PRECLINICAL ANALYSIS OF RADIOLABELED ANTI-GD2 IMMUNOGLOBULIN-G

BACKGROUND. Unlabeled murine monoclonal anti-GD2 immunoglobulin (Ig)G (14G2a) reactive with nervous system diganglioside and neuroblastoma, melanoma, and small cell lung carcinoma produces tumor regression. How ever, serious acute abdominal pain, paresthesia, hypotension and hyper tension, syndrome of inappropriate secretion of antidiuretic hormone ( SIADH), and occasional motor weakness occur. Studies in preclinical an imal models can elucidate the mechanism of the observed neurotoxicity and lead to anti-GD2 antibody treatment with a higher therapeutic rati o. METHODS. One mg of 14G2a or control Ige was labeled with 1-2 mCi of indium-111 and administered intravenously to beagles (n = 8). In 2 do gs, additional high dose (200 mg) unlabeled 14G2a was given over 5 day s, Whole body gamma camera images and SPECT scans were obtained repeat edly over 7 days. On Day 7, sciatic nerve conduction studies were perf ormed, and after euthanasia radioactivity was determined in major orga ns. RESULTS. Unlabeled high dose 14G2a administered to mice, rats, or rabbits did not cause neurotoxicity within 3 weeks. GD2 antigens were shown by immunochemistry to be present in brain and peripheral nerve t issues of rodents and beagles. After in vivo administration of radiola beled 14G2a, canine lymph nodes showed specific uptake, but only minim al radioactivity was found in the nervous system. Dogs that received a dditional high dose unlabeled 14G2a showed much higher lymph node upta ke and follicular lymph node hyperplasia. Low motor response amplitude s on nerve conduction studies were noted. CONCLUSIONS. A radioisotope label on Ige and its visualization in a large series of animal models indicate that a low protein dose of anti-GD2 IgG will not cause neurol ogic side effects in patients. High protein dose anti-GD2 Ige may enha nce antineoplastic effects and contribute to neurotoxicity through sti mulation of normal lymphocytes with subsequent release of cytokines. ( C) 1997 American Cancer Society.