WO2002079517A1 - Methods and compositions for using mhc class ii invariant chain polypeptide as a receptor for macrophage migration inhibitory factor - Google Patents

Methods and compositions for using mhc class ii invariant chain polypeptide as a receptor for macrophage migration inhibitory factor Download PDF

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Publication number
WO2002079517A1
WO2002079517A1 PCT/US2002/009580 US0209580W WO02079517A1 WO 2002079517 A1 WO2002079517 A1 WO 2002079517A1 US 0209580 W US0209580 W US 0209580W WO 02079517 A1 WO02079517 A1 WO 02079517A1
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WIPO (PCT)
Prior art keywords
mif
polypeptide
antagonist
fragment
cell
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PCT/US2002/009580
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English (en)
French (fr)
Inventor
Richard J. Bucala
Seamas Donnelly
Lin Leng
Christine N. Metz
Robert Mitchell
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Cytokine Pharmasciences Inc
Picower Institute for Medical Research
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Cytokine Pharmasciences Inc
Picower Institute for Medical Research
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Priority to DE60236921T priority Critical patent/DE60236921D1/de
Priority to AT02725395T priority patent/ATE473294T1/de
Priority to DK02725395.4T priority patent/DK1383919T3/da
Priority to CA2455915A priority patent/CA2455915C/en
Priority to JP2002577925A priority patent/JP4202763B2/ja
Priority to AU2002255961A priority patent/AU2002255961B2/en
Priority to EP02725395A priority patent/EP1383919B1/en
Publication of WO2002079517A1 publication Critical patent/WO2002079517A1/en
Anticipated expiration legal-status Critical
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Definitions

  • MHC class II invariant chain polypeptide, li also known as CD74
  • MIF macrophage migration inhibitory factor
  • Macrophage migration inhibitory factor (MIF)
  • MIF Macrophage migration inhibitory factor
  • MIF has been linked to cancer 32 .
  • MIF is critically involved in the expression of innate and acquired
  • MIF is released by a variety of cell types and is a necessary factor for the
  • MIF -/- mice are highly resistant to endotoxic shock 3 , and immunoneutralization of
  • MIF confers protection against septic shock 25 and a variety of immuno-inflammatory pathologies such as delayed-type hypersensitivity 26 , arthritis 27 , and glomerulonephritis 28 . MIF's actions on cells also show a number of
  • MIF may function as an isomerase 4 .
  • the MHC class Il-associated invariant chain, li (CD74) 10 has been
  • the invention is based in part upon the identification, utilizing expression
  • polypeptide, Ii (or CD74) 10 is a cellular receptor for MIF.
  • MIF binds to the
  • Ii extracellular domain of Ii, a Type II membrane protein, and Ii is required for
  • MIF-induced cell activation and/or phenotypic changes including , for instance,
  • the inventive relationship provides a mechanism for MIF's
  • one aspect of the present invention relates to methods for
  • a biochemical (i.e., acellular) binding assay comprising:
  • MHC class II invariant chain (Ii) polypeptide contacting an MHC class II invariant chain (Ii) polypeptide with MIF in the presence and absence of a test compound, and comparing the binding interaction of
  • an enhancer of MIF binding activity and a compound that negatively modulates the interaction of MIF with the Ii polypeptide is identified as an inhibitor of MIF
  • Enhancers so identified are candidate therapeutic agonists or
  • test compound may reinforce the binding of
  • test compound that competes with MIF for binding to the Ii polypeptide or otherwise inhibits the interaction of the MIF with the Ii polypeptide
  • the la polypeptide comprises the complete la sequence
  • the binding assay may be a cellular binding assay
  • CD74 expressed (either normally or as a consequence of genetic
  • affinity is identified as an enhancer of MIF binding activity and a compound that
  • the cellular assay is a signaling assay, in which the activity
  • the signaling assay is an ERK-1/2 activation assay.
  • Ii polypeptide is identified as an enhancer of MIF signaling activity and a
  • Enhancers so identified are candidate therapeutic agonists or enhancers of MIF,
  • inhibitors so identified are candidate therapeutic antagonists of MIF.
  • the cellular assay is a cellular activity or cell phenotype
  • the activity or phenotype assay is a
  • a test compound that positively modulates the chosen cellular activity A test compound that positively modulates the chosen cellular activity
  • phenotypic change mediated by MIF via interaction with the Ii polypeptide is identified as an enhancer of MIF cellular activity and a compound that negatively
  • Enhancers so identified are candidate therapeutic agonists or enhancers of
  • inhibitors so identified are candidate therapeutic antagonists of MIF.
  • the invention also provides an enhancer of MIF, including an agonist, or an inhibitor, including an antagonist of MIF, identified by any of the methods above.
  • an enhancer of MIF including an agonist, or an inhibitor, including an antagonist of MIF, identified by any of the methods above.
  • One form of such an agonist or antagonist would be an antibody or antigen-binding
  • Anti-CD74 antibodies and
  • CD74-binding fragments thereof are known in the art.
  • antibody may be a monoclonal antibody and also may be a human, humanized or
  • chimeric antibody made by any conventional method.
  • polypeptide which binds MIF and thereby mediates the effect of MIF.
  • the antagonist or inhibitor inhibits, in a first instance, binding of MIF to the Ii polypeptide; in a second instance, signaling initiated by MIF:Ii interaction; and in a third instance, a change in cellular activity, metabolism or phenotype effected by
  • the antagonist or inhibitor may be an
  • inhibitor may be soluble Ii polypeptide or a soluble MIF-binding fragment thereof
  • the cell comprising Ii
  • polypeptide is present in a mammal and the antagonist or other inhibitor is
  • the antagonist or inhibitor is administered in an amount effective to treat the condition or disorder.
  • the mammal may be suffering from cancer or an
  • the antagonist or inhibitor is administered in an amount
  • septic shock may be, for instance, septic shock or arthritis.
  • one aspect of the invention is a method of inhibiting an
  • MIF activity of MIF which method comprises: contacting MIF with an MHC class II
  • fragment of the MHC class II invariant chain (Ii) polypeptide which binds to MIF may be a soluble form of the polypeptide, particularly a soluble form that
  • the MIF to be inhibited is in a mammal and the Ii
  • polypeptide or a fragment thereof is administered to the mammal in a
  • fragment thereof is administered in an amount effective to treat the disorder.
  • the MIF antagonist or inhibitor is administered in an amount
  • the infecting pathogen (whether a virus, bacterial, fungus, or especially, a parasite)
  • Yet another aspect of the invention relates to a method of purifying MIF
  • polypeptide may be immobilized on a solid support matrix.
  • the invention also provides a solid support matrix.
  • MIF:Ii polypeptide fragment complex thereby formed.
  • Still another method provided by the invention is a method for reducing an
  • This method comprises: providing to the cell an antisense nucleic
  • the antisense nucleic acid molecule specifically binds to a
  • the cell comprising the Ii polypeptide may be in a mammal, for instance, a mammal
  • the mammal may be suffering from a cancer
  • the inflammatory disorder such as septic shock or arthritis.
  • the inflammatory disorder such as septic shock or arthritis.
  • antisense nucleic acid is administered in a pharmaceutical composition, in an
  • FIG. 1 illustrates high affinity binding of MIF to THP-1 monocytes.
  • Alexa-MIF shows full retention of dose-dependent MIF biological activity as
  • CM complete medium
  • SFM serum-free medium
  • Alexa-MIF binding was performed in the presence of 1 ⁇ g/ml unlabeled, rMIF
  • THP-1 cells were grown on cover slips, incubated with INF ⁇ (1 ng/ml) for 72 hrs and stained with Alexa-MIF (left panel) or Alexa-MIF plus excess,
  • FIG. 2 show that Ii is a cell surface binding protein for MIF a, Sequential
  • IC, TM, and EC are the intracellular, transmembrane, and extracellular domains.
  • Ml and Ml 7 refer to two sites of alternative translation initiation, c, Flow
  • FIG. 3 illustraes Ii mediation of MIF stimulation of ERK-1/2 (p44/ ⁇ 42) ⁇
  • COS-7 cells were transfected with an Ii vector and stimulated with 50 ng/ml MIF
  • FIG. 4 illustrates western blots of MIF-induced phosphorylation a, MIF
  • Anti-Ii inhibits MIF-induced proliferation of human
  • fibroblasts also. Antibodies were added to a final concentration of 50 ⁇ g/ml. The
  • FIG. 5 shows the complete nucleotide sequence (SEQ ID NO: 1)
  • Alexa-MIF Alexa 488-MIF
  • ERK extracellular-signal-regulated kinase
  • Ii MHC class Il-associated invariant chain (CD74)
  • INF ⁇ interferon- ⁇
  • mAb monoclonal antibody
  • MIF monoclonal antibody
  • MIF binds to the extracellular domain of Ii, a Type II membrane protein, and Ii is
  • IFN ⁇ interferon- ⁇
  • THP-1 monocytes and constructed a mammalian expression library in the lambdaZAP-CMV vector 15 .
  • Library aliquots representing a total of 1.5 x 10 7 recombinants were transfected into COS-7 cells, which we had established
  • Anti-Ii mAb directed against the extracellular portion of the protein.
  • binding epitope was localized to a 40 amino acid region contained within the Ii extracellular domain (FIG. 2D).
  • MIF extends the lifespan of primary murine fibroblasts 8 , and both MIF's
  • Fibroblasts express low levels of
  • Ii is a homotrimer 23
  • the Ii intracellular domain consists of 30-46 amino acids, depending on which of two in-phase
  • initiation codons are utilized 16 .
  • Monocyte-encoded Ii has been shown to enhance T cell proliferative responses, and this accessory function of Ii has been linked to a
  • MIF-bound Ii is a stimulating ligand for CD44-mediated MAP kinase activation.
  • CD44 is a highly polymorphic Type I transmembrane glycoprotein 24 , and CD44 likely mediates some of the downstream consequences of MIF binding to Ii.
  • Agents active in this regard (agonists and antagonists and other inhibitors) have predicted therapeutic utility in diseases and conditions
  • Trojan horse-type vehicles by which to concentrate a desired label or toxin in cells displaying cell surface Ii. Briefly, a desired label or toxic entity is associated
  • invariant chain polypeptide binds to and causes the intemalization of the modified
  • the Ii-displaying cells may be exposed to the modified MIF ligand in
  • Ii-displaying cells may be specifically designed
  • MIF ligand which may be
  • chemotherapeutic drugs such as doxorubicin
  • chelators such as DTP A, to which detectable labels such as fluorescent molecules or cytotoxic agents such as heavy metals or
  • radionuclides can be complexed; and toxins such as Pseudomonas exotoxin, and
  • Human recombinant MIF was purified from an E.coli expression system as
  • homotrimer was 1 :3, as determined by matrix-assisted laser-desorption ionization
  • THP-1 cells (2.5 xlO 5 cells/ml) were cultured in DMEM/10% FBS with or without
  • IFN ⁇ (1 ng/ml, R&D Systems, Minneapolis, MN) for 72 hrs. After washing,
  • transfectants were incubated with Alexa-MIF together with 50 ⁇ g/ml of an anti-Ii
  • THP-1 cells (1 x 10 6 ) were incubated for 45 mins at 4°C in PBS/1%
  • Alexa-MIF or Alexa-MIF plus 50 ng/ ⁇ l unlabeled, rMIF.
  • cDNA was prepared from the poly(A) + RNA of IFN ⁇ -activated, THP-1
  • dextran method 30 The transfected cells were incubated with Alexa-MIF for 45 min
  • Plasmid DNA was extracted from sorted cells using the Easy DNA kit (Invitrogen,
  • T ⁇ T Reticulocyte Lysate system (Promega, Madison WI). The binding of [ 35 S]- labeled Ii to immobilized MIF was assessed by a 3 hr incubation at room
  • fibroblasts by immunoassay of cytoplasmic histone-associated D ⁇ A fragments (Roche Biochemicals, Indianapolis, IN) 8 . Proliferation studies were performed by a
  • MIF inhibitory factor
  • MIF inhibitory factor
  • MIF macrophage migration inhibitory factor
  • MIF murine lymphoma

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JP2007504158A (ja) * 2003-08-29 2007-03-01 サイトカイン・ファーマサイエンシズ・インコーポレーテッド マクロファージ遊走阻止因子（ｍｉｆ）を心臓由来心筋抑制因子として含む、処置方法およびバイオアッセイ
US7235546B2 (en) 2003-02-14 2007-06-26 Avanir Pharmaceuticals Inhibitors of macrophage migration inhibitory factor and methods for identifying the same
US7365200B2 (en) 2005-03-24 2008-04-29 Avanir Pharmaceuticals Thienopyridinone derivatives as macrophage migration inhibitory factor inhibitors
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US7238809B2 (en) 2001-05-24 2007-07-03 Avanir Pharmaceuticals Process for the preparation of inhibitors of macrophage migration inhibitory factor
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US7514225B2 (en) 2001-05-24 2009-04-07 Avanir Pharmaceuticals Method for screening an agent that modulates activity of macrophage migration inhibitory factor
US7105519B2 (en) 2001-05-24 2006-09-12 Avanir Pharmaceuticals Inhibitors of macrophage migration inhibitory factor and methods for identifying the same
US7084141B2 (en) 2001-05-24 2006-08-01 Avanir Pharmaceuticals Inhibitors of macrophase migration inhibitory factor and methods for identifying the same
US7435737B2 (en) 2001-05-24 2008-10-14 Avanir Pharmaceutials Inhibitors of macrophage migration inhibitory factor and methods for identifying the same
US7432374B2 (en) 2001-05-24 2008-10-07 Avanir Pharmaceuticals Inhibitors of macrophage migration inhibitory factor and methods for identifying the same
EP2270505A1 (en) * 2002-04-26 2011-01-05 Takeda Pharmaceutical Company Limited A method of screening a cell death inhibitor using macrophage migration inhibitory factor (MIF)
US8173360B2 (en) 2002-04-26 2012-05-08 Takeda Pharmaceutical Company Limited Cell death inhibitor
US7312221B2 (en) 2003-02-14 2007-12-25 Avanir Pharmaceuticals Inhibitors of macrophage migration inhibitory factor and methods for identifying the same
US7235546B2 (en) 2003-02-14 2007-06-26 Avanir Pharmaceuticals Inhibitors of macrophage migration inhibitory factor and methods for identifying the same
US7312220B2 (en) 2003-02-14 2007-12-25 Avanir Pharmaceuticals Inhibitors of macrophage migration inhibitory factor and methods for identifying the same
JP2007504158A (ja) * 2003-08-29 2007-03-01 サイトカイン・ファーマサイエンシズ・インコーポレーテッド マクロファージ遊走阻止因子（ｍｉｆ）を心臓由来心筋抑制因子として含む、処置方法およびバイオアッセイ
US7365200B2 (en) 2005-03-24 2008-04-29 Avanir Pharmaceuticals Thienopyridinone derivatives as macrophage migration inhibitory factor inhibitors
US9238689B2 (en) 2011-07-15 2016-01-19 Morpho Sys AG Antibodies that are cross-reactive for macrophage migration inhibitory factor (MIF) and D-dopachrome tautomerase (D-DT)

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