An immunotoxin for the treatment of T-acute lymphoblastic leukemic meningitis: studies in rhesus monkeys

Andrew A. Hertler, David M. Schlossman, Michael J. Borowitz, David G. Poplack, Arthur E. Frankel

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Abstract

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 p M. Immunoperoxidase testing showed no binding of WT1 to normal human tissues other than lymph nodes. Thirteen animals received one or more intrathecal 60-μg 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.

Original languageEnglish (US)
Pages (from-to)59-66
Number of pages8
JournalCancer Immunology Immunotherapy
Volume28
Issue number1
DOIs
StatePublished - Jan 1989

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Immunotoxins
Macaca mulatta
Meningitis
Ricin
Haplorhini
Cerebrospinal Fluid
Antibodies
Anti-Idiotypic Antibodies
T-Cell Leukemia
Leukocytosis
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Eosinophils
Half-Life
Therapeutics
Pharmacokinetics
Lymph Nodes
Monoclonal Antibodies
Serum

ASJC Scopus subject areas

  • Oncology
  • Immunology
  • Cancer Research

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An immunotoxin for the treatment of T-acute lymphoblastic leukemic meningitis : studies in rhesus monkeys. / Hertler, Andrew A.; Schlossman, David M.; Borowitz, Michael J.; Poplack, David G.; Frankel, Arthur E.

In: Cancer Immunology Immunotherapy, Vol. 28, No. 1, 01.1989, p. 59-66.

Research output: Contribution to journalArticle

Hertler, Andrew A. ; Schlossman, David M. ; Borowitz, Michael J. ; Poplack, David G. ; Frankel, Arthur E. / An immunotoxin for the treatment of T-acute lymphoblastic leukemic meningitis : studies in rhesus monkeys. In: Cancer Immunology Immunotherapy. 1989 ; Vol. 28, No. 1. pp. 59-66.
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