The antibody-based delivery of interleukin-12 to the tumor neo-vasculature eradicates cancer in combination with paclitaxel
Menée in vitro et à l'aide de trois modèles murins, cette étude évalue l'activité antitumorale d'une nouvelle immunocytokine, formée par un anticorps et l'interleukine 12, en combinaison avec du paclitaxel
Résumé en anglais
Purpose:Interleukin-12 (IL12) is a potent proinflammatory cytokine with antitumor activity. Its heterodimeric nature makes it compatible with a large variety of different immunocytokine formats. Here we report the design, production and characterization of a novel immunocytokine, based on the fusion of the F8 antibody (specific to the alternatively spliced EDA domain of fibronectin, a marker of tumor neo-vasculature) with IL12 (termed IL12-F8-F8). Experimental Design:We developed a novel immunocytokine based on the sequential fusion of interleukin-12 as a single polypeptide with two F8 antibodies in single-chain Fv (scFv) format. The fusion protein was characterized in vitro and its targeting performance was assessed in vivo. The immunocytokine antitumor activity was studied as monotherapy as well as in combination therapies in three different murine tumor models. Moreover, depletion experiments and tumor analysis revealed a dominant role of NK cells for the mechanism of action Results:IL12-F8-F8 can be produced in mammalian cells, yielding a product of good pharmaceutical quality, capable of selective localization on the tumor neo-vasculature in vivo, as judged by quantitative biodistribution analysis with radioiodinated protein preparations. The protein potently inhibited tumor growth in three different immunocompetent syngeneic models of cancer. The treatment was generally well tolerated. Moreover, the IL12-F8-F8 fusion protein could be produced both with murine interleukin-12 (mIL12) and with human interleukin-12 (hIL12). Conclusions:The potent antitumor activity of mIL12-F8-F8, studied alone or in combination with paclitaxel in different tumor models, paves the way to the clinical development of the fully human immunocytokine.
