PD-011 Safety and efficacy analysis of imalumab, an anti-oxidized macrophage migration inhibitory factor (oxMIF) antibody, alone or in combination with 5-fluorouracil/leucovorin (5-FU/LV) or panitumumab, in patients with metastatic colorectal cancer (mCRC)

Mahalingam, Devalingam; Patel, Manish R.; Sachdev, Jasgit C.; Hart, Lowell L.; Halama, Niels; Ramanathan, Ramesh K.; Sarantopoulos, John; Liu, X.; Yazji, S.; Jäger, Dirk; Adib, Deyaa; Kerschbaumer, Randolf J.; Yoon, Mi-jung; Manzur, G.Ç.; Starodub, Alexander; Sivarajan, K.; Wertheim, M. S.; Thambi, Paul; Jones, Michael; Goel, Sanjay; Nemunaitis, John; Tsimberidou, A.

doi:10.1093/annonc/mdw200.11

Cited by 17 publications

(12 citation statements)

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“…Since MIF has been directly implicated in the regulation of endothelial differentiation [84], we believe that MIF as a tumor promoter proves again that monocytes-derived ECs can be a subpopulation of M2-TAMs, reaching the tumor to favor angiogenesis by also making part of the blood vessel structures. Interestingly, an oxidized isoform of MIF was identified as a prognostic biomarker and therapeutic target in inflammatory disease and cancer [85,86], showing again that the pro-oxidative tumor microenvironment is playing a role in angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Monocytes as Endothelial Progenitor Cells (EPCs), Another Brick in the Wall to Disentangle Tumor Angiogenesis

Lopes‐Coelho

Silva

Gouveia-Fernandes

et al. 2020

Cells

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Bone marrow contains endothelial progenitor cells (EPCs) that, upon pro-angiogenic stimuli, migrate and differentiate into endothelial cells (ECs) and contribute to re-endothelialization and neo-vascularization. There are currently no reliable markers to characterize EPCs, leading to their inaccurate identification. In the past, we showed that, in a panel of tumors, some cells on the vessel wall co-expressed CD14 (monocytic marker) and CD31 (EC marker), indicating a putative differentiation route of monocytes into ECs. Herein, we disclosed monocytes as potential EPCs, using in vitro and in vivo models, and also addressed the cancer context. Monocytes acquired the capacity to express ECs markers and were able to be incorporated into blood vessels, contributing to cancer progression, by being incorporated in tumor neo-vasculature. Reactive oxygen species (ROS) push monocytes to EC differentiation, and this phenotype is reverted by cysteine (a scavenger and precursor of glutathione), which indicates that angiogenesis is controlled by the interplay between the oxidative stress and the scavenging capacity of the tumor microenvironment.Over the last decade, different studies reported EPCs as essential in restoring injured vessels. EPCs belong to a subset of cells, arising from hematopoietic stem cells in bone marrow; upon pro-angiogenic stimuli, they proliferate, migrate, and differentiate into endothelial cells (ECs) [4][5][6]. Some reports addressing EPCs and disease, such as systemic sclerosis, showed contradictory and discrepant results about EPCs mobilization and differentiation; in part, because there is a lack of a precise panel of cell surface markers used for the characterization of this subset of cells [4][5][6][7][8][9][10]. In mouse embryonic vascular endothelium, erythro-myeloid progenitors (EMPs) can differentiate into ECs [11] and in a mouse model of carotid injury, monocytes (CD14 + cells) are capable of improving re-endothelialization [12]. In vivo and in vitro targeting of Tie2-monocytes decreases angiogenesis by abrogating EC proliferation [13][14][15] and an in vivo CCR2 (chemokine (C-C motif) receptor 2) knockout impairs monocytes recruitment and VEGFA (also named VEGF, vascular endothelial growth factor) expression, accompanied by a reduction in the angiogenesis rate [16]. The release of cytokines and pro-angiogenic factors (e.g., VEGFA, VEGFC, and VEGFD, TNFα (tumor necrosis factor α), IL-8 (interleukin-8), and FGF-2 (fibroblast growth factor-2), and extracellular matrix (ECM) modifying proteins (e.g., metalloproteinase-9 (MMP-9)) by macrophages enhances the tissue's ability to support capillary sprouting and vascular density [17,18]. The precise mechanism by which monocytes influence angiogenesis in tissue development, homeostasis, and diseases is not fully understood. However, different studies, have shown that under in vitro pro-angiogenic pressure, blood mononuclear cells can acquire endothelial markers and morphology [19][20][21]. In addition, in a previous study, we showed that some ECs sim...

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Section: Discussionmentioning

confidence: 99%

Monocytes as Endothelial Progenitor Cells (EPCs), Another Brick in the Wall to Disentangle Tumor Angiogenesis

Lopes‐Coelho

Silva

Gouveia-Fernandes

et al. 2020

Cells

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“…96 From the existing anti-MIF antibodies successfully tested in pre-clinical inflammation, cancer and atherosclerosis models, only the MIF antibody imalumab has so far advanced into phase 1/2a clinical trials (NCT01765790) against colorectal cancer and lupus nephritis. 97 Imalumab has an anti-inflammatory capacity as it reduces circulating TNF-α, monocyte chemoattractant protein-1 and IL-6, and attenuates disease progression in mouse models of glomerulonephritis and cancer. Based on biochemical and immunochemical experiments, it was suggested that this antibody recognizes an oxidized form of MIF with the oxidoreductase motif of MIF trapped in an oxidized state, and that Cys-81 serves as a molecular redox switch between the latent reduced form of MIF and its oxidized state.…”

Section: Antibody-based Anti-mif Strategiesmentioning

confidence: 99%

Macrophage Migration Inhibitory Factor (MIF)-Based Therapeutic Concepts in Atherosclerosis and Inflammation

et al. 2019

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Chemokines orchestrate leukocyte recruitment in atherosclerosis and their blockade is a promising anti-atherosclerotic strategy, but few chemokine-based approaches have advanced into clinical trials, in part owing to the complexity and redundancy of the chemokine network. Macrophage migration inhibitory factor (MIF) is a pivotal mediator of atherosclerotic lesion formation. It has been characterized as an inflammatory cytokine and atypical chemokine that promotes atherogenic leukocyte recruitment and lesional inflammation through interactions with the chemokine receptors CXCR2 and CXCR4, but also exhibits phase-specific CD74-mediated cardioprotective activity. The unique structural properties of MIF and its homologue MIF-2/D-DT offer intriguing therapeutic opportunities including small molecule-, antibody- and peptide-based approaches that may hold promise as inhibitors of atherosclerosis, while sparing tissue-protective classical chemokine pathways. In this review, we summarize the pros and cons of anti-MIF protein strategies and discuss their molecular characteristics and receptor specificities with a focus on cardiovascular disease.

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“…Here, we provided evidence that MIF is highly expressed in BLEL of the lacrimal gland, which combined with the strong correlation previously revealed between MIF and D-DT concentration [ 58 ] suggest that, like MIF, D-DT may also be overexpressed in BLEL and should be in future, considered for further examination in the pathogenesis of BLEL. Recently, Phase I and Phase II studies have been carried out with specific MIF monoclonal antibodies in patients with cancer and systemic lupus erythematosus (SLE) [ 89 – 92 ], and can also be tested in patients with BLEL.…”

Section: Discussionmentioning

confidence: 99%

Macrophage migration inhibitory factor contributes to the pathogenesis of benign lymphoepithelial lesion of the lacrimal gland

Adzavon

Zhao

et al. 2018

Cell Commun Signal

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BackgroundBenign Lymphoepithelial Lesion (BLEL) is a rare disease observed in the adult population. Despite the growing numbers of people suffering from BLEL, the etiology and mechanisms underlying its pathogenesis remain unknown.MethodsIn the present study, we used gene and cytokines expression profiling, western blot and immunohistochemistry to get further insight into the cellular and molecular mechanisms involved in the pathogenesis of BLEL of the lacrimal gland.ResultsThe results showed that Macrophage Migration Inhibitory Factor (MIF) was the most highly expressed cytokine in BLEL, and its expression positively correlated with the expression of Th2 and Th17 cells cytokines. MIF was found to regulate biological functions and pathways involved in BLEL pathogenesis, such as proliferation, resistance to apoptosis, MAPK and PI3K/Akt pathways. We also found that MIF promotes fibrosis in BLEL by inducing BLEL fibroblast differentiation into myofibroblasts as well as the synthesis and the deposit of extracellular matrix in BLEL tissues.ConclusionsOur findings demonstrate the contribution of MIF to the pathogenesis of BLEL of the lacrimal gland and suggested MIF as a promising therapeutic target for its treatment.Electronic supplementary materialThe online version of this article (10.1186/s12964-018-0284-4) contains supplementary material, which is available to authorized users.

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PD-011 Safety and efficacy analysis of imalumab, an anti-oxidized macrophage migration inhibitory factor (oxMIF) antibody, alone or in combination with 5-fluorouracil/leucovorin (5-FU/LV) or panitumumab, in patients with metastatic colorectal cancer (mCRC)

Cited by 17 publications

References 0 publications

Monocytes as Endothelial Progenitor Cells (EPCs), Another Brick in the Wall to Disentangle Tumor Angiogenesis

Monocytes as Endothelial Progenitor Cells (EPCs), Another Brick in the Wall to Disentangle Tumor Angiogenesis

Macrophage Migration Inhibitory Factor (MIF)-Based Therapeutic Concepts in Atherosclerosis and Inflammation

Macrophage migration inhibitory factor contributes to the pathogenesis of benign lymphoepithelial lesion of the lacrimal gland

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