P1.10 - A fully human anti-oxMIF antibody penetrates colorectal cancer metastases and accumulates in cancer tissue

Abstract

ABSTRACT Background: Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine known to exacerbate tumor growth. MIF expression correlates with tumor aggressiveness and metastatic potential. We discovered a novel, conformational isoform of MIF, which we designated “oxMIF” because it can be mimicked in vitro by mild oxidation of recombinant MIF. We found oxMIF expressed in pancreatic ductal adenocarcinoma (PDAC) tissue (stage I, II and III disease), as well as in tissue from colorectal carcinoma (CRC) and lung cancer. OxMIF was, in general, not detected in healthy control tissue. A new class of fully human monoclonal antibodies (mAbs) specifically targeting oxMIF demonstrated efficacy in vivo and inhibited tumor signaling pathways associated with tumor proliferation and progression in vitro. Material and Methods: We developed immunohistochemistry (IHC) methods that allow the detection of oxMIF in human and animal-derived tissue. Results: In a murine genetic model of PDAC, intravenously injected I131-labelled anti-oxMIF mAbs accumulated in the pancreas (primary tumor site), as well as in liver and lung (sites of metastasis). Subsequently, we investigated the biodistribution of anti-oxMIF mAbs in more detail using a syngeneic mouse model of chronic lymphocytic leukemia (eµ-myc CLL model): IHC analysis of lymph nodes from mAb-treated mice confirmed co-localization of oxMIF and anti-oxMIF mAbs in cancerous tissue. Finally, we applied our IHC methods to assess tissue penetration of anti-oxMIF mAb in liver metastases from patients with late-stage colorectal cancer participating in a phase 1 clinical study (ClinicalTrials.gov identifier: NCT01765790). We demonstrated that the antibody was able (i) to penetrate metastases, (ii) to co-localize with oxMIF in tumor cells and in stromal tissue and (iii) to accumulate during the course of treatment. While accumulating in tumor tissue, the antibody was cleared from the plasma with a half-life (half plasma steady-state concentration) of approximately 7 days. Conclusion: Treatment with fully human anti-oxMIF mAbs enables targeting of oxMIF in metastases of patients with CRC. We suggest that oxMIF reflects a compelling new therapeutic target in solid tumors and a tissue biomarker with diagnostic and prognostic value.