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Antibody-Pseudomonas Exotoxin A Conjugates Cytotoxic to Human Breast Cancer Cells in Vitro

Department of Protein Chemistry, Cetus Corporation, Emeryville, California 94608

Breast tumor selective antibodies (MAB) conjugated to Pseudomonas exotoxin A (PE) formed immunotoxins with potent cytotoxicities for human breast tumor cell lines. The most effective of the MAB-PE conjugates were about 500-fold more toxic to the breast tumor target cell lines than to the nontarget human fibroblast cell line. Specificity of cytotoxicity by MAB-PE conjugates was demonstrated by protection of target cells in the presence of excess unconjugated homologous antibody. A MAB-PE conjugate inhibited protein synthesis more rapidly than the corresponding MAB-ricin toxin A chain (RTA) conjugate. Generally, there was a direct correlation between the cytotoxicity of RTA and PE when conjugated to the same MAB: MABs that made highly cytotoxic RTA conjugates made effective PE conjugates and MABs that made poorly cytotoxic RTA conjugates made PE conjugates of low cytotoxicity; however, one MAB-PE immunotoxin was cytotoxic to the human breast tumor cell lines, whereas the corresponding MAB-RTA immunotoxin was noncytotoxic at the highest dose tested. In contrast to MAB-RTA conjugates, which require a cleavable (disulfide) linkage for maximal in vitro cytotoxicity, MAB-PE conjugates were about equally cytotoxic when linked by either a cleavable or noncleavable (thioether) bond.

Received 10/21/85. Revised 3/ 7/86. Accepted 4/ 2/86.