Abstract 2654: Human antibodies specific for oxidized macrophage migration inhibitory factor (oxMIF) synergize with chemotherapeutic agents in animal models of cancer

Abstract

Abstract Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with pleiotropic biologic effects and is pathologically associated with several types of cancer. oxMIF is an immunological and conformational distinct isoform of MIF that can be mimicked in vitro by mild oxidation of recombinant MIF. Fully human monoclonal antibodies that specifically target oxMIF were shown to inhibit downstream signaling pathways associated with tumor proliferation and progression in vitro and in vivo. We assessed the potential of anti-oxMIF antibodies combined with standard chemotherapeutic agents on the proliferation of cancer cell lines in vitro and in vivo in xenograft models. In vitro, anti-oxMIF sensitization of the prostate cancer cell lines PC3 or LnCAP significantly reduced the half maximal effective concentration (EC50) of mitoxantrone by 30% and 40%, respectively. In the ovarian cancer cell lines A2780, EC50 of cisplatin was reduced by 70% after sensitization with anti-oxMIF. In vivo, mice bearing pancreatic cancer xenografts (COLO357, BxPC3 or MiaPaCa2) treated with anti-oxMIF in combination with gemcitabine had a strong survival advantage compared with mice treated with either monotherapy. This effect was accompanied by a decrease of tumor volumes up to 70% and an increase in the expression of caspase 3 in mice bearing COLO357 xenografts. In addition, combining gemcitabine with anti-oxMIF treatment normalized blood vessel density inside the tumors, decreased their permeability by 25%, and decreased tumor VEGF levels by 40%, whereas gemcitabine alone had the opposite effect. In mice bearing the ovarian human cancer cell line A2780 xenografts, combining anti-oxMIF antibodies with cisplatin led to a 45% reduction of tumor weights. Anti-oxMIF specific antibodies decreased proliferation, angiogenesis and inflammation inside tumor xenografts, but were not cytotoxic (no antibody-dependent cell cytotoxicity or complement-dependent cytotoxicity). These experiments demonstrated synergistic effects between anti-oxMIF antibodies and cytotoxic chemotherapy. Combination treatments were superior to the corresponding monotherapies and led to a stronger inhibition of tumor growth and angiogenesis. A phase 1 clinical study of a novel human antibody that selectively targets oxMIF is currently ongoing in patients with solid malignancies (ClinicalTrials.gov identifier: NCT01765790). Citation Format: Patrice Douillard, Thorsten Hagemann, Michael Freissmuth, Michael Thiele, Alexander Schinagl, Dirk Völkel, Friedrich Scheiflinger, Randolf Kerschbaumer. Human antibodies specific for oxidized macrophage migration inhibitory factor (oxMIF) synergize with chemotherapeutic agents in animal models of cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2654. doi:10.1158/1538-7445.AM2014-2654