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*
Lexigen Pharmaceuticals Corp., Lexington, MA 02137; and
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
IL-12 is a complex cytokine in both its structure and its range of
biologic activities. Fusions of this heterodimeric molecule with an
intact antitumor Ab were made to test the feasibility and efficacy of
targeting IL-12 to tumors to elicit a local immune response. Fusion
proteins composed of the human p35 and p40 subunits had IL-12
bioactivities that were nearly as potent on human immune cells as the
rIL-12 standard, but were inactive on mouse cells. Hybrid IL-12 fusion
proteins composed of mouse p35 and human p40, fused to Ab, were capable
of inducing IFN-
, but were much less active on mouse spleen cells
than a mouse IL-12 standard. Despite this relatively low activity, the
hybrid fusion protein was as effective in a SCID mouse model as a fully
active Ab-IL-2 fusion protein in eliminating established pulmonary
metastases of CT26 colon carcinoma. Specific targeting of a human IL-12
fusion protein to metastatic prostate carcinoma xenografts was also
shown to be effective in SCID mice transplanted with human
lymphocyte-activated killer cells. These results demonstrate the
importance of directing this potent cytokine to the tumor
microenvironment and suggest an important alternative to systemic IL-12
administration or gene therapy for increasing its therapeutic index.
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