Evaluation of²²⁵Ac for Vascular Targeted Radioimmunotherapy of Lung Tumors

Abstract

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 approximately 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, 225Ac was delivered to lung efficiently (> 300% ID/g). The 225Ac was slowly released from the lung with an initial t1/2 = 49 h, and the released 225Ac accumulated in the liver. Injection of free HEHA was only partially successful in scavenging free 225Ac. In addition to the slow release of 225Ac from the chelate, data indicated that decay daughters of 225Ac were also released from the lung. Immediately after organ harvest, the level of 213Bi, 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 225Ac MAb 201B of 1.0 microCi, 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 microCi or more of the 225Ac radioconjugate died of a wasting syndrome within days with a dose dependent relationship. We conclude that the potential for 225Ac as a radioimmunotherapeutic agent is compromised not only by the slow release of 225Ac from the HEHA chelator, but most importantly by the radiotoxicity associated with decay daughter radioisotopes released from the target organ.

Alpha-Particle Emitting Atomic Generator (Actinium-225)-Labeled Trastuzumab (Herceptin) Targeting of Breast Cancer Spheroids

“…Studies, in vitro and in animal models, have shown that this radionuclide is ϳ1000-fold more effective per unit radioactivity than 213 Bi, a first generation ␣-emitter that is currently under clinical inves-tigation (15,16). Studies in animals, however, have also shown that depending on the administration route, target, and chelation chemistry, it is also substantially more toxic (17)(18)(19). The increased efficacy arises because 225 Ac has a longer half-life (10 days versus 45.6 min for 213 Bi), increasing the total number of decays per unit of radioactivity, allowing prolonged irradiation of targeted cells, and because its decay leads to the release of three ␣-particle emitting daughters.…”

Pretargeted α Emitting Radioimmunotherapy Using 213Bi 1,4,7,10-Tetraazacyclododecane-N,N′,N″,N‴-Tetraacetic Acid-Biotin

“…The use of 212 Bi-antiTac monoclonal antibody resulted in marrow toxicity (42). Studies with 225 Ac showed that a dose of 1 Ci resulted in a wasting syndrome with marrow ablation, splenic atrophy, and some gastrointestinal toxicity (49,50).…”

Radioimmunotherapy for Non-Hodgkin's Lymphoma

“…15 Actinium-225 16 and Bismuth-212 17 emit dense α-particles that confer much higher energy and have a potentially significant increased ability to eradicate tumor masses, but their short half-lives, difficult radiochemistry and toxicity to non-target tissues have, to date, restrict their use. 125 I, 123 I, and 111 In emit Auger particles which need to penetrate the cell nucleus in order to cause DNA strand breaks.…”