Resistance of myeloid leukaemia cell lines to ricin a-chain immunotoxins

Andreas Engert, Alex Brown, Philip Thorpe

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Abstract

Nineteen monoclonal antibodies that recognize antigens on myeloid leukaemia cells were screened upon HL60, KGI, U937 and K562 cells for their ability to form effective ricin A-chain immunotoxins. The screening was performed using an indirect assay in which the cells were treated firstly with the test antibody and then with a Fab′ immunotoxin directed against mouse immunoglobulin. Only two antibodies, MEM75 and 120-2A3, both directed against the transferrin receptor (TfR) were predicted to form immunotoxins that would inhibit protein synthesis by the cells by 50% at a concentration (IC50) of 10-8 M or less. This prediction was subsequently confirmed using several of the antibodies directly conjugated to ricin A-chain. By contrast, the same immunotoxins were highly toxic to non-myeloid cells which shared the target antigens. A comparison was made between the rates of endocytosis and degradation by HL60 cells of an anti-TfR immunotoxin 120-2A3 dgA, that was effective at killing myeloid cells, and a CD33 immunotoxin, p67-7·dgA, that bound to myeloid cells but did not kill them. The difference in potency of the two immunotoxins on HL60 cells was not due to deficient uptake of p67-7·dgA but was probably due to the more rapid intracellular degradation of p67-7·dgA. Fast and effective degradation in lysosomes, if a general finding, could explain the poor susceptibility of myeloid cells to ricin A-chain immunotoxins.

Original languageEnglish (US)
Pages (from-to)1079-1086
Number of pages8
JournalLeukemia Research
Volume15
Issue number11
DOIs
StatePublished - 1991

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Keywords

  • Acute myeloid leukaemia
  • CD33
  • endocytosis
  • immunotoxin
  • ricin A-chain
  • transferrin receptor

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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