Intrathecal administration of an anti-ganglioside antibody results in specific accumulation within meningeal neoplastic xenografts in nude rats

Intrathecal (IT) administration of monoclonal antibodies (MAbs) represents a new therapeutic approach For the treatment of leptomeningeal (LM) cancer, which is presently rapidly fatal. In this study, we quantitated the accumu lation of an intrathecally administered anti-ganglioside G(D2) MAb (3F8) wi thin leptomeningeal neoplastic xenografts of G(D2) positive melanoma and ne uroblastoma in nude rats by measuring concentrations of radiolabeled and un modified MAbs and by immunohistochemistry. Intrathecal administration of I- 125-3F8 resulted in area under the tissue concentration versus time curve ( AUC) values in SK-MEL-1 melanoma xenografts (53.1 mu Ci*h/g) that were 14-f old greater than in corresponding blood (3.9 mu Ci*h/g), whereas IT adminis tration of a control nonspecific MAb resulted in AUC values in tumors (7.1 mu Ci*h/g) that were less than those in blood (9.5 mu Ci*h/g). Administrati on of acetazolamide and furosemide, which slow the clearance of IgG MAb fro m rat cerebrospinal fluid resulted in a fivefold increase in AUC of I-125-3 F8 in melanoma (262.9 mu Ci*h/g). The highest concentrationof I-125-MAb in tumor after IT administration was seen at the first sampling time of 2 h, a nd this fell to 50% of maximum values at 8-16 h. Pharmacokinetic analysis o f unmodified MAb demonstrated retention of MAb, within the LM space of anim als with tumor. The concentration of MAb 3F8 appearing in serum after IT ad ministration was 10-fold lower in animals with melanoma xenografts than in those without turner implants. Radiation dose estimates after intraventricu lar administration of radiolabeled MAb indicated delivery to turner of 1,87 0 rad/mCi of I-125-3F8 but only 40 rad/mCi of I-125-labeled control MAb. Th ese results indicate that anti-ganglioside MAbs and other MAbs directed to tumor-associated antigens are excellent candidates for IT treatment of appr opriate leptomeningeal cancers in humans.