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

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/antigelonin 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.

• Authors: S Sforzini, A Bolognesi, R Meazza, S Marciano, P Casalini, H Dürkop, P L Tazzari, H Stein, F Stirpe, S Ferrini
• Journal: British journal of haematology (Br J Haematol) Vol. 90 Issue 3 Pg. 572-7 (Jul 1995) ISSN: 0007-1048 [Print] England
• PMID: 7646996 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Bispecific
• Immunotoxins
• Ki-1 Antigen
• Plant Proteins
• Ribosome Inactivating Proteins, Type 1
• GEL protein, Gelonium multiflorum

Topics

• Antibodies, Bispecific (administration & dosage)
• Cytotoxicity, Immunologic
• Dose-Response Relationship, Immunologic
• Drug Resistance
• Hodgkin Disease (drug therapy, immunology)
• Humans
• Immunotoxins (therapeutic use)
• Ki-1 Antigen (immunology)
• Plant Proteins (administration & dosage, immunology, therapeutic use)
• Ribosome Inactivating Proteins, Type 1
• Tumor Cells, Cultured