Evaluation of 225Ac 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 long 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 site chelating ligand, HEHA, has been chemically modified for coupling to targeting proteins without loss of chelating ability. HEHA was coupled with MAb 201B which binds to thrombomodulin and accumulates efficiently in murine lung. Ac-225 was bound to the HEHA-MAb 201B conjugate and injected into BALB/c mice bearing lung tumor colonies of EMT-6 mammary carcinoma. Biodistribution 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 released from the lung with an initial t(1/2) = 49 h, and the released Ac-225 accumulated in the liver. Injection of free HEHA was only partially successful in scavenging free Ac-225. I, addition to the slow release of Ac-225 from the chelate, data indicated that decay daughters of Ac-225 were also released from the lung. Immediately after organ harvest, the level of Bi-213, the 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 the 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 radioimmunotherapeutic agent is compromised not only by the slow release of Ac-225 from the HEHA chelator, but most importantly by the radiotoxicity associated with decay daughter radioisotopes released from the target organ.