Characterization, epitope identification and mechanisms of the anti-septic capacity of monoclonal antibodies against macrophage migration inhibitory factor

Zhang, Yang; Zeng, Xiaogang; Chen, Sha; Zhang, Zhujun; Li, Peng; Yi, Weijing; Huang, Hongtao; Yao, J. L.; Li, Shuhui; Hu, Chuanmin

doi:10.1016/j.intimp.2011.04.017

Cited by 10 publications

(8 citation statements)

References 28 publications

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“…The finding that HuScFv inhibited the tautomerase activity of rMIF to a greater extent than that of native MIF may indicate the presence of other proteins containing the tautomerase activities in U937 cell lysate (2). In vitro neutralization of MIF-mediated enzymatic activity suggested the possibility of using HuScFv to reduce MIF-induced pro-inflammatory reactions, similar to the inhibitors or specific monoclonal antibodies as demonstrated in previous studies (21,43). Experiments on in vivo neutralization tests are required to evaluate anti-inflammatory activities of MIF-specific HuScFv (30).…”

Section: Discussionsupporting

confidence: 61%

Human single-chain variable fragment antibody inhibits macrophage migration inhibitory factor tautomerase activity

Tarasuk

Poungpair

Ungsupravate

et al. 2014

International Journal of Molecular Medicine

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Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine, secreted from a variety of immune cells, that regulates innate and adaptive immune responses. Elevation of MIF levels in plasma correlates with the severity of inflammatory diseases in humans. Inhibition of MIF or its tautomerase activity ameliorates disease severity by reducing inflammatory responses. In this study, the human single-chain variable fragment (HuScFv) antibody specific to MIF was selected from the human antibody phage display library by using purified recombinant full-length human MIF (rMIF) as the target antigen. Monoclonal HuScFv was produced from phage-transformed bacteria and tested for their binding activities to rMIF by indirect enzyme-linked immunosorbent assay as well as to native MIF by western blot analysis and immunofluorescence assay. The HuScFv with highest binding signal to rMIF also inhibited the tautomerase activities of both rMIF and native MIF in human monoblastic leukemia (U937) cells in a dose-dependent manner. Mimotope searching and molecular docking concordantly demonstrated that the HuScFv interacted with Lys32 and Ile64 in the MIF tautomerase active site. To the best of our knowledge, this is the first study to focus on MIF-specific fully-human antibody fragment with a tautomerase-inhibitory effect that has potential to be developed as anti-inflammatory biomolecules for human use.

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Section: Discussionsupporting

confidence: 61%

Human single-chain variable fragment antibody inhibits macrophage migration inhibitory factor tautomerase activity

Tarasuk

Poungpair

Ungsupravate

et al. 2014

International Journal of Molecular Medicine

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“…Whereas several small-molecule inhibitors of the biologic activity of MIF have been documented (65,69,70), to our knowledge, this is the first report to establish that an MIF antagonist, when appropriately engineered, can prevent lethal endotoxemia when administered as a single injection. Although monoclonal/polyclonal anti-MIF Abs were also found to exert protective effects (34,35,71), Nbs have an advantage in that they can be tailored into multifunctional formats as demonstrated herein. This may be particularly relevant given the recent discovery of the second CD74 ligand, MIF-2, which has a spectrum of action that is similar to that of MIF (72).…”

Section: Discussionmentioning

confidence: 90%

Novel half‐life extended anti‐MIF nanobodies protect against endotoxic shock

et al. 2018

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Sepsis-leading to septic shock-is the leading cause of death in intensive care units. The systemic inflammatory response to infection, which is initiated by activated myeloid cells, plays a key role in the lethal outcome. Macrophage migration inhibitory factor (MIF) is an upstream immunoregulatory mediator, released by myeloid cells, that underlies a common genetic susceptibility to different infections and septic shock. Accordingly, strategies that are aimed at inhibiting the action of MIF have therapeutic potential. Here, we report the isolation and characterization of tailorable, small, affinity-matured nanobodies (Nbs; single-domain antigen-binding fragments derived from camelid heavy-chain Abs) directed against MIF. Of importance, these bioengineered Nbs bind both human and mouse MIFs with nanomolar affinity. NbE5 and NbE10 inhibit key MIF functions that can exacerbate septic shock, such as the tautomerase activity of MIF (by blocking catalytic pocket residues that are critical for MIF's conformation and receptor binding), the TNF-inducing potential, and the ability of MIF to antagonize glucocorticoid action. A lead NbE10, tailored to be a multivalent, half-life extended construct (NbE10-NbAlb8-NbE10), attenuated lethality in murine endotoxemia when administered via single injection, either prophylactically or therapeutically. Hence, Nbs, with their structural and pharmacologic advantages over currently available inhibitors, may be an effective, novel approach to interfere with the action of MIF in septic shock and other conditions of inflammatory end-organ damage.-Sparkes, A., De Baetselier, P., Brys, L., Cabrito, I., Sterckx, Y. G.-J., Schoonooghe, S., Muyldermans, S., Raes, G., Bucala, R., Vanlandschoot, P., Van Ginderachter, J. A., Stijlemans, B. Novel half-life extended anti-MIF nanobodies protect against endotoxic shock.

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“…14,16,18,19,37,95 The epitope recognized by NIH/IIID.9 has not been characterized, but it has been suggested that it recognizes a solvent-exposed region of MIF in the middle part of the sequence, 95 similar to mAb clone 1C10 (Bernhagen et al, unpublished), but unlike clone F11, which blocks cecal ligation and puncture-induced sepsis and is directed against the Nterminal of murine MIF. 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.…”

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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Characterization, epitope identification and mechanisms of the anti-septic capacity of monoclonal antibodies against macrophage migration inhibitory factor

Cited by 10 publications

References 28 publications

Human single-chain variable fragment antibody inhibits macrophage migration inhibitory factor tautomerase activity

Human single-chain variable fragment antibody inhibits macrophage migration inhibitory factor tautomerase activity

Novel half‐life extended anti‐MIF nanobodies protect against endotoxic shock

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

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