EFFICACY OF COMPARTMENTAL ADMINISTRATION OF IMMUNOTOXIN LMB-1 (B3-LYSPE38) IN A RAT MODEL OF CARCINOMATOUS MENINGITIS

LMB-1 (B3-LysPE38) is an immunotoxin composed of the tumor-reactive mo noclonal antibody B3 and a genetically engineered form of Pseudomonas exotoxin, Monoclonal antibody B3 reacts with a carbohydrate epitope th at is found on a number of solid tumors (e.g., breast, ovarian, and lu ng carcinomas) that frequently invade the intrathecal space, causing n eoplastic meningitis, The Pseudomonas exotoxin has been engineered to remove the binding domain to eliminate nonspecific binding, A model of human neoplastic meningitis using rats bearing the human epidermoid c arcinoma A431 was used for therapeutic studies of immunotoxin LMB-1, T herapy was initiated 3 days after injection of the tumor cells, which was one third of the median survival time of untreated rats, A single intrathecal injection of 40 mu g increased median survival from 9 days with saline injection to 16 days (78%, P < 0.001), and a single dose of 200 mu g increased median survival to 25 days (188%, P < 0.001), Th ree doses of 40 or 200 mu g given on days 3, 6, and 8 significantly in creased the median survival of 9.5 days associated with saline injecti on to 40.5 days (326% increase) and 33.0 days (247% increase), respect ively, with two long-term survivors (191-day survival) in each treatme nt group, LMB-1 had no therapeutic effect on the treatment of two B3 a ntigen-negative neoplastic meningitis models, Treatment of the antigen -positive A431 neoplastic meningitis with B3 alone or a nonspecific mo noclonal, MOPC, coupled to the engineered Pseudomonas exotoxin produce d no survival effects, Nontumor-bearing athymic rats showed no toxicit y with a single dose of either 40 mu g or 200 mu g, or 3 doses of 40 m u g. However, when they were given three doses of 200 mu g, these rats showed weight loss and loss of neurological function, and two of eigh t animals died, These studies indicate that, in the range of the most therapeutically effective dosage, the immunotoxin LMB-1 is tolerated i n the intrathecal space and should be considered for human intrathecal trials.