ERADICATION OF ESTABLISHED HEPATIC HUMAN NEUROBLASTOMA METASTASES IN MICE WITH SEVERE COMBINED IMMUNODEFICIENCY BY ANTIBODY-TARGETED INTERLEUKIN-2

A major problem in the treatment of solid tumors is the eradication of established, disseminated metastases. Here we describe an effective t reatment for established experimental hepatic metastases of human neur oblastoma in C. B.-17 scid/scid mice. This was accomplished with an an tibody-cytokine fusion protein, combining the unique targeting ability of antibodies with the multifunctional activity of cytokines. An anti -(ganglioside GD2) antibody (ch14.18) fusion protein with interleukin- 2 (ch14.18-IL2), constructed by fusion of a synthetic sequence coding for human interleukin-2 (IL-2) to the carboxyl end of the C gamma 1 ge ne of ch14.18, was tested for its therapeutic efficacy against xenogra fted human neuroblastoma in vivo. The ch14.18-IL2 fusion protein marke dly inhibited growth of established hepatic metastases in SCID (severe combined immunodeficiency) mice previously reconstituted with human l ymphokine-activated killer cells. Animals treated with ch14.18-IL2 sho wed an absence of macroscopic liver metastasis. In contrast, treatment with combinations of ch14.18 and recombinant IL2 at dose levels equiv alent to the fusion protein only reduced the tumor load. Survival time s of SCID mice treated with the fusion protein were more than double t hat of control animals. These results demonstrate that an immunotherap eutic approach using a cytokine targeted by an antibody to tumor sites is highly effective in eradicating the growth of established tumor me tastases.