Reduction of the nonspecific animal toxicity of anti-Tac(Fv)-PE38 by mutations in the framework regions of the Fv which lower the isoelectric point

Masanori Onda, Robert J. Kreitman, George Vasmatzis, Byungkook Lee, Ira Pastan

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Anti-Tac(Fv)-PE38, also called LMB-2, is a very active recombinant immunotoxin that has produced eight responses, including a durable clinical complete remission in a recently completed phase I trial of leukemias and lymphomas. Dose escalation was limited by liver toxicity. We have noted that the Fv of anti-Tac has an isoelectric point (pI) of 10.2. We hypothesize that the overall positive charge on the Fv portion of anti-Tac(Fv)-PE38 contributes to nonspecific binding to liver cells and results in dose- limiting liver toxicity. We have used a mouse model to investigate the basis of this toxicity and found that lowering the pI of the Fv of anti-Tac from 10.2 to 6.82 by selective mutation of surface residues causes a 3-fold decrease in animal toxicity and hepatic necrosis. Tiffs change in pI did not significantly alter the CD25 binding affinity, the cytotoxic activity toward target cells, or antitumor activity, resulting in a 3-fold improvement in the therapeutic index. If this decreased toxicity occurs in humans, it should greatly increase the clinical utility of this immunotoxin.

Original languageEnglish (US)
Pages (from-to)6072-6077
Number of pages6
JournalJournal of Immunology
Volume163
Issue number11
StatePublished - Dec 1 1999

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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