Inhibition of AIDS-Associated Kaposi's Sarcoma Cell Growth by DAB 389 -Interleukin 6

Abstract

Acquired immune deficiency syndrome-associated Kaposi's sarcoma (AIDS-KS)-derived spindle cells produce and use interleukin 6 (IL-6) among several other cytokines as a growth factor. In this study we show that AIDS-KS cells express approximately 1100 high-affinity IL-6 receptors (IL-6R) per cell with a dissociation constant (K _d) of 110 pM. Furthermore, AIDS-KS cells express the IL-6Rα subunit, detected as a single 5.0-kb messenger ribonucleic acid species, and the high-affinity converting, signal-transducing IL-6Rβ subunit designated as gp130. Similarly, tumor tissue obtained from patients with KS and AIDS expresses IL-6R messenger ribonucleic acid. We have exploited the chimeric fusion toxin DAB₃₈₉-IL-6, which exerts cellular toxicity only to the cells expressing IL-6R. This chimeric protein was engineered by fusion of a truncated diphtheria toxin structural gene, in which the region encoding the native receptor-binding domain was removed and replaced with the gene encoding IL-6. DAB₃₈₉-IL-6 inhibited protein synthesis in AIDS-KS-derived spindle cells at very low concentrations (IC₅₀ of 3.4 X 10^-11 M). Similarly, inhibition of cell viability by DAB₃₈₉-IL-6 was observed at equivalent dose levels (IC₅₀ of 5 X 10^-11). These effects on protein synthesis and cell viability can be abrogated by recombinant human IL-6, indicating receptor specificity. Thus, DAB₃₈₉-IL-6 is a potential agent for the treatment of AIDS-associated KS.