Differential sensitivity of CD30+ neoplastic cells to gelonin delivered by anti-CD30/anti-gelonin bispecific antibodies

S. Sforzini, A. Bolognesi, R. Meazza, S. Marciano, P. Casalini, H. Durkop, P. L. Tazzari, H. Stein, F. Stirpe, S. Ferrini

Research output: Contribution to journalArticlepeer-review

Abstract

Lymphocyte activation antigens, such as CD30, represent suitable target molecules for antibody-driven drug delivery in haemopoietic malignancies. A ribosome-inactivating protein (RIP) type 1 of potential interest for mAb targeting is gelonin which displays a lower toxicity, as compared to other RIPs. In this study, two anti-CD30/anti-gelonin bispecific monoclonal antibodies (bimAbs), secreted by hybrid hybridomas, were used to deliver this RIP to CD30+ tumour cells. The two bimAbs, termed D4 and A18, were produced using the same anti-CD30 mAb and two anti-gelonin mAbs, directed to unrelated epitopes of the gelonin molecule. These bimAbs enhanced gelonin toxicity (IC50 5 x 10-8 M, in the absence of mAbs) against the CD30+ L540 Hodgkin's lymphoma cell line in a protein synthesis inhibition assay. Thus, in the presence of 10-9 M D4 bimAb, protein synthesis was inhibited with an IC50 of 5 x 10-10 M as gelonin, whereas with A18 bimAb the IC50 was 8 x 10-11 M. More interestingly, the combined use of the two bimAbs had a synergistic effect, since the IC50 of gelonin reached 6 x 10-12 M. Among CD30 tumour cell lines, the Hodgkin's lymphoma L428 was also sensitive to gelonin delivered by bimAbs (IC50 6 x 10-11 M), whereas the COLE Hodgkin's cell line and the T-ALL Jurkat were completely resistant to the toxic effect of gelonin and bimAbs. COLE and Jurkat cells were also resistant to a gelonin/anti-CD30 conventional immunotoxin, whereas they were sensitive to a saporin/anti-CD30 immunotoxin. This suggests that the resistance to gelonin is not related to a lack of internalization through the CD30 molecule but is associated with some property of the RIP.

Original languageEnglish
Pages (from-to)572-577
Number of pages6
JournalBritish Journal of Haematology
Volume90
Issue number3
Publication statusPublished - 1995

Keywords

  • Bispecific monoclonal antibodies
  • CD30
  • Cytotoxicity
  • Gelonin
  • Hodgkin's lymphoma

ASJC Scopus subject areas

  • Hematology

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