In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 2475-2475
Abstract:
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, disease-related conformational isoform of MIF which we have designated “oxMIF” because it can be mimicked in vitro by mild oxidation of recombinant MIF. A new class of fully human monoclonal antibodies (mAbs) specifically targeting oxMIF demonstrated efficacy in vivo and inhibited signaling pathways associated with tumor proliferation and progression in vitro. By developing novel immunohistochemistry (IHC) methods we were able to differentially detect oxMIF and to determine biodistribution of human anti-oxMIF mAbs in human and animal-derived tissue. First, we observed by IHC that in human pancreatic ductal adenocarcinoma (PDAC) tissue, oxMIF is specifically expressed in tumor cells and in tumor stroma within pancreatic intraepithelial lesions. In contrast, we could not detect oxMIF in healthy control tissue, whereas MIF (sum of oxMIF and its reduced isoform) was abundantly expressed in both, tissue from PDAC patients and tissue from healthy subjects. Then, in a murine genetic model of PDAC, we assessed the biodistribution of anti-oxMIF mAbs: intravenously injected I131-labelled anti-oxMIF mAbs significantly 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 the tissue penetration of anti-oxMIF mAb in liver metastases from late stage colorectal cancer patients (Ph 1 clinical study; ClinicalTrials.gov identifier: NCT01765790): we demonstrated that the antibody was able to penetrate metastases and to accumulate in tumor cells and in stromal tissue during the course of treatment. Our previous and current studies clearly demonstrate that oxMIF is a disease-related isoform of MIF that can be detected in malignant tissue and that treatment with fully human anti-oxMIF mAbs enables neutralization of oxMIF in tumor tissue. We therefore suggest that oxMIF reflects a potent new therapeutic target in solid tumors with diagnostic and prognostic value. A phase 1 clinical study of a novel fully human anti-oxMIF mAb is currently ongoing in patients with solid malignancies (ClinicalTrials.gov identifier: NCT01765790). Citation Format: Alexander Schinagl, Michael Thiele, Patrice Douillard, Deyaa Adib, Xiaochun Liu, Salim Yazji, Friedrich Scheiflinger, Randolf Kerschbaumer. A novel class of fully human monoclonal anti-oxMIF antibodies penetrates metastases and accumulates in tumor tissue. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2475. doi:10.1158/1538-7445.AM2015-2475
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2015-2475
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2015
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2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
