ERADICATION OF HUMAN HEPATIC AND PULMONARY MELANOMA METASTASES IN SCID MICE BY ANTIBODY-INTERLEUKIN-2 FUSION PROTEINS

Antibody-cytokine fusion proteins combine the unique targeting ability of antibodies with the multifunctional activity of cytokines, Here, w e demonstrate the therapeutic efficacy of such constructs for the trea tment of hepatic and pulmonary metastases of different melanoma cell l ines, Two antibody-interleukin 2 (IL-2) fusion proteins, ch225-IL2 and ch14.18-IL2, constructed by fusion of a synthetic sequence coding for human IL 2 to the carboxyl end of the C gamma 1 gene of the correspon ding antibodies, were tested for their therapeutic efficacy against xe nografted human melanoma in vivo. Tumor-specific fusion proteins compl etely inhibited the growth of hepatic and pulmonary metastases in C.B- 17 scid/scid mice previously reconstituted with human lymphokine activ ated killer cells, whereas treatment with combinations of the correspo nding antibodies plus recombinant IL-2 only reduced the tumor load, Ev en when treatment with fusion proteins was delayed up to 8 days after inoculation of tumor cells, it still resulted in complete eradication of micrometastases that were established at that time point, Selection of tumor cell lines expressing or lacking the targeted antigen of the administered fusion protein proved the specificity of the observed an titumor effect, Biodistribution analysis demonstrated that the tumor-s pecific fusion protein accumulated not only in subcutaneous tumors but also in lungs and livers affected with micrometastases, Survival time s of animals treated with the fusion protein were more than doubled as compared to those treated with the combination of the corresponding a ntibody plus IL-2. Our data demonstrate that an immunotherapeutic appr oach using cytokines targeted by antibodies to tumor sites has potent effects against disseminated human melanoma.