An immunotoxin for the treatment of T-acute lymphoblastic leukemic meningitis: studies in rhesus monkeys.
Monoclonal antibody WT1 (anti-CD7), conjugated to ricin A chain, was administered intrathecally to rhesus monkeys to test its suitability for use in the therapy of leukemic meningitis. The WT1-SMPT-dgRTA conjugate was cytotoxic to CEM (T-lymphoblastic leukemia) cells in vitro with an ID50 of 53 pM. Immunoperoxidase testing showed no binding of WT1 to normal human tissues other than lymph nodes. Thirteen animals received one or more intrathecal 60-micrograms doses of WT1-SMPT-dgRTA. All monkeys receiving repeated doses developed a cerebrospinal fluid (CSF) pleocytosis (primarily eosinophils), which was generally resolving by 3-4 weeks after therapy. Pharmacokinetic studies showed a half-life of 99 min, consistent with CSF clearance by bulk flow. Peak CSF immunotoxin concentrations exceeded the ID50 for CEM cells by more than 2 log units and a concentration exceeding the ID50 was maintained for as long as 24 h. All eight monkeys receiving repeated doses of immunotoxin developed serum antibodies against both WT1 and ricin A chain. In six of these monkeys antibodies were also present in the CSF. Both anti-WT1 and anti-(ricin A chain) antibodies were able to inhibit in vitro cytotoxicity of the immunotoxin for CEM cells; however, only anti-WT1 antibodies could block immunotoxin binding to the cell surface. No monkey developed anti-immunotoxin antibodies fewer than 7 days after the initiation of therapy, suggesting that repeated doses could be administered for up to 1 week without inhibition of clinical activity.
Division of Hematology and Oncology, Duke University Medical Center, Durham, NC 27710.
A A
AA
Hertler
D M
DM
Schlossman
M J
MJ
Borowitz
D G
DG
Poplack
A E
AE
Frankel
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000633:toxicity; D000917:Antibody Formation; D001666:Binding Sites, Antibody; D001667:Binding, Competitive; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D000922:Immunotoxins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007278:Injections, Spinal; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000276:immunology; D008253:Macaca mulatta; D008581:Meningitis / Q000188:drug therapy* / Q000276:immunology; D009423:Nervous System Neoplasms / Q000188:drug therapy* / Q000276:immunology; D012276:Ricin / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D013388:Succinimides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D013388:Succinimides; C058151:4-succinimidyloxycarbonyl-alpha-methyl-alpha(2-pyridyldithio)toluene; D012276:Ricin