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

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Abstract
Summary. 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‐CD 3 0/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 × 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 ICs0 of 5 × 1CT10M as gelonin, whereas with A18 bimAb the ICS0 was 8 × 1CT11 M. More interestingly, the combined use of the two bimAbs had a synergistic effect, since the IC50 of gelonin reached 6 × 10_12M. Among CD30 tumour cell lines, the Hodgkin's lymphoma L428 was also sensitive to gelonin delivered by bimAbs (IC50 6 × 1CTU 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.