Evaluation of Ac-225 for vascular targeted radioimmunotherapy of lung tumors

Several alpha particle emitting radioisotopes have been studied for use in radioimmunotherapy. Ac-225 has the potential advantages of a relatively lon g half life of 10 days, and a yield of 4 alpha emissions in its decay chain with a total energy release of similar to 28 MeV. A new, 12 coordination s ite chelating ligand, HEHA, has been chemically modified for coupling to ta rgeting proteins without loss of chelating ability. HEHA was coupled with M Ab 201B which binds to thrombomodulin and accumulates efficiently in murine lung. Ac-225 was bound to the HEHA-MAb 201B conjugate and injected into BA LB/c mice bearing lung tumor colonies of EMT-6 mammary carcinoma. Biodistri bution data at 1 and 4 h postinjection indicated that, as expected, Ac-225 was delivered to lung efficiently (>300 % ID/g). The Ac-225 was slowly rele ased from the lung with an initial t(1/2) = 49 h, and the released Ac-225 a ccumulated in the liver. Injection of free HEHA was only partially successf ul in scavenging free Ac-225. I, addition to the slow release of Ac-225 fro m the chelate, data indicated that decay daughters of Ac-225 were also rele ased from the lung. Immediately after organ harvest, the level of Bi-213, t he third alpha-decay daughter was found to be deficient in the lungs and to be in excess in the kidney, relative to equilibrium values. Injected doses of Ac-225 MAb 201B of 1.0 mu Ci, delivering a minimum calculated absorbed dose of about 6 Gy to the lungs, was effective in killing lung tumors, but also proved acutely radiotoxic. Animals treated with 1.0 mu Ci or move of t he Ac-225 radioconjugate died of a wasting syndrome within days with a dose dependent relationship. We conclude that the potential for Ac-225 as a rad ioimmunotherapeutic agent is compromised not only by the slow release of Ac -225 from the HEHA chelator, but most importantly by the radiotoxicity asso ciated with decay daughter radioisotopes released from the target organ.