not for 30 and 120 minutes, indicating high in vivo stability of 213Bi-PAI2 and the need for pre-injection purification of conjugates. The acute toxicity limit by weight loss was more than 450 MBq/kg. Mild to moderate, patchy tubular necrosis was observed accompanied by slight urea increase. Radiation nephritis was the source of lethal delayed toxicity arising at 20 - 30 weeks post-treatment, for which the maximum tolerance dose was 110 MBq/kg. Kidney uptake was not significantly decreased by lysine at 185 MBq/kg, nor was there any change in delayed toxicity