Sensitivity of human glioma cells to cytotoxic heteroconjugates

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Abstract
Several anti‐human glioma cytotoxic conjugates were studied in vitro. Monoclonal antibodies (MAbs) to the GE 2 gliomaassociated antigen (anti‐GE 2) and MAbs to HLA‐DR antigens (D1/12) or human diferric transferrin (Tfn) were linked to the potent cytotoxin ricin (anti‐GE 2‐ricin) or to its A subunit (anti‐GE 2‐RTA, D1/12‐RTA, Tfn‐RTA). Anti‐GE 2‐RTA had low cytotoxic activity in both the absence and the presence of lysosomotropic substances inhibiting intracellular degradation. Anti‐GE 2‐rich was about 1,000 times more toxic than RTA alone, but showed only 14‐fold target specificity. D1/12‐RTA was about 20 times more toxic than RTA and its cytotoxic effect increased about 6‐ to 7‐fold when cell‐surface HLADR antigen expression was enhanced by IFN‐γ treatment. Human diferric Tfn linked to RTA demonstrated the highest cytotoxic activity, being about 5,000 times more toxic than RTA alone for glioma cells and about 6,000 times more toxic for Jurkat cells in the presence of the carboxylic ionofore monensin. Rich toxin was only about 5 times more toxic for Jurkat and glioma cells than Tfn‐RTA‐monensin. Tfn‐RTA was over 100,000 times more potent than the chemotherapeutic agent BCNU in reducing glioma cell survival in vitro. Addition of 80% human pooled cerebrospinal fluid (CSF) reduced Tfn‐RTA toxicity about 10‐fold. Kinetics of Tfn‐RTA cytotoxicity at non‐saturating concentrations indicated that over 80% of target cells could be killed within 8–10 hr in the absence and within 10–12 hr in the presence of human pooled CSF.