Abstract A153: Imalumab, a first-in-class anti-oxidized macrophage migration inhibitory factor (oxMIF) antibody penetrates tumor tissues and shows antitumor activity in patients

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 disease related conformational isoform of MIF, which we designated “oxMIF” because it can be mimicked in vitro by mild oxidation of recombinant MIF (Thiele et al., 2015, J. Immunol.). We found oxMIF expressed in different types of cancer tissue but not in healthy control tissues. A new class of fully human monoclonal antibodies specifically targeting oxMIF (Kerschbaumer et al., 2012, J. Biol. Chem) demonstrated efficacy in vivo and inhibited tumor signaling pathways associated with tumor proliferation and progression in vitro (Hussain et al., 2013, Mol. Cancer Ther.). Imalumab is Baxalta's lead candidate anti-oxMIF antibody which is currently tested in a phase I clinical trial (ClinicalTrials.gov identifier: NCT01765790). Methods: Biodistribution of anti-oxMIF antibodies was assessed (i) in a murine genetic model of pancreatic cancer and (ii) in biopsies from phase 1 late stage patients with metastatic colorectal cancer (mCRC) who did receive imalumab intravenously (28-days cycles; 4 dose schedules) once weekly. Pre- and on-therapy tumor biopsies of CRC liver metastases from these treated patients were analyzed for antibody tissue penetration using newly developed immunohistochemistry (IHC) methods; in parallel biopsies were also analyzed for phosphoproteins and cytokines/chemokines content by multiplex. Results: In a murine genetic model of pancreatic cancer, intravenously injected I131-labelled anti-oxMIF antibody accumulated in the pancreas (primary tumor site), as well as in liver and lung (sites of metastasis). Analysis of biopsies from phase 1 patients with late stage mCRC revealed similar results as imalumab 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. In parallel, analysis of intratumoral phosphoproteins and cytokines showed that imalumab down regulates tumorigenic and pro-inflammatory signals (e.g. Akt, MEK, MAPK, Btk) and pro-inflammatory cytokines (e.g. TNF-α and TNF-β) while up-regulating anti-inflammatory cytokines like IL-1ra and IL-10. Conclusion: Imalumab shows single agent antitumor activity in heavily pretreated patients with mCRC. These observations are in line with in vitro and animal studies using anti-oxMIF antibodies (Hussain et al., 2013, Mol. Cancer Ther.) and literature data on MIF tumorigenic functions. Based on these data, a 10 mg/kg dose has been recommended for a phase 2a study of imalumab in combination with 5-FU/Leucovorin or Panitumumab versus standard of care treatment in subjects with mCRC. Patient recruitment for this study is currently ongoing (ClinicalTrials.gov Identifier: NCT02448810) Citation Format: Patrice Douillard, Michael Thiele, Alexander Schinagl, Niels Halama, Dirk Jaeger, Salim Yazji, Friedrich Scheiflinger, Randolf Kerschbaumer. Imalumab, a first-in-class anti-oxidized macrophage migration inhibitory factor (oxMIF) antibody penetrates tumor tissues and shows antitumor activity in patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A153.

Oxidized MIF is an Alzheimer’s Disease drug target relaying external risk factors to tau pathology

“…A phase 1 study of one of these antibodies, imalumab, in patients with solid tumors have been published (Mahalingam et al, 2020). However, in the absence of follow up publications, earlier clinical studies on imalumab in antitumor therapy seem to have been abandoned (Douillard et al, 2015) and thus the clinical usefulness of oxMIF-specific antibody therapy remains, as opposed to, for example the class of compounds presented here, to be demonstrated.…”