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 accumulation of an intrathecally administered anti-ganglioside G D2 MAb (3F8) within leptomeningeal neoplastic xenografts of G D2 positive melanoma and neuroblastoma in nude rats by measuring concentrations of radiolabeled and unmodified MAbs and by immunohistochemistry. Intrathecal administration of 125 I-3F8 resulted in area under the tissue concentration versus time curve (AUC) values in SK-MEL- melanoma xenografts (53.1 μCi * h/g) that were 14-fold greater than in corresponding blood (3.9 μCi * h/g), whereas IT administration of a control nonspecific MAb resulted in AUC values in tumors (7.1 μCi * h/g) that were less than those in blood (9.5 μCi * h/g). Administration of acetazolamide and furosemide, which slow the clearance of IgG MAb from rat cerebrospinal fluid resulted in a fivefold increase in AUC of 125 I-3F8 in melanoma (262.9 μCi * h/g). The highest concentration of 125 I-MAb in tumor after IT administration was seen at the first sampling time of 2 h, and this fell to 50% of maximum values at 8-16 h. Pharmacokinetic analysis of unmodified MAb demonstrated retention of MAb within the LM space of animals with tumor. The concentration of MAb 3F8 appearing in serum after IT administration was 10-fold lower in animals with melanoma xenografts than in those without tumor implants. Radiation dose estimates after intraventricular administration of radiolabeled MAb indicated delivery to tumor of 1,870 rad/mCi of 125 I-3F8 but only 40 rad/mCi of 125 I-labeled control MAb. These results indicate that anti-ganglioside MAbs and other MAbs directed to tumor-associated antigens are excellent candidates for IT treatment of appropriate leptomeningeal cancers in humans.