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1.
Br J Clin Pharmacol ; 86(9): 1836-1848, 2020 09.
Article in English | MEDLINE | ID: mdl-32207164

ABSTRACT

AIM: Preclinical evidence suggests that oxidized macrophage migration inhibitory factor (oxMIF) may be involved in carcinogenesis. This phase 1 study (NCT01765790) assessed the safety, tolerability, pharmacokinetics and antitumour activity of imalumab, an oxMIF inhibitor, in patients with advanced cancer using '3 + 3' dose escalation. METHODS: In Schedule 1, patients with solid tumours received doses from 1 to 50 mg/kg IV every 2 weeks. In Schedule 2, patients with metastatic colorectal adenocarcinoma, non-small-cell lung, or ovarian cancer received weekly doses of 10 or 25 mg/kg IV (1 cycle = 28 days). Treatment continued until disease progression, unacceptable toxicity, dose-limiting toxicity, or withdrawal of consent. RESULTS: Fifty of 68 enrolled patients received imalumab. The most common treatment-related adverse events (TRAEs) included fatigue (10%) and vomiting (6%); four grade 3 serious TRAEs (two patients) occurred. The dose-limiting toxicity was allergic alveolitis (one patient, 50 mg/kg every 2 weeks). The maximum tolerated and biologically active doses were 37.5 mg/kg every 2 weeks and 10 mg/kg weekly, respectively. Of 39 assessed patients, 13 had stable disease (≥4 months in 8 patients). CONCLUSIONS: Imalumab had a maximum tolerated dose of 37.5 mg/kg every 2 weeks in patients with advanced solid tumours, with a biologically active dose of 10 mg/kg weekly. Further investigation will help define the role of oxMIF as a cancer treatment target.


Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Macrophage Migration-Inhibitory Factors , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Female , Humans , Lung Neoplasms/drug therapy , Macrophage Migration-Inhibitory Factors/therapeutic use , Male , Maximum Tolerated Dose , Neoplasms/drug therapy , Treatment Outcome
2.
Oncotarget ; 7(45): 73486-73496, 2016 11 08.
Article in English | MEDLINE | ID: mdl-27636991

ABSTRACT

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine, which was shown to be upregulated in cancers and to exhibit tumor promoting properties. Unlike other cytokines, MIF is ubiquitously present in the circulation and tissue of healthy subjects. We recently described a previously unrecognized, disease-related isoform of MIF, designated oxMIF, which is present in the circulation of patients with different inflammatory diseases. In this article, we report that oxMIF is also linked to different solid tumors as it is specifically expressed in tumor tissue from patients with colorectal, pancreatic, ovarian and lung cancer. Furthermore, oxMIF can be specifically targeted by a subset of phage display-derived fully human, monoclonal anti-MIF antibodies (mAbs) that were shown to neutralize pro-tumorigenic activities of MIF in vivo. We further demonstrate that anti-oxMIF mAbs sensitize human cancer cell lines (LNCaP, PC3, A2780 and A2780ADR) to the action of cytotoxic drugs (mitoxantrone, cisplatin and doxorubicin) in vitro and in an A2780 xenograft mouse model of ovarian cancer. We conclude that oxMIF is the disease related isoform of MIF in solid tumors and a potential new diagnostic marker and drug target in cancer.


Subject(s)
Biomarkers, Tumor , Macrophage Migration-Inhibitory Factors/metabolism , Neoplasms/metabolism , Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology , Case-Control Studies , Cell Line, Tumor , Drug Synergism , Humans , Macrophage Migration-Inhibitory Factors/antagonists & inhibitors , Macrophage Migration-Inhibitory Factors/blood , Molecular Targeted Therapy , Neoplasms/blood , Neoplasms/drug therapy , Neoplasms/pathology , Oxidation-Reduction
3.
J Immunol ; 195(5): 2343-52, 2015 Sep 01.
Article in English | MEDLINE | ID: mdl-26209628

ABSTRACT

Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine and counterregulator of glucocorticoids, is a potential therapeutic target. MIF is markedly different from other cytokines because it is constitutively expressed, stored in the cytoplasm, and present in the circulation of healthy subjects. Thus, the concept of targeting MIF for therapeutic intervention is challenging because of the need to neutralize a ubiquitous protein. In this article, we report that MIF occurs in two redox-dependent conformational isoforms. We show that one of the two isoforms of MIF, that is, oxidized MIF (oxMIF), is specifically recognized by three mAbs directed against MIF. Surprisingly, oxMIF is selectively expressed in the plasma and on the cell surface of immune cells of patients with different inflammatory diseases. In patients with acute infections or chronic inflammation, oxMIF expression correlated with inflammatory flare-ups. In addition, anti-oxMIF mAbs alleviated disease severity in mouse models of acute and chronic enterocolitis and improved, in synergy with glucocorticoids, renal function in a rat model of crescentic glomerulonephritis. We conclude that oxMIF represents the disease-related isoform of MIF; oxMIF is therefore a new diagnostic marker for inflammation and a relevant target for anti-inflammatory therapy.


Subject(s)
Inflammation/immunology , Inflammation/prevention & control , Macrophage Migration-Inhibitory Factors/immunology , Molecular Targeted Therapy/methods , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Blotting, Western , Dexamethasone/immunology , Dexamethasone/therapeutic use , Disease Models, Animal , Enterocolitis/immunology , Enterocolitis/metabolism , Enterocolitis/prevention & control , Flow Cytometry , Glomerulonephritis/immunology , Glomerulonephritis/metabolism , Glomerulonephritis/prevention & control , Glucocorticoids/immunology , Glucocorticoids/therapeutic use , Humans , Inflammation/metabolism , Macrophage Migration-Inhibitory Factors/chemistry , Macrophage Migration-Inhibitory Factors/metabolism , Male , Mice, Inbred C57BL , Mice, Knockout , Oxidation-Reduction , Protein Conformation , Protein Isoforms/chemistry , Protein Isoforms/immunology , Protein Isoforms/metabolism , Rabbits , Rats, Inbred WKY
4.
Mol Cancer Ther ; 12(7): 1223-34, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23619302

ABSTRACT

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine, originally discovered for its eponymous effect and now known for pleiotropic biologic properties in immunology and oncology. Circulating MIF levels are elevated in several types of human cancer including prostate cancer. MIF is released presumably by both stromal and tumor cells and enhances malignant growth and metastasis by diverse mechanisms, such as stimulating tumor cell proliferation, suppressing apoptotic death, facilitating invasion of the extracellular matrix, and promoting angiogenesis. Recently described fully human anti-MIF antibodies were tested in vitro and in vivo for their ability to influence growth rate and invasion of the human PC3 prostate cancer cell line. In vitro, the selected candidate antibodies BaxG03, BaxB01, and BaxM159 reduced cell growth and viability by inhibiting MIF-induced phosphorylation of the central kinases p44/42 mitogen-activated protein kinase [extracellular signal-regulated kinase-1 and -2 (ERK1/2)] and protein kinase B (AKT). Incubation of cells in the presence of the antibodies also promoted activation of caspase-3/7. The antibodies furthermore inhibited MIF-promoted invasion and chemotaxis as transmigration through Matrigel along a MIF gradient was impaired. In vivo, pharmacokinetic parameters (half-life, volume of distribution, and bioavailability) of the antibodies were determined and a proof-of-concept was obtained in a PC3-xenograft mouse model. Treatment with human anti-MIF antibodies blunted xenograft tumor growth in a dose-dependent manner. We therefore conclude that the anti-MIF antibodies described neutralize some of the key tumor-promoting activities of MIF and thus limit tumor growth in vivo.


Subject(s)
Antibodies, Monoclonal/pharmacology , Cell Movement/drug effects , Macrophage Migration-Inhibitory Factors/immunology , Prostatic Neoplasms/drug therapy , Animals , Antibodies, Monoclonal/immunology , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Models, Animal , Humans , Male , Mice , Mice, Nude , Prostatic Neoplasms/immunology , Prostatic Neoplasms/pathology , Signal Transduction , Xenograft Model Antitumor Assays
5.
J Biol Chem ; 287(10): 7446-55, 2012 Mar 02.
Article in English | MEDLINE | ID: mdl-22238348

ABSTRACT

The macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that recently emerged as an attractive therapeutic target for a variety of diseases. A diverse panel of fully human anti-MIF antibodies was generated by selection from a phage display library and extensively analyzed in vitro. Epitope mapping studies identified antibodies specific for linear as well as structural epitopes. Experimental animal studies revealed that only those antibodies binding epitopes within amino acids 50-68 or 86-102 of the MIF molecule exerted protective effects in models of sepsis or contact hypersensitivity. Within the MIF protein, these two binding regions form a ß-sheet structure that includes the MIF oxidoreductase motif. We therefore conclude that this ß-sheet structure is a crucial region for MIF activity and a promising target for anti-MIF antibody therapy.


Subject(s)
Antibodies, Monoclonal/chemistry , Antibodies, Neutralizing/chemistry , Intramolecular Oxidoreductases/chemistry , Macrophage Migration-Inhibitory Factors/chemistry , Amino Acid Motifs , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/therapeutic use , Dermatitis, Contact/drug therapy , Dermatitis, Contact/immunology , Disease Models, Animal , Humans , Intramolecular Oxidoreductases/immunology , Macrophage Migration-Inhibitory Factors/immunology , Mice , Sepsis/drug therapy , Sepsis/immunology
6.
Inflammation ; 28(4): 221-9, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15673164

ABSTRACT

To compare the functional activity of native HMGB1 proteins from eukaryotic sources with HMGB1 from prokaryotic sources the cDNAs of human and murine HMGB1 were cloned and the proteins expressed in bacteria. Tissue-derived HMGB1 from calf thymus and HMGB1 secreted from Chinese hamster ovary (CHO) cells were purified. Human whole blood, THP-1 cells, and NIH/3T3 cells were exposed to HMGB1 proteins and the induction of tumor necrosis factor-alpha (TNF-alpha) release in whole blood and monocytic THP-1 cells and a proliferation assay in NIH/3T3 cells were used to study functional activity of HMGB1s in vitro. Native and recombinant HMGB1s induced TNF-alpha release in human blood and in THP-1 cells dose-dependently, but recombinant HMGB1s were more effective. Cell proliferation was induced by native and recombinant HMGB1s. The native HMGB1 proteins from eukaryotic sources exert the same (though less pronounced) biological activity in vitro as recombinant HMGB1 proteins from prokaryotic sources.


Subject(s)
HMGB1 Protein/physiology , Recombinant Proteins/pharmacology , Amino Acid Sequence , Animals , CHO Cells , Cattle , Cell Line, Tumor , Cell Proliferation , Cricetinae , Genetic Vectors , HMGB1 Protein/antagonists & inhibitors , HMGB1 Protein/isolation & purification , Humans , Mice , Molecular Sequence Data , NIH 3T3 Cells , Pyruvates/pharmacology , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/isolation & purification , Recombinant Fusion Proteins/pharmacology , Recombinant Proteins/genetics , Recombinant Proteins/isolation & purification , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolism
7.
Transfusion ; 43(12): 1677-82, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14641863

ABSTRACT

BACKGROUND: Transmissible spongiform encephalopathy (TSE) represents a spectrum of diseases affecting humans and animals. A definitive diagnosis of TSEs is only possible by postmortem identification of pathologic prion protein in brain tissue that has been treated with protease. The pathologic protein is detected by Western blot analysis or ELISA methods. The bovine spongiform encephalopathy crisis and occurrence of a new variant of CJD has increased demand for rapid and simple assays. STUDY DESIGN AND METHODS: A dipstick assay has been developed for prion diagnosis based on a sandwich ELISA specific for prion protein, and crystalline bacterial cell-surface layers (S-layers) were used as an immobilization matrix. The usefulness of the dipstick assay was evaluated by determining the detection limit, comparison with other methods, and analysis of CJD samples. RESULTS: The sensitivity of the prion dipsticks was similar to that published for time-resolved fluorescence ELISA methods. After protease treatment, pathologic prion protein could be detected specifically. CONCLUSION: The dipstick assay is a sensitive and specific test useful for the detection of prion protein. The simplicity of the S-layer dipstick lends itself to a variety of potential applications including field diagnostics.


Subject(s)
Antigens, Bacterial , Creutzfeldt-Jakob Syndrome/pathology , Enzyme-Linked Immunosorbent Assay/methods , Prions/analysis , Antigens, Bacterial/immunology , Bacterial Outer Membrane Proteins/immunology , Blotting, Western , Brain/pathology , Crystallization , Endopeptidase K , Epitopes , Humans , Prions/immunology , Prions/isolation & purification , Reagent Kits, Diagnostic , Sensitivity and Specificity
9.
Blood ; 100(10): 3626-32, 2002 Nov 15.
Article in English | MEDLINE | ID: mdl-12393399

ABSTRACT

Deficient von Willebrand factor (VWF) degradation has been associated with thrombotic thrombocytopenic purpura (TTP). In hereditary TTP, the specific VWF-cleaving protease (VWF-cp) is absent or functionally defective, whereas in the nonfamilial, acquired form of TTP, an autoantibody inhibiting VWF-cp activity is found transiently in most patients. The gene encoding for VWF-cp has recently been identified as a member of the metalloprotease family and designated ADAMTS13, but the functional activity of the ADAMTS13 gene product has not been verified. To establish the functional activity of recombinant VWF-cp, we cloned the complete cDNA sequence in a eukaryotic expression vector and transiently expressed the encoded recombinant ADAMTS13 in HEK 293 cells. The expressed protein degraded VWF multimers and proteolytically cleaved VWF to the same fragments as those generated by plasma VWF-cp. Furthermore, recombinant ADAMTS13-mediated degradation of VWF multimers was entirely inhibited in the presence of plasma from a patient with acquired TTP. These data show that ADAMTS13 is responsible for the physiologic proteolytic degradation of VWF multimers.


Subject(s)
Cloning, Molecular , Metalloendopeptidases/genetics , ADAM Proteins , ADAMTS13 Protein , DNA, Complementary , Dimerization , Humans , Metalloendopeptidases/biosynthesis , Metalloendopeptidases/metabolism , Peptide Fragments/analysis , Purpura, Thrombotic Thrombocytopenic/enzymology , RNA, Messenger/metabolism , Recombinant Proteins/biosynthesis , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Tissue Distribution , von Willebrand Factor/metabolism
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