ANTIBODY-IL-12 FUSION PROTEINS ARE EFFECTIVE IN SCID MOUSE MODELS OF PROSTATE AND COLON-CARCINOMA METASTASES

IL-12 is a complex cytokine in both its structure and its range of bio logic activities. Fusions of this heterodimeric molecule with an intac t antitumor Ab were made to test the feasibility and efficacy of targe ting IL-12 to tumors to elicit a local immune response. Fusion protein s composed of the human p35 and p40 subunits had IL-12 bioactivities t hat were nearly as potent on human immune cells as the rIL-12 standard , but were inactive on mouse cells. Hybrid IL-12 fusion proteins compo sed of mouse p35 and human p40, fused to Ab, were capable of inducing IFN-gamma, but were much less active on mouse spleen cells than a mous e IL-12 standard. Despite this relatively low activity, the hybrid fus ion protein was as effective in a SCID mouse model as a fully active A b-IL-2 fusion protein in eliminating established pulmonary metastases of CT26 colon carcinoma. Specific targeting of a human IL-12 fusion pr otein to metastatic prostate carcinoma xenografts was also shown to be effective in SCID mice transplanted with human lymphocyte-activated k iller cells. These results demonstrate the importance of directing thi s potent cytokine to the tumor microenvironment and suggest an importa nt alternative to systemic IL-12 administration or gene therapy for in creasing its therapeutic index.