DIFFERENTIAL SENSITIVITY OF CD30(-CELLS TO GELONIN DELIVERED BY ANTI-CD30() NEOPLASTIC)ANTI-GELONIN BISPECIFIC ANTIBODIES/

Lymphocyte activation antigens, such as CD30, represent suitable targe t molecules for antibody-driven drug delivery in haemopoietic malignan cies. A ribosome-inactivating protein (RIP) type 1 of potential intere st for mAb targeting is gelonin, which displays a lower toxicity, as c ompared to other RIPs. In this study, two anti-CD30/anti-gelonin bispe cific monoclonal antibodies (bimAbs), secreted by hybrid hybridomas, w ere 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 molec ule. These bimAbs enhanced gelonin toxicity (IC50 5 x 10(-8) M, in the absence of mAbs) against the CD30(+) L540 Hodgkin's lymphoma cell lin e 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 1 0(-10) M as gelonin, whereas with AIX bimAb the IC50 was 8 x 10(-11) M . More interestingly, the combined use of the two bimAbs had a synergi stic effect, since the IC50 Of gelonin reached 6 x 10(-12) M. Among CD 30 tumour cell lines, the Hodgkin's lymphoma L428 was also sensitive t o gelonin delivered by bimAbs (IC50 6 x 10(-11) M), whereas the COLE H odgkin's cell line and the T-ALL Jurkat were completely resistant to t he toxic effect of gelonin and bimAbs. COLE and Jurkat cells were also resistant to a gelonin/anti-CD30 conventional immunotoxin, whereas th ey were sensitive to a saporin/anti-CD30 immunotoxin, This suggests th at the resistance to gelonin is not related to a lack of internalizati on through the CD30 molecule but is associated with some property of t he RIP.