177Lu-antibody conjugates for single-cell kill of B-lymphoma cells in vitro and for therapy of micrometastases in vivo

Antibodies (Abs) conjugated to Lu-177, a relatively low-energy beta-particle emitter, were evaluated in vitro for their cytotoxic activity and in vivo for their therapeutic activity against disseminated B-cell lymphoma xenografts in SCID mice. Lu-177 was compared with other beta-particle emitters (I-131 and Y-90), and also with emitters of low-energy electrons (LEEs, meaning Auger and conversion electrons of < 50 keV). The Abs used reacted with CD20, CD74 or HLA-DR, and the target cell was the Raji B lymphoma. Like the other beta-particle emitters, Lu-177 was a potent and specific toxic agent in vitro, when conjugated to Abs recognizing high-density antigens. It appeared to be slightly less potent than I-131 per decay, but this difference was relatively small, and would not be a major factor in the selection of the optimal radionuclide for clinical use. The nonspecific toxicity from Lu-177 was less than from Y-90, but Lu-177 still produced greater nonspecific toxicity in vitro than LEE emitters. The maximum tolerated dose (MTD) of Lu-177-anti-CD74 in SCID mice was 1.81 MBq (49 mu Ci)/mouse. When this dose was administered on day 5 after tumor inoculation, significant protection was obtained, but considerably less than the protection obtained in previous experiments with LEE emitters In-111 and Ga-67. In conclusion, Lu-177 has advantages over other available beta-particle emitters as a therapeutic agent, but its efficacy in the treatment of micrometastases seems to be less than that of LEE emitters, due to greater nonspecific toxicity. This conclusion, however, may not apply to therapy of macroscopic tumors. (c) 2005 Elsevier Inc. All rights reserved.