WO2018007442A1 - Traitement de maladies associées à l'il-6r - Google Patents

Traitement de maladies associées à l'il-6r Download PDF

Info

Publication number
WO2018007442A1
WO2018007442A1 PCT/EP2017/066769 EP2017066769W WO2018007442A1 WO 2018007442 A1 WO2018007442 A1 WO 2018007442A1 EP 2017066769 W EP2017066769 W EP 2017066769W WO 2018007442 A1 WO2018007442 A1 WO 2018007442A1
Authority
WO
WIPO (PCT)
Prior art keywords
polypeptide
dose
administered
filled syringe
seq
Prior art date
Application number
PCT/EP2017/066769
Other languages
English (en)
Inventor
Sven HOEFMAN
Maria-Laura Sargentini-Maier
Katrien VAN BENEDEN
Original Assignee
Ablynx N.V.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ablynx N.V. filed Critical Ablynx N.V.
Publication of WO2018007442A1 publication Critical patent/WO2018007442A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • 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
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific

Definitions

  • the present invention provides methods for the treatment of IL-6R related diseases. More specifically, the present invention provides specific dose regimens of immunoglobulin single variable domains that bind IL-6R for subcutaneous administration to subjects suffering an IL-6R related disease.
  • IL-6 is a pleiotropic cytokine with a wide range of biological activities.
  • the IL-6 pathway functions through the interaction of IL-6 with its receptor IL-6R.
  • This cytokine-receptor complex interacts with a third partner, the adaptor molecule glycoprotein 130 (gpl30), responsible for signal transduction and activation of the cell (Jones et al. 2011, J. Clin. Investig. 121: 3375-83).
  • IL-6R is present not only as a membrane bound form but also as a soluble form.
  • slL-6R can interact with IL-6 and this complex can activate gpl30-positive cells without the presence of membrane-bound (m)IL-6R on the surface of the cells.
  • IL-6 is a pleiotropic cytokine
  • its function is highly diverse. Many studies revealed that this molecule, by binding to the target IL-6R and gpl30, plays a role in the immune, hematopoietic, hepatic, and neuronal systems (Maini 2008, Plenary lecture EULAR conference 2008; Jones et al. 2005, J. Interferon Cytokine Res. 25: 241-253).
  • IL-6 overproduction and signaling are involved in various diseases and disorders, such as sepsis (Starnes et al. 1999, J. Immunol. 148: 1968) and various forms of cancer such as multiple myeloma disease (MM), renal cell carcinoma (RCC), plasma cell leukemia (Klein et al. 1991, Blood 78: 1198-204), lymphoma, B-lymphoproliferative disorder (BLPD) and prostate cancer.
  • MM multiple myeloma disease
  • RCC renal cell carcinoma
  • plasma cell leukemia Klein et al. 1991, Blood 78: 1198-204
  • lymphoma B-lymphoproliferative disorder (BLPD) and prostate cancer.
  • Non-limiting examples of other diseases caused by excessive IL-6 production or signaling include bone resorption (osteoporosis) (Roodman et al. 1992, J. Bone Miner. Res. 7: 475-8; Jilka et al. 1992, Science 257: 88-91), cachexia (Strassman et al. 1992, J. Clin. Invest. 89: 1681-1684), psoriasis, mesangial proliferative glomerulonephritis, Kaposi's sarcoma, AIDS-related lymphoma (Emilie et al. 1994, Int. J. Immunopharmacol.
  • inflammatory diseases and disorder such as rheumatoid arthritis (RA), systemic onset juvenile idiopathic arthritis (JIA), hypergammaglobulinemia (Grau et al. 1990, J. Exp. Med. 172: 1505-8), Crohn's disease, ulcerative colitis, systemic lupus erythematosus (SLE), multiple sclerosis, Castleman's disease, IgM gammopathy, cardiac myxoma, asthma (in particular allergic asthma) and autoimmune insulin- dependent diabetes mellitus (Campbell et al. 1991, J. Clin. Invest. 87: 739-742).
  • RA Rheumatoid arthritis
  • RA Rheumatoid arthritis
  • Initial treatment options include disease-modifying anti-rheumatic drugs (DMARDs), non- steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, analgesics, surgery, physiotherapy, and occupational therapy.
  • DMARDs disease-modifying anti-rheumatic drugs
  • NSAIDs non- steroidal anti-inflammatory drugs
  • corticosteroids analgesics
  • the synthetic DMARDs most commonly used include methotrexate (MTX), sulfasalazine, leflunomide, hydroxychloroquine, cyclosporine A, and glucocorticoids.
  • the therapeutic benefits of DMARDs in RA include control of signs and symptoms, improvement of functional status and of quality of life, and retardation of joint damage progression (Firestein et al. 2006, Kelley's Textbook of Rheumatology (8 th ed.) Elsevier, p. 1119-1143).
  • TNF ⁇ tumor necrosis factor alpha
  • selective T-cell co-stimulation molecule such as cytotoxic T-lymphocyte-associated protein 4
  • CD20 cluster of differentiation 20
  • IL-1 interleukin-1
  • IL-6 interleukin-6 receptor
  • anti-TNF ⁇ agents and other biological DMARDs have been established as effective treatment options for RA, there are reasons to study the effectiveness of new therapeutic agents. For example, there is a subset of the patient population that does not achieve a clinical response, defined as American College of Rheumatology (ACR) 20 response, and only a small proportion achieve a high level ACR response (ACR50 or ACR70) (Dennis et al. 2002, J. Biol. Chem. 277: 35035-35043).
  • ACR American College of Rheumatology
  • rheumatoid arthritis may not be effective for all patients and/or may lose effectiveness over time for various reasons such as disease burden, low drug serum levels, rapid clearance, and immunogenicity, in addition to other limitations with respect to safety, dosing regimen, and route of administration.
  • available therapies to treat, for example, IL-6 related autoimmune conditions may only be appropriate for acute care because longer-term use of these therapies (e.g. steroids) can lead to the development of secondary medical conditions requiring further treatment.
  • IL-6 related disease including rheumatoid arthritis (RA)
  • RA rheumatoid arthritis
  • SEQ ID NO: 34 is a bivalent Nanobody consisting of two humanized and sequence-optimized variable domains derived from heavy chain-only llama antibodies. One domain (SEQ ID NO: 1) binds to IL-6R. The second domain (SEQ ID NO: 38) binds to human serum albumin (HSA). SEQ ID NO: 34 was extensively characterized in vitro (see for example WO 2010/115998).
  • SEQ ID NO: 34 A study assessing the safety, PK, PD, and efficacy after intravenous (i.v.) administration of SEQ ID NO: 34 in RA patients is described in WO 2013/041722.
  • This placebo-controlled study included 28 subjects in an initial single ascending dose (SAD) part where single i.v. doses of 0.3, 1, 3, or 6 mg/kg were administered.
  • SAD single ascending dose
  • MAD multiple ascending dose
  • Intravenous (i.v.) injections are generally performed by the physician or by the medical professional staff. Therefore, the patient is expected to visit a health care professional regularly in order to receive treatment. Besides the discomfort created, the time taken up by this type of application often leads to unsatisfactory compliance by the patient, particularly for chronic diseases.
  • Subcutaneous (s.c.) injection renders the possibility to the patient to self-administer the drug and consequently improve patients' convenience.
  • Drawbacks of subcutaneous administration include the incomplete bioavailability after subcutaneous administration (Richter et al. 2012, AAPS J. 14: 559-570; Macdonald et al. 2010, Curr. Opin. Mol. Ther. 12: 461-470) and the relative slow subcutaneous absorption (Zheng et al. 2012, MAbs 4: 243-255).
  • the subcutaneous bioavailability estimates are mostly around 60-80% (Richter and Jacobsen 2014, Drug Metab. Dispos. 2014, Aug 6).
  • t max time to maximum serum concentrations
  • t max time to maximum serum concentrations
  • a biotherapeutic is directly injected into the systemic circulation.
  • the biotherapeutic is injected into the extracellular space of the subcutaneous tissue, from where it has to be absorbed by blood or lymph capillaries in order to reach the systemic circulation.
  • FcRn neonatal Fc receptor
  • FcRn binding may prevent IgG from catabolism in subcutaneous tissue/lymphatics or may enhance the FcRn mediated transcytosis across the vascular endothelium (Richter et al., 2012).
  • Subcutaneously administration of immunoglobulin single variable domains and their bioavailability and absorption rate has not yet been reported. These molecules do not possess an Fc region.
  • the present disclosure demonstrates that subcutaneous administration of an immunoglobulin single variable domain provides a good bioavailability of more than 80% and an unexpectedly short time to maximum serum concentrations (t max ).
  • Subcutaneous administration of an immunoglobulin single variable domain that binds and blocks IL-6R (SEQ ID NO: 34) resulted in a bioavailability of more than 80%.
  • Maximum serum concentrations of the immunoglobulin single variable domain were already reached after about 1-3 days.
  • the present invention provides dose regimens for subcutaneous administration of immunoglobulin single variable domains to human subjects. More specifically, the present invention provides dose regimens for subcutaneous administration of immunoglobulin single variable domains that bind and block IL-6R to human subjects suffering an IL-6R related disease.
  • the present invention relates to a method for the treatment of an IL-6R related disease in a human subject, said method comprising the administration to a human subject suffering from the IL-6R related disease, of a polypeptide comprising, consisting essentially of, or consisting of at least one immunoglobulin single variable domain that binds IL-6R and that blocks IL-6 binding to IL- 6R, wherein the polypeptide is administered subcutaneously at a dose of 75-300 mg every week to every month or at a dose equivalent to 75-300 mg every week to every month.
  • the immunoglobulin single variable domain binds IL-6R with a K D of 5x10 -11 M or less.
  • the present invention relates to a method for the treatment of an IL-6R related disease in a human subject, said method comprising the administration to a human subject suffering from the IL-6R related disease, of a polypeptide comprising, consisting essentially of, or consisting of at least one immunoglobulin single variable domain that binds IL-6R with a K D of 5x10 -11 M or less, wherein the polypeptide is administered subcutaneously at a dose of 75-300 mg every week to every month or at a dose equivalent to 75-300 mg every week to every month.
  • the dissociation constant (K D ) may be measured by, for example, surface plasmon resonance.
  • the immunoglobulin single variable domain blocks IL-6 binding to IL- 6R with an IC50 of 10 -9 M or less.
  • the present invention relates to a method for the treatment of an IL-6R related disease in a human subject, said method comprising the administration to a human subject suffering from the IL-6R related disease, of a polypeptide comprising, consisting essentially of, or consisting of at least one immunoglobulin single variable domain that blocks IL-6 binding to IL-6R with an IC50 of 10 -9 M or less, wherein the polypeptide is administered
  • the IC50 may be measured by, for example, a TF-1 potency assay.
  • the IC50 may be measured by, for example, a TF-1 proliferation assay at 100 lU/mL IL-6.
  • the present invention relates to a method for the treatment of an IL-6R related disease in a human subject, said method comprising the administration to a human subject suffering from the IL-6R related disease, of a polypeptide comprising, consisting essentially of, or consisting of at least one immunoglobulin single variable domain that binds IL-6R with a K D of 5x10 -11 M or less and that blocks IL-6 binding to IL-6R with an IC50 of 10 -9 M or less, wherein the polypeptide is administered subcutaneously at a dose of 75-300 mg every week to every month or at a dose equivalent to 75-300 mg every week to every month.
  • the K D may be measured by, for example, surface plasmon resonance.
  • the IC50 may be measured by, for example, a TF-1 potency assay.
  • the IC50 may be measured by, for example, a TF-1 proliferation assay at 100 lU/mL IL-6.
  • the present invention also provides a polypeptide (also referred to herein as "polypeptide of the invention") comprising, consisting essentially of, or consisting of an immunoglobulin single variable domain that binds IL-6R and that blocks IL-6 binding to IL-6R, for use in the treatment of an IL-6R related disease in a human subject, wherein the polypeptide is administered subcutaneously to a human subject suffering the IL-6R related disease at a dose of 75-300 mg every week to every month or at a dose equivalent to 75-300 mg every week to every month.
  • the immunoglobulin single variable domain binds IL-6R with a K D of 5x10 -11 M or less.
  • the present invention relates to a polypeptide (also referred to herein as "polypeptide of the invention") comprising, consisting essentially of, or consisting of an
  • the K D may be measured by, for example, surface plasmon resonance.
  • the immunoglobulin single variable domain blocks IL-6 binding to IL- 6R with an IC50 of 10 -9 M or less.
  • the present invention relates to a polypeptide (also referred to herein as "polypeptide of the invention") comprising, consisting essentially of, or consisting of an immunoglobulin single variable domain that blocks IL-6 binding to IL-6R with an IC50 of 10 -9 M, for use in the treatment of an IL-6R related disease in a human subject, wherein the polypeptide is administered subcutaneously to a human subject suffering the IL-6R related disease at a dose of 75-300 mg every week to every month or at a dose equivalent to 75-300 mg every week to every month.
  • the IC50 may be measured by, for example, a TF-1 potency assay.
  • the IC50 may be measured by, for example, a TF-1 proliferation assay at 100 lU/mL IL-6.
  • the present invention provides a polypeptide (also referred to herein as "polypeptide of the invention") comprising, consisting essentially of, or consisting of an immunoglobulin single variable domain that binds IL-6R with a K D of 5x10 -11 M or less and that blocks IL-6 binding to IL-6R with an IC50 of 10 -9 M, for use in the treatment of an IL-6R related disease in a human subject, wherein the polypeptide is administered subcutaneously to a human subject suffering the IL-6R related disease at a dose of 75-300 mg every week to every month or at a dose equivalent to 75-300 mg every week to every month.
  • the K D may be measured by, for example, surface plasmon resonance.
  • the IC50 may be measured by, for example, a TF-1 potency assay.
  • the IC50 may be measured by, for example, a TF-1 proliferation assay at 100 lU/mL IL-6.
  • the human subject treated with the polypeptide of the invention may be suffering from any IL- 6R related disease (as further defined herein).
  • the human subject is suffering from rheumatoid arthritis.
  • the human subject is suffering from active rheumatoid arthritis.
  • the human subject is suffering from active rheumatoid arthritis despite methotrexate therapy.
  • the human subject is suffering from active rheumatoid arthritis and is intolerant to MTX.
  • the immunoglobulin single variable domain encompassed in the polypeptide of the invention administered subcutaneously may be any immunoglobulin single variable domain that binds IL-6R.
  • the immunoglobulin single variable domain binds IL-6R with a K D of 5x10 -11 M or less.
  • the immunoglobulin single variable domain blocks IL-6 binding to IL-6R with an IC50 of 10 -9 M or less.
  • the immunoglobulin single variable domain binds IL-6R with a K D of 5x10 11 M or less and blocks IL-6 binding to IL-6R with an IC50 of 10 -9 M or less.
  • the K D may be measured by, for example, surface plasmon resonance.
  • the IC50 may be measured by, for example, a TF-1 potency assay.
  • the IC50 may be measured by, for example, a TF-1 proliferation assay at 100 lU/mL IL-6.
  • the immunoglobulin single variable domain encompassed in the polypeptide of the invention administered subcutaneously comprises a CDRl having the amino acid sequence of SEQ ID NO: 17, a CDR2 having the amino acid sequence of SEQ ID NO: 21, and a CDR3 having the amino acid sequence of SEQ ID NO: 30.
  • the immunoglobulin single variable domain encompassed in the polypeptide of the invention administered subcutaneously is selected from SEQ ID NOs: 1-10.
  • the polypeptide of the invention that is administered subcutaneously may additionally comprise an immunoglobulin single variable domain that binds human serum albumin.
  • the additional immunoglobulin single variable domain that binds human serum albumin is selected from SEQ ID NOs: 37-39.
  • the polypeptide of the invention that is administered subcutaneously has the amino acid sequence of SEQ ID NO: 34.
  • the present invention relates to a method for the treatment of an IL-6R related disease in a human subject, said method comprising the administration to a human subject suffering from the IL-6R related disease, of a polypeptide with SEQ ID NO: 34, wherein the polypeptide is administered subcutaneously at a dose of 75-300 mg every week to every month or at a dose equivalent to 75-300 mg every week to every month.
  • the polypeptide of the invention is administered subcutaneously every week to every month. In one aspect, the polypeptide of the invention is administered every week. In one aspect, the polypeptide of the invention is administered every two weeks. In one aspect, the polypeptide of the invention is administered every four weeks. In one aspect, the polypeptide of the invention is administered every month.
  • the polypeptide of the invention is administered subcutaneously at a dose of 75-300 mg. In one aspect, the polypeptide of the invention is administered at a dose of 75-150 mg, such as e.g. 75 mg. In one aspect, the polypeptide of the invention is administered at a dose of 150-200 mg, such as e.g. 150 mg. In one aspect, the polypeptide of the invention is administered at a dose of 200-250 mg, such as e.g. 225 mg. In one aspect, the polypeptide of the invention is administered at a dose of 250- 300 mg, such as e.g. 300 mg.
  • the polypeptide of the invention may be administered as a monotherapy or as a combination therapy. In one aspect, the polypeptide of the invention is administered as a monotherapy.
  • the pharmaceutical composition comprising the polypeptide of the invention is loaded into a pre-filled syringe (also referred to herein as "pre-filled syringe of the invention").
  • the present invention also relates to pre-filled syringes containing the polypeptide of the invention.
  • the present invention relates to a pre-filled syringe containing a
  • composition comprising a polypeptide comprising, consisting essentially of, or consisting of an immunoglobulin single variable domain that binds IL-6R and that blocks IL-6 binding to IL-6R.
  • the present invention relates to a pre-filled syringe containing a
  • the present invention relates to a pre-filled syringe containing a pharmaceutical composition comprising a polypeptide comprising, consisting essentially of, or consisting of an immunoglobulin single variable domain that blocks IL-6 binding to IL-6R with an IC50 of 10 -9 M.
  • the present invention relates to a pre-filled syringe containing a pharmaceutical composition
  • a pharmaceutical composition comprising a polypeptide comprising, consisting essentially of, or consisting of an immunoglobulin single variable domain that binds IL-6R with a K D of 5x10 -11 M or less and that blocks IL-6 binding to IL- 6R with an IC50 of 10 -9 M.
  • the K D may be measured by, for example, surface plasmon resonance.
  • the IC50 may be measured by, for example, a TF-1 potency assay.
  • the IC50 may be measured by, for example, a TF-1 proliferation assay at 100 lU/mL IL-6.
  • the pre-filled syringe contains a polypeptide comprising, consisting essentially of, or consisting of an immunoglobulin single variable domain with a CDR1 having the amino acid sequence of SEQ ID NO: 17, a CDR2 having the amino acid sequence of SEQ ID NO: 21, and a CDR3 having the amino acid sequence of SEQ ID NO: 30.
  • the pre-filled syringe contains a polypeptide comprising, consisting essentially of, or consisting of an immunoglobulin single variable domain selected from SEQ ID NOs: 1-10.
  • the pre-filled syringe contains a polypeptide that comprises an immunoglobulin single variable domain that binds IL-6R and that additionally comprises an immunoglobulin single variable domain that binds human serum albumin.
  • the immunoglobulin single variable domain that binds human serum albumin has an amino acid sequence selected from SEQ ID NO: 37- 39.
  • the pre-filled syringe contains a polypeptide with SEQ ID NO: 34. Accordingly, the present invention relates to a pre-filled syringe containing a pharmaceutical composition comprising a polypeptide with SEQ ID NO: 34.
  • the pre-filled syringe can be any size that is suitable for subcutaneous administration. In one aspect, a 0.5 ml syringe is used. In one aspect, a 1 ml syringe is used.
  • the polypeptide of the invention can be present in the pharmaceutical composition at any concentration which is suitable for subcutaneous administration. In one aspect, the polypeptide is present in the pharmaceutical composition at a concentration of 150 mg/ml.
  • a 1 ml syringe is used with a 150 mg/ml pharmaceutical composition of the polypeptide of the invention and, as such, the pre-filled syringe contains 150 mg of polypeptide of the invention. Accordingly, a dose of 150 mg can be obtained by subcutaneous administration of the pharmaceutical composition present in one such pre-filled syringe. A dose of 300 mg can be obtained by subcutaneous administration of the pharmaceutical composition present in two such pre-filled syringes.
  • a 0.5 ml syringe is used with a 150 mg/ml pharmaceutical composition of the polypeptide of the invention and, as such, the pre-filled syringe contains 75 mg of polypeptide of the invention. Accordingly, a dose of 75 mg can be obtained by subcutaneous administration of the pharmaceutical composition present in one such pre-filled syringe. A dose of 150 mg can be obtained by subcutaneous administration of the pharmaceutical composition present in two such pre-filled syringes. A dose of 225 mg can be obtained by subcutaneous administration of the pharmaceutical composition present in one such 1 ml pre-filled syringes and 1 such 0.5 ml pre- filled syringe.
  • the pre-filled syringe of the invention is used for the treatment of an IL-6 related disease in a human subject.
  • the present invention relates to a pre-filled syringe containing a pharmaceutical composition comprising the polypeptide of the invention for use in the treatment of an IL-6R related disease in a human subject.
  • the present invention further relates to a pre-filled syringe containing a pharmaceutical composition comprising the polypeptide of the invention for use in the treatment of an IL-6R related disease in a human subject, wherein the polypeptide is administered subcutaneously.
  • the present invention also relates to a pre-filled syringe containing a pharmaceutical composition comprising the polypeptide of the invention for use in the treatment of an IL-6R related disease in a human subject, wherein the polypeptide is administered subcutaneously at a dose of 75-300 mg every week to every month or at a dose equivalent to 75-300 mg every week to every month.
  • the human subject treated with the pre-filled syringe of the present invention may be suffering from any IL-6R related disease (as further defined herein).
  • the human subject is suffering from rheumatoid arthritis.
  • the human subject is suffering from active rheumatoid arthritis.
  • the human subject is suffering from active rheumatoid arthritis despite methotrexate therapy.
  • the human subject is suffering from active rheumatoid arthritis and is intolerant to MTX.
  • the polypeptide of the invention present in the pre-filled syringe is administered subcutaneously at a dose of 75-300 mg every week to every month or at a dose equivalent to 75-300 mg every week to every month.
  • the polypeptide in the pre-filled syringe is administered every week.
  • the polypeptide in the pre-filled syringe is administered every two weeks.
  • the polypeptide in the pre-filled syringe is administered every four weeks.
  • the polypeptide in the pre-filled syringe is administered every month. In one aspect, the polypeptide in the pre-filled syringe is administered at a dose of 75-150 mg.
  • the polypeptide in the pre-filled syringe is administered at a dose of 75 mg.
  • the polypeptide in the pre-filled syringe is administered at a dose of 150-200 mg.
  • the polypeptide in the pre-filled syringe is administered at a dose of 150 mg.
  • the polypeptide in the pre-filled syringe is administered at a dose of 200-250 mg.
  • the polypeptide in the pre-filled syringe is administered at a dose of 225 mg.
  • the polypeptide in the pre-filled syringe is administered at a dose of 250-300 mg.
  • the polypeptide in the pre-filled syringe is administered at a dose of 300 mg.
  • the polypeptide present in the pre-filled syringe may be administered as a monotherapy or as a combination therapy. In one aspect, the polypeptide present in the pre-filled syringe is administered as a monotherapy.
  • Figures 1A and IB are a pair of graphs depicting the geometric mean serum concentration-time profiles of SEQ ID NO: 34 after s.c. and i.v. administration in healthy human subjects: Figure 1A: Linear; Figure IB: Semi-Logarithmic.
  • Figure 2 is a graph depicting IL-6 serum concentrations after s.c. and i.v. administration of SEQ ID NO: 34 in healthy human subjects.
  • Figure 3 is a graph depicting slL-6R plasma concentrations after s.c. and i.v. administration of SEQ ID NO: 34 in healthy human subjects.
  • Figure 4 is a graph depicting model-predicted PK profiles of SEQ ID NO: 34 following s.c.
  • SEQ ID NO: 34 administration of SEQ ID NO: 34 at a dose of 75 and 150 mg q4w and 150 and 225 mg q2w.
  • the PK profiles were simulated by sampling a thousand RA patients from the expected body weight distribution as specified in Example 2.
  • Figure 5 is a graph depicting model-predicted median DAS28 response following s.c.
  • Figure 6 shows the patient disposition in the clinical study as described in Example 3.
  • Figure 7 is a graph depicting the HAQ-DI mean change from baseline over time following s.c. administration of SEQ ID NO: 34 at a dose of 150 mg q4w, 150 mg q2w, and 225 mg q2w and of tocilizumab at a dose of 162 mg qlw or q2w, as described in Example 3.
  • Figure 8 is a graph depicting the mean ACR20/50/70 response at week 12 following s.c.
  • SEQ ID NO: 34 administration of SEQ ID NO: 34 at a dose of 150 mg q4w, 150 mg q2w, and 225 mg q2w and of tocilizumab at a dose of 162 mg qlw or q2w, as described in Example 3.
  • Figure 9 is a graph depicting the remission and low disease activity at week 12 following s.c. administration of SEQ ID NO: 34 at a dose of 150 mg q4w, 150 mg q2w, and 225 mg q2w and of tocilizumab (TCZ) at a dose of 162 mg qlw or q2w, as described in Example 3.
  • TCZ tocilizumab
  • Figure 10 is a graph depicting model-predicted DAS28(CRP) change from baseline (DAS28 baseline value of 4.93) and actual DAS28(CRP) change from baseline over time following s.c.
  • SEQ ID NO: 34 administration of SEQ ID NO: 34 at a dose of 150 mg q4w, 150 mg q2w, and 225 mg q2w and of tocilizumab at a dose of 162 mg qlw or q2w.
  • the model-predicted DAS28(CRP) response was based on simulations performed using the same 1000 RA patients as for the simulated PK profiles.
  • a nucleic acid sequence or amino acid sequence is considered to be "(in) essentially isolated (form)" - for example, compared to the reaction medium or cultivation medium from which it has been obtained - when it has been separated from at least one other component with which it is usually associated in said source or medium, such as another nucleic acid, another
  • nucleic acid sequence or amino acid sequence is considered “essentially isolated” when it has been purified at least 2-fold, in particular at least 10- fold, more in particular at least 100-fold, and up to 1000-fold or more.
  • a nucleic acid sequence or amino acid sequence that is "in essentially isolated form” is preferably essentially homogeneous, as determined using a suitable technique, such as a suitable chromatographical technique, such as polyacrylamide-gel electrophoresis.
  • nucleotide sequence or amino acid sequence is said to "comprise” another nucleotide sequence or amino acid sequence, respectively, or to “essentially consist of” another nucleotide sequence or amino acid sequence, this may mean that the latter nucleotide sequence or amino acid sequence has been incorporated into the first mentioned nucleotide sequence or amino acid sequence, respectively, but more usually this generally means that the first mentioned nucleotide sequence or amino acid sequence comprises within its sequence a stretch of nucleotides or amino acid residues, respectively, that has the same nucleotide sequence or amino acid sequence, respectively, as the latter sequence, irrespective of how the first mentioned sequence has actually been generated or obtained (which may for example be by any suitable method described herein).
  • a polypeptide of the invention when a polypeptide of the invention is said to comprise an immunoglobulin single variable domain, this may mean that said immunoglobulin single variable domain sequence has been incorporated into the sequence of the polypeptide of the invention, but more usually this generally means that the polypeptide of the invention contains within its sequence the sequence of the immunoglobulin single variable domains irrespective of how said polypeptide of the invention has been generated or obtained.
  • the first mentioned nucleic acid or nucleotide sequence is preferably such that, when it is expressed into an expression product (e.g. a
  • the amino acid sequence encoded by the latter nucleotide sequence forms part of said expression product (in other words, that the latter nucleotide sequence is in the same reading frame as the first mentioned, larger nucleic acid or nucleotide sequence).
  • the immunoglobulin single variable domain used in the method of the invention either is exactly the same as the polypeptide of the invention or corresponds to the polypeptide of the invention which has a limited number of amino acid residues, such as 1-20 amino acid residues, for example 1-10 amino acid residues and preferably 1-6 amino acid residues, such as 1, 2, 3, 4, 5 or 6 amino acid residues, added at the amino terminal end, at the carboxy terminal end, or at both the amino terminal end and the carboxy terminal end of the immunoglobulin single variable domain.
  • sequence as used herein (for example in terms like “immunoglobulin sequence”, “variable domain sequence”, “immunoglobulin single variable domain sequence”, “VHH sequence” or “protein sequence), should generally be understood to include both the relevant amino acid sequence as well as nucleic acid sequences or nucleotide sequences encoding the same, unless the context requires a more limited interpretation.
  • amino acid sequence such as an immunoglobulin single variable domain, an antibody, a polypeptide of the invention, or generally an antigen binding protein or polypeptide or a fragment thereof
  • an amino acid sequence that can (specifically) bind to, that has affinity for and/or that has specificity for a specific antigenic determinant, epitope, antigen or protein (or for at least one part, fragment or epitope thereof) is said to be "against" or "directed against” said antigenic determinant, epitope, antigen or protein.
  • the affinity denotes the strength or stability of a molecular interaction.
  • the affinity is commonly given as by the K D , or dissociation constant, which has units of mol/liter (or M).
  • the affinity can also be expressed as an association constant, K A , which equals 1/K D and has units of (mol/liter) -1 (or M -1 ).
  • K A association constant
  • the K D for biological interactions which are considered meaningful are typically in the range of 10 -10 M (0.1 nM) to 10 -5 M (10000 nM). The stronger an interaction is, the lower is its K D .
  • antigen-binding proteins such as the immunoglobulin single variable domains and/or polypeptides of the invention
  • K D dissociation constant
  • K A association constant
  • any K D value greater than 10 -4 mol/liter is generally considered to indicate non-specific binding.
  • a monovalent immunoglobulin sequence of the invention will bind to the desired antigen with an affinity less than 500 nM, preferably less than 200 nM, more preferably less than 10 nM, such as e.g. less than 500 pM or 5xlO -u M or less.
  • the K D can also be expressed as the ratio of the dissociation rate constant of a complex, denoted as k 0 ff, to the rate of its association, denoted k o
  • the on-rate k on has units M V 1 .
  • the on-rate may vary between 10 2 to about 10 7 , approaching the diffusion-limited association rate
  • the off-rate is related to the half-life of a given molecular interaction by the relation
  • the off-rate may vary between 10 -6 s -1 (near irreversible complex with a ti/ 2 of multiple days) to
  • the affinity of a molecular interaction between two molecules can be measured via different techniques known per se, such as the well-known surface plasmon resonance (SPR) biosensor technique (see for example Ober et al. 2001, Intern. Immunology 13: 1551-1559) where one molecule is immobilized on the biosensor chip and the other molecule is passed over the immobilized molecule under flow conditions yielding k on , k Off measurements and hence K D (or K A ) values.
  • SPR surface plasmon resonance
  • K D or K A
  • the measured K D may correspond to the apparent K D if the measuring process somehow influences the intrinsic binding affinity of the implied molecules for example by artifacts related to the coating on the biosensor of one molecule. Also, an apparent K D may be measured if one molecule contains more than one recognition sites for the other molecule. In such situation the measured affinity may be affected by the avidity of the interaction by the two molecules.
  • K D K D and apparent K D should be treated with equal importance or relevance.
  • “Avidity” is the measure of the strength of binding between an antigen-binding molecule (such as an immunoglobulin single variable domain or polypeptide of the invention) and the pertinent antigen. Avidity is related to both the affinity between an antigenic determinant and its antigen binding site on the antigen-binding molecule and the number of pertinent binding sites present on the antigen-binding molecule.
  • the term "specificity" refers to the number of different types of antigens or antigenic determinants to which a particular antigen-binding molecule or antigen-binding protein (such as an immunoglobulin single variable domain or a polypeptide of the invention) can bind.
  • the specificity of an antigen-binding protein can be determined based on affinity and/or avidity.
  • Specific binding of an antigen-binding protein to an antigen or antigenic determinant can be determined in any suitable manner known per se, including, for example, Scatchard analysis and/or competitive binding assays, such as radioimmunoassays (RIA), enzyme immunoassays (EIA) and sandwich competition assays, and the different variants thereof known per se in the art; as well as the other techniques mentioned herein.
  • Scatchard analysis and/or competitive binding assays such as radioimmunoassays (RIA), enzyme immunoassays (EIA) and sandwich competition assays, and the different variants thereof known per se in the art; as well as the other techniques mentioned herein.
  • Blocking IL-6 binding to IL-6R means that the immunoglobulin single variable domain is capable of competing with IL-6 for binding to the IL-6 receptor. As such, binding of IL-6 to IL-6R is blocked, inhibited or reduced compared to the binding of IL-6 to its IL-6R without the presence of the immunoglobulin single variable domain. Immunoglobulin single variable domains that "block IL-6 binding to IL-6” bind to an epitope on IL-6R close to the IL-6 interaction side on IL-6R. "Blocking IL-6 binding to IL-6R" by the immunoglobulin and/or polypeptide of the invention can be determined, for example, in the TF-1 assay as described by Kitamura et al.
  • the immunoglobulin single variable domain present in the polypeptide of the invention may have IC50 values (at 100 lU/mL IL-6) between 10 nM and 50 pM, preferably between 5 nM and 50 pM, more preferably between 1 nM and 50 pM or less, such as e.g. 10 -9 M or less or about 750 or 500 pM or less.
  • the amino acid sequences of the invention may have IC50 values (at 5000 lU/mL IL-6) between 50 nM and 1 nM, preferably between 25 nM and 1 nM, more preferably between 10 nM and 1 nM or less, such as about 8 nM or less.
  • the "half-life" of a polypeptide of the invention can generally be defined as the time taken for the serum concentration of the polypeptide to be reduced by 50%, in vivo, for example due to degradation of the sequence or compound and/or clearance or sequestration of the sequence or compound by natural mechanisms.
  • the in vivo half-life of a polypeptide of the invention can be determined in any manner known per se, such as by pharmacokinetic analysis. Suitable techniques will be clear to the person skilled in the art, and may for example generally involve the steps of suitably administering to a warm-blooded animal (i.e.
  • a human or to another suitable mammal such as a mouse, rabbit, rat, pig, dog or a primate, for example monkeys from the genus Macaca (such as, and in particular, cynomolgus monkeys (Macaca fascicularis) and/or rhesus monkeys (Macaca mulatto)) and baboon (Papio ursinus)), a suitable dose of the polypeptide of the invention; collecting blood samples or other samples from said animal; determining the level or concentration of the polypeptide of the invention in said blood sample; and calculating, from (a plot of) the data thus obtained, the time until the level or concentration of the polypeptide of the invention has been reduced by 50% compared to the initial level upon dosing.
  • a suitable mammal such as a mouse, rabbit, rat, pig, dog or a primate
  • Macaca such as, and in particular, cynomolgus monkeys (Macaca fascicularis) and/or
  • the half-life can be expressed using parameters such as the tl/2-alpha, tl/2-beta and the area under the curve (AUC).
  • an "increase in half-life” refers to an increase in any one of these parameters, such as any two of these parameters, or essentially all three these parameters.
  • increase in half-life or “increased half-life” in particular refers to an increase in the tl/2-beta, either with or without an increase in the tl/2-alpha and/or the AUC or both.
  • Bioavailability refers to the fraction (or percent) of the administered dose systemically absorbed intact.
  • concentration of drug in the systemic circulation and, as such, refers to the rate of drug input into the systemic circulation.
  • dose refers to an amount of polypeptide of the invention that is administered to the subject.
  • dosing refers to the administration of the polypeptide of the invention.
  • a “dose regimen” refers to the schedule of doses of the polypeptide of the invention per unit of time.
  • an “equivalent dose (to an indicated dose regimen)” or “a dose equivalent to (an indicated dose regiment)" as used in the present invention means that the amount of polypeptide administered to the subject per unit of time is identical to the amount of polypeptide administered to the subject per unit of time in the indicated dose regimen.
  • weekly or “every week”, “biweekly” or “every 2 weeks”, “4 weekly” or “every 4 weeks” and “monthly” or “every month” in the context of "weekly”, “biweekly”, “4 weekly” and “monthly” administration and/or "weekly”, “biweekly”, “4 weekly” and “monthly” dosing schedule, as used herein, refer to the time course of administering the polypeptide of the invention to the subject to achieve the treatment of the IL-6R related disease.
  • a “weekly” dosing regimen the polypeptide of the invention is administered every week, such as every 5-9 days, more preferably, every 6-8 days, and most preferably, every 7 days.
  • the polypeptide of the invention is administered every 2 weeks, such as every 9-19 days, more preferably, every 11-17 days, even more preferably, every 13-15 days, and most preferably, every 14 days.
  • a "4 weekly” dosing regimen the polypeptide of the invention is administered every 4 weeks, such as every 23-33 days, more preferably, every 25-31 days, even more preferably, every 27-29 days, and most preferably, every 28 days.
  • a "monthly” dosing regimen the polypeptide of the invention is administered every month, such as every 25-34 days, more preferably, every 26-33 days, even more preferably, every 27-32 days, and most preferably, every 28-31 days.
  • Polypeptides of the invention may be non-naturally occurring.
  • the polypeptides of the invention may have been designed, manufactured, synthesized, and/or recombined to produce a non-naturally occurring sequence.
  • immunoglobulin sequence whether used herein to refer to a heavy chain antibody or to a conventional 4-chain antibody - is used as a general term to include both the full-size antibody, the individual chains thereof, as well as all parts, domains or fragments thereof (including but not limited to antigen-binding domains or fragments such as V HH domains or V H /V L domains, respectively).
  • sequence as used herein (for example in terms like “immunoglobulin sequence”, “antibody sequence”, “variable domain sequence”, “V HH sequence” or “protein sequence”), should generally be understood to include both the relevant amino acid sequence as well as nucleic acids or nucleotide sequences encoding the same, unless the context requires a more limited interpretation.
  • immunoglobulin single variable domain defines molecules wherein the antigen binding site is present on, and formed by, a single immunoglobulin domain. This sets immunoglobulin single variable domains apart from
  • VH heavy chain variable domain
  • VL light chain variable domain
  • CDRs complementarity determining regions
  • the binding site of an immunoglobulin single variable domain is formed by a single VH or VL domain.
  • the antigen binding site of an immunoglobulin single variable domain is formed by no more than three CDRs.
  • immunoglobulin single variable domain and "single variable domain” hence does not comprise conventional immunoglobulins or their fragments which require interaction of at least two variable domains for the formation of an antigen binding site. However, these terms do comprise fragments of conventional immunoglobulins wherein the antigen binding site is formed by a single variable domain.
  • immunoglobulin single variable domains will be amino acid sequences that essentially consist of 4 framework regions (FRl to FR4 respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively).
  • Such immunoglobulin single variable domains and fragments are most preferably such that they comprise an immunoglobulin fold or are capable for forming, under suitable conditions, an immunoglobulin fold.
  • the immunoglobulin single variable domain may for example comprise a light chain variable domain sequence (e.g. a VL-sequence) or a suitable fragment thereof; or a heavy chain variable domain sequence (e.g.
  • VHH sequence a VH-sequence or VHH sequence
  • a suitable fragment thereof as long as it is capable of forming a single antigen binding unit (i.e. a functional antigen binding unit that essentially consists of the immunoglobulin single variable domain, such that the single antigen binding domain does not need to interact with another variable domain to form a functional antigen binding unit, as is for example the case for the variable domains that are present in for example conventional antibodies and scFv fragments that need to interact with another variable domain - e.g. through a VH/VL interaction - to form a functional antigen binding domain).
  • a single antigen binding unit i.e. a functional antigen binding unit that essentially consists of the immunoglobulin single variable domain, such that the single antigen binding domain does not need to interact with another variable domain to form a functional antigen binding unit, as is for example the case for the variable domains that are present in for example conventional antibodies and scFv fragments that need to interact with another variable domain
  • the immunoglobulin single variable domains are light chain variable domain sequences (e.g. a VL-sequence), or heavy chain variable domain sequences (e.g. a VH-sequence); more specifically, the immunoglobulin single variable domains can be heavy chain variable domain sequences that are derived from a conventional four-chain antibody or heavy chain variable domain sequences that are derived from a heavy chain antibody.
  • the single variable domain or immunoglobulin single variable domain may be a (single) domain antibody (or an amino acid sequence that is suitable for use as a (single) domain antibody), a "dAb” or dAb (or an amino acid sequence that is suitable for use as a dAb) or a Nanobody (as defined herein, and including but not limited to a VHH sequence); other immunoglobulin single variable domains, or any suitable fragment of any one thereof.
  • (single) domain antibodies reference is also made to the patent and non-patent publications cited herein, as well as to EP 0 368 684.
  • dAb's reference is for example made to Ward et al. 1989 (Nature 341: 544-6), to Holt et al. 2003 (Trends Biotechnol. 21: 484-490); as well as to for example WO 04/068820, WO 06/030220, WO 06/003388 and other published patent applications of Domantis Ltd. It should also be noted that, although less preferred in the context of the present invention because they are not of mammalian origin, immunoglobulin single variable domains can be derived from certain species of shark (for example, the so-called "IgNAR domains", see for example WO 05/18629).
  • the immunoglobulin single variable domain may be a NANOBODY ® (as defined herein) or a suitable fragment thereof.
  • NANOBODY ® as defined herein
  • Nanobody 9 Nanobodies ® and Nanoclone ® are registered trademarks ofAblynx N.V.
  • WO 08/020079 page 16
  • an immunoglobulin sequence in particular an immunoglobulin single variable domain can be considered - without however being limited thereto - to be comprised of four framework regions or "FR's", which are referred to in the art and herein as "Framework region 1" or “FR1”; as “Framework region 2" or “FR2”; as “Framework region 3" or “FR3”; and as “Framework region 4" or “FR4", respectively; which framework regions are interrupted by three complementary determining regions or "CDR's", which are referred to in the art as
  • the total number of amino acid residues in an immunoglobulin single variable domain can be in the region of 110-120, is preferably 112-115, and is most preferably 113. It should however be noted that parts, fragments, analogs or derivatives of an immunoglobulin single variable domain are not particularly limited as to their length and/or size, as long as such parts, fragments, analogs or derivatives meet the further requirements outlined herein and are also preferably suitable for the purposes described herein.
  • Nanobodies in particular VHH sequences and partially humanized Nanobodies
  • Nanobodies including humanization and/or camelization of Nanobodies, as well as other modifications, parts or fragments, derivatives or "Nanobody fusions", multivalent constructs (including some non-limiting examples of linker sequences) and different modifications to increase the half-life of the Nanobodies and their preparations can be found e.g. in WO 08/101985 and WO 08/142164.
  • immunoglobulin single variable domain or “single variable domain” comprises polypeptides which are derived from a non-human source, preferably a camelid, preferably a camel heavy chain antibody. They may be humanized, as previously described. Moreover, the term comprises polypeptides derived from non-camelid sources, e.g. mouse or human, which have been “camelized”, as previously described.
  • immunoglobulin single variable domain encompasses immunoglobulin sequences of different origin, comprising mouse, rat, rabbit, donkey, human and camelid immunoglobulin sequences. It also includes fully human, humanized or chimeric immunoglobulin sequences. For example, it comprises camelid immunoglobulin sequences (such as e.g. VHHs) and humanized camelid immunoglobulin sequences (such as e.g. humanized VHHs), or camelized immunoglobulin single variable domains, e.g. camelized dAb as described by Ward et al (see for example WO
  • Immunoglobulin single variable domains (and polypeptides comprising the same) that are directed against IL-6R have been described in WO 2008/020079 and WO 2010/115998.
  • Preferred immunoglobulin single variable domains for use in the polypeptides of the invention include the improved Nanobodies described in WO 2010/115998.
  • Preferred immunoglobulin single variable domains that specifically bind IL-6R in some aspects have an apparent K D for binding to IL-6R, as determined by Biacore assay (surface plasmon resonance), of 1 nM to 1 pM (moles/litre) or less, preferably 500 pM to 1 pM (moles/litre) or less, more preferably 100 pM to 1 pM (moles/litre) or less, or even more preferably about 50 pM to 1 pM or less, such as 5xlO -n M or less.
  • Biacore assay surface plasmon resonance
  • Preferred immunoglobulin single variable domains that specifically bind IL-6 in some aspects block binding of IL-6 to IL-6R, as e.g. measured in a TF-1 proliferation assay as described for example in WO 2010/115998 and/or by Kitamura et al. (1989, J.
  • IC50 values at 100 lU/mL IL-6) between 10 nM and 50 pM, preferably between 5 nM and 50 pM, more preferably between 1 nM and 50 pM or less, such as about 750 or 500 pM or less or 10 -9 M or less and/or with an IC50 values (at 5000 lU/mL IL-6) between 50 nM and 1 nM, preferably between 25 nM and 1 nM, more preferably between 10 nM and 1 nM or less, such as about 8 nM or less.
  • preferred immunoglobulin single variable domains may essentially consist of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:
  • CDR1 is chosen from the group consisting of: SEQ ID NOs: 17-19;
  • CDR2 is chosen from the group consisting of: SEQ ID NO's: 21-28;
  • CDR3 is chosen from the group consisting of: SEQ ID NO's: 30-32.
  • the immunoglobulin single variable domain used in the polypeptide of the invention essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3
  • CDR1 to CDR3 complementarity determining regions
  • CDR1 is chosen from SEQ ID NO: 17;
  • CDR2 is chosen from SEQ ID NO: 21;
  • CDR3 is chosen from SEQ ID NO: 30.
  • Preferred immunoglobulin single variable domains for use in the polypeptide of the invention include SEQ ID NO's: 1-10, more particularly SEQ ID NO's: 1, 6, and 8-10 of which SEQ ID NO: 1 is particularly preferred.
  • the immunoglobulin single variable domains for use in the method of the invention may form part of a polypeptide (referred herein as "polypeptide of the invention"), which may comprise, consist essentially of, or consist of one or more immunoglobulin single variable domains that specifically binds IL-6R and which may optionally further comprise one or more further amino acid sequences (all optionally linked via one or more suitable linkers).
  • polypeptide of the invention may comprise, consist essentially of, or consist of one or more immunoglobulin single variable domains that specifically binds IL-6R and which may optionally further comprise one or more further amino acid sequences (all optionally linked via one or more suitable linkers).
  • immunoglobulin single variable domain may also encompass such polypeptide of the invention.
  • the one or more immunoglobulin single variable domains may be used as a binding unit in such a polypeptide, which may optionally contain one or more further amino acid sequences that can serve as a binding unit, so as to provide a monovalent, multivalent or multispecific polypeptide of the invention, respectively (for multivalent and multispecific polypeptides containing one or more VHH domains and their preparation, reference is also made to Conrath et al. 2001 (J. Biol. Chem. 276: 7346-7350), as well as to for example WO 96/34103, WO 99/23221 and WO 2010/115998).
  • polypeptides of the invention may encompass constructs comprising two or more antigen binding units in the form of single variable domains.
  • two (or more) immunoglobulin single variable domains with the same or different antigen specificity can be linked to form e.g. a bivalent, trivalent or multivalent construct.
  • an immunoglobulin single variable domain according to the invention may comprise two or three immunoglobulin single variable domains directed against the same target (i.e. IL-6R), or one or two immunoglobulin single variable domains directed against target A (i.e. IL-6R), and one
  • immunoglobulin single variable domain against target B Such constructs and modifications thereof, which the skilled person can readily envisage, are all encompassed by the term immunoglobulin single variable domain as used herein.
  • the polypeptide of the invention that comprises, consists essentially of, or consists of one or more immunoglobulin single variable domains that specifically bind IL-6R, may further comprise one or more other groups, residues, moieties or binding units. Such further groups, residues, moieties, binding units may or may not provide further functionality to the immunoglobulin single variable domain (and/or to the polypeptide in which it is present) and may or may not modify the properties of the immunoglobulin single variable domain.
  • such further groups, residues, moieties or binding units may be one or more additional amino acid sequences, such that the compound, construct or polypeptide is a (fusion) protein or (fusion) polypeptide.
  • said one or more other groups, residues, moieties or binding units are immunoglobulin sequences, preferably
  • said one or more other groups, residues, moieties or binding units are chosen from the group consisting of domain antibodies, amino acid sequences that are suitable for use as a domain antibody, single domain antibodies, amino acid sequences that are suitable for use as a single domain antibody, "dAb”'s, amino acid sequences that are suitable for use as a dAb, or Nanobodies.
  • such groups, residues, moieties or binding units may for example be chemical groups, residues, moieties, which may or may not by themselves be biologically and/or
  • such groups may be linked to the one or more immunoglobulin single variable domain so as to provide a "derivative" of the
  • the one or more immunoglobulin single variable domains and the one or more groups, residues, moieties or binding units may be linked directly to each other and/or via one or more suitable linkers or spacers.
  • the linkers may also be amino acid sequences, so that the resulting polypeptide is a fusion (protein) or fusion (polypeptide).
  • Suitable spacers or linkers for use in multivalent and/or multispecific polypeptides will be clear to the skilled person, and may generally be any linker or spacer used in the art to link amino acid sequences.
  • said linker or spacer is suitable for use in constructing proteins or
  • polypeptides that are intended for pharmaceutical use.
  • Some particularly preferred spacers include the spacers and linkers that are used in the art to link antibody fragments or antibody domains. These include the linkers mentioned in the general background patent and non-patent publications cited above, as well as for example linkers that are used in the art to construct diabodies or ScFv fragments (in this respect, however, it should be noted that, whereas in diabodies and in ScFv fragments, the linker sequence used should have a length, a degree of flexibility and other properties that allow the pertinent V H and V L domains to come together to form the complete antigen-binding site, there is no particular limitation on the length or the flexibility of the linker used in the polypeptide of the invention, since each amino acid sequence or Nanobody by itself forms a complete antigen-binding site).
  • a linker may be a suitable amino acid sequence, and in particular amino acid sequences of between 1 and 50, preferably between 1 and 30, such as between 1 and 20 or between 1 and 10 amino acid residues.
  • Widely used peptide linkers comprise Gly-Ser repeats, e.g. (Gly)4-Ser in one, two, three, four, five, six or more repeats, or for example of the type (gly x ser y ) z , such as (for example (gly 4 ser) 3 or (gly 3 ser 2 ) 3 , as described in WO 99/42077, or hinge-like regions such as the hinge regions of naturally occurring heavy chain antibodies or similar sequences (such as described in WO 94/04678).
  • Some other particularly preferred linkers are poly-alanine (such as AAA), as well as the linkers mentioned in Table A-5, of which Ala (AAA), 7GS (GS-7), GS8 (GS-8) and 9GS (GS-9) are particularly preferred.
  • linkers generally comprise organic compounds or polymers, in particular those suitable for use in proteins for pharmaceutical use.
  • poly(ethyleneglycol) moieties have been used to link antibody domains, see for example WO 04/081026.
  • a polypeptide of the invention is prepared that has an increased half-life, compared to the corresponding immunoglobulin single variable domain.
  • polypeptides of the invention that comprise such half-life extending moieties for example include, without limitation, polypeptides in which the immunoglobulin single variable domain is suitable linked to one or more serum proteins or fragments thereof (such as (human) serum albumin or suitable fragments thereof) or to one or more binding units or peptides that can bind to serum proteins (such as, for example, domain antibodies, amino acid sequences that are suitable for use as a domain antibody, single domain antibodies, amino acid sequences that are suitable for use as a single domain antibody, "dAb"'s, amino acid sequences that are suitable for use as a dAb, or Nanobodies that can bind to serum proteins such as serum albumin (such as human serum albumin), serum immunoglobulins such as IgG, or transferrin); or polypeptides in which the one or more immunoglobulin single variable domain
  • a preferred polypeptide of the invention comprises one or more immunoglobulin single variable domains against IL-6 , e.g. according to SEQ ID NO's: 1-10, in particular SEQ ID NO: 1, in combination with at least one binding domain or peptide suitable for extending serum half-life (preferably ⁇ 1/2 ⁇ ) of the construct.
  • the "serum-albumin binding domain or peptide” may be any suitable serum-albumin binding peptide or binding domain capable of increasing the half-life (preferably ⁇ 1/2 ⁇ ) of the construct (compared to the same construct without the serum-albumin binding peptide or binding domain).
  • the polypeptide sequence suitable for extending serum half-life is a polypeptide sequence capable of binding to a serum protein with a long serum half-life, such as serum albumin, transferring, IgG, etc., in particular serum albumin.
  • Polypeptide sequences capable of binding to serum albumin have previously been described and may in particular be serum albumin binding peptides as described in WO 08/068280 by applicant (and in particular WO 09/127691 and WO 2011/095545, both by applicant), or a serum albumin binding immunoglobulin single variable domains (such as a serum-albumin binding Nanobody; for example SEQ ID NOs 37-39, for which reference is for example made to WO 06/122787 and Table A-4).
  • the one or more immunoglobulin single variable domain binding to IL-6R and the amino acid sequences or domains suitable for extending serum half-life can be fused with or without a linker, e.g. a peptide linker.
  • one or more immunoglobulin single variable domains against IL-6R e.g. according to SEQ ID NO's: 1-10, in particular SEQ ID NO: 1 is linked to a serum albumin binding immunoglobulin single variable domains, such as for example SEQ ID NO's: 37-39.
  • Preferred polypeptides of the invention include SEQ ID NO's: 34-36, particularly SEQ ID NO: 34.
  • SEQ ID NO: 34 is a bivalent polypeptide consisting of 2 humanized and sequence-optimized immunoglobulin variable domains derived from heavy chain-only llama antibodies.
  • One domain (SEQ ID NO: 1) binds to human IL-6R and the second domain (SEQ ID NO: 38) binds to human serum albumin (HSA), as a means to improve the PK properties of the polypeptide (half-life extension).
  • the polypeptides of the invention may be produced by a method comprising the following steps: a) expressing, in a suitable host cell or host organism or in another suitable expression system, a nucleic acid or nucleotide sequence, or a genetic construct encoding the polypeptide of the invention;
  • the method for producing the polypeptide of the invention may comprise the steps of:
  • the polypeptide of the invention is produced in a bacterial cell, in particular a bacterial cell suitable for large scale pharmaceutical production.
  • the polypeptide of the invention is produced in a yeast cell, in particular a yeast cell suitable for large scale pharmaceutical production.
  • the polypeptide of the invention is produced in a mammalian cell, in particular in a human cell or in a cell of a human cell line, and more in particular in a human cell or in a cell of a human cell line that is suitable for large scale pharmaceutical production.
  • preferred heterologous hosts for the (industrial) production of immunoglobulin single variable domains or immunoglobulin single variable domain-containing protein therapeutics include strains of E. coli, Pichia pastoris, S. cerevisiae that are suitable for large scale expression/production/fermentation, and in particular for large scale pharmaceutical expression/production/fermentation. Suitable examples of such strains will be clear to the skilled person. Such strains and production/expression systems are also made available by companies such as Biovitrum (Uppsala, Sweden).
  • mammalian cell lines in particular Chinese hamster ovary (CHO) cells, can be used for large scale expression/production/fermentation, and in particular for large scale pharmaceutical expression/production/fermentation.
  • CHO Chinese hamster ovary
  • the polypeptide of the invention may then be isolated from the host cell/host organism and/or from the medium in which said host cell or host organism was cultivated, using protein isolation and/or purification techniques known per se, such as (preparative) chromatography and/or electrophoresis techniques, differential precipitation techniques, affinity techniques (e.g. using a specific, cleavable amino acid sequence fused with the polypeptide of the invention) and/or preparative immunological techniques (i.e. using antibodies against the amino acid sequence to be isolated).
  • protein isolation and/or purification techniques known per se such as (preparative) chromatography and/or electrophoresis techniques, differential precipitation techniques, affinity techniques (e.g. using a specific, cleavable amino acid sequence fused with the polypeptide of the invention) and/or preparative immunological techniques (i.e. using antibodies against the amino acid sequence to be isolated).
  • compositions and pharmaceutical administration are provided.
  • the polypeptides of the invention may be formulated as a pharmaceutical preparation, compositions or formulations (used interchangeably) comprising at least one polypeptide of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally one or more further pharmaceutically active polypeptides and/or compounds.
  • a formulation should be in a form suitable for subcutaneous administration.
  • polypeptides of the invention can be formulated in any suitable manner which is suitable for subcutaneous administration known per se, for which reference is for example made to the general background patent and non-patent publications cited above (and in particular to WO 04/041862, WO 04/041863, WO 04/041865 and WO 04/041867) as well as to the standard handbooks, such as
  • Preparations for subcutaneous administration may for example be sterile solutions, suspensions, dispersions or emulsions that are suitable for infusion or injection.
  • Suitable carriers or diluents for such preparations for example include, without limitation, sterile water and aqueous buffers (such as e.g. histidine or citrate buffers) and solutions such as physiological phosphate-buffered saline, Ringer's solutions, dextrose solution, and Hank's solution; water oils; glycerol; ethanol; glycols such as propylene glycol, as well as mineral oils, animal oils and vegetable oils, for example peanut oil, soybean oil, as well as suitable mixtures thereof.
  • aqueous solutions or suspensions will be preferred.
  • the invention also encompasses products obtainable by further processing of a liquid formulation, such as a frozen, lyophilized or spray dried product.
  • a liquid formulation such as a frozen, lyophilized or spray dried product.
  • these solid products can become liquid formulations as described herein (but are not limited thereto).
  • the term "formulation" encompasses both liquid and solid formulations.
  • solid formulations are understood as derivable from the liquid formulations (e.g. by freezing, freeze-drying or spray-drying), and hence have characteristics that are defined by the features specified for liquid formulations herein.
  • the invention does not exclude reconstitution that leads to a composition that deviates from the original composition before e.g. freeze- or spray drying.
  • Sterile injectable solutions are prepared by incorporating the polypeptides of the invention in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • compositions for use with the polypeptides of the invention include, without being limiting, histidine buffer at pH 6.5, sucrose and polysorbate 80 (such as e.g. 15 mM histidine buffer pH 6.5, 8% sucrose and 0.01 % polysorbate 80).
  • the concentration of the polypeptides of the invention in a liquid composition will be from about 0.1-25 wt-%, preferably from about 0.5-10 wt-%, although the amounts are not limited to these ranges and may be higher or lower weight percentages depending on the need for higher or lower doses that can be administered in a volume that is suitable.
  • concentrations of 150 mg/mL have been used for subcutaneous administration of the polypeptide of the invention. It is expected that other concentrations having values around these concentrations (and also outside these values, i.e., higher or lower than these values) therefore also can be used. For example, concentrations of 10, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 120, 150 mg/mL or more can be used.
  • Pre-filled syringes are highly suitable for subcutaneous administration of therapeutics.
  • the pharmaceutical composition is loaded into a pre-filled syringe.
  • the present invention also relates to a pre-filled syringe containing a pharmaceutical composition comprising the polypeptide of the invention.
  • the pre-filled syringe contains a pharmaceutical composition that comprises SEQ ID NO: 34.
  • the polypeptide (such as SEQ ID NO: 34) of the invention can be present in the pre-filled syringe at any suitable concentration such as 10, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 120, 150 mg/mL or more.
  • the polypeptide of the invention (such as SEQ ID NO: 34) is present in the pre-filled syringe at a concentration of 150 mg/mL.
  • the volume of the pre-filled syringe is preferably from 0.25 to 5.0 ml, such as from 0.25 to 2 ml, most preferably from 0.5 to 1 ml, such as 0.5 ml or 1 ml.
  • the polypeptide of the invention is administered at a dose of 75-300 mg.
  • the desired dose may conveniently be presented in a single dose or as divided doses, for example, as two separate subcutaneous injections.
  • one single injection can be used with a 0.5 ml pre-filled syringe comprising the polypeptide of the invention at a concentration of 150 mg/mL.
  • one single injection can be used with a 1 ml pre-filled syringe comprising the polypeptide of the invention at a concentration of 150 mg/mL.
  • two injections can be used, one with a 0.5 mL pre-filled syringe and one with a 1 ml pre-filled syringe respectively, each pre-filled syringe comprising the polypeptide of the invention at a concentration of 150 mg/mL.
  • two injections can be used, each with a 1 ml pre-filled syringe comprising the polypeptide of the invention at a concentration of 150 mg/mL.
  • the polypeptide of the invention is administered subcutaneously every week (weekly). Based on the bioavailability study as described in the examples section, a preferred dose for weekly subcutaneous administration of the polypeptides is 75-150 mg, such as a weekly dose of 75 mg, 150-200 mg, such as a weekly dose of 150 mg, 200-250 mg, such as a weekly dose of 225 mg, or even 250-300 mg, such as a weekly dose of 300 mg, or at a dose equivalent thereto.
  • the polypeptide of the invention is administered subcutaneously every 2 weeks (biweekly).
  • a preferred dose for biweekly subcutaneous administration of the polypeptides is 75-150 mg, such as a biweekly dose of 75 mg, 150-200 mg, such as a biweekly dose of 150 mg, 200-250 mg, such as a biweekly dose of 225 mg, or even 250-300 mg, such as a biweekly dose of 300 mg, or at a dose equivalent thereto.
  • the polypeptide of the invention is administered subcutaneously every 4 weeks (4 weekly). Based on the bioavailability study as described in the examples section, a preferred dose for 4 weekly subcutaneous administration of the polypeptides is 75-150 mg, such as a 4 weekly dose of 75 mg, 150-200 mg, such as a 4 weekly dose of 150 mg, 200-250 mg, such as a 4 weekly dose of 225 mg, or even 250-300 mg, such as a 4 weekly dose of 300 mg, or at a dose equivalent thereto.
  • the polypeptide of the invention is administered subcutaneously every month (monthly). Based on the bioavailability study as described in the examples section, a preferred dose for monthly subcutaneous administration of the polypeptides is 75-150 mg, such as a monthly dose of 75 mg, 150-200 mg, such as a monthly dose of 150 mg, 200-250 mg, such as a monthly dose of 225 mg, or even 250-300 mg, such as a monthly dose of 300 mg, or at a dose equivalent thereto.
  • the present invention relates to pre-filled syringe comprising the polypeptide of the invention for the treatment of an IL-6 related disease in a human subject, said method comprising subcutaneous administration to a human subject suffering the IL-6R related disease, of a polypeptide of the invention at the selected dosing schedule. More specifically, the present invention relates to pre-filled syringe comprising the polypeptide of the invention for the treatment of an IL-6R related disease in a human subject, said method comprising subcutaneous administration to a human subject suffering the IL-6 related disease, of a polypeptide of the invention at a dose of 75-300 mg every week to every month, or at a dose equivalent to 75-300 mg every week to every month.
  • the polypeptide in the pre-filled syringe is administered at a dose of 75-300 mg every week or at a dose equivalent to 75-300 mg every week. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 75-150 mg every week or at a dose equivalent to 75- 150 mg every week. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 75 mg every week or at a dose equivalent to 75 mg every week. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 150-200 mg every week or at a dose equivalent to 150-200 mg every week.
  • the polypeptide in the pre-filled syringe is administered at a dose of 150 mg every week or at a dose equivalent to 150 mg every week. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 200-250 mg every week or at a dose equivalent to 200-250 mg every week. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 225 mg every week or at a dose equivalent to 225 mg every week. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 250-300 mg every week or at a dose equivalent to 250-300 mg every week. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 300 mg every week or at a dose equivalent to 300 mg every week.
  • the polypeptide in the pre-filled syringe is administered at a dose of 75-300 mg every 2 weeks or at a dose equivalent to 75-300 mg every 2 weeks. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 75-150 mg every 2 weeks or at a dose equivalent to 75-150 mg every 2 weeks. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 75 mg every 2 weeks or at a dose equivalent to 75 mg every 2 weeks. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 150-200 mg every 2 weeks or at a dose equivalent to 150-200 mg every 2 weeks.
  • the polypeptide in the pre-filled syringe is administered at a dose of 150 mg every 2 weeks or at a dose equivalent to 150 mg every 2 weeks. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 200-250 mg every 2 weeks or at a dose equivalent to 200-250 mg every 2 weeks. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 225 mg every 2 weeks or at a dose equivalent to 225 mg every 2 weeks. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 250-300 mg every 2 weeks or at a dose equivalent to 250-300 mg every 2 weeks. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 300 mg every 2 weeks or at a dose equivalent to 300 mg every 2 weeks.
  • the polypeptide in the pre-filled syringe is administered at a dose of 75-300 mg every 4 weeks or at a dose equivalent to 75-300 mg every 4 weeks. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 75-150 mg every 4 weeks or at a dose equivalent to 75-150 mg every 4 weeks. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 75 mg every 4 weeks or at a dose equivalent to 75 mg every 4 weeks. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 150-200 mg every 4 weeks or at a dose equivalent to 150-200 mg every 4 weeks.
  • the polypeptide in the pre-filled syringe is administered at a dose of 150 mg every 4 weeks or at a dose equivalent to 150 mg every 4 weeks. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 200-250 mg every 4 weeks or at a dose equivalent to 200-250 mg every 4 weeks. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 225 mg every 4 weeks or at a dose equivalent to 225 mg every 4 weeks. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 250-300 mg every 4 weeks or at a dose equivalent to 250-300 mg every 4 weeks. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 300 mg every 4 weeks or at a dose equivalent to 300 mg every 4 weeks.
  • the polypeptide in the pre-filled syringe is administered at a dose of 75-300 mg every month or at a dose equivalent to 75-300 mg every month. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 75-150 mg every month or at a dose equivalent to 75- 150 mg every month. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 75 mg every month or at a dose equivalent to 75 mg every month. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 150-200 mg every month or at a dose equivalent to 150-200 mg every month.
  • the polypeptide in the pre-filled syringe is administered at a dose of 150 mg every month or at a dose equivalent to 150 mg every month. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 200-250 mg every month or at a dose equivalent to 200-250 mg every month. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 225 mg every month or at a dose equivalent to 225 mg every month. In one aspect the polypeptide in the pre-filled syringe is administered at a dose of 250-300 mg every month or at a dose equivalent to 250-300 mg every month. In one aspect the polypeptide in the pre- filled syringe is administered at a dose of 300 mg every month or at a dose equivalent to 300 mg every month.
  • the human subject is suffering from rheumatoid arthritis. In one aspect, the human subject is suffering from active rheumatoid arthritis. In one aspect, the human subject is suffering from active rheumatoid arthritis despite methotrexate therapy. In one aspect, the human subject is suffering from rheumatoid arthritis and is intolerant to MTX. In one aspect, the human subject is suffering from rheumatoid arthritis and continuation of MTX treatment is inappropriate.
  • the human subject is suffering from systemic lupus erythematosus. In one aspect, the human subject is suffering from moderate to severe active systemic lupus erythematosus.
  • the present invention provides methods and dosing schedules for subcutaneous administration of polypeptides that bind and block IL-6R. As such, these methods and dosing schedules can be used for the prevention and treatment (as defined herein) of diseases and/or disorders related to IL-6 mediated signaling, also referred to herein as IL-6R related diseases.
  • diseases and/or disorders related to IL-6 mediated signaling can be defined as diseases and/or disorders that can be prevented and/or treated, respectively, by suitably
  • a subject in need thereof i.e. having the disease and/or disorder or at least one symptom thereof and/or at risk of attracting or developing the disease or disorder
  • a polypeptide of the invention and in particular, of a pharmaceutically active amount thereof
  • a known active principle active against IL-6, IL-6R, the IL-6/IL-6R complex (optionally in further complex with gpl30) or a biological pathway or mechanism in which IL-6 and IL-6R are involved (and in particular, of a pharmaceutically active amount thereof).
  • Diseases and/or disorders related to IL-6 mediated signaling encompass diseases and disorders associated with IL-6R, with IL-6, with the IL-6/IL-6R complex (optionally in further complex with gpl30), and/or with the signaling pathway(s) and/or the biological functions and responses in which IL-6 , IL-6R and/or the IL-6/IL-6R complex (optionally in further complex with gpl30) are involved, and in particular diseases and disorders associated with IL-6R, with IL-6, with the IL-6/IL-6R complex (optionally in further complex with gpl30), and/or with the signaling pathway(s) and/or the biological functions and responses in which IL-6R, IL-6 and/or the IL-6/IL-6R complex (optionally in further complex with gpl30) are involved, which are characterized by excessive and/or unwanted signaling mediated by IL-6 or by the pathway(s) in which IL-6 is involved.
  • diseases and disorders are also generally referred to
  • the invention thus also relates to a polypeptide of the invention for use in the prevention and treatment (as defined herein) of these "IL-6R related diseases” and/or “diseases and/or disorders related to IL-6 mediated signaling" wherein the polypeptide is administered subcutaneously at the dosing schedule provided by the present invention.
  • prevention and/or treatment not only comprises preventing and/or treating the disease, but also generally comprises preventing the onset of the disease, slowing or reversing the progress of disease, preventing or slowing the onset of one or more symptoms associated with the disease, reducing and/or alleviating one or more symptoms associated with the disease, reducing the severity and/or the duration of the disease and/or of any symptoms associated therewith and/or preventing a further increase in the severity of the disease and/or of any symptoms associated therewith, preventing, reducing or reversing any physiological damage caused by the disease, and generally any pharmacological action that is beneficial to the patient being treated.
  • the subject to be treated may be a human being.
  • the subject to be treated will in particular be a person suffering from, or at risk of, the diseases and/or disorders mentioned herein.
  • the subject may be a person suffering from, or at risk of, a disease and/or disorder related to IL-6 mediated signaling and/or a disease in which IL-6 activity is detrimental.
  • the subject treated is a person suffering from rheumatoid arthritis (RA). More specifically, the subject treated is a person diagnosed with RA according to the 2010 European League against Rheumatism [EULARj/American College of Rheumatology [ACR] classification criteria.
  • RA rheumatoid arthritis
  • the subject treated has an ACR functional class l-lll.
  • the subject treated is suffering from moderate to severe RA.
  • the subject treated is suffering from active RA.
  • Active RA is defined in the present invention by persistent disease activity with at least 6 swollen and 6 tender joints (66/68-joint count), at the time of screening and baseline, and C-reactive protein (CRP) > 1.2 x upper limit of normal (ULN) at screening.
  • CRP C-reactive protein
  • the subject treated is suffering from active RA despite methotrexate therapy.
  • the subject has received previous or current treatment with MTX, and is considered intolerant to MTX, and/or for whom continued treatment with MTX is considered inappropriate, or has contraindications for MTX use.
  • Patients and physicians may discontinue MTX- treatment for a number of reasons, including gastrointestinal, hepatic, dermatologic as well as neurologic AEs.
  • the subject treated is a person suffering from RA and intolerant to MTX and/or the human subject treated is suffering from RA for whom continuation of MTX treatment is inappropriate.
  • the polypeptide of the invention is administered subcutaneously at a dose of 75-300 mg every week to every month or at a dose equivalent to 75-300 mg every week to every month.
  • the desired dose may conveniently be presented in a single dose or as divided doses, for example, as two separate subcutaneous injections (as described above).
  • the polypeptide of the invention is administered subcutaneously every week (weekly). Based on the bioavailability study as described in the examples section, a preferred dose for weekly subcutaneous administration of the polypeptides is 75-150 mg, such as a weekly dose of 75 mg or a dose equivalent to 75 mg every week. Another preferred dose for weekly subcutaneous administration of the polypeptides is 150-200 mg, such as a weekly dose of 150 mg or a dose equivalent to 150 mg every week. Another preferred dose for weekly subcutaneous administration of the polypeptides is 200-250 mg, such as a weekly dose of 225 mg or a dose equivalent to 225 mg every week. Another preferred dose for weekly subcutaneous administration of the polypeptides is 250-300 mg, such as a weekly dose of 300 mg or a dose equivalent to 300 mg every week.
  • the present invention relates to a method and a polypeptide of the invention for (use in) treatment of an IL-6 related disease, wherein the polypeptide of the invention is administered subcutaneously at a dose of 75-150 mg every week, such as a weekly dose of 75 mg or a dose equivalent to 75 mg every week, or 150-200 mg every week, such as a weekly dose of 150 mg or a dose equivalent to 150 mg every week, or 200-250 mg every week, such as a weekly dose of 225 mg or a dose equivalent to 225 mg every week, or 250-300 mg every week, such as a weekly dose of 300 mg or a dose equivalent to 300 mg every week.
  • a dose of 75-150 mg every week such as a weekly dose of 75 mg or a dose equivalent to 75 mg every week, or 150-200 mg every week, such as a weekly dose of 150 mg or a dose equivalent to 150 mg every week, or 200-250 mg every week, such as a weekly dose of 225 mg or a dose equivalent to 225 mg every week,
  • the present invention relates to a method and a polypeptide of the invention for (use in) treatment of RA, wherein the polypeptide of the invention is administered subcutaneously at a dose of 75-150 mg every week, such as a weekly dose of 75 mg or a dose equivalent to 75 mg every week, or 150-200 mg every week, such as a weekly dose of 150 mg or a dose equivalent to 150 mg every week, or 200-250 mg every week, such as a weekly dose of 225 mg or a dose equivalent to 225 mg every week, or 250-300 mg every week, such as a weekly dose of 300 mg or a dose equivalent to 300 mg every week.
  • the present invention relates to a method and a polypeptide of the invention for (use in) treatment of active RA, wherein the polypeptide of the invention is administered
  • a dose of 75-150 mg every week such as a weekly dose of 75 mg or a dose equivalent to 75 mg every week, or 150-200 mg every week, such as a weekly dose of 150 mg or a dose equivalent to 150 mg every week, or 200-250 mg every week, such as a weekly dose of 225 mg or a dose equivalent to 225 mg every week, or 250-300 mg every week, such as a weekly dose of 300 mg or a dose equivalent to 300 mg every week.
  • the present invention relates to a method and a polypeptide of the invention for (use in) treatment of active RA despite MTX therapy, wherein the polypeptide of the invention is administered subcutaneously at a dose of 75-150 mg every week, such as a weekly dose of 75 mg or a dose equivalent to 75 mg every week, or 150-200 mg every week, such as a weekly dose of 150 mg or a dose equivalent to 150 mg every week, or 200-250 mg every week, such as a weekly dose of 225 mg or a dose equivalent to 225 mg every week, or 250-300 mg every week, such as a weekly dose of 300 mg or a dose equivalent to 300 mg every week.
  • a dose of 75-150 mg every week such as a weekly dose of 75 mg or a dose equivalent to 75 mg every week, or 150-200 mg every week, such as a weekly dose of 150 mg or a dose equivalent to 150 mg every week, or 200-250 mg every week, such as a weekly dose of 225 mg or a dose equivalent to 225 mg
  • the polypeptide of the invention is administered subcutaneously every 2 weeks (biweekly). Based on the bioavailability study as described in the examples section, a preferred dose for biweekly subcutaneous administration of the polypeptides is 75-150 mg, such as a biweekly dose of 75 mg or a dose equivalent to 75 mg every 2 weeks. Another preferred dose for biweekly subcutaneous administration of the polypeptides is 150-200 mg, such as a biweekly dose of 150 mg or a dose equivalent to 150 mg every 2 weeks. Another preferred dose for biweekly subcutaneous administration of the polypeptides is 200-250 mg, such as a biweekly dose of 225 mg or a dose equivalent to 225 mg every 2 weeks. Another preferred dose for biweekly subcutaneous administration of the polypeptides is 250-300 mg, such as a biweekly dose of 300 mg or a dose equivalent to 300 mg every 2 weeks.
  • the present invention relates to a method and a polypeptide of the invention for (use in) treatment of an IL-6 related disease, wherein the polypeptide of the invention is administered subcutaneously at a dose of 75-150 mg every two weeks, such as a biweekly dose of 75 mg or a dose equivalent to 75 mg every two weeks, or 150-200 mg every two weeks, such as a biweekly dose of 150 mg or a dose equivalent to 150 mg every two weeks, or 200-250 mg every two weeks, such as a biweekly dose of 225 mg or a dose equivalent to 225 mg every two weeks, or 250- 300 mg every two weeks, such as a biweekly dose of 300 mg or a dose equivalent to 300 mg every two weeks.
  • a dose of 75-150 mg every two weeks such as a biweekly dose of 75 mg or a dose equivalent to 75 mg every two weeks, or 150-200 mg every two weeks, such as a biweekly dose of 150 mg or a dose equivalent to 150 mg every two weeks, or 200-250 mg every
  • the present invention relates to a method and a polypeptide of the invention for (use in) treatment of RA, wherein the polypeptide of the invention is administered subcutaneously at a dose of 75-150 mg every two weeks, such as a biweekly dose of 75 mg or a dose equivalent to 75 mg every two weeks, or 150-200 mg every two weeks, such as a biweekly dose of 150 mg or a dose equivalent to 150 mg every two weeks, or 200-250 mg every two weeks, such as a biweekly dose of 225 mg or a dose equivalent to 225 mg every two weeks, or 250-300 mg every two weeks, such as a biweekly dose of 300 mg or a dose equivalent to 300 mg every two weeks.
  • a dose of 75-150 mg every two weeks such as a biweekly dose of 75 mg or a dose equivalent to 75 mg every two weeks, or 150-200 mg every two weeks, such as a biweekly dose of 150 mg or a dose equivalent to 150 mg every two weeks, or 200-250 mg every two weeks, such
  • the present invention relates to a method and a polypeptide of the invention for (use in) treatment of active RA, wherein the polypeptide of the invention is administered subcutaneously at a dose of 75-150 mg every two weeks, such as a biweekly dose of 75 mg or a dose equivalent to 75 mg every two weeks, or 150-200 mg every two weeks, such as a biweekly dose of 150 mg or a dose equivalent to 150 mg every two weeks, or 200-250 mg every two weeks, such as a biweekly dose of 225 mg or a dose equivalent to 225 mg every two weeks, or 250-300 mg every two weeks, such as a biweekly dose of 300 mg or a dose equivalent to 300 mg every two weeks.
  • a dose of 75-150 mg every two weeks such as a biweekly dose of 75 mg or a dose equivalent to 75 mg every two weeks, or 150-200 mg every two weeks, such as a biweekly dose of 150 mg or a dose equivalent to 150 mg every two weeks, or 200-250 mg every two weeks,
  • the present invention relates to a method and a polypeptide of the invention for (use in) treatment of active RA despite MTX therapy, wherein the polypeptide of the invention is administered subcutaneously at a dose of 75-150 mg every two weeks, such as a biweekly dose of 75 mg or a dose equivalent to 75 mg every two weeks, or 150-200 mg every two weeks, such as a biweekly dose of 150 mg or a dose equivalent to 150 mg every two weeks, or 200-250 mg every two weeks, such as a biweekly dose of 225 mg or a dose equivalent to 225 mg every two weeks, or 250-300 mg every two weeks, such as a biweekly dose of 300 mg or a dose equivalent to 300 mg every two weeks.
  • a dose of 75-150 mg every two weeks such as a biweekly dose of 75 mg or a dose equivalent to 75 mg every two weeks, or 150-200 mg every two weeks, such as a biweekly dose of 150 mg or a dose equivalent to 150 mg every two weeks, or 200-
  • the polypeptide of the invention is administered subcutaneously every 4 weeks (4 weekly). Based on the bioavailability study as described in the examples section, a preferred dose for 4 weekly subcutaneous administration of the polypeptides is 75-150 mg, such as a 4 weekly dose of 75 mg or a dose equivalent to 75 mg every 4 weeks. Another preferred dose for 4 weekly subcutaneous administration of the polypeptides is 150-200 mg, such as a 4 weekly dose of 150 mg or a dose equivalent to 150 mg every 4 weeks. Another preferred dose for 4 weekly subcutaneous administration of the polypeptides is 200-250 mg, such as a 4 weekly dose of 225 mg or a dose equivalent to 225 mg every 4 weeks. Another preferred dose for 4 weekly subcutaneous
  • administration of the polypeptides is 250-300 mg, such as a 4 weekly dose of 300 mg or a dose equivalent to 300 mg every 4 weeks.
  • the present invention relates to a method and a polypeptide of the invention for (use in) treatment of an IL-6 related disease, wherein the polypeptide of the invention is administered subcutaneously at a dose of 75-150 mg every four weeks, such as a 4 weekly dose of 75 mg or a dose equivalent to 75 mg every 4 weeks, or 150-200 mg every four weeks, such as a 4 weekly dose of 150 mg or a dose equivalent to 150 mg every 4 weeks, or 200-250 mg every four weeks, such as a 4 weekly dose of 225 mg or a dose equivalent to 225 mg every 4 weeks, or 250-300 mg every four weeks, such as a 4 weekly dose of 300 mg or a dose equivalent to 300 mg every 4 weeks.
  • a 4 weekly dose of 75 mg or a dose equivalent to 75 mg every 4 weeks such as a 4 weekly dose of 75 mg or a dose equivalent to 75 mg every 4 weeks, or 150-200 mg every four weeks, such as a 4 weekly dose of 150 mg or a dose equivalent to 150 mg every 4 weeks, or 200-250
  • the present invention relates to a method and a polypeptide of the invention for (use in) treatment of RA, wherein the polypeptide of the invention is administered subcutaneously at a dose of 75-150 mg every four weeks, such as a 4 weekly dose of 75 mg or a dose equivalent to 75 mg every 4 weeks, or 150-200 mg every four weeks, such as a 4 weekly dose of 150 mg or a dose equivalent to 150 mg every 4 weeks, or 200-250 mg every four weeks, such as a 4 weekly dose of 225 mg or a dose equivalent to 225 mg every 4 weeks, or 250-300 mg every four weeks, such as a 4 weekly dose of 300 mg or a dose equivalent to 300 mg every 4 weeks.
  • a 4 weekly dose of 75 mg or a dose equivalent to 75 mg every 4 weeks such as a 4 weekly dose of 75 mg or a dose equivalent to 75 mg every 4 weeks, or 150-200 mg every four weeks, such as a 4 weekly dose of 150 mg or a dose equivalent to 150 mg every 4 weeks, or 200-250 mg every four weeks
  • the present invention relates to a method and a polypeptide of the invention for (use in) treatment of active RA, wherein the polypeptide of the invention is administered subcutaneously at a dose of 75-150 mg every four weeks, such as a 4 weekly dose of 75 mg or a dose equivalent to 75 mg every 4 weeks, or 150-200 mg every four weeks, such as a 4 weekly dose of 150 mg or a dose equivalent to 150 mg every 4 weeks, or 200-250 mg every four weeks, such as a 4 weekly dose of 225 mg or a dose equivalent to 225 mg every 4 weeks, or 250-300 mg every four weeks, such as a 4 weekly dose of 300 mg or a dose equivalent to 300 mg every 4 weeks.
  • a 4 weekly dose of 75 mg or a dose equivalent to 75 mg every 4 weeks such as a 4 weekly dose of 75 mg or a dose equivalent to 75 mg every 4 weeks, or 150-200 mg every four weeks, such as a 4 weekly dose of 150 mg or a dose equivalent to 150 mg every 4 weeks, or 200-250 mg every four
  • the present invention relates to a method and a polypeptide of the invention for (use in) treatment of active RA despite MTX therapy, wherein the polypeptide of the invention is administered subcutaneously at a dose of 75-150 mg every four weeks, such as a 4 weekly dose of 75 mg or a dose equivalent to 75 mg every 4 weeks, or 150-200 mg every four weeks, such as a 4 weekly dose of 150 mg or a dose equivalent to 150 mg every 4 weeks, or 200-250 mg every four weeks, such as a 4 weekly dose of 225 mg or a dose equivalent to 225 mg every 4 weeks, or 250-300 mg every four weeks, such as a 4 weekly dose of 300 mg or a dose equivalent to 300 mg every 4 weeks.
  • a 4 weekly dose of 75 mg or a dose equivalent to 75 mg every 4 weeks such as a 4 weekly dose of 75 mg or a dose equivalent to 75 mg every 4 weeks, or 150-200 mg every four weeks, such as a 4 weekly dose of 150 mg or a dose equivalent to 150 mg every 4 weeks, or
  • the polypeptide of the invention is administered subcutaneously every month (monthly). Based on the bioavailability study as described in the examples section, a preferred dose for monthly subcutaneous administration of the polypeptides is 75-150 mg, such as a monthly dose of 75 mg or a dose equivalent to 75 mg every month. Another preferred dose for monthly subcutaneous administration of the polypeptides is 150-200 mg, such as a monthly dose of 150 mg or a dose equivalent to 150 mg every month. Another preferred dose for monthly subcutaneous administration of the polypeptides is 200-250 mg, such as a monthly dose of 225 mg or a dose equivalent to 225 mg every month. Another preferred dose for monthly subcutaneous administration of the polypeptides is 250-300 mg, such as a monthly dose of 300 mg or a dose equivalent to 300 mg every month.
  • the present invention relates to a method and a polypeptide of the invention for (use in) treatment of an IL-6R related disease, wherein the polypeptide of the invention is administered subcutaneously at a dose of 75-150 mg every month, such as a monthly dose of 75 mg or a dose equivalent to 75 mg every month, or 150-200 mg every month, such as a monthly dose of 150 mg or a dose equivalent to 150 mg every month, or 200-250 mg every month, such as a monthly dose of 225 mg or a dose equivalent to 225 mg every month, or 250-300 mg every month, such as a monthly dose of 300 mg or a dose equivalent to 300 mg every month.
  • a dose of 75-150 mg every month such as a monthly dose of 75 mg or a dose equivalent to 75 mg every month, or 150-200 mg every month
  • a monthly dose of 150 mg or a dose equivalent to 150 mg every month such as a monthly dose of 150 mg or a dose equivalent to 150 mg every month, or 200-250 mg every month, such as
  • the present invention relates to a method and a polypeptide of the invention for (use in) treatment of RA, wherein the polypeptide of the invention is administered subcutaneously at a dose of 75-150 mg every month, such as a monthly dose of 75 mg or a dose equivalent to 75 mg every month, or 150-200 mg every month, such as a monthly dose of 150 mg or a dose equivalent to 150 mg every month, or 200-250 mg every month, such as a monthly dose of 225 mg or a dose equivalent to 225 mg every month, or 250-300 mg every month, such as a monthly dose of 300 mg or a dose equivalent to 300 mg every month.
  • a dose of 75-150 mg every month such as a monthly dose of 75 mg or a dose equivalent to 75 mg every month, or 150-200 mg every month
  • a monthly dose of 150 mg or a dose equivalent to 150 mg every month such as a monthly dose of 150 mg or a dose equivalent to 150 mg every month, or 200-250 mg every month
  • the present invention relates to a method and a polypeptide of the invention for (use in) treatment of active RA, wherein the polypeptide of the invention is administered subcutaneously at a dose of 75-150 mg every month, such as a monthly dose of 75 mg or a dose equivalent to 75 mg every month, or 150-200 mg every month, such as a monthly dose of 150 mg or a dose equivalent to 150 mg every month, or 200-250 mg every month, such as a monthly dose of 225 mg or a dose equivalent to 225 mg every month, or 250-300 mg every month, such as a monthly dose of 300 mg or a dose equivalent to 300 mg every month.
  • a dose of 75-150 mg every month such as a monthly dose of 75 mg or a dose equivalent to 75 mg every month, or 150-200 mg every month
  • a monthly dose of 150 mg or a dose equivalent to 150 mg every month such as a monthly dose of 150 mg or a dose equivalent to 150 mg every month, or 200-250 mg every month
  • the present invention relates to a method and a polypeptide of the invention for (use in) treatment of active RA despite MTX therapy, wherein the polypeptide of the invention is administered subcutaneously at a dose of 75-150 mg every month, such as a monthly dose of 75 mg or a dose equivalent to 75 mg every month, or 150-200 mg every month, such as a monthly dose of 150 mg or a dose equivalent to 150 mg every month, or 200-250 mg every month, such as a monthly dose of 225 mg or a dose equivalent to 225 mg every month, or 250-300 mg every month, such as a monthly dose of 300 mg or a dose equivalent to 300 mg every month.
  • a dose of 75-150 mg every month such as a monthly dose of 75 mg or a dose equivalent to 75 mg every month, or 150-200 mg every month
  • a monthly dose of 150 mg or a dose equivalent to 150 mg every month such as a monthly dose of 150 mg or a dose equivalent to 150 mg every month, or 200-250 mg every month, such
  • polypeptide of the invention is SEQ ID NO: 34.
  • the polypeptide of the invention is administered subcutaneously to subjects suffering the IL-6R related disease, such as e.g. RA, at the selected dosing schedules such that treatment occurs.
  • markers of IL-6 mediated signaling are selected from soluble interleukin-6 receptor (slL-6R), interleukin-6 (IL-6), C-reactive protein (CRP), erythrocyte
  • ESR sedimentation rate
  • fibrinogen anti-dsDNA
  • complement C3, complement C4, complement CH50 matrix metalloproteinase
  • CXCL13 C-X-C motif Chemokine 13
  • ELISA enzyme-linked immunosorbent assays
  • EIA enzyme immunoassay
  • radioimmunoassays radioimmunoassays
  • immunoenzymetric assays Chemical, colorimetric and enzymatic based assays also may be used when suitable.
  • Soluble IL-6R includes (plasma) slL-6R free from IL-6 and (plasma) slL-6R free from polypeptide of the invention as well as (plasma) slL-6R in complex with IL-6, and (plasma) slL-6R in an immune complex with the polypeptide of the invention.
  • Plasma slL-6R is free or bound to IL-6 before administration of the polypeptide of the invention.
  • the slL-6R binds to the polypeptide of the invention to form a slL-6R/polypeptide of the invention immune complex.
  • slL-6R and/or plasma slL-6R levels can be determined by any method as described herein and/or known in the art. Preferred methods for determining slL-6R levels include immunoassays such as flow cytometry, inhibition assay, immunoprecipitation, immunohistochemistry (Frozen) and ELISA (such as e.g.
  • IL-6 includes serum IL-6 free from IL-6R as well as serum IL-6 in complex with IL-6R.
  • Serum IL-6 levels are free or bound to IL-6R before administration of the polypeptide of the invention. Following administration of the polypeptide of the invention IL-6 temporarily increases. This increase is most likely caused by IL-6R blockade inhibiting clearance of IL-6 from the blood.
  • Serum IL-6 levels can be determined by any method as described herein and/or known in the art. Preferred methods for determining IL-6 levels include immunoassays such as flow cytometry, inhibition assay, immunoprecipitation, immunohistochemistry (Frozen) and ELISA (such as e.g.
  • Human IL-6 QUANTIGLO ® ELISA Kit from R&D Systems, Minneapolis, MN (cat# Q6000B); Human IL-6 ELISA READY-SET-GO ! ® from eBioscience Ltd., Hatfield, United Kingdom; Human lnterleukin-6 (IL6 / IFNB2) ELISA Kit from Sino Biological Inc., Beijing, China; Interleukin 6 (IL 6) ELISA Kit, human from Biosupply, UK).
  • CRP C-reactive protein
  • the level of CRP in serum can be determined by any method as described herein and/or known in the art. Methods include (without being limiting) immunoassays such as the C-reactive protein detection kit (Difco Laboratories, Detroit, Michigan, US), the Human C-Reactive Protein ELISA Kit (Abnova Corporation, Taipei, Taiwan R.O.C.), the Human CRP ELISA Kit, High sensitivity (American Diagnostic GmbH, Pfungstadt, Germany), the Human CRP ELISA Kit (Antigenix America Inc., NY, US) and the IMMAGE ® Immunochemistry System (Beckman Coulter Inc., Brea, CA, US; Kit Recorder #447280).
  • immunoassays such as the C-reactive protein detection kit (Difco Laboratories, Detroit, Michigan, US), the Human C-Reactive Protein ELISA Kit (Abnova Corporation, Taipei, Taiwan R.O.C.), the Human CRP ELISA Kit, High sensitivity (American Diagnostic GmbH, Pfungstadt, Germany), the Human C
  • ESR Erythrocyte Sedimentation Rate
  • the ESR can further be determined (without being limiting) with the Greiner ESR tube (Cat. No. 454076), or with the Preanalytics - VACUETTE ® Evacuated Collection Tubes (Greiner Bio-One, Wemmel, Belgium), with SEDIPLUS ® S 2000 (Sarstedt; Numbrecht, Germany), or with SEDITAINERTM (Product Number: 366016; Becton Dickinson, NJ USA).
  • Fibrinogen is a soluble 340 kDa glycoprotein, synthesized in the liver by hepatocytes, that is converted by thrombin into fibrin during blood coagulation.
  • the concentration in blood plasma is 1.5-4.0 g/L (normally measured using the Clauss method) or about 7 ⁇ .
  • fibrin plays a key role in the inflammatory response and development of rheumatoid arthritis. It may be elevated in any form of inflammation, as it is an acute-phase protein (Gilliam et al. 2011, Pediatric Rheumatology 9: 8).
  • the fibrinogen level can be determined by any method as described herein and/or known in the art. Methods include (without being limiting) the STA ® Fibrinogen 5 (Stago, Parsippany, NJ, USA) for quantitative determination of fibrinogen by the Clauss method, the STA COMPACT ® , a fully automated, benchtop, Haemostasis analyser for clotting, chromogenic and immunological assays using random access mode (Stago, Parsippany, NJ, USA), ACL TOP ® 500 CTS (Beckman Coulter Inc., Brea, CA, US) and CEVERON ® alpha (TC technoclone, Vienna, Austria).
  • MMP-3 is an enzyme that degrades collagen types II, III, IV, IX, and X, proteoglycans, fibronectin, laminin, and elastin.
  • MMP-3 can also activate other MMPs such as MMP-1, MMP-7, and MMP-9, rendering MMP-3 crucial in connective tissue remodeling (Ye et al. 1996 J. Biol. Chem. 271: 13055-60).
  • the enzyme is also thought to be involved in wound repair, progression of
  • the MMP-3 level can be determined by any method as described herein and/or known in the art. Methods include (without being limiting) the Human Total MMP-3 Quantikine ® ELISA' from R&D Systems, MMP-3 Human ELISA Kit from ThermoFicher Scientific, or the Human MMP3 ELISA Kit from Abeam (abl00607).
  • Chemokine (C-X-C motif) ligand 13 (CXCL13), also known as B lymphocyte chemoattractant (BLC) or B cell-attracting chemokine 1 (BCA-1), is a small cytokine belonging to the CXC chemokine family. This chemokine is selectively chemotactic for B cells belonging to both the B-l and B-2 subsets, and elicits its effects by interacting with chemokine receptor CXCR5 (Legler et al. 1998 J. Exp. Med. 187: 655-60; Ansel et al. 2002 Immunity 16: 67-76). CXCL13 and its receptor CXCR5 control the organization of B cells within follicles of lymphoid tissues (Ansel et al. 2000 Nature 406: 309-14).
  • the CXCL13 level can be determined by any method as described herein and/or known in the art. Methods include (without being limiting) the Human CXCL13/BLC/BCA-1 Quantikine ® ELISA' from R&D Systems, the CXCL13 Human ELISA Kit from Thermo Fischer Scientific, or the CXCL13 ELISA Kits from Biocompare.
  • the efficacy of the RA treatment can be determined by various parameters including (without being limiting), ACR 20, 50, 70 and 90 response over time, ACR-N index of improvement over time, DAS 28 (using CRP and ESR) score over time, proportion of subjects with EULAR response over time, proportion of subjects in remission over time (making use of following definitions: DAS28, CDAI, SDAI, Boolean remission), including inhibition of structural damages, change from baseline in disease activity over time (making use of following disease activity scores (DAS28, SDAI, CDAI), change from baseline in HAQ-DI over time, the proportion of HAQ-DI responders over time, the changes from baseline in the physical and mental component scores of the SF-36, the change from baseline in FACIT-F, duration of morning stiffness.
  • DAS28, CDAI, SDAI, Boolean remission including inhibition of structural damages, change from baseline in disease activity over time (making use of following disease activity scores (DAS28, SDAI, CDAI), change from baseline in H
  • AC responses are a broadly accepted clinical response measure to demonstrate reduction in RA signs and symptoms and sensitive enough to differentiate from placebo effects.
  • ACR responses are presented as the numerical measurement of improvement in multiple disease assessment criteria.
  • ACR20/50/70/90 responses are defined as below (2010 European League against
  • TJC tender/painful joint count
  • HAQ-DI Questionnaire Disability Index
  • CRP C-reactive protein
  • the ACR-N Index of Improvement (Williams 1991, J. Fla. Med. Assoc. 78: 517-519; Abdel-Razzak et al. 1993, 44: 707-715) is defined as the minimum of the following 3 criteria:
  • TJCs tender joint counts
  • VAS Patient's assessment of pain
  • VASPA Patient's global assessment of disease activity
  • VASPHA - Physician's global assessment of disease activity
  • Patient's assessment of pain can be performed by asking the subject: "How much pain have you had because of your condition over the past week?" and then instructing to place a mark between 0 ("no pain") and 100 mm ("pain as bad it could be") on the VAS scale to indicate how severe the pain has been.
  • Patient's Global Assessment of Disease Activity can be performed by instructing the subject as follows: "Considering all the ways in which illness and health conditions may affect you at this time, please make a mark between 0 ("very well") and 100 mm ("very bad") on the VAS scale to show how you are doing.”
  • Physician's Global Assessment of Disease Activity (100 mm-VASPHA) can be performed by asking the physician to make a mark between 0 ("very good”) and 100 mm ("very bad”) on the VAS scale to indicate disease activity (independent of the subject's self-assessment).
  • HAQ-DI Health Assessment Questionnaire Disability Index
  • SF-36 Short Form
  • SF-36 consists of 36 items that can be summarized into 8 domains: physical functioning, role limitations due to physical health problems (role-physical), bodily pain, general health, vitality, social functioning, role limitations due to emotional problems (role-emotional), and mental health.
  • Two summary measures, the physical component summary and the mental component summary, can be derived based on these domain scores.
  • the concepts measured by the SF-36 are not specific to any disease, allowing comparison of relative burden of different diseases, in addition to the relative benefit of different treatments.
  • FACIT-F or FACIT-Fatigue is a collection of health-related quality of life questionnaires that assess multidimensional health status in people with various chronic illnesses, including A.
  • the DAS28 based on erythrocyte sedimentation rate is a statistically derived index combining TJC (28 joints), SJC (28 joints), ESR, and VASPA (Briso et al. 2008, J. Immunol., 180: 7102- 7106).
  • CRP can be used as alternative to ESR in the calculation of DAS28.
  • CRP is a more direct measure of inflammation than ESR, and it is more sensitive to short-term changes.
  • CRP is considered at least as valid as ESR to measure RA disease activity.
  • the DAS28 using CRP is a statistically derived index combining TJC (28 joints), SJC (28 joints), CRP, and VASPA.
  • Boolean remission is determined according to following criteria (Felson et al. 2011, American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Annals of the rheumatic diseases 70: 404-13):
  • the CDAI clinical score is determined according to following criteria (Felson, et al. 2011; Aletaha and Smolen 2007, Clinical rheumatology 21: 663-75):
  • CDAI TJC28 + SJC28 + VASPA + VASPHA
  • the SDAI clinical score is determined according to following criteria (Aletaha and Smolen 2007)
  • SDAI TJC28 + SJC28 + VASPA + VASPHA + CRP
  • EULAR response is assessed by comparing a subject's DAS28 score (using CRP and ESR) relative to baseline as follows:
  • Example 1 Evaluation of the bioavailability of SEQ ID NO: 34 after subcutaneous and intravenous administration in healthy volunteers
  • PK pharmacokinetics
  • PD pharmacodynamics
  • i.v. intravenous
  • 70 human subjects were assigned to 1 of 5 treatment arms (with 14 subjects per treatment arm) and received one of the following single doses of SEQ ID NO: 34: 150 mg s.c, 300 mg s.c, 300 mg i.v., 50 mg s.c, or 50 mg i.v..
  • Subjects in the i.v. groups of the study received a single dose of SEQ ID NO: 34 as i.v. infusion at a fixed infusion rate of 1.5 mL/min.
  • Subjects in the s.c. parts of the study received a single dose of SEQ ID NO: 34 via s.c. injection in the abdominal region.
  • subjects were monitored for approximately 2 months for subjects in the 50 mg and 150 mg treatment arms and approximately 3 months for subjects in the 300 mg treatment arms, to allow adequate follow-up of PD. A total of 67 subjects completed the study.
  • total active SEQ ID NO: 34 concentrations in human serum samples was performed using a validated enzyme-linked immunosorbent assay (ELISA).
  • ELISA enzyme-linked immunosorbent assay
  • an anti-SEQ ID NO: 34 Nanobody was used to capture SEQ ID NO: 34.
  • a complexation of the serum samples with human slL-6 was performed. The complexes were detected with a mouse anti-human IL-6R antibody, followed by rabbit anti-mouse immunoglobulin G-horseradish peroxidase allowing detection via spectrophotometry.
  • Mean serum concentrations of SEQ ID NO: 34 increased with increasing dose following single dose administration of SEQ ID NO: 34 as i.v. infusion (50 mg and 300 mg) or s.c. injection (50 mg, 150 mg and 300 mg) ( Figure 1). Following i.v. administration, mean serum concentration-time profiles of SEQ ID NO: 34 displayed a biphasic decline characterized by a dose-dependent disposition phase followed by a faster terminal elimination phase. After s.c. administration, mean SEQ ID NO: 34 serum concentrations increased with a peak already occurring at approximately 48h post-dose and gradually declined thereafter.
  • PK Pharmacokinetics
  • Supportive Standard Non Compartmental PK Analysis (PK NCA) has been performed in clinical pharmacology studies, providing further insight on the understanding of the pharmacokinetic behaviour of SEQ ID NO: 34.
  • the PK of SEQ ID NO: 34 was characterized by non-linear kinetics over the tested dose-range (0.3-6 mg/kg iv doses, 50-300 mg s.c. doses) explained by concentration-dependent clearance (CL). Overall, after multiple dose the accumulation was limited, and PK parameters did not change over-time. After subcutaneous administration, PK NCA results indicated an apparent dose-dependent bioavailability, higher and almost complete at the highest tested dose.
  • PK model An empirical bi-compartmental disposition model with parallel linear (first-order) and nonlinear saturable clearance characterized well the observed exposure after single and multiple intravenous administration. The volume of distribution was limited, indicating that SEQ ID NO: 34 was restricted to the systemic circulation, and rather constant across dose-levels. The non-linear component of the clearance, likely reflecting an elimination occurring after the drug binds to its IL-6R target, was saturated at relatively low serum concentrations, indicating that at higher levels of exposure the total CL is mainly determined by linear processes.
  • SEQ ID NO: 34 The pharmacodynamics of single subcutaneous (s.c.) and intravenous (i.v.) doses of SEQ ID NO: 34 was assessed by measurement of the plasma total soluble interleukin-6 receptor (slL-6R) concentration and the serum interleukin-6 (IL-6) concentration. Blood samples were taken for analysis of IL-6 and slL-6R at 24 hours, 6 days, 11 days, 18 days, 25 days, 32 days, 39 days (150 mg and 300 mg treatment arms only), 46 days (150 mg and 300 mg treatment arms only), and 53 days (300 mg treatment arm only) after dosing.
  • slL-6R plasma total soluble interleukin-6 receptor
  • IL-6 serum interleukin-6
  • Baseline slL-6R plasma concentrations were comparable for all treatment groups with mean baseline concentrations ranging between 38.4 ng/mL and 42.6 ng/mL.
  • mean slL-6R concentrations increased rapidly. A dose-related effect was observed on the magnitude and the duration of the increased slL-6R concentrations.
  • mean slL-6R levels had returned to baseline values at follow-up (i.e., Day 60 for the 50 mg and 150 mg dose groups and Day 83 for the 300 mg dose groups) (Figure 3).
  • ADA pre-existing antibodies and treatment emergent (TE) ADA were detected in 11% and 10% of the subjects, respectively.
  • TE treatment emergent
  • % (6/70) were classified as equivocal since in those subjects no TE ADA response was detected but pre-existing antibodies were present at levels possibly defying TE ADA.
  • Example 1 The PK and PD results obtained in Example 1 were used to bridge from i.v. to s.c. administration, and to determine the appropriate doses for a study in subjects suffering RA.
  • Simulations of the PK model were based on the expected body weight distribution of RA patients.
  • RA patients were sampled from a distribution with mean body weight of 78 kg, with a standard deviation of 19 kg and a minimum and maximum body weight of 40 kg and 150 kg, respectively.
  • the predicted C min at steady state (C min,ss ) was derived and compared with the DAS28 EC 50 (SEQ ID NO: 34 concentration resulting in half-maximal effect of SEQ ID NO: 34 on the DAS28 efficacy measure) estimated by the PK-DAS28 model.
  • the doses 75 and 150 mg q4w and 150 and 225 mg q2w of SEQ ID NO: 34 were selected as adequate doses to assess the exposure-response relationship of SEQ ID NO: 34 in RA patients. Through simulations, it was shown that these doses would be covered by adequate safety margins, when comparing the model predicted human exposure with the observed exposure in the toxicity studies.
  • Figure 4 shows the model-predicted PK profiles of SEQ ID NO: 34 simulated by sampling a thousand RA patients from the expected body weight distribution as specified above following s.c. administration of SEQ ID NO: 34 at a dose of 75 and 150 mg q4w and 150 and 225 mg q2w.
  • Figure 5 shows the model-predicted median DAS28 response based on simulations performed using the same 1000 RA patients as for the simulated PK profiles following s.c. administration of SEQ ID NO: 34 at a dose of 75 and 150 mg q4w and 150 and 225 mg q2w (DAS28 baseline value of 4.93).
  • Example 3 Subcutaneous administration of SEQ ID NO: 34 to RA patients (monotherapy)
  • a multicenter study of SEQ ID NO: 34 administered s.c. as monotherapy was conducted in subjects with moderate to severe RA who were intolerant to MTX or whom continued MTX treatment was inappropriate. 251 subjects were randomized in 4 treatment arms in a 1:1:1:1 ratio as follows: randomized double-blind arms with 150 mg of SEQ ID NO: 34 q4w (62 subjects; 1 mL of a 150 mg/ml SEQ ID NO: 34 composition), 150 mg of SEQ ID NO: 34 q2w (62 subjects; 1 mL of a 150 mg/ml SEQ ID NO: 34 composition), 225 mg of SEQ ID NO: 34 q2w (63 subjects; 1.5 mL of a 150 mg/ml SEQ ID NO: 34 composition), and an open-label arm with 162 mg of tocilizumab (TCZ) (RoActemra, Roche - Actemra, Genentech, Inc.) qlw (60 subjects) or q2w (4 subjects).
  • SEQ ID NO: 34 was administered subcutaneously using a single-use pre-filled syringe comprising a pharmaceutical composition with SEQ ID NO: 34 at a concentration of 150 mg/ml. Note that since there is a difference in approved dosing frequency in the US (q2w) versus the EU (qlw), 2 different dosing regimens for TCZ were included in the study. Subjects received the dosing regimen approved in their region. Baseline demographics were reflective of a typical RA population with similar disease activity across the randomized groups (Table B-l).
  • Subjects assigned to the SEQ ID NO: 34 and TCZ q2w treatment groups returned for 7 ambulatory visits planned on Weeks 0, 2, 4, 6, 8, 10, and 12.
  • Subjects assigned to the qlw TCZ- arm returned for 13 ambulatory visits planned on Weeks 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12.
  • the reduction of signs and symptoms of RA was evaluated by calculating the proportion of subjects achieving an ACR20 response at week 12.
  • higher levels of response as measured by ACR50 and ACR70 response rates, and measures of remission, using the DAS28, Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), as well as the Boolean remission definition, was used as supportive evidence of efficacy.
  • endpoints including ACR responses and disease activity scores, were documented over time, including earlier time points (i.e., at Week 2 up to and including Week 10).
  • HAQ-DI Health Assessment Questionnaire- Disability Index
  • SF-36 Short Form
  • FACIT-F Functional Assessment of Chronic Illness Therapy-Fatigue
  • tenderness or swelling was noted, a "1" was entered for that joint in the appropriate field. If tenderness or swelling was absent, a "0" was entered for that joint in the appropriate field.
  • Patient's Global Assessment of Disease Activity (100 mmm-VASPA) was performed as part of ACR response, DAS28 score, SDAI, CDAI, and Boolean remission. The subject had to complete the patient's global assessment independently of the physician when completing the physician global assessment.
  • Physician's Global Assessment of Disease Activity (100 mm-VASPHA) was performed as part of ACR response, SDAI, and CDAI. The physician had to complete the physician's global assessment independently of the subject when completing the patient's global assessment. The physician made a mark between 0 ("very good") and 100 mm ("very bad") on the VAS scale to indicate disease activity (independent of the subject's self-assessment).
  • CRP C-reactive protein
  • CRP concentration was to be provided in mg/L.
  • ESR Erythrocyte Sedimentation Rate
  • ESR levels in serum any method available in the art could be used such as e.g. the commercially available Greiner ESR tube or the Preanalytics - VACUETTE ® Evacuated Collection Tubes (Greiner Bio-One GmbH, Kremsmuenster, Austria), the Sarstedt SEDIPLUS ® 2000 (Sarstedt, Numbrecht, Germany), or the Becton Dickinson SEDITAINER ® (Becton Dickinson, Franklin Lakes, NJ, USA).
  • the ESR concentration was to be provided in mm/h. Health Assessment Questionnaire Disability Index
  • HAQ-DI Health Assessment Questionnaire Disability Index
  • HAQ-DI score at week 12 and HAQ-DI change from baseline obtained for the different treatment groups are depicted in Figure 7 and Table B-2.
  • SEQ ID NO: 34 appeared to have a rapid positive impact on patients' physical function.
  • the SF-36 consists of 36 items that can be summarized into 8 domains: physical functioning, role limitations due to physical health problems (role-physical), bodily pain, general health, vitality, social functioning, role limitations due to emotional problems (role-emotional), and mental health.
  • Two summary measures, the physical component summary and the mental component summary, can be derived based on these domain scores.
  • the concepts measured by the SF-36 are not specific to any disease, allowing comparison of relative burden of different diseases, in addition to the relative benefit of different treatments.
  • the FACIT Measurement System is a collection of health-related quality of life questionnaires that assess multidimensional health status in people with various chronic illnesses, including RA.
  • ACR responses were measured according to the 2010 European League against Rheumatism [EULARj/American College of Rheumatology [ACR] classification criteria.
  • ACR20/50/70 responses were defined as below: • > 20/50/70% improvement in tender/painful joint count (TJC) (68 joints) relative to baseline AND
  • HAQ-DI Health Assessment Questionnaire Disability Index
  • CRP C-reactive protein
  • the ACR20/50/70 response measured for the different treatment groups at week 12 is shown in Figure 8.
  • SEQ ID NO:34 appeared to be very effective with less frequent administration than tocilizumab.
  • the ACR-N Index of Improvement was defined as the minimum of the following 3 criteria:
  • TJCs tender joint counts
  • VAS Patient's Assessment of Pain
  • VASPA Global Assessment of Disease Activity
  • VASPHA Physician's Global Assessment of Disease Activity
  • the DAS28 based on erythrocyte sedimentation rate is a statistically derived index combining TJC (28 joints), SJC (28 joints), ESR, and VASPA (Briso et al. 2008, J. Immunol., 180: 7102- 7106).
  • CRP can be used in addition to ESR in the calculation of DAS28.
  • CRP is a more direct measure of inflammation than ESR, and it is more sensitive to short-term changes.
  • CRP is considered at least as valid as ESR to measure RA disease activity.
  • the DAS28 using CRP is a statistically derived index combining TJC (28 joints), SJC (28 joints), CRP, and VASPA.
  • Figure 10 shows the obtained DAS28 C RP changes from baseline during the 12 week study compared to the model-predicted DAS28 C RP change from baseline (calculated from the model- predicted median DAS28 response as described in Example 2 and Figure 5; DAS28 baseline value of 4.93).
  • the actually obtained DAS28 C RP improved faster and more extensively than the model- predicted DAS28 C RP (based on previous - Phase 1 - clinical data).
  • SEQ ID NO: 34 induced either clinical remission or low disease activity in up to 60% of patients.
  • EULAR response was assessed by comparing a subject's DAS28 score (using CRP and ESR) relative to baseline as follows.
  • the Disease Activity Score was determined using 28 joint counts (DAS28 using CRP and erythrocyte sedimentation rate [ESR]).
  • DAI Simplified Disease Activity Index
  • CDAI Clinical Disease Activity Index
  • the CDAI clinical score was determined according to following criteria (Felson, et al. 2011; Aletaha and Smolen 2007, Clinical rheumatology 21: 663-75):
  • CDAI TJC28 + SJC28 + VASPA + VASPHA
  • the SDAI clinical score was determined according to following criteria (Aletaha and Smolen 2007):
  • SDAI TJC28 + SJC28 + VASPA + VASPHA + CRP
  • Remission was determined using disease remission parameters: DAS28, Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), Boolean.
  • SDAI Simplified Disease Activity Index
  • CDAI Clinical Disease Activity Index
  • Boolean remission was determined according to following criteria (Felson et al. 2011, American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Annals of the rheumatic diseases 70: 404-13):
  • SEQ ID NO: 34 Blood samples were taken for analysis of SEQ ID NO: 34 in serum at 2, 4, 6, 8, 10, and 12 weeks after dosing. The determination of total active SEQ ID NO: 34 concentrations in human serum samples was performed using a validated enzyme-linked immunosorbent assay (ELISA) similar as described in Example 1.
  • ELISA enzyme-linked immunosorbent assay
  • SEQ ID NO: 34 The effect of SEQ ID NO: 34 on the PD biomarkers soluble IL-6 receptor (slL-6R), C-reactive protein (CRP), fibrinogen and erythrocyte sedimentation rate (ESR) was evaluated descriptively.
  • MMP-3 matrix metalloproteinase-3
  • CXCL13 chemokine ligand 13
  • blood samples were taken at 2, 4, 6, 10, 12, and
  • the 'Human Total MMP-3 Quantikine ® ELISA' from R&D Systems was validated for the quantitative determination of total human matrix metalloproteinase 3 (MMP-3) levels in serum samples from the rheumatoid arthritis (RA) patients.
  • MMP-3 total human matrix metalloproteinase 3
  • the assay principle was described in the package insert of the kit. The assay was performed using all reagents provided in the kit with the exception of 2N sulfuric acid, which was replaced by in-house made 2N hydrochloric acid (HCI). The assay was performed following all instructions of the package insert except for the determination of the optical density, which was correctly determined at wavelength 450 nm but without wavelength correction at 540 nm or 570 nm as mentioned in the package insert.
  • CXCL13/BLC/BCA-1 Quantikine ® ELISA' from R&D Systems was validated for the quantitative determination of total human Cystein -X-Cystein (C-X-C)-motif Ligand 13 (CXCL-13) levels in serum samples from rheumatoid Arthritis (RA) patients.
  • the calibrator curve ranged from 3.60 to 250 pg/mL instead of the range indicated in the kit insert (7.80 to 500 pg/mL);
  • the optical density was determined at wavelength 450 nm as indicated, but without wavelength correction at 540 nm or 570 nm.
  • the acute phase protein CRP was analyzed as inflammatory biomarker as well as a more distal PD biomarker (compared to the proximal target engagement biomarkers slL-6R).
  • ESR Erythrocyte sedimentation rate
  • ESR concentrations decreased rapidly from week 2 onwards by 2-fold for all treatment groups of SEQ ID NO: 34 (SEQ ID NO: 34 150 mg q2w, SEQ ID NO: 34 150 mg q4w and 225 mg q2w) and for the TCZ group. After SEQ ID NO: 34 or TCZ treatment discontinuation, an increase in ESR was observed at follow up. Safety
  • Safety and tolerability assessments included evaluation of (serious) AEs and injection site reactions, laboratory assessment, urinalysis, ECG, vital signs, and physical examination. To assess immunogenicity, the presence of ADA was measured in serum until the follow-up visit.
  • Table B-1 Baseline demographics and disease activity of the subjects across the randomized treatment groups in the clinical study as described in Example 3
  • TJC tender joint count
  • SJC swollen joint count
  • CRP C-reactive protein
  • DAS28 CRP disease activity score in 28 joints using CRP
  • HAQ-DI health assessment questionnaire disability score for RA.
  • Table B-2 HAQ-DI score and HAQ-DI change from baseline at week 12 for the subjects across the randomized treatment groups in the clinical study as described in Example 3

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne des méthodes pour le traitement de maladies associées à l'IL-6R. De manière plus spécifique, l'invention concerne des schémas posologiques spécifiques et des seringues pré-remplies pour une administration sous-cutanée, à des sujets souffrant d'une maladie associée au IL-6R, de domaines variables uniques d'immunoglobulines qui se lient à l'IL-6R
PCT/EP2017/066769 2016-07-06 2017-07-05 Traitement de maladies associées à l'il-6r WO2018007442A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201662358648P 2016-07-06 2016-07-06
US62/358,648 2016-07-06
US201762518781P 2017-06-13 2017-06-13
US62/518,781 2017-06-13

Publications (1)

Publication Number Publication Date
WO2018007442A1 true WO2018007442A1 (fr) 2018-01-11

Family

ID=59363115

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2017/066769 WO2018007442A1 (fr) 2016-07-06 2017-07-05 Traitement de maladies associées à l'il-6r

Country Status (1)

Country Link
WO (1) WO2018007442A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020219960A1 (fr) * 2019-04-24 2020-10-29 Sanofi Biotechnology Procédés de diagnostic et de traitement de la polyarthrite rhumatoïde

Citations (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0368684A1 (fr) 1988-11-11 1990-05-16 Medical Research Council Clonage de séquences d'immunoglobulines de domaines variables.
WO1991001743A1 (fr) 1989-08-01 1991-02-21 Cemu Bioteknik Ab Conjugues de proteines ou de peptides stabilises
WO1994004678A1 (fr) 1992-08-21 1994-03-03 Casterman Cecile Immunoglobulines exemptes de chaines legeres
WO1994025591A1 (fr) 1993-04-29 1994-11-10 Unilever N.V. PRODUCTION D'ANTICORPS OU DE FRAGMENTS FONCTIONNALISES D'ANTICORPS, DERIVES DES IMMUNOGLOBULINES A CHAINE LOURDE DE $i(CAMELIDAE)
WO1995004079A1 (fr) 1993-08-02 1995-02-09 Raymond Hamers Vecteur recombinant contenant une sequence d'un gene de lipoproteine pour l'expression de sequences de nucleotides
WO1996034103A1 (fr) 1995-04-25 1996-10-31 Vrije Universiteit Brussel Fragments variables d'immunoglobulines et leur utilisation dans un but therapeutique ou veterinaire
WO1997049805A2 (fr) 1996-06-27 1997-12-31 Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw Molecules de reconnaissance ayant une interaction specifique avec le site actif ou la fissure d'une molecule cible
WO1999023221A2 (fr) 1997-10-27 1999-05-14 Unilever Plc Proteines multivalentes de fixation de l'antigene
WO1999037681A2 (fr) 1998-01-26 1999-07-29 Unilever Plc Procede servant a preparer des fragments d'anticorps
WO1999042077A2 (fr) 1998-02-19 1999-08-26 Xcyte Therapies, Inc. Compositions et procedes de regulation de l'activation des lymphocytes
WO2000040968A1 (fr) 1999-01-05 2000-07-13 Unilever Plc Fixation de fragments d'anticorps a des supports solides
WO2000043507A1 (fr) 1999-01-19 2000-07-27 Unilever Plc Procede de production de fragments d'anticorps
WO2000065057A1 (fr) 1999-04-22 2000-11-02 Unilever Plc Inhibition d'une infection virale au moyen de proteines de liaison a l'antigene monovalentes
WO2001021817A1 (fr) 1999-09-24 2001-03-29 Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw Phages recombinants capables de penetrer dans des cellules hotes via une interaction specifique avec un recepteur artificiel
WO2001040310A2 (fr) 1999-11-29 2001-06-07 Unilever Plc Immobilisation de proteines
WO2001044301A1 (fr) 1999-11-29 2001-06-21 Unilever Plc Immobilisation de molecules de liaison d'antigene a domaine unique
WO2001045746A2 (fr) 1999-12-24 2001-06-28 Genentech, Inc. Methodes et compositions permettant de prolonger les demi-vies d'elimination de composes bioactifs
EP1134231A1 (fr) 2000-03-14 2001-09-19 Unilever N.V. Domaines variables de la chaine lourde d'anticorps contre des enzymes humaines alimentaires et leurs utilisations
WO2001090190A2 (fr) 2000-05-26 2001-11-29 National Research Council Of Canada Fragments d'anticorps de fixation d'antigenes monodomaines, derives d'anticorps de lamas
WO2002048193A2 (fr) 2000-12-13 2002-06-20 Unilever N.V. Réseaux de protéines
WO2002076489A1 (fr) 2001-03-09 2002-10-03 Dyax Corp. Groupes de liaison d'albumine serique
WO2003025020A1 (fr) 2001-09-13 2003-03-27 Institute For Antibodies Co., Ltd. Procede pour creer une banque d'anticorps de chameaux
WO2003035694A2 (fr) 2001-10-24 2003-05-01 Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw Anticorps fonctionnels a chaine lourde, fragments de ces derniers, bibliotheque de ces derniers et procedes de production
WO2003050531A2 (fr) 2001-12-11 2003-06-19 Algonomics N.V. Procede d'affichage de boucles de domaines d'immunoglobuline dans differents contextes
WO2003054016A2 (fr) 2001-12-21 2003-07-03 Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw Procede de clonage de sequences de domaines variables
WO2003055527A2 (fr) 2002-01-03 2003-07-10 Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw Nouveaux immunoconjugues utiles pour le traitement de tumeurs
WO2004003019A2 (fr) 2002-06-28 2004-01-08 Domantis Limited Ligand
WO2004041862A2 (fr) 2002-11-08 2004-05-21 Ablynx N.V. Anticorps a domaine unique diriges contre le facteur de necrose tumorale alpha et leurs utilisations
WO2004041867A2 (fr) 2002-11-08 2004-05-21 Ablynx N.V. Procede d'administration de polypeptides therapeutiques et polypeptides associes
WO2004062551A2 (fr) 2003-01-10 2004-07-29 Ablynx N.V. Polypeptides therapeutiques, leurs homologues, leurs fragments, que l'on utilise dans la modulation de l'agregation plaquettaire
WO2004068820A2 (fr) 2003-01-23 2004-08-12 Unspam, Llc. Procede et appareil destines a un systeme de liste de numeros interdits a ne pas divulguer
WO2004081026A2 (fr) 2003-06-30 2004-09-23 Domantis Limited Polypeptides
WO2005018629A1 (fr) 2003-08-12 2005-03-03 Yarbrough William M Traitement de l'acne simple et procede d'utilisation
WO2005044858A1 (fr) 2003-11-07 2005-05-19 Ablynx N.V. Polypeptide vhh de camelidae, anticorps a domaine unique diriges contre le recepteur de facteur de croissance epidermique et utilisations de ceux-ci
WO2006003388A2 (fr) 2004-06-30 2006-01-12 Domantis Limited Compositions et procedes pour le traitement de troubles inflammatoires
WO2006030220A1 (fr) 2004-09-17 2006-03-23 Domantis Limited Compositions monovalentes pour la liaison au cd40l et procedes d'utilisation
WO2006040153A2 (fr) 2004-10-13 2006-04-20 Ablynx N.V. Nanocorps™ contre la proteine beta-amyloide et polypeptides les renfermant pour le traitement de maladies degeneratives neurales, telles que la maladie d'alzheimer
WO2006079372A1 (fr) 2005-01-31 2006-08-03 Ablynx N.V. Procede de generation de sequences a domaine variable d'anticorps a chaine lourde
WO2006122825A2 (fr) 2005-05-20 2006-11-23 Ablynx Nv 'nanobodies™' (nanocorps) perfectionnes pour traiter des troubles medies par une agregation
WO2006122786A2 (fr) 2005-05-18 2006-11-23 Ablynx Nv Nanocorpstm; utilises contre le facteur-alpha de necrose tumorale
WO2008020079A1 (fr) 2006-08-18 2008-02-21 Ablynx N.V. Séquences d'acides aminés dirigées contre l'il-6r et polypeptides les contenant utilisés pour le traitement de maladies et de troubles associés au signal médié par il-6
WO2008068280A1 (fr) 2006-12-05 2008-06-12 Ablynx N.V. Peptides capables de se lier à des protéines sériques
WO2008101985A2 (fr) 2007-02-21 2008-08-28 Ablynx N.V. Séquences d'acides aminés dirigées contre le facteur de croissance de l'endothélium vasculaire et polypeptides comprenant ces séquences, pour le traitement de troubles et de maladies se caractérisant par une angiogenèse pathologique ou une néovascularisation
WO2008142164A2 (fr) 2007-05-24 2008-11-27 Ablynx N.V. Séquences d'acides aminés dirigées contre rank-l et polypeptides comprenant ces dernières, destinés au traitement de maladies et affections osseuses
WO2009127691A1 (fr) 2008-04-17 2009-10-22 Ablynx N.V. Peptides capables de se lier à des protéines sériques et composés, constructions et polypeptides les comprenant
WO2010115998A2 (fr) 2009-04-10 2010-10-14 Ablynx Nv Séquences d'acides aminés améliorées directement contre il-6r et polypeptides comprenant celles-ci pour le traitement de maladies et de troubles associés à il-6r
WO2011026948A1 (fr) 2009-09-03 2011-03-10 Ablynx N.V. Formulations stables de polypeptides et leurs utilisations
WO2011095545A1 (fr) 2010-02-05 2011-08-11 Ablynx Nv Peptides capables de se lier à la sérumalbumine, et composés, constructions, et polypeptides comprenant de tels peptides
WO2013041722A1 (fr) 2011-09-23 2013-03-28 Ablynx Nv Inhibition prolongée d'une signalisation à médiation par l'interleukine-6
WO2016062766A1 (fr) * 2014-10-21 2016-04-28 Ablynx Nv Traitement de maladies associées à il-6r

Patent Citations (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0368684A1 (fr) 1988-11-11 1990-05-16 Medical Research Council Clonage de séquences d'immunoglobulines de domaines variables.
WO1991001743A1 (fr) 1989-08-01 1991-02-21 Cemu Bioteknik Ab Conjugues de proteines ou de peptides stabilises
WO1994004678A1 (fr) 1992-08-21 1994-03-03 Casterman Cecile Immunoglobulines exemptes de chaines legeres
WO1994025591A1 (fr) 1993-04-29 1994-11-10 Unilever N.V. PRODUCTION D'ANTICORPS OU DE FRAGMENTS FONCTIONNALISES D'ANTICORPS, DERIVES DES IMMUNOGLOBULINES A CHAINE LOURDE DE $i(CAMELIDAE)
WO1995004079A1 (fr) 1993-08-02 1995-02-09 Raymond Hamers Vecteur recombinant contenant une sequence d'un gene de lipoproteine pour l'expression de sequences de nucleotides
WO1996034103A1 (fr) 1995-04-25 1996-10-31 Vrije Universiteit Brussel Fragments variables d'immunoglobulines et leur utilisation dans un but therapeutique ou veterinaire
WO1997049805A2 (fr) 1996-06-27 1997-12-31 Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw Molecules de reconnaissance ayant une interaction specifique avec le site actif ou la fissure d'une molecule cible
WO1999023221A2 (fr) 1997-10-27 1999-05-14 Unilever Plc Proteines multivalentes de fixation de l'antigene
WO1999037681A2 (fr) 1998-01-26 1999-07-29 Unilever Plc Procede servant a preparer des fragments d'anticorps
WO1999042077A2 (fr) 1998-02-19 1999-08-26 Xcyte Therapies, Inc. Compositions et procedes de regulation de l'activation des lymphocytes
WO2000040968A1 (fr) 1999-01-05 2000-07-13 Unilever Plc Fixation de fragments d'anticorps a des supports solides
WO2000043507A1 (fr) 1999-01-19 2000-07-27 Unilever Plc Procede de production de fragments d'anticorps
WO2000065057A1 (fr) 1999-04-22 2000-11-02 Unilever Plc Inhibition d'une infection virale au moyen de proteines de liaison a l'antigene monovalentes
WO2001021817A1 (fr) 1999-09-24 2001-03-29 Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw Phages recombinants capables de penetrer dans des cellules hotes via une interaction specifique avec un recepteur artificiel
WO2001040310A2 (fr) 1999-11-29 2001-06-07 Unilever Plc Immobilisation de proteines
WO2001044301A1 (fr) 1999-11-29 2001-06-21 Unilever Plc Immobilisation de molecules de liaison d'antigene a domaine unique
WO2001045746A2 (fr) 1999-12-24 2001-06-28 Genentech, Inc. Methodes et compositions permettant de prolonger les demi-vies d'elimination de composes bioactifs
EP1134231A1 (fr) 2000-03-14 2001-09-19 Unilever N.V. Domaines variables de la chaine lourde d'anticorps contre des enzymes humaines alimentaires et leurs utilisations
WO2001090190A2 (fr) 2000-05-26 2001-11-29 National Research Council Of Canada Fragments d'anticorps de fixation d'antigenes monodomaines, derives d'anticorps de lamas
WO2002048193A2 (fr) 2000-12-13 2002-06-20 Unilever N.V. Réseaux de protéines
WO2002076489A1 (fr) 2001-03-09 2002-10-03 Dyax Corp. Groupes de liaison d'albumine serique
WO2003025020A1 (fr) 2001-09-13 2003-03-27 Institute For Antibodies Co., Ltd. Procede pour creer une banque d'anticorps de chameaux
WO2003035694A2 (fr) 2001-10-24 2003-05-01 Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw Anticorps fonctionnels a chaine lourde, fragments de ces derniers, bibliotheque de ces derniers et procedes de production
WO2003050531A2 (fr) 2001-12-11 2003-06-19 Algonomics N.V. Procede d'affichage de boucles de domaines d'immunoglobuline dans differents contextes
WO2003054016A2 (fr) 2001-12-21 2003-07-03 Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw Procede de clonage de sequences de domaines variables
WO2003055527A2 (fr) 2002-01-03 2003-07-10 Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw Nouveaux immunoconjugues utiles pour le traitement de tumeurs
WO2004003019A2 (fr) 2002-06-28 2004-01-08 Domantis Limited Ligand
WO2004041862A2 (fr) 2002-11-08 2004-05-21 Ablynx N.V. Anticorps a domaine unique diriges contre le facteur de necrose tumorale alpha et leurs utilisations
WO2004041865A2 (fr) 2002-11-08 2004-05-21 Ablynx N.V. Anticorps a domaine unique stabilises
WO2004041867A2 (fr) 2002-11-08 2004-05-21 Ablynx N.V. Procede d'administration de polypeptides therapeutiques et polypeptides associes
WO2004041863A2 (fr) 2002-11-08 2004-05-21 Ablynx N.V. Anticorps a domaine unique diriges contre un interferon gamma et leurs utilisations
WO2004062551A2 (fr) 2003-01-10 2004-07-29 Ablynx N.V. Polypeptides therapeutiques, leurs homologues, leurs fragments, que l'on utilise dans la modulation de l'agregation plaquettaire
WO2004068820A2 (fr) 2003-01-23 2004-08-12 Unspam, Llc. Procede et appareil destines a un systeme de liste de numeros interdits a ne pas divulguer
WO2004081026A2 (fr) 2003-06-30 2004-09-23 Domantis Limited Polypeptides
WO2005018629A1 (fr) 2003-08-12 2005-03-03 Yarbrough William M Traitement de l'acne simple et procede d'utilisation
WO2005044858A1 (fr) 2003-11-07 2005-05-19 Ablynx N.V. Polypeptide vhh de camelidae, anticorps a domaine unique diriges contre le recepteur de facteur de croissance epidermique et utilisations de ceux-ci
WO2006003388A2 (fr) 2004-06-30 2006-01-12 Domantis Limited Compositions et procedes pour le traitement de troubles inflammatoires
WO2006030220A1 (fr) 2004-09-17 2006-03-23 Domantis Limited Compositions monovalentes pour la liaison au cd40l et procedes d'utilisation
WO2006040153A2 (fr) 2004-10-13 2006-04-20 Ablynx N.V. Nanocorps™ contre la proteine beta-amyloide et polypeptides les renfermant pour le traitement de maladies degeneratives neurales, telles que la maladie d'alzheimer
WO2006079372A1 (fr) 2005-01-31 2006-08-03 Ablynx N.V. Procede de generation de sequences a domaine variable d'anticorps a chaine lourde
WO2006122786A2 (fr) 2005-05-18 2006-11-23 Ablynx Nv Nanocorpstm; utilises contre le facteur-alpha de necrose tumorale
WO2006122787A1 (fr) 2005-05-18 2006-11-23 Ablynx Nv Proteines de liaison a l'albumine serique
WO2006122825A2 (fr) 2005-05-20 2006-11-23 Ablynx Nv 'nanobodies™' (nanocorps) perfectionnes pour traiter des troubles medies par une agregation
WO2008020079A1 (fr) 2006-08-18 2008-02-21 Ablynx N.V. Séquences d'acides aminés dirigées contre l'il-6r et polypeptides les contenant utilisés pour le traitement de maladies et de troubles associés au signal médié par il-6
WO2008068280A1 (fr) 2006-12-05 2008-06-12 Ablynx N.V. Peptides capables de se lier à des protéines sériques
WO2008101985A2 (fr) 2007-02-21 2008-08-28 Ablynx N.V. Séquences d'acides aminés dirigées contre le facteur de croissance de l'endothélium vasculaire et polypeptides comprenant ces séquences, pour le traitement de troubles et de maladies se caractérisant par une angiogenèse pathologique ou une néovascularisation
WO2008142164A2 (fr) 2007-05-24 2008-11-27 Ablynx N.V. Séquences d'acides aminés dirigées contre rank-l et polypeptides comprenant ces dernières, destinés au traitement de maladies et affections osseuses
WO2009127691A1 (fr) 2008-04-17 2009-10-22 Ablynx N.V. Peptides capables de se lier à des protéines sériques et composés, constructions et polypeptides les comprenant
WO2010115998A2 (fr) 2009-04-10 2010-10-14 Ablynx Nv Séquences d'acides aminés améliorées directement contre il-6r et polypeptides comprenant celles-ci pour le traitement de maladies et de troubles associés à il-6r
WO2011026948A1 (fr) 2009-09-03 2011-03-10 Ablynx N.V. Formulations stables de polypeptides et leurs utilisations
WO2011095545A1 (fr) 2010-02-05 2011-08-11 Ablynx Nv Peptides capables de se lier à la sérumalbumine, et composés, constructions, et polypeptides comprenant de tels peptides
WO2013041722A1 (fr) 2011-09-23 2013-03-28 Ablynx Nv Inhibition prolongée d'une signalisation à médiation par l'interleukine-6
WO2016062766A1 (fr) * 2014-10-21 2016-04-28 Ablynx Nv Traitement de maladies associées à il-6r

Non-Patent Citations (62)

* Cited by examiner, † Cited by third party
Title
"Remington, the Science and Practice of Pharmacy, 21th Edition,", 2005, LIPPINCOTT WILLIAMS AND WILKINS
"Remington's Pharmaceutical Sciences, 18th Ed.,", 1990, MACK PUBLISHING COMPANY
ALETAHA; SMOLEN, CLINICAL RHEUMATOLOGY, vol. 21, 2007, pages 663 - 75
ANSEL ET AL., IMMUNITY, vol. 16, 2002, pages 67 - 76
ANSEL ET AL., NATURE, vol. 406, 2000, pages 309 - 14
BETZ; W. MULLER, INT. IMMUNOL., vol. 10, 1998, pages 1175 - 1184
BRISO ET AL., J. IMMUNOL., vol. 180, 2008, pages 7102 - 7106
CAMPBELL ET AL., J. CLIN. INVEST, vol. 87, 1991, pages 739 - 742
CONRATH ET AL., J. BIOL. CHEM., vol. 276, 2001, pages 7346 - 7350
COPPIETERS ET AL., ARTHRITIS RHEUM., vol. 54, 2006, pages 1856 - 1866
DAVIES; RIECHMANN, FEBS LETT., vol. 339, 1994, pages 285
DENNIS ET AL., J. BIOL. CHEM., vol. 277, 2002, pages 35035 - 35043
DRAKE ET AL., ANALYTICAL BIOCHEMISTRY, vol. 328, 2004, pages 35 - 43
EMERY, INT. J. CLIN. RHEUM., vol. 5, 2010, pages 17 - 24
EMILIE ET AL., INT. J. IMMUNOPHARMACOL., vol. 16, 1994, pages 391 - 6
F. AUSUBEL ET AL.: "Current protocols in molecular biology", 1987, GREEN PUBLISHING AND WILEY INTERSCIENCE
FELSON ET AL.: "American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials", ANNALS OF THE RHEUMATIC DISEASES, vol. 70, 2011, pages 404 - 13
FIRESTEIN ET AL.: "Kelley's Textbook of Rheumatology (8th ed.)", 2006, ELSEVIER, pages: 1119 - 1143
FRIGUET ET AL., J. IMMUNOL. METHODS, vol. 77, 1985, pages 305 - 19
GIBALDI AND PERRON: "Pharmacokinetics, 2nd Rev. edition", 1982, MARCEL DEKKER,
GILLIAM ET AL., PEDIATRIC RHEUMATOLOGY, vol. 9, 2011, pages 8
GONZALES ET AL., TUMOUR BIOL., vol. 26, no. 1, 2005, pages 31 - 43
GRAU ET AL., J. EXP. MED., vol. 172, 1990, pages 1505 - 8
HOLT ET AL., TRENDS BIOTECHNOL., vol. 21, 2003, pages 484 - 490
HOLZ J-B ET AL: "TWENTY-FOUR WEEKS OF TREATMENT WITH A NOVEL ANTI-IL-6 RECEPTOR NANOBODY (R) (ALX-0061) RESULTED IN 84% ACR20 IMPROVEMENT AND 58% DAS28 REMISSION IN A PHASE I/II STUDY IN RA", ANNALS OF THE RHEUMATIC DISE, BRITISH MEDICAL ASSOCIATION, GB, vol. 72, no. Suppl. 3, 1 June 2013 (2013-06-01), pages 64, XP009187263, ISSN: 0003-4967, DOI: 10.1136/ANNRHEUMDIS-2013-EULAR.248 *
IRVING ET AL., J. IMMUNOL. METHODS, vol. 248, no. 1-2, 2001, pages 31 - 45
ISHIHARA; HIRANO, BIOCHIM. BIOPHYS. ACTA, vol. 1592, 2002, pages 281 - 96
JANEWAY ET AL.: "Immunobiology (6th Ed.),", 2005, GARLAND SCIENCE PUBLISHING/ CHURCHILL LIVINGSTONE
JILKA ET AL., SCIENCE, vol. 257, 1992, pages 88 - 91
JONES ET AL., J. CLIN. INVESTIG., vol. 121, 2011, pages 3375 - 83
JONES ET AL., J. INTERFERON CYTOKINE RES., vol. 25, 2005, pages 241 - 253
KENNETH ET AL.: "Chemical Stability of Pharmaceuticals: A Handbook for Pharmacists", 1996
KITAMURA ET AL., J. CELL PHYSIOL., vol. 140, 1989, pages 323
KLEIN ET AL., BLOOD, vol. 78, 1991, pages 1198 - 204
LEGLER ET AL., J. EXP. MED., vol. 187, 1998, pages 655 - 60
LEVIN; WEISS, MOL. BIOSYST., vol. 2, no. 1, 2006, pages 49 - 57
LEWIN: "Genes II", 1985, JOHN WILEY & SONS
MAARTEN VAN ROY ET AL: "The preclinical pharmacology of the high affinity anti-IL-6R Nanobody ALX-0061 supports its clinical development in rheumatoid arthritis", ARTHRITIS RESEARCH & THERAPY, vol. 17, no. 1, 1 January 2015 (2015-01-01), XP055229232, DOI: 10.1186/s13075-015-0651-0 *
MACDONALD ET AL., CURR. OPIN. MOL. THER., vol. 12, 2010, pages 461 - 470
MAINI, PLENARY LECTURE EULAR CONFERENCE 2008, 2008
MUYLDERMANS, REVIEWS IN MOLECULAR BIOTECHNOLOGY, vol. 74, 2001, pages 277 - 302
N.N. ET AL: "Topline results from the Phase IIb monotherapy study of vobarilizumab, ALX-0061 (anti-IL-6R), in patients with moderate to severe RA", PRESENTATION BY ABLYNX, 7 July 2016 (2016-07-07), XP055405907, Retrieved from the Internet <URL:http://www.ablynx.com/uploads/data/files/160706 alx-0061 c202 webcast_final.pdf> [retrieved on 20170912] *
NISHIMOTO ET AL., BLOOD, vol. 112, 2008, pages 3959 - 3964
OBER ET AL., INTERN. IMMUNOLOGY, vol. 13, 2001, pages 1551 - 1559
OLD ET AL.: "Principles of Gene Manipulation: An Introduction to Genetic Engineering, 2nd edition,", 1981, UNIVERSITY OF CALIFORNIA PRESS
PRESTA, ADV. DRUG DELIV. REV., vol. 58, no. 5-6, 2006, pages 640 - 56
PROTEIN ENGINEERING, vol. 9, 1996, pages 531
RICHTER ET AL., AAPS J., vol. 14, 2012, pages 559 - 570
RICHTER; JACOBSEN, DRUG METAB. DISPOS., 6 August 2014 (2014-08-06)
ROITT ET AL.: "Immunology (6th. Ed.)", 2001, ELSEVIER
ROITT ET AL.: "Roitt's Essential Immunology, 10th Ed.", 2001, BLACKWELL PUBLISHING
ROODMAN ET AL., J. BONE MINER. RES., vol. 7, 1992, pages 475 - 8
SAMBROOK ET AL.: "Molecular Cloning: A Laboratory Manual ( 2nd.Ed.)", vol. 1-3, 1989, COLD SPRING HARBOR LABORATORY PRESS
SCHMITZ ET AL., PLACENTA, vol. 21, no. A, 2000, pages 106 - 12
STARNES ET AL., J. IMMUNOL., vol. 148, 1999, pages 1968
STRASSMAN ET AL., J. CLIN. INVEST., vol. 89, 1992, pages 1681 - 1684
WAETZIG; ROSE-JOHN, EXP. OPINION THERAP. TARGETS, vol. 16, 2012, pages 225 - 36
WARD ET AL., NATURE, vol. 341, 1989, pages 544 - 6
WILLIAMS, J. FLA. MED. ASSOC., vol. 78, 1991, pages 517 - 519
WOLFE F. ET AL., ARTHRITIS & RHEUMATISM, vol. 42, 1999, pages 1797 - 1808
YE ET AL., J. BIOL. CHEM., vol. 271, 1996, pages 13055 - 60
ZHENG ET AL., MABS, vol. 4, 2012, pages 243 - 255

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020219960A1 (fr) * 2019-04-24 2020-10-29 Sanofi Biotechnology Procédés de diagnostic et de traitement de la polyarthrite rhumatoïde
CN114651010A (zh) * 2019-04-24 2022-06-21 赛诺菲生物技术公司 类风湿性关节炎的诊断和治疗方法

Similar Documents

Publication Publication Date Title
US11008393B2 (en) Pharmaceutical compositions comprising a polypeptide that binds to IL-6
RU2729379C1 (ru) Анти-tigit антигенсвязывающие белки и способы их применения
US11149089B2 (en) Method for treating rheumatoid arthritis by administering IL-6 receptor antibodies
JP6159684B2 (ja) Ｉｌ−６ｒ関連疾患及び障害の治療のためのｉｌ−６ｒに指向性を有する改善されたアミノ酸配列及びこれを含むポリペプチド
JP2010500876A (ja) Ｉｌ−６媒介性シグナル伝達に関連する疾患及び障害の治療のための、ｉｌ−６ｒに指向性を有するアミノ酸配列及びこれを含むポリペプチド
JP2010502208A (ja) 半減期の長い血清アルブミン結合タンパク質
TW201726731A (zh) 對TNF-α、IL-17A及IL-17F具特異性之多重特異性抗體分子
WO2021143826A1 (fr) Protéine de mort cellulaire 1 anti-programmée recombinante et préparation d&#39;anticorps bispécifique anti-cluster d&#39;antigène de différenciation 137 et son utilisation
JP2019162119A (ja) Ｉｌ−１７ｃに対する抗体
TW202239763A (zh) 包含靶向ＩＬ－６和ＴＮＦ－α的免疫球蛋白單可變結構域的多肽
AU2015307868B2 (en) Method for treating psoriasis patient which received anti-TNF-alpha antibody therapy
JP2023510928A (ja) 抗ｂｔｌａ抗体医薬組成物及びその使用
TW202229338A (zh) 包含靶向ｉｌ－１３和ｏｘ４０ｌ的免疫球蛋白單可變結構域的多肽
WO2018029182A1 (fr) Anticorps à domaine variable unique d&#39;il-6r pour le traitement de maladies liées à l&#39;il-6r
KR101581517B1 (ko) Tgf-알파 및 에피레굴린에 결합하는 항체
WO2018007442A1 (fr) Traitement de maladies associées à l&#39;il-6r
JP7490329B2 (ja) クローン病を治療するための医薬組成物
US20180111988A1 (en) Pharmaceutical composition for treating rheumatoid arthritis
JP2017154975A (ja) クローン病を治療するための医薬組成物
TW201925234A (zh) 抗huTNFR1治療非酒精性脂肪性肝炎
CN116783214A (zh) 包含靶向il-13和ox40l的免疫球蛋白单可变结构域的多肽
EP3159007A1 (fr) Composition pharmaceutique pour le traitement de la polyarthrite rhumatoïde

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17740332

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17740332

Country of ref document: EP

Kind code of ref document: A1