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  • C07K14/52—Cytokines; Lymphokines; Interferons
  • C07K14/555—Interferons [IFN]
  • C07K14/56—IFN-alpha
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  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/21—Interferons [IFN]
  • A61K38/212—IFN-alpha
• • A—HUMAN NECESSITIES
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  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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  • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
  • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
  • A61K47/642—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the peptide or protein in the drug conjugate being a cytokine, e.g. IL2, chemokine, growth factors or interferons being the inactive part of the conjugate
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  • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2869—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against hormone receptors
• • C—CHEMISTRY; METALLURGY
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  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
  • C07K2317/22—Immunoglobulins specific features characterized by taxonomic origin from camelids, e.g. camel, llama or dromedary
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  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
  • C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2319/00—Fusion polypeptide
• • C—CHEMISTRY; METALLURGY
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  • C07K—PEPTIDES
  • C07K2319/00—Fusion polypeptide
  • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2319/00—Fusion polypeptide
  • C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
  • C07K2319/74—Fusion polypeptide containing domain for protein-protein interaction containing a fusion for binding to a cell surface receptor

Definitions

• the present invention relates to a fusion protein, comprising a cytokine antagonist and a targeting moiety, preferably an antibody or antibody like molecule.
• the cytokine antagonist is a modified cytokine which binds to the receptor, but doesn't induce the receptor signalling.
• the invention relates further to a fusion protein according to the invention for use in treatment of cancer or for use in treatment of autoimmune diseases.
• Cytokines are critical mediators of defence mechanisms against microbial invasion and tumorigenesis. However, their production and activities must be tightly regulated to prevent an excessive activity that can culminate in the uncontrolled inflammation and tissue injury, as characteristically observed with many autoimmune diseases.
• Rheumatoid arthritis is the classic example of an autoimmune disease where TNFa, I L-1 , and IL-6 play a prominent role in the recruitment of lymphocytes and other types of leukocytes that mediate a progressive joint destruction. TNF inhibitors have been shown to decrease symptoms, slow disease progression, and improve the quality of life for many patients with rheumatoid arthritis (Moreland, 2009).
• a mAb neutralizing IL-12 and IL-23 provides a potential therapy for psoriasis (Elliott et al., 2009) and a recombinant human IL-1 receptor antagonist, (anakinra, KineretTM), first approved by the FDA in 2001 for the treatment of rheumatoid arthritis, is a promising agent for the treatment of many IL-1 - mediated autoinflammatory diseases (Goldbach-Mansky, 2009).
• IL17A is the best characterized member of the IL17 family of cytokines. This pleiotropic cytokine interacts with a receptor composed of IL17RA and IL17RC subunits.
• the IL17RA chain is ubiquitously expressed, including haematopoietic, immune, epithelial, endothelial cell types, as well as fibroblasts.
• IL17A is typically produced by Th17 cells upon activation by a subset of cytokines including IL-1 , IL-6, IL-21 and TGFp, and propagates early inflammatory signals that serve to bridge innate and adaptive immune responses.
• IL17 is a potent activator of neutrophils and plays an important role in the immune defence against various extracellular pathogens.
• IL17A promotes autoimmune pathologies (Gaffen, 2009; Shen & Gaffen, 2008).
• Brodalumab, Secukinumab and Ixekizumab target the IL17A/IL17R axis for treatment of auto-immune diseases such as psoriasis and Crohn's disease. All may inflict adverse side effects including enhanced risk of infections (Hueber et al. 2012; Spuls & Hooft, 2012).
• IL17A antagonists may therefore offer a significant advantage over completely antagonising IL17 function.
• ILI a and ⁇ _ ⁇ are the founding members of the IL1 cytokine family. Both are pleiotropic and function through a ubiquitously expressed receptor complex composed of IL-1 receptor type-l (IL-1 RI) and IL-1 receptor accessory protein (IL-1 RAcP). Overactivation of this IL-1 axis is associated with many human pathologies including rheumatoid arthritis (RA), chronic obstructive pulmonary disease (COPD), asthma, inflammatory bowel diseases, multiple sclerosis, atherosclerosis and Alzheimer's disease.
• RA rheumatoid arthritis
• COPD chronic obstructive pulmonary disease
• asthma inflammatory bowel diseases
• multiple sclerosis multiple sclerosis
• atherosclerosis atherosclerosis
• Alzheimer's disease Alzheimer's disease.
• IL-1 immune cells of different lineages are activated by IL-1 , including innate immune cells such as dendritic cells, macrophages and neutrophils, and also cells involved in the adaptive immune response including naive, Th17 and CD8+ T cells, and B cells (reviewed in Sims and Smith, 2010).
• Recombinant human IL- 1 RA IL1 receptor antagonist, aka anakinra
• autoinflammatory diseases Disperello, 201 1 .
• One of the major side effects of prolonged treatment with anakinra is however the increased occurrence of infections.
• IL-1 activity on only a subset of (immune) cells therefore may offer a safer alternative. It can be envisaged that targeted inhibition of IL-1 action on selected innate immune cells, leaving its activity on the T cell compartment intact, may still show efficacy for the treatment of inflammatory diseases, without affecting the host defence against pathogens.
• TSLP thymic stromal lymphopoietin
• IL-7Ra IL-7 receptor
• TSLPRa TSLPRa
• TSLP promotes Th2-type inflammation by acting on several distinct cell types, including dendritic cells, CD4 and CD8 T cells, B cells, NKT cells, mast cells, eosinophils and basophils.
• TSLP can have a protective role in inflammatory diseases driven by exacerbated Th1 and Th17 responses, such as Inflammatory Bowel Disease (reviewed in He and Geha, 2010 and Roan et al., 2012).
• the main problem with the therapeutic approaches aiming to neutralize cytokine actions is that the cytokine antagonists are not targeted towards cells or tissues that are specifically involved in the onset of the autoimmune or autoinflammatory diseases.
• a long term systemic neutralization of type I IFN activity by a monoclonal antibody or an IFN receptor antagonist carry an important risk in term of viral infection susceptibility and tumor development since type I IFN is a family of proteins essential in the control of viral infections and for establishing immune responses, particularly those controlling cancer cell growth (Gajewski et al., 2012).
• a systemic neutralization of IL-1 activity will impact the expansion, effector function, tissue localization, and memory response of antigen-cytotoxic T cells during immune responses (Ben-Sasson et al., 2013).
• the invention is exemplified by targeting the action of a type I IFN antagonist to specific cell types expressing a given cell surface marker.
• Such a method is applied to the design and construction of a targeted IFN antagonist that inhibits the action of endogenous IFN specifically on the cell subset culpably involved in the onset of autoimmune diseases, leaving the other cells and organs fully responsive.
• Oncolytic viruses are advancing through clinical trials (Russell et al., 2012). Oncolytic viruses are often designed for having attenuated replication capacity in normal tissues by engineering their sensitivity to the normal cellular interferon-mediated antiviral responses.
• An example is an oncolytic vesicular stomatitis virus coding for interferon ⁇ (Naik et al., 2012). The therapeutic effect of such viruses is expected to be a consequence of the defect of the IFN response exhibited by many tumor cells.
• the genetic heterogeneity of tumors that impact the IFN response is highly variable and impairs the efficacy of virus-mediated tumor lysis (Naik and Russell, 2009).
• a first aspect of the invention is a fusion protein comprising a cytokine antagonist and a targeting moiety consisting of an antibody or an antibody like molecule.
• a cytokine antagonist as used here can be any cytokine antagonist known to the person skilled in the art, including but not limited to a soluble receptor, a cytokine binding antibody or a mutant cytokine.
• said cytokine antagonist is a mutant cytokine, even more preferably a mutant which binds to the receptor, but is not or only weakly inducing the cytokine signalling.
• the affinity of the mutant for the receptor is comparable to that of the wild type cytokine, even more preferable it has a higher affinity; preferably the signalling induced by the mutant is less than 20% of that of the wild type, even more preferably less than 10% of that of the wild type, even more preferably less than 5%, even more preferably less than 1 %. Most preferably, the binding of the mutant cytokine does not result in detectable signalling. Such mutant can act as a competitive inhibitor of cytokine signalling.
• An antibody or antibody like molecule as used here is a protein specifically designed to bind another molecule, preferably a proteineous molecule, and comprising the specific binding domains.
• said antibody or antibody like molecule can be a heavy chain antibody (hcAb), single domain antibody (sdAb), minibody (Tramontano et al., 1994), the variable domain of camelid heavy chain antibody (VHH), the variable domain of the new antigen receptor (VNAR), affibody (Nygren et al., 2008), alphabody (WO2010066740), designed ankyrin-repeat domain (DARPins) (Stumpp et al., 2008), anticalin (Skerra et al., 2008), knottin (Kolmar et al., 2008) and engineered CH2 domain (nanoantibodies; Dimitrov, 2009).
• hcAb heavy chain antibody
• sdAb single domain antibody
• minibody Tramontano et al., 1994
• VHH camelid heavy chain antibody
• VNAR variable domain of the new antigen receptor
• affibody Nygren et al., 2008
• alphabody WO201006
• said antibody or antibody like molecule consists of a single polypeptide chain, even more preferably, said antibody is not post-translationally modified.
• Prost-translational modification indicates the modifications carried out by living cell during or after the protein synthesis, but excludes modifications, preferably chemical modifications, carried out on the isolated protein such as, but not limited to pegylation Even more preferably said antibody or antibody-like molecule comprises the complementary determining regions, derived from an antibody.
• said targeting antibody or antibody-like molecule is a nanobody.
• said cytokine antagonist and said targeting moiety are connected by a linker, preferably a GGS linker.
• a linker preferably a GGS linker.
• said GGS linker contains at least 5 GGS repeats, more preferably at least 10 GGS repeats, even more preferably at least 15 GGS repeats, most preferably at least 20 GGS repeats.
• the cytokine antagonist according to the invention is an interferon antagonist; even more preferably, it is an IFNa2-R120E mutant.
• the cytokine antagonist according to the invention is an antagonist of a cytokine of the IL17 family, preferably an IL17A antagonist.
• the cytokine antagonist according to the invention is an antagonist of the IL1 cytokine family, preferably an ILI a or ILp antagonist.
• the cytokine antagonist according to the invention is a TSLP antagonist.
• the antibody or antibody-like molecule is directed against a cancer cell marker.
• Cancer cell markers are known to the person skilled in the art, and include, but are not limited to CD19, CD20, CD22, CD30, CD33, CD37, CD56, CD70, CD74, CD138, AGS16, HER2, MUC1 , GPNMB and PMSA.
• said cancer marker is CD20 or HER2.
• the antibody or antibody-like molecule is directed against a marker on an immune cell, preferably an inflammatory cytokine producing immune cell.
• An immune cell as used here, is a cell that belongs to the immune system, including but not limited to monocytes, dendritic cells and T-cells.
• said immune cell is a proinflammatory cytokine producing cell.
• Markers of inflammatory cytokine producing cells include but are not limited to CD4, CD1 1 b, CD26, sialoadhesin and flt3 receptor.
• Another aspect of the invention is a fusion protein according to the invention for use in treatment of cancer. Still another aspect of the invention is a fusion protein according to the invention for use in treatment of autoimmune diseases.
• Another aspect of the invention is a method to treat cancer, comprising (i) determination the type of cancer and the suitable targeting marker(s) for the cancer cells in a patient suffering from cancer (ii) providing to said patient in need of the treatment a fusion protein comprising a cytokine antagonist and a targeting moiety consisting of an antibody or an antibody-like molecule according to the invention, possibly with a suitable excipient. It is obvious for the person skilled in the art that the targeting moiety of step (ii) will be directed to the targeting marker identified in step (i).
• Possible cancer cell markers are known to the person skilled in the art, and include, but are not limited to CD19, CD20, CD22, CD30, CD33, CD37, CD56, CD70, CD74, CD138, AGS16, HER2, MUC1 , GPNMB and PMSA.
• Still another aspect of the invention is a method to treat an autoimmune disease, comprising (i) determination in a patient suffering from an autoimmune disease the suitable targeting marker(s) for the immune cells cells cells (ii) providing to said patient in need of the treatment a fusion protein comprising a cytokine antagonist and a targeting moiety consisting of an antibody or an antibody-like molecule according to the invention, possibly with a suitable excipient.
• Immune cells include but are not limited to dendritic cells, CD4 and CD8 T cells, B cells, NKT cells, mast cells, eosinophils and basophils.
• Figure 1 Representation of the structural elements of the nanobody-hlFNa2-R120E fusion protein.
• Figure 2 Quantification of the luciferase activity induced by 10 pM hl FNa2 in the presence or absence (untreated) of the 4-1 1 -hl FNa2-R120E fusion protein on HL1 16 (A) and HL1 16- ml_R10 (B) cells.
• Figure 3 Quantification of the luciferase activity induced by 1 pM IFN3 in the presence or absence (untreated) of the 4-1 1 -hl FNa2-R120E fusion protein on HL1 16 (A) and HL1 16- ml_R10 (B) cells.
• Figure 4 FACS analysis of pY701 -STAT1 in CD19 positive and negative human PBMCs left untreated (left panel), treated with 50 pM of hl FNa2 (center) or with 50 pM of hl FNa2 in the presence of the CD20-targeted I FN antagonist.
• Nanobody-I FN antagonist fusion construction Nanobody-I FN antagonist fusion construction.
• Hek 293T cells were transfected with the protein fusion constructs using the standard lipofectamin method (Invitrogen). 48 hours after the transfection culture mediums were harvested and stored at -20°C. Cell lines
• Hek 293T cells were grown in DMEM supplemented with 10% FCS.
• the HL1 16 clone (Uze et al., 1994) is derived from the human HT1080 cell line. It contains the firefly luciferase gene controlled by the IFN-inducible 6-16 promoter.
• the derived HL1 16-mLR10 clone which expresses the murine leptin receptor was described (PCT/EP2013/050787).
• Antagonistic IFN activities were measured by quantifying the inhibition of the luciferase activity induced in HL1 16 cells and on the HL1 16-ml_R10 expressing the rmLR by IFNa2 or IFN3.
• the IC50 values were calculated using nonlinear data regression with Prism software (GraphPad).
• Luciferase activities were determined on a Berthold Centra LB960 luminometer using a luciferase substrate buffer (20 mM Tricine, 1.07 mM (MgC03)4Mg(OH)2 « 5H20, 2.67 mM MgS04 « 7H20, 0.1 mM EDTA, 33.3 mM dithiothreitol, 270 ⁇ coenzyme A, 470 ⁇ luciferin, 530 ⁇ ATP, final pH 7.8) after 6hr IFN stimulation.
• a luciferase substrate buffer (20 mM Tricine, 1.07 mM (MgC03)4Mg(OH)2 « 5H20, 2.67 mM MgS04 « 7H20, 0.1 mM EDTA, 33.3 mM dithiothreitol, 270 ⁇ coenzyme A, 470 ⁇ luciferin, 530 ⁇ ATP, final pH 7.8) after 6hr IFN stimulation.
• Example 1 The nanobody-IFNa2-R120E fusion protein.
• the nanobody 4-1 1 directed against the murine leptin receptor was fused to the IFNa2 mutant R120E as described in the materials and methods
• Figure 1 shows a schematic representation of the nanobody-IFN antagonist fusion protein constructed with the nanobody 4-1 1 against the murine leptin receptor and the human IFNa2- R120E (numbering as in Piehler et al., 2000).
• Example 2 Targeted inhibition of IFNa activity on mLR-expressing cells
• Example 3 Targeted inhibition of IFN activity on mLR-expressing cells
• the IFN3 shows the highest affinity for the IFNa/ ⁇ receptor. We thus tested whether the 4-1 1 -IFNa2-R120E fusion protein exerts also an antagonistic activity against IFN3 action.
• Parental HL1 16 cells and the derived HL1 16-mLR10 cells which express the mouse leptin receptor were treated for 6 hours with 1 pM IFN3 in the presence of several dilutions of culture medium conditioned by Hek 293T cells expressing the 4-1 1 -IFNa2-R120E fusion protein.
• the 1 pM IFN3 dose was chosen because it corresponds to the IFN3 EC50 on both cell lines. Cells were then lysed and the IFN-induced luciferase activity was quantified.
• the 4-1 1 -IFNa2-R120E fusion protein was unable to inhibit IFNa2 action on untargeted HL1 16 cells (Figure 3A).
• its dose-dependent inhibition effect is clear on HL1 16-mLR10 cells which express the target of the 4-1 1 nanobody ( Figure 3B).
• the type I IFN antagonist IFNa2-R120E was fused to the anti-human CD20 nanobody 2HCD25 through a linker sequence made with 20 repeats of GGS motif.
• the fusion protein was produced in E. coli and purified by Immobilized Metal Affinity chromatography (IMAC).
• IMAC Immobilized Metal Affinity chromatography
• PBMCs peripheral blood mononuclear cells
• FIG 4 shows that the IFN antagonist linked to the nanobody specific for CD20 inhibits the IFN action specifically in the major part of the B cell population, leaving intact the IFN response in the CD19 negative cell population.
• Example 5 The CD20-targeted type I IFN antagonist inhibits the antiproliferative activity of type I IFN.
• the fusion protein of the 2HCD25 nanobody and IFNa2-R120E inhibits IFN-induced STAT1 phosphorylation specifically in B-cells.
• Daudi cells are a human lymphoblastoid B-cell line expressing CD20. Daudi cells were seeded at 2.0x105 cells/ml and were left untreated or cultured for 72 h in the presence of 2 pM IFNa2 alone or in combination with various CD20-targeted IFN antagonists. They were then counted to estimate the efficacy of the inhibition of proliferation induced by IFNa2.
• Figure 5 shows that the CD20-targeted IFN antagonist fully inhibits the antiproliferative activity of IFNa2. It also shows that decreasing the IFN-IFNAR2 affinity decreases the antagonistic activity, proving that the inhibitory effect is indeed due to the binding of the targeted antagonist.
• IL-1 enhances expansion, effector function, tissue localization, and memory response of antigen-specific CD8 T cells. J Exp Med 210, 491 -502.
• Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer. J. Exp Med 208, 469-478).
• Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1 , Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia. Blood 1 15, 5312-5321 .

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