THERAPY FOR COLON-CARCINOMA XENOGRAFTS WITH BISPECIFIC ANTIBODY-TARGETED, IODINE-131-LABELED BIVALENT HAPTEN

BACKGROUND. One of the main limitations of radioimmunotherapy (RIT) is the secondary toxicity related to the poor therapeutic indices achiev ed with labeled whole immunoglobulin (Ig)G or F(ab')(2) fragments. To overcome this problem, eve have developed a two-step targeting method, which we refer to as the Affinity Enhancement System (AES), using a r adiolabeled bivalent hapten and a bispecific antibody recognizing the hapten and a target cell antigen. This method has been applied success fully to immunoscintigraphy in carcinoembryonic antigen (CEA)expressin g carcinoma patients and increased tumor to normal tissue uptake ratio s have been achieved. The aim of the current study was to evaluate the application of AES to RIT of CEA-expressing solid tumors in an animal model. METHODS. Nude mice grafted with LS174T human colorectal carcin oma were treated either with 111 megabecquerels (MBq) of iodine-131 la beled bivalent diethylenetriamine pentaacetic acid (DTPA) hapten 20 ho urs after pretargeting by anti-CEA x anti-DTPA-indium bispecific antib ody or 12 MBq of iodine-131 labeled anti-CEA IgG. RESULTS. Treatment w ith the Ige induced only a growth delay of 53 +/- 5 days but all tumor s progressed. Treatment with the AES was highly efficient because tumo r growth inhibition was achieved over 150 days. Hematologic and overal l toxicity of both treatments were equivalent. CONCLUSIONS. The long t erm tumor regression consecutive to AES RIT represents a very signific ant improvement over the use of directly labeled Igc. Toxicity consecu tive to AES or Ige RIT were similar despite an administered activity n early ten times higher with the AES. However, given the efficacy of th e AES treatment, a lower dose may afford lower toxicity and significan t antitumor effect. (C) 1997 American Cancer Society.