EP4153613A1 - Inhibiteur dérivé d'il-1-r1 de l'il-1b et son utilisation - Google Patents

Inhibiteur dérivé d'il-1-r1 de l'il-1b et son utilisation

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Publication number
EP4153613A1
EP4153613A1 EP20936359.7A EP20936359A EP4153613A1 EP 4153613 A1 EP4153613 A1 EP 4153613A1 EP 20936359 A EP20936359 A EP 20936359A EP 4153613 A1 EP4153613 A1 EP 4153613A1
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EP
European Patent Office
Prior art keywords
disease
composition
seq
human
polypeptide
Prior art date
Legal status (The legal status 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 status listed.)
Pending
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EP20936359.7A
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German (de)
English (en)
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EP4153613A4 (fr
Inventor
Yan Lavrovsky
Alexey REPIK
Mikhail Samsonov
Sergei BARBASHOV
Vasily IGNATIEV
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R Pharm Overseas Inc
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R Pharm Overseas Inc
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Publication of EP4153613A1 publication Critical patent/EP4153613A1/fr
Publication of EP4153613A4 publication Critical patent/EP4153613A4/fr
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • C07K14/7155—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Definitions

  • the invention relates to the field of biological pharmaceuticals as well as their use in conditions associated with inflammatory disorders (e.g. rheumatoid arthritis, Crohn’s disease, etc.), diabetes, cardiovascular disease and gout. More specifically, the invention relates to a heterodimeric IL-lRl/lL-lRAcP -derived composition that is capable of inhibiting IL-1 ⁇ cytokine.
  • the interleukin-1 (IL-1) family of cytokines comprises 11 proteins (IL-1F1 to IL-1F11) encoded by 11 distinct genes in humans and mice.
  • IL-l-type cytokines are major mediators of innate immune reactions, and blockade of the founding members IL-1 or IL-1 ⁇ by the interleukin- 1 receptor antagonist (IL-1RA) has demonstrated a central role of IL-1 in a number of human autoinflammatory diseases.
  • IL-1 or IL-1 ⁇ rapidly increase messenger RNA expression of hundreds of genes in multiple different cell types.
  • the potent proinflammatory activities of IL-1 and IL-1 ⁇ are restricted at three major levels: (i) synthesis and release, (ii) membrane receptors, and (iii) intracellular signal transduction.
  • This pathway summarizes extracellular and intracellular signaling of IL-1 or IL-1 ⁇ , including positive- and negative-feedback mechanisms that amplify or terminate the IL-1 response.
  • a complex sequence of combinatorial phosphorylation and ubiquitination events results in activation of nuclear factor kappa-B signaling and the JNK and p38 mitogen-activated protein kinase pathways, which, cooperatively, induce the expression of canonical IL-1 target genes (such as IL-6, IL-8, MCP-1, COX-2, IB, IL-1, IL-1 ⁇ , MKP-1) by transcriptional and posttranscriptional mechanisms.
  • canonical IL-1 target genes such as IL-6, IL-8, MCP-1, COX-2, IB, IL-1, IL-1 ⁇ , MKP-1
  • IL-1 interleukin-1
  • IL-18 and IL-33 cytokines
  • TLRs Toll-like-receptors
  • cytotoxic stresses see Weber A, et ah, Sci Signal., 2010 Jan 19;3(105), the entire teachings of which are incorporated by reference herein).
  • IL-1 and IL-1 ⁇ independently bind the type I IL-1 receptor (IL-lRl), which is ubiquitously expressed.
  • a third specific ligand, the IL-1 receptor antagonist (IL-IRA) binds the IL-1RI with similar specificity and affinity but does not activate the receptor and trigger downstream signaling.
  • the IL-1 receptor accessory protein (IL-lRAcP) serves as a co-receptor that is required for signal transduction of IL-l/IL-lRI complexes, and this co-receptor is also necessary for activation of IL- 1R1 by other IL-1 family members, in particular IL-18 and IL-33.
  • the type II IL-1 receptor (IL- 1R2) binds IL-1 and IL-1 ⁇ but lacks a signaling-competent cytosolic part and thus serves as a decoy receptor.
  • the IL-1RA, the plasma membrane-anchored IL-1R2, and the naturally occurring "shed" domains of each of the extracellular IL-1 receptor chains (termed sIL-lRI, sIL-lRII, and sIL-lRAcP, where "s” stands for soluble) provide inducible negative regulators of IL-1 signaling in the extracellular space whose abundance, which is regulated by a combination of increased transcription and controlled release, can limit or terminate IL-1 effects.
  • the initial step in IL-1 signal transduction is a ligand-induced conformational change in the first extracellular domain of the IL-IRI that facilitates recruitment of IL-lRacP.
  • TIR Toll- and IL-lR-like domains
  • the trimeric complex rapidly assembles two intracellular signaling proteins, myeloid differentiation primary response gene 88 (MYD88) and interleukin- 1 receptor-activated protein kinase (IRAK) 4.
  • MYD88 myeloid differentiation primary response gene 88
  • IRAK interleukin- 1 receptor-activated protein kinase
  • Mice lacking MYD88 or IRAK4 show severe defects in IL-1 signaling.
  • humans with mutations in the IRAK4 gene have defects in IL-IRI and Toll-like receptor (TLR) signaling.
  • IL-1, IL-IRI, IL-RAcP, MYD88, and IRAK4 form a stable IL-l-induced first signaling module.
  • This is paralleled by the (auto)phosphorylation of IRAK4, which subsequently phosphorylates IRAKI and IRAK2, and then this is followed by the recruitment and oligomerization of tumor necrosis factor-associated factor (TRAF) 6.
  • IRAKI and 2 function as both adaptors and protein kinases to transmit downstream signals.
  • Complexes of IRAKI, IRAK2, and TRAF6 dissociate from the initial receptor complex, and cells lacking these proteins have impaired activation of the transcription factors nuclear factor kappa-B (NF-kappa-B) and activator protein 1 (AP-1).
  • IL-1 has been linked to the pathology of diabetes, cardiovascular disease, gout, certain types of arthritis (e.g. rheumatoid arthritis (RA)), as well as a number of less prevalent autoimmune diseases, such as familial Mediterranean fever (FMF), Behcet disease, etc. (Ozen S, Bilginer Y. “A clinical guide to autoinflammatory diseases: familial Mediterranean fever and next-of-kin”, Nat. Rev.
  • Rilonacept is an IL-1 antagonist which includes an IL-l-specific fusion protein which comprises an IL-1 binding portion of the extracellular domain of human ILl-RAcP, an IL-1 binding portion of the extracellular domain of human IL-IRI, and a multimerizing component.
  • This IL-l-specific fusion protein is described in U.S. Pat. No. 6,472,179, U.S. patent publication No. 2003/0143697, published 31 Jul. 2003, U.S. Pat. No. 7,361,350, and U.S. patent publication No. 2005/0197293, published 8 Sep. 2005 (all of which are incorporated by reference herein in their entirety).
  • Rilonacept under the trade name ARCALYST was approved by U.S.
  • FDA Food and Drug Administration
  • Cryopyrin-Associated Periodic Syndromes including Familial Cold Auto-inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS) in adults and children 12 and older.
  • FCAS Familial Cold Auto-inflammatory Syndrome
  • MFS Muckle-Wells Syndrome
  • the present invention provides for a heterodimeric protein composition capable of binding human IL-1 ⁇ (GenBank: AAH08678.1).
  • the protein composition comprises a first polypeptide which includes a first amino acid sequence which contains amino acids 18 through 333 of human IL1-R1 (GenBank: AAM88423.1), and a second amino acid sequence which contains a first mutant of a Fc portion of human immunoglobulin gamma- 1 Fc (GenBank: J00228.1).
  • the protein composition also comprises a second polypeptide which includes another first amino acid sequence containing amino acids 21 through 358 of human ILl-RAcP (GenBank: BAA25421.1), and another second amino acid sequence which contains a second mutant of the Fc portion of human immunoglobulin gamma-1 Fc.
  • the first and second mutants are selected as to favor heterodimeric assembly between the first and second mutants over any homodimeric assembly.
  • the protein composition may be capable of exhibiting human IL- 1 ⁇ /IL- l F2 binding activity with a Kd valus of no more than about 10 U M.
  • the first polypeptide of the protein composition may contain amino acid sequence of SEQ ID NO. 1, while the second polypeptide may contain amino acid sequence of SEQ ID NO. 2.
  • the present invention provides for a heterodimeric protein composition, containing a first polypeptide including amino acid sequence of SEQ ID NO. 8 and a second polypeptide including amino acid sequence of SEQ ID NO. 9.
  • the present invention provides for a therapeutic composition which contains a heterodimeric protein composition, including a first polypeptide containing amino acid sequence of SEQ ID NO. 8 and a second polypeptide containing amino acid sequence of SEQ ID NO. 9.
  • the therapeutic composition may also contain about 6% (m/v) sucrose, about 3% (m/v) polyethylene glycol having an average molecular weight of 3350 Da, about 50 mM sodium chloride, and about 20 mM L-Histidine pH from about 4.5 to about 7.0.
  • the pH value may be about 6.5.
  • the present invention provides for a therapeutic composition.
  • the therapeutic composition comprises a heterodimeric protein composition capable of binding human IL-1 ⁇ .
  • the protein composition comprises a first polypeptide which includes a first amino acid sequence which contains amino acids 18 through 333 of human IL1-R1, and a second amino acid sequence which contains a first mutant of the Fc portion of human immunoglobulin gamma-1 Fc.
  • the protein composition also comprises a second polypeptide which includes another first amino acid sequence containing amino acids 21 through 358 of human ILl-RAcP, and another second amino acid sequence which contains a second mutant of the Fc portion of human immunoglobulin gamma- 1 Fc.
  • the first and second mutants are selected as to favor heterodimeric assembly between the first and second mutants over any homodimeric assembly.
  • the protein composition may be capable of exhibiting human IL-1 ⁇ /IL- l F2 binding activity with a Kd values of no more than about 10 -11 M.
  • the therapeutic composition may exhibit a half- life of the heterodimeric protein composition in systemic circulation in mice after a subcutaneous administration at a dose of 5 mg/kg of at least about 97 hours, as assayed by human Fc ELISA.
  • the therapeutic composition may exhibit a half-life of the heterodimeric protein composition in systemic circulation in Cynomolgus monkeys after a subcutaneous administration at a dose of 10 mg/kg of at least about 3 days, as assayed by human Fc ELISA.
  • the therapeutic composition may comprise a heterodimeric protein comprised of a first polypeptide containing amino acid sequence of SEQ ID NO. 1 and a second polypeptide containing amino acid sequence of SEQ ID NO. 2.
  • the therapeutic composition may also contain about 6% (m/v) sucrose, about 3% (m/v) polyethylene glycol with an average molecular weight of about 3350 Da, about 50 mM sodium chloride, and about 20 mM L-Histidine pH 6.5.
  • the present invention provides for a therapeutic composition which contains a heterodimeric protein composition, including a first polypeptide containing amino acid sequence of SEQ ID NO. 8 and a second polypeptide containing amino acid sequence of SEQ ID NO. 9.
  • the therapeutic composition may also contain about 6% (m/v) sucrose, about 3% (m/v) polyethylene glycol having an average molecular weight of 3350 Da, about 50 mM sodium chloride, and about 20 mM L-Histidine pH from about 4.5 to about 7.0.
  • the pH value may be about 6.5.
  • the present teachings provide for a substance or a composition containing a heterodimeric protein assembly including a polypeptide of SEQ ID NO. 8 and another polypeptide of SEQ ID NO. 9 for use in the treatment of certain disorders or diseases associated with IL-1 ⁇ modulation, including, but not limited to, arthritis, gout, rheumatoid arthritis, cryopyrin-associated periodic syndromes (CAPS), scleroderma, diabetes, atherosclerosis, dry eye syndrome, ocular allergy, uveitis, recurrent pericarditis, familial Mediterranean fever (FMF), ST- elevation myocardial infarction (STEMI), acute respiratory distress syndrom e/cytokine release storm (ARSD/CRS), Schnitzler syndrome, postoperative incisional pain, chronic kidney disease (CKD), PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis) syndrome, hemophagocytic lymphohistiocytos
  • the present teachings provide for a method of treating or preventing a disease or condition associated with modulation of activity of human IL-1 ⁇ .
  • the method includes administering to a patient in need for treating or preventing a disease associated with modulation of activity of human IL-1 ⁇ a therapeutically effective amount of a pharmaceutical composition including a heterodimeric protein containing a first polypeptide including amino acid sequence of SEQ ID NO. 8 and a second polypeptide comprising amino acid sequence of SEQ ID NO. 9.
  • Diseases associated with IL-1 ⁇ modulation include, but are not limited to, arthritis, gout, rheumatoid arthritis, cryopyrin-associated periodic syndromes (CAPS), scleroderma, diabetes, atherosclerosis, dry eye syndrome, ocular allergy, uveitis, recurrent pericarditis, familial Mediterranean fever (FMF), ST-elevation myocardial infarction (STEMI), acute respiratory distress syndrom e/cytokine release storm (ARSD/CRS), Schnitzler syndrome, postoperative incisional pain, chronic kidney disease (CKD), PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis) syndrome, hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS), pyoderma gangrenosum, Kawasaki disease, acne vulgaris, atopic dermatitis, Behcet disease, breast cancer, non-small cell lung cancer,
  • Figure 1 illustratively shows a heterodimeric protein assembly of the present teachings comprising an extracellular portion of IL1-R1 fused with an IgG-Fc domain (Fc-II) via a flexible linker and an extracellular portion of ILl-RAcP fused with another IgG-Fc domain (Fc-V) via another flexible linker;
  • Fc-II IgG-Fc domain
  • Fc-V IgG-Fc domain
  • Figure 2 shows a representative series of buffer-normalized sensograms at various concentrations of IL-1 ⁇ /IL-lF2, the lowest curve represents IL-1 ⁇ /IL- l F2 concentration of 0.919 nM and each subsequent curve represents 1.838, 3.676, 7.35, 14.7 and 29.4 nM respectively;
  • Figure 3 shows a representative IL1 binding data, relative response was calculated by subtraction of ‘buffer only’ background, error bars reflect standard deviation values calculated by Bioacore T200 Evaluation Software package;
  • Figure 4 shows representative ‘Response vs. Concentration’ curve, concentration of IL- 1 ⁇ /IL- l F2 is shown on the X-axis in Mol and Response in RU (Req) is shown on the Y-axis;
  • Figure 5 shows concentration of ILlR-FcV-RAcP-FcII heterodimer (in ng/ml) in the serum of the initial set of three Cynomolgus Monkey after a single subcutaneous administration at a dose of 10 mg/kg (vertical bars represent standard deviation values at various time points);
  • Figure 6 shows concentration of ILlR-FcV-RAcP-FcII heterodimer (in ng/ml) in the serum of the follow-up set of three Cynomolgus Monkey after a single subcutaneous administration at a dose of 10 mg/kg, the three curves shown represent measurements taken from three individual animals designated FI 290, F1269 and F 1254;
  • Figure 7 shows ILlR-FcV-RAcP-FcII heterodimer titration curve of mouse IL6 secretion induced by mouse IL-1B /IL-lF2in MEFs, the insert table shows curve fitting results using 4- parameter algorithm and curve interpolation for determination of the IC50 value;
  • Figure 8 shows ILlR-FcV-RAcP-FcII heterodimer titration curve of human IL6 secretion induced by human IL-IB /IL-1F2 in MRC5 cells, the insert table shows curve fitting results using 4-parameter algorithm and curve interpolation for determination of the IC50 value;
  • Figure 9 shows ILlR-FcV-RAcP-FcII heterodimer titration curve of human IL6 secretion induced by M. Rhesus IL-IB /IL-lF2in MRC5 cells, the insert table shows curve fitting results using 4-parameter algorithm and curve interpolation for determination of the IC50 value.
  • the teachings disclosed herein are based, in part, upon engineering of a heterodimeric protein assembly that is capable of binding to human IL-1 ⁇ and attenuating its function.
  • the heterodimeric protein assembly of the present teachings comprises extracellular portions of ILl-Rl (GenBank: AAM88423.1) and of IL-lRAcP (GenBank: BAA25421.1), or functional fragments thereof. Each, the ILl-Rl portion and the IL-lRAcP portion, is fused to a distinct mutant of Fc portion of the human Ig Gamma-1 (GenBank: J00228.1).
  • the two distinct Fc mutants in the heterodimeric protein assembly are engineered as to favor the heteromeric dimer formation between the two Fc mutants over any homomeric assembly.
  • a DNA expression vector has been constructed for overproducing the heterodimeric protein assembly in a heterologous protein expression system, and mammalian cells have been prepared stably expressing the heterodimeric protein assembly to a high expression level.
  • a protein purification procedure has been devised allowing obtaining a physiologically relevant substantially pure preparation of the heterodimeric protein assembly of the present teachings.
  • purified protein molecule demonstrates a high degree of specific activity in an in vitro Enzyme-Linked Immunosorbent Assay (ELISA) using human IL- 1b (GenBank: AAH08678.1).
  • the protein molecule exhibits an acceptable pharmacokinetics profile upon subcutaneous animal administration, while not resulting in any body weight loss or adverse clinical events.
  • Design, preparation and preliminary characterization of composition of matter of the present teachings are disclosed, in part, in an International Patent Application Publication No. WO/2014/035361, published on March 6, 2014, and International Patent Application Serial No. PCT/US/2013/026349, filed on February 15, 2013, both of which are incorporated herein by reference in their entirety.
  • the terms “about” and “approximately” may mean values that are within an order of magnitude, preferably within 5- fold and more preferably within 2-fold of a given value. Numerical quantities given herein are approximate unless stated otherwise, meaning that the term “about” or “approximately” can be inferred when not expressly stated.
  • the methods of the invention may include steps of comparing sequences to each other, including wild-type sequence to one or more mutants (sequence variants).
  • Such comparisons typically comprise alignments of polymer sequences, e.g., using sequence alignment programs and/or algorithms that are well known in the art (for example, BLAST, FASTA and MEGALIGN, to name a few).
  • sequence alignment programs and/or algorithms that are well known in the art (for example, BLAST, FASTA and MEGALIGN, to name a few).
  • sequence alignment programs and/or algorithms that are well known in the art (for example, BLAST, FASTA and MEGALIGN, to name a few).
  • the methods of the invention may include statistical calculations, e.g. determination of IC50 or EC50 values, etc..
  • the skilled artisan can readily appreciate that such can be performed using a variety of commercially available software, e.g. PRISM (GraphPad Software Inc, La Jolla, CA, USA) or similar.
  • homologous in all its grammatical forms and spelling variations, refers to the relationship between two proteins that possess a “common evolutionary origin,” including proteins from super families in the same species of organism, as well as homologous proteins from different species of organism. Such proteins (and their encoding nucleic acids) have sequence homology, as reflected by their sequence similarity, whether in terms of percent identity or by the presence of specific residues or motifs and conserved positions.
  • homologous when modified with an adverb such as "highly,” may refer to sequence similarity and may or may not relate to a common evolutionary origin.
  • sequence similarity in all its grammatical forms, refers to the degree of identity or correspondence between nucleic acid or amino acid sequences that may or may not share a common evolutionary origin.
  • polypeptides described herein may be comprised of more than one contiguous amino acid chain, thus forming dimers or other oligomeric formations.
  • the polypeptides of the present teachings for use in mammals are expressed in mammalian cells that allow for proper post-translational modifications, such as CHO or HEK293 cell lines, although other mammalian expression cell lines are expected to be useful as well. It is therefore anticipated that the polypeptides of the present teachings may be post-translationally modified without substantially effecting its biological function.
  • fusion proteins having at least a biologically active portion of the human IL1-R1 or IL-lRAcP or a functional fragment thereof, and one or more fusion domains.
  • fusion domains include, but are not limited to, polyhistidine, Glu-Glu, glutathione S transferase (GST), thioredoxin, protein A, protein G, an immunoglobulin heavy chain constant region (e.g., an Fc), maltose binding protein (MBP), or human serum albumin.
  • a fusion domain may be selected so as to confer a desired property.
  • the ILl-Rl or IL- lRAcP polypeptide portions may be fused with a domain that stabilizes the ILl-Rl or IL-lRAcP polypeptides in vivo (a "stabilizer” domain), optionally via a suitable peptide linker.
  • a stabilizer means anything that increases the half life of a polypeptide in systemic circulation, regardless of whether this is because of decreased destruction, decreased clearance, or other pharmacokinetic effect. Fusions with the Fc portion of an immunoglobulin are known to confer desirable pharmacokinetic properties on certain proteins. Likewise, fusions to human serum albumin can confer desirable properties.
  • fusion domains that may be selected include multimerizing (e.g., dimerizing, tetramerizing) domains and functional domains that confer an additional biological function, e.g. promoting accumulation at the targeted site of action in vivo.
  • multimerizing e.g., dimerizing, tetramerizing
  • functional domains that confer an additional biological function, e.g. promoting accumulation at the targeted site of action in vivo.
  • the heterodimeric protein assemblies of the present teachings comprise an extracellular portion of IL1-R1, or a functional fragment thereof, fused with a IgG-Fc domain, and an extracellular portion IL-lRAcP, or a functional fragment thereof, fused with another IgG-Fc domain.
  • the IgG-Fc domain and the another IgG-Fc domain are chosen as to favor a heterodimeric protein assembly over any homodimeric protein assembly.
  • the extracellular portion of IL1-R1 may be fused with the IgG-Fc domain via a flexible linker, while IL-lRAcP, or a functional fragment thereof, may be fused with the another IgG-Fc domain via the flexible linker of the same amino acid sequence or via another flexible linker.
  • the extracellular portion of ILl-Rl fused with IgG-Fc domain (Fc-II) via a flexible linker may comprise the amino acid sequence of SEQ ID NO. 1
  • IL-lRAcP fused with another IgG-Fc domain (Fc-V) via a flexible linker may comprise the amino acid sequence of SEQ. ID NO. 2.
  • hlLl-Rl-hlgGl-Fc polypeptide SEQ ID NO. 1
  • the present teachings provides for a recombinant DNA molecule having an open reading frame coding for a polypeptide comprising the leading 333 amino acids of the human IL1-R1 fused with IgG-Fc domain (Fc-II) via a flexible linker, and for another recombinant DNA molecule having an open reading frame coding for another polypeptide comprising the leading 358 amino acids of the human IL-lRAcP fused with another IgG-Fc domain (Fc-V) via a flexible linker.
  • the polypeptide comprising the leading 333 amino acids of the human ILl-Rl fused with IgG-Fc domain (Fc-II) via a flexible linker comprises the amino acid sequence of SEQ. ID NO. 3.
  • the corresponding to it DNA molecule may comprise the nucleotide sequence of SEQ ID NO. 4.
  • the another polypeptide comprises the leading 358 amino acids of the human IL-lRAcP fused with another IgG-Fc domain (Fc-V) via a flexible linker may comprise the amino acid sequence of SEQ. ID NO. 5.
  • the corresponding to it DNA molecule may comprise the nucleotide sequence of SEQ ID NO. 6.
  • hlLl-Rl-hlgGl-Fc polypeptide SEQ ID NO. 3
  • FPPKPKDTLM ISRTPEVTCV W DVSHEDPE VKFNWYVDGV EVHNAKTKPR EEQYNSTYRV 420 VSVLTVLHQD WLNGKEYKCK VSNKALPAPI EKTISKAKGQ PREPQVCTLP PSRDELTKNQ 480 VSLSCAVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG SFKLVSKLTV DKSRWQQGNV 540 FSCSV HEAL HNHYTQKSLS LSPGK 565 hlLl-Rl-hlgGl-Fc DNA (SEQ ID NO. 4)
  • CTGTCTCCGG GTAAA 1695 hIL- 1 RAcP-hlgG 1 -F c polypeptide (SEQ ID NO. 5) TLLWCW SL YFYGILQSDA SERCDDWGLD T RQIQVFED EPARIKCPLF EHFLKFNYST 60 AHSAGLTLIW YWTRQDRDLE EPINFRLPEN RISKEKDVLW FRPTLLNDTG NYTC LRNTT 120 YCSKVAFPLE VVQKDSCFNS P KLPVHKLY IEYGIQRITC PNVDGYFPSS VKPTITWY G 180 CYKIQNFN V IPEG NLSFL IALISNNGNY TCVVTYPENG RTFHLTRTLT VKVVGSPKNA 240 VPPVIHSPND HW YEKEPGE ELLIPCTVYF SFL DSRNEV WWTIDGKKPD DITIDVTINE 300 SISHSRTEDE TRTQILSIKK VTSEDLKRSY VCHAR
  • the present invention provides for a recombinant mammalian expression plasmid for high expression of a polypeptide comprising the leading 333 amino acids of the human IL1-R1 fused with IgG-Fc domain (Fc-II) via a flexible linker, and for another recombinant DNA molecule having an open reading frame coding for another polypeptide comprising the leading 358 amino acids of the human IL-lRAcP fused with another IgG-Fc domain (Fc-V) via a flexible linker.
  • This plasmid comprises two cytomegalovirus (CMV) promoters to drive transcription of the two genes coding for said polypeptide and said another polypeptide, each followed by a transcription termination sequence and a polyadenylation sequence.
  • CMV cytomegalovirus
  • the plasmid also contains an origin of replication and a gene conferring ampicillin resistance, for supporting plasmid propagation and selection in bacteria.
  • the plasmid further contains a gene for Glutamine synthetase, a selectable marker widely used for establishing stable CHOK1 and NSO cell lines.
  • the mammalian expression plasmid of the present teachings comprises the nucleotide sequence of SEQ ID NO. 7.
  • hIL 1 -R 1 -hlgG 1 -F c-II/ IL-lRAcP- hlgGl-Fc-V expression plasmid (SEQ ID NO. 7)
  • the present teachings provide for a mammalian expression system for production of a heterodimeric protein assembly comprising a polypeptide comprising amino acid residues 18 through 333 of the human IL1-R1 fused with IgG-Fc domain (Fc-II) via a flexible linker, and another polypeptide comprising amino acid residues 21 through 358 of the human IL- lRAcP fused with another IgG-Fc domain (Fc-V) via a flexible linker.
  • the mammalian expression system of the present teachings comprises Chinese hamster ovary cells (CHO-K1) harboring a plasmid comprising nucleotide sequence of SEQ ID NO. 7.
  • the mammalian expression system of the present teachings yields a heterodimeric protein assembly comprising a polypeptide of SEQ ID NO. 8 and another polypeptide of SEQ ID NO. 9.
  • hlLl-Rl-hlgGl-Fc polypeptide SEQ ID NO. 8.
  • the present teachings provide for a substance or a composition, comprising a heterodimeric protein assembly comprising a polypeptide of SEQ ID NO. 8 and another polypeptide of SEQ ID NO. 9, for use in the treatment of certain disorders or diseases associated with IL-1 ⁇ modulation, including, but not limited to, arthritis, gout, rheumatoid arthritis, cryopyrin-associated periodic syndromes (CAPS), scleroderma, diabetes, atherosclerosis, dry eye syndrome, ocular allergy, uveitis, recurrent pericarditis, familial Mediterranean fever (FMF), ST- elevation myocardial infarction (STEMI), acute respiratory distress syndrom e/cytokine release storm (ARSD/CRS), Schnitzler syndrome, postoperative incisional pain, chronic kidney disease (CKD), PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis) syndrome, hemophagocytic lymphohistio
  • the present teachings provide for a method of treating or preventing a disease or condition associated with modulation of activity of human IL-1 ⁇ .
  • the method includes administering to a patient in need for treating or preventing a disease associated with modulation of activity of human IL-1 ⁇ a therapeutically effective amount of a pharmaceutical composition including a heterodimeric protein including a first polypeptide including amino acid sequence of SEQ ID NO. 8 and a second polypeptide comprising amino acid sequence of SEQ ID NO. 9.
  • Diseases associated with IL-1 ⁇ modulation include, but are not limited to, arthritis, gout, rheumatoid arthritis, cryopyrin-associated periodic syndromes (CAPS), scleroderma, diabetes, atherosclerosis, dry eye syndrome, ocular allergy, uveitis, recurrent pericarditis, familial Mediterranean fever (FMF), ST-elevation myocardial infarction (STEMI), acute respiratory distress syndrom e/cytokine release storm (ARSD/CRS), Schnitzler syndrome, postoperative incisional pain, chronic kidney disease (CKD), PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis) syndrome, hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS), pyoderma gangrenosum, Kawasaki disease, acne vulgaris, atopic dermatitis, Behcet disease, breast cancer, non-small cell lung cancer,
  • Example 1 Preparation of polypeptides of the present invention.
  • hlLl-Rl-hlgGl-Fc polypeptide of SEQ ID NO. 1 and hlL-lRAcP-hlgGl-Fc polypeptide of SEQ ID NO. 2 were co-expressed in CHO-K1 using molecular biology, cell culture and protein biochemistry techniques known in the art and described in PCT Publication WO/2014/035361, and PCT Application Serial No. PCT/US/2013/026349.
  • CHO-K1 cells expressing the polypeptides were harvested and lysed utilizing well established protocols.
  • the supernatant containing expressed polypeptides was first applied to a Protein A affinity column.
  • the pH adjusted Protein A column eluate was further purified by anion-exchange chromatography (AIEX) utilizing Q Sepharose resin.
  • AIEX flowthrough was analyzed by size-exclusion HPLC (SEC-HPLC), SDS-PAGE and other analytical techniques, as appropriate.
  • a therapeutic composition comprising hlLl-Rl-hlgGl-Fc and hlL- lRAcP-hlgGl-Fc polypeptides was formulated to contain 40 mg/ml of the polypeptides, 6% (m/v) sucrose, 3% (m/v) polyethylene (PEG) 3350, 50 mM sodium chloride, and 20 mM L-Histidine pH from about 4.5 to about 7.0, preferably about 6.5 .
  • polypeptides contained in the final product were analyzed as outlined in the following example. Unexpectedly, the polypeptides in the final product predominantly contained hlLl-Rl-hlgGl-Fc polypeptide of SEQ ID NO. 8 and hlL-lRAcP-hlgGl-Fc polypeptide of SEQ ID NO. 9.
  • Example 2 Peptide Mapping and Characterization of polypeptides of the present invention.
  • Solvent B Acetonitrile (ACN) with 0.1% formic acid
  • Tandem Mass Spectrometry Analysis Spectra were acquired using a QTOF 6550 mass spectrometer (Agilent Technologies, Santa Clara, CA). The mass spectrometer was operated in positive ion mode. Mass spectra were acquired over m/z 350-2000 at 20,000 resolution (m/z 1521) and data-dependent acquisition selected the top 10 most abundant precursor ions for tandem mass spectrometry by CID fragmentation using an isolation width of 4.0 Da, formula of (slope)*(m/z)/100 + offset was used for collision energy. Dynamic exclusion was used to minimize redundancy of MS/MS collection and maximize peptide identifications.
  • a concatenated forward-reverse database was constructed to calculate the in situ false discovery rate (FDR). Cutoff scores were dynamically assigned to each data set to maintain the false discovery rate at less than 0.1% at the peptide level. Manual inspection was also applied for every uniquely identified peptides of each of the analyzed samples.
  • Example 3 Evaluation of polypeptides of the present teachings affinity binding to RANKL using Surface Plasmon Resonance (SPR) assay.
  • SPR Surface Plasmon Resonance
  • the binding affinity of prepared polypeptides of ILlR-FcV-RAcP-FcII heterodimer to IL-1 ⁇ /IL-lF2 was measured using a specially designed Surface Plasmon Resonance (SPR) assay.
  • SPR Surface Plasmon Resonance
  • the assay was carried out using capturing method where anti human IgG were cross-linked to the surface of sensor chip for capturing ILlR-FcV-RAcP-FcII heterodimer via its IgG (Fc) fragments.
  • Series of different concentrations of IL-1 ⁇ /IL-lF2 were used for calculation of the dissociation constant (Kd).
  • BiaCore T200 Instrument # 12108, GE Healthcare, with Biacore T200 Control and Evaluation Software packages.
  • ILlR-FcV-RAcP-FcII heterodimer stock solution 20 mg/ml of the polypeptides, 6% (m/v) sucrose, 3% (m/v) PEG3350, 50 mM sodium chloride, and 20 mM L-Histidine pH 6.5.
  • IL-1 ⁇ /IL-lF2 Human recombinant, E.
  • CM5 Sensor Chip was placed into the instrument and primed with Biacore running buffer, lx HBS-EP, for 6 min at 10 m ⁇ /min, repeated twice. All steps were carried out at 25°C. Channels 1 and 2 was used for the experiment and channels 3 and 4 were reserved as a backup;
  • Anti -Human IgG from the kit 0.5 mg/ml in 0.15 M NaCl, was diluted 20-fold in Immobilization Buffer (10 mM Na-acetate pH 5.0) to a final concentration of 25 pg/ml;
  • Reagents for immobilization procedure were prepared as follows: EDC (1 -ethyl-3 -(3- dimethylaminopropyl)-carbodiimide) - 0.4 M in Milli-Q water; NHS (N- hydroxysuccinimide) - 0.1 M in Milli-Q water; 1 M Ethanolamine-HCl pH 8.5 in Milli-Q water;
  • Immobilization Anti -Human IgG were injected into the chip at 10 m ⁇ /min for 5 min;
  • the chip was washed with lx HBS-EP 2 times at 10 m ⁇ /min for 6 min and then the “dry” working cycle without addition of any protein component was run twice.
  • the working cycle consisted of Ligand (ILlR-FcV-RAcP-FcII heterodimer) Loading Step of 1 min, Wash Step of 3 min, Sample (IL-1) Loading Step of 1 min, Wash step of 16.7 min, Chip Regeneration Step, 1 min, 3 M MgCl 2 . All steps were run at 10 m ⁇ /min except Sample Loading Step that was run at 30 ⁇ l/min;
  • the goal of this experiment was to measure association constant for ILlR-FcV-RAcP- FcII heterodimer and IL-1 ⁇ /IL- l F2.
  • Anti-human IgG were covalently immobilized on CM5 Sensor Chip then ILlR-FcV-RAcP-FcII heterodimer was loaded and followed by various concentrations of human IL-1 ⁇ /IL- l F2 Series of sensograms were generated and used for calculation of Kd value.
  • Human IL-1 ⁇ /IL- l F2 were used at the concentrations specified in Table 2 where concentration of 3.676 nM was run two time independently as an internal control for the instrument reproducibility;
  • Kd Steady-State data analysis using 1 : 1 Langmuir binding model was used. According to this method, Kd is calculated from series of plots of steady-state analyte binding levels (Req) against concentration. The obtained data are summarized in Table 2.
  • IL-1 ⁇ /IL- l F2 concentrations and binding (Relative Response). Standard Deviation values, %, were calculated by Biacore T200 Evaluation Software and then converted into Standard Deviation by multiplying Rmax* StDev %. The StDev values are plotted as error bars on Figure 3.
  • Example 4 Pharmacokinetics (PK) of ILlR-FcV-RAcP-FcII heterodimer after subcutaneous administration in mice.
  • Polypeptides of ILlR-FcV-RAcP-FcII heterodimer were co-expressed and purified essentially as described in the forgoing examples.
  • the polypeptides were formulated in the following buffer: 1% w/v Sucrose, lOOmM Sodium Chloride, 20 mM L-Arginine Hydrochloride, 25 mM Sodium Bicarbonate, pH 6.3.
  • the dosing stock concentration used was 0.5 mg/mL of the polypeptide.
  • mice Fourteen male DBA/1 mice were randomized by body weight into seven groups of two animals on Day 0 of the study.
  • a single dose of ILlR-FcV-RAcP-FcII heterodimer (5 mg/kg in 10 ml/kg) was administered subcutaneously (dorsally) on Day 0 to mice in six of the groups.
  • the mice in the remaining group remained untreated and were bled via cardiac puncture for plasma preparation on Day 0 of the study.
  • Plasma was prepared from blood samples collected from mice in the treated groups via the orbital sinus or terminal cardiac puncture at specified times throughout the study. Body weights were recorded for all animals on the treatment day (Day 0) and then three times per week, including the termination day of each group.
  • Body weight change was not measured in groups culled for sample collection at 0 hours and within 36 hours of dose administration. Mean body weight loss between Day 0 and termination of the groups culled between 96 hours and 21 days post-dose was minimal. No mice lost body weight exceeding ethical limits.
  • plasma samples were analyzed by Enzyme Linked Immunosorbent Assay (ELISA) for Hu-Fc proteins. Quantification of Hu-Fc in mouse plasma samples by ELISA was used as a read-out for circulating levels of ILlR-FcV-RAcP-FcII heterodimer. The assay was performed on samples from all mice in the study.
  • ELISA Enzyme Linked Immunosorbent Assay
  • the polypeptides (detected as Human-Fc protein) were detected in the plasma of animals at all time-points post-dose.
  • One Phase Decay Model equation using Prism 5.0c (GraphPad Software Inc, La Jolla, CA, USA) was then used to determine pharmacokinetics of the polypeptides as detected by Hu-Fc ELISA.
  • Peak circulating level of Hu-Fc (Cmax) was determined to be 1.284 ⁇ g/mL, and time to peak circulating levels (Tmax) was 24 hours post-dose.
  • the half-life (Tl/2) was 97 hours, 31 minutes and the rate constant (K) was 0.0071 hr-1.
  • Hu-Fc was below the level of detection in the plasma of the untreated animals. The results of the study are summarized in Table 4.
  • an additional 3 male Cynomolgus monkeys received a single dose of ILlR-FcV-RAcP- FcII heterodimer by subcutaneous administration on Day 1 at a dose level of 10 mg/kg and blood samples were collected at designated time points until Day 21.
  • the results of the bioanalysis from the follow-up additional set of three animals are shown in Figure 5. All the animals were observed once daily for any reactions to treatment during the study. Body weights were measured and recorded prior to dosing. Blood samples for pharmacokinetic analysis were collected at the designated time points. The collected serum samples were stored at -80 °C for bioanalysis. The determination of plasma concentrations of the polypeptides was performed using ELISA method.
  • Cynomolgus monkeys (values in parenthesis are mean CV%) All animals were widely exposed to ILlR-FcV-RAcP-FcII heterodimer. The observed inter-individual variability was relatively high with a CV% of about 60%. The latter was explained by the lowest drug exposure found in animal F1290 ( Figure 6), which was at least 5-fold less exposed to ILlR-FcV-RAcP-FcII heterodimer than the remaining two animals. The maximal concentration (Cmax) was reached between 1st and 2nd days. The estimated Tl/2 was evaluated to be about 4 days.
  • Example 6 Interspecies Specific Activity of of ILlR-FcV-RAcP-FcII heterodimer.
  • ILlR-FcV-RAcP-FcII is a heterodimer comprised of soluble portions of human IL-IR and IL-lRAcP each linked to a unique IgGl Fc portion. Sequence alignment of the 333 amino acid portion of the human IL-IR with relevant portions from several species demonstrates only a modest sequence identity (-64%) with IL-IR portions from rodents (mouse, rat). However, the sequence identity is much higher between human IL-IR and those of other primates (e.g. 91% with marmoset monkey).
  • Mouse Embryo Fibroblasts used for the experiments.
  • DMEM Dulbecco’s Modification of Eagle’s Medium, high glucose (4.5 g/L), Invitrogen,
  • IL-1 ⁇ IL-1F2 Human recombinant, E. coli-derived, Alai 17-Ser269, Accession # NP_000567, R&D systems, Cat # 201-LB, Lot # AD1412111
  • IL-1 ⁇ IL-1F2 M. Rhesus recombinant, E. coli-derived, Alai 17-Ser269, Accession # P48090, R&D systems, Cat # 1318-RL, Lot # GUG0110111
  • This assay employs the quantitative sandwich enzyme immunoassay technique.
  • a monoclonal antibody specific for IL-6 has been pre-coated onto a microplate.
  • Standards and samples are pipetted into the wells and any IL-6 present is bound by the immobilized antibody.
  • an enzyme-linked polyclonal antibody specific for IL-6 is added to the wells.
  • a substrate solution is added to the wells and color develops in proportion to the amount of IL-6 bound in the initial step. The color development is stopped and the intensity of the color is measured.
  • the IL6 production data were calculated from the calibration curve shown on Figure 9.
  • the insert table shows curve fitting results using 4-parameter algorithm and curve interpolation for determination of the IC50 value.
  • the calculated ILlR-FcV-RAcP-FcII heterodimer IC50 value for mouse IL-1B /IL-1F2 is >210 ng/ml.
  • ILlR-FcV-RAcP-FcII heterodimer is an efficient inhibitor of human IL-1 ⁇ /IL-1F2, but not mouse IL-IB /IL-1F2 signaling pathway: ILlR-FcV- RAcP-FcII heterodimer IC50 value for human IL-IB /IL-1F2 is 0.19 ng/ml and for mouse IL-IB /IL-1F2- >200 ng/ml (0.95 pM and >1000 pM respectively, assuming molecular mass of ILIR- FcV-RAcP-FcII heterodimer as 200 kDa).
  • ILlR-FcV-RAcP-FcII heterodimer titration curve of human IL6 secretion induced by human IL-IB /IL-1F2 in MRC5 cells is shown in Figure 8.
  • the calculated IC50 value of ILlR-FcV-RAcP-FcII heterodimer against human IL-IB /IL-1F2 (X- column in the Curve Interpolation table) is 0.22 ng/mL.
  • ILlR-FcV-RAcP-FcII heterodimer titration curve of human IL6 secretion induced by M. Rhesus IL-IB /IL-1F2 in MRC5 cells is shown in Figure 9.
  • the calculated ILlR-FcV-RAcP-FcII heterodimer IC50 value for human IL- IB /IL-1F2 is 0.38 ng/ml.
  • IL-6 recovery from ILlR-FcV-RAcP-FcII heterodimer preparation with a final concentration of 200 ng/ml was 95%.
  • ILlR-FcV-RAcP-FcII heterodimer is an efficient inhibitor of both human andM Rhesus IL-1B /IL-1F2 signaling pathway:
  • ILlR-FcV-RAcP-FcII heterodimer IC50 value for human IL-1B /IL-1F2 is 0.19 ng/ml and for M.
  • IL-6 production upon treatment of mouse or human cells with IL-IB /IL-1F2 was used a functional test for inhibitory properties of a novel drug candidate ILlR-FcV- RAcP-FcII heterodimer against human, mouse and M. Rhesus orthologs of IL-IB /IL-1F2.
  • Suitable cell lines were identified and experimental conditions including cell density, treatment duration linear range for IL6 detection and were optimized for all three orthologs. The obtained data are summarized in Table 6.

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Abstract

L'invention concerne une composition thérapeutique qui peut être utilisée pour traiter ou prévenir des maladies associées à la modulation de l'activité de l'IL-1β humaine. Dans certains aspects, la composition fournie par la présente invention repose sur la production par ingénierie d'un ensemble protéinique hétérodimère pouvant se lier à l'IL-1β humaine et atténuer sa fonction. L'ensemble protéinique hétérodimère comprend des portions extracellulaires d'IL1-R1 humain et d'IL-1RAcP humaine, ou leurs fragments fonctionnels. Chacune de la portion d'IL1-R1 et de la portion d'IL-1RAcP est fusionnée à un mutant distinct de la portion Fc de l'Ig Gamma-1 humaine. Les deux mutants distincts Fc dans l'ensemble protéinique hétérodimère sont produits par ingénierie de manière à favoriser la formation du dimère hétéromère entre les deux mutants Fc par rapport à n'importe quel ensemble homomère. La composition thérapeutique a été formulée pour être administrée à des êtres humains et des animaux.
EP20936359.7A 2020-05-22 2020-05-22 Inhibiteur dérivé d'il-1-r1 de l'il-1b et son utilisation Pending EP4153613A4 (fr)

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