WO2022139580A1 - Blood gene expression biomarkers to predict response in patients with inflammatory bowel diseases - Google Patents
Blood gene expression biomarkers to predict response in patients with inflammatory bowel diseases Download PDFInfo
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- WO2022139580A1 WO2022139580A1 PCT/NL2021/050781 NL2021050781W WO2022139580A1 WO 2022139580 A1 WO2022139580 A1 WO 2022139580A1 NL 2021050781 W NL2021050781 W NL 2021050781W WO 2022139580 A1 WO2022139580 A1 WO 2022139580A1
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- sgp
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- igkv1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/118—Prognosis of disease development
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/158—Expression markers
Definitions
- the present invention relates to an sgp 130 protein, exemplified by olamkicept, for use in treating individuals for inflammatory bowel diseases (IBD).
- IBD inflammatory bowel diseases
- the invention provides a panel of gene expression biomarkers that predict response in patients with inflammatory bowel disease after a single administration of as sgp 130 protein, such as olamkicept.
- IBD Inflammatory bowel diseases
- CD Crohn's disease
- UC ulcerative colitis
- the therapy of IBD has been greatly improved by the introduction of specific therapies directed against single molecular targets.
- the first targeted therapies that were introduced and are still most widely used in clinical practice are monoclonal antibodies directed against the cytokine tumor necrosis factor-alpha (TNF), i.e. infliximab, adalimumab and golimumab, meanwhile complemented by generics.
- TNF tumor necrosis factor-alpha
- IBD interleukin- 12/-23 antibodies
- tofacitinib Janus kinase inhibitors
- Biomarkers may be classified as, e.g., prognostic or predictive.
- a prognostic biomarker provides information regarding likely patient outcome irrespective of treatment.
- a predictive biomarker indicates the likely benefit of treatment.
- predictive biomarkers are measured before treatment (i.e., at baseline) and provide information on the probability of response to treatment.
- Another type of predictive biomarkers are those identified whose expression changes dynamically over time and which are identified from the differential expression of genes between baseline and early time points after therapy induction.
- Interleukin-6 is a pleiotropic cytokine which is produced by haematopoietic and non-haematopoietic cells in response to infection and tissue damage and is involved in the pathophysiology of IBD (Garbers et al. 2018, Nat. Rev. Drug Discov. 17:395). IL-6 exerts its multiple functions through two main signaling pathways, which both require signal transduction by a pre-formed dimer of the transmembrane co-receptor gp!30 (Scheller et al. 2014, Semin. Immunol. 26:2). In classic signaling, IL-6 uses the membrane-bound IL-6 receptor (IL-6R), which is mainly expressed by hepatocytes and leukocytes.
- IL-6R membrane-bound IL-6 receptor
- circulating soluble IL-6R (sIL-6R) produced by proteolytic cleavage or alternative splicing recruits IL-6 to form IL-6/sIL- 6R complexes, which could activate the ubiquitously expressed gpl30 on nearly any body cell (Garbers et al. 2018, Nat. Rev. Drug Discov. 17:395).
- sIL-6R soluble IL-6R
- Such ubiquitous trans- signaling is physiologically prevented by an excess of soluble gpl30 isoforms (sgp 130) acting as a buffer in the blood (Jostock et al. 2001, Eur. J. Biochem. 268:160).
- the selective IL-6/sIL-6R complex trap olamkicept consists of two sgp 130 domains fused to the crystallisable fragment of human immunoglobulin G1 (EP1148065B1; Jostock et al. 2001, Eur. J. Biochem. 268:160). Olamkicept (optimized sgp 130Fc; W02008000516) was efficacious in a large series of animal models (Rose- John et al. 2017, Nat. Rev. Rheumatol. 13:399; Garbers et al. 2018, Nat. Rev. Drug Discov.
- the disclosure provides one or more biomarkers for predicting a response to treatment with an sgp 130 protein in an individual suffering from inflammatory bowel disease, said biomarker selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, S0CS3, and TESC.
- said biomarker selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG
- the disclosure provides a method of identifying an individual suffering from inflammatory bowel disease that will likely respond to treatment with an sgp 130 protein, comprising measuring, from an individual to whom sgp 130 protein was administered, blood expression levels of one or more biomarkers selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD 177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4- 1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC, wherein a decrease of blood expression levels of the at least one or more biomarkers identifies the individual as likely to respond to said treatment.
- the disclosure provides an in-vitro method of identifying receptivity to sgp 130 comprising measuring expression levels of one or more biomarkers selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC in a blood sample, wherein the blood sample is obtained from a subject to whom an initial dose of sgp 130 protein was administered, preferably wherein expression levels of two or more of the biomarkers are selected.
- biomarkers selected from AC005392.2, AL035661.1
- the disclosure provides an in-vitro method of measuring expression levels of one or more biomarkers, preferably two or more biomarkers, selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, S0CS3, and TESC in a blood sample, wherein the blood sample is obtained from a subject to whom an initial dose of sgp 130 protein was administered.
- biomarkers preferably two or more biomarkers, selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD
- the disclosure provides an in-vitro method of predicting response to sgp 130, preferably for predicting clinical remission in response to sgp 130, in an individual comprising measuring blood expression levels of one or more biomarkers, preferably two or more biomarkers, selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC, wherein the blood expression levels are measured 7-28 days after administration of the sgp 130 protein.
- biomarkers preferably two or more biomarkers,
- the blood expression levels of the one or more biomarkers are measured 7- 28 days, preferably 7-21 days, more preferably 7-14 days, and even more preferably 14 days after administration of the sgp 130 protein.
- the blood expression levels of the one or more biomarkers are determined by RNA -sequencing.
- the response to treatment is clinical remission.
- the response to treatment is endoscopic remission.
- the disclosure provides an sgp 130 protein for use in treating inflammatory bowel disease in an individual, where the individual, having reduced blood expression levels of one or more biomarkers selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC at 7-28 days, preferably 7-21 days, and even more preferably 14 days after receiving a first dose of the sgp 130 protein, receives at least a second dose of the sgp 130 protein.
- biomarkers selected from AC005392.2,
- the disclosure provides a method for treating an inflammatory bowel disease in an individual, said method comprising administering at least a first dose of an sgp 130 protein to an individual in need thereof, and administering a further dose of the sgp 130 polypeptide dimer if said individual has reduced blood expression levels of one or more biomarkers selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC, preferably wherein the method further comprises measuring blood expression levels of the one or more biomarkers
- the blood expression levels of the one or more biomarkers are measured 7-28 days, preferably 7-21 days, more preferably 7- 14 days, and even more preferably 14 days after administration of the first dose of the sgp 130 protein.
- the sgp 130 protein is administered to the individual every 7-28 days, preferably every 7-14 days.
- the administered doses of sgp 130 protein are 60 mg tol g, preferably 150 mg to 600 mg.
- the inflammatory bowel disease is ulcerative colitis.
- the inflammatory bowel disease is Crohn's disease.
- the inflammatory bowel disease is mild to moderate.
- the inflammatory bowel disease is moderate to severe.
- the sgp 130 protein is a polypeptide dimer comprising two monomers, each monomer having at least 90% sequence identity to SEQ ID NO: 1, wherein the monomers comprise the gpl30 D6 domain comprising the amino acids at positions 585-595 of SEQ ID NO:1, an Fc domain hinge region comprising the amino acids at positions 609-612 of SEQ ID NO:1, and the monomers do not comprise a linker between the gp 130 part and the Fc domain.
- the expression of at least two biomarkers, at least three biomarkers, or at least four biomarkers is determined.
- the biomarker is selected from AC005392.2, AL035661.1, ANXA3, CD177, CYSTM1, FCGR1A, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, S100A12, S100A9, SLC1A3, S0CS3, and TESC.
- the biomarker is selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, and TESC.
- Figure 1 Exemplary differential regulation of secreted frizzled-related protein-2 (SFRP2) gene expression in peripheral blood of patients with inflammatory bowel diseases (IBD), depending on whether or not the patients achieved clinical remission in response to treatment with olamkicept.
- SFRP2 frizzled-related protein-2
- the disclosure provides biomarkers for predicting response to treatment with an sgp 130 protein.
- Treatment with sgp 130 proteins is known in the art and is also encompassed in some aspects of the invention.
- the biomarkers are useful for predicting response in an individual suffering from inflammatory bowel disease.
- Inflammatory bowel disease such as Crohn's disease (CD) and ulcerative colitis (UC)
- CD Crohn's disease
- UC ulcerative colitis
- IBD Inflammatory bowel disease
- CD Crohn's disease
- UC ulcerative colitis
- Alterations in the epithelial mucosal barrier with increased intestinal permeability lead to an enhanced exposure of the mucosal immune system to luminal antigens, which causes an inappropriate activation of the intestinal immune system in patients.
- sgp 130 proteins described herein inhibit excessive IL-6 trans-signalling by selectively targeting and neutralizing IL-6/sIL-6R complexes and are therefore considered to only inhibit IL-6 trans-signalling in the desired therapeutic concentrations, leaving classic signalling and its many physiological functions, as well as its acute inflammatory defence mechanisms, intact.
- sgp 130 proteins like olamkicept are found to have an efficacy similar to global IL 6 blockade, e.g., by the anti-IL-6R antibody tocilizumab or the anti-IL-6 antibody sirukumab, but with significantly fewer side effects, especially without general immunosuppression.
- the sgp 130 proteins described herein preferably comprise gpl30-Fc monomers, such as olamkicept, having the sequence corresponding to SEQ ID NO:1.
- these gpl30-Fc monomers form gpl30-Fc polypeptide dimers.
- Such gpl30-Fc polypeptide dimers as described herein comprise polypeptides having at least 90%, 95%, 97%, 98%, 99% or 99.5% sequence identity to SEQ ID NO: 1.
- the polypeptide comprises the gpl30 D6 domain (in particular the amino acid residues TFTTPKFAQGE: amino acid positions 585-595 of SEQ ID NO:1), the amino acid residues AEGA in the Fc domain hinge region (amino acid positions 609- 612 of SEQ ID NO:1) and does not comprise a linker between the gpl30 part and the Fc domain.
- the disclosure provides a polypeptide dimer comprising two monomers having an amino acid sequence at least 90% sequence identify to SEQ ID NO: 1, wherein the amino acid sequence comprises the gpl30 D6 domain, AEGA in the Fc domain hinge region, and there is no linker present between the gpl30 part and the Fc domain.
- the dimers comprise two monomers of SEQ ID NO: 1 linked by a disulfide bridge.
- the dimers comprise two monomers of SEQ ID NO: 2 linked by a disulfide bridge.
- the invention provides compositions comprising a plurality of sgp 130 proteins described herein (e.g., a plurality of polypeptide monomers and/or polypeptide dimers described herein).
- the DNA encoding the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2 may be cloned into the vector such that the signal peptide is linked in-frame to the amino terminus of the amino acid sequence of the antibody chain.
- the vector may be introduced (e.g. transfected) into a host cell a mammalian cell such as a Chinese hamster ovary (CHO) cell. The transfected cells are cultured to express the dimer.
- the cells and culture media may then be collected and polypeptide dimers are purified, e.g., by chromatography column steps (e.g., MAbSelect Sure, SP Sepharose, Capto Q).
- the dimer can also be concentrated and/or treated with viral reduction/ inactivation steps.
- the gpl30 proteins When used as a treatment, it is desirable for the gpl30 proteins to be substantially free of galactose-alpha-l,3-galactose moieties, as these are associated with an immunogenic response.
- the polypeptide dimer contains no greater than 6 % of galactose-alpha-l,3-galactose per mole polypeptide.
- the polypeptide dimer contains no greater than 4 mole %, 3 mole %, 2 mole %, 1 mole %, 0.5 mole %, 0.2 mole %, 0.1 mole % or even an undetectable level of galactose- alpha- 1,3- galactose (e.g., as measured by WAX-HPLC, NP-HPLC or WAX, preferably as determined by WAX-HPLC).
- an undetectable level of galactose- alpha- 1,3- galactose e.g., as measured by WAX-HPLC, NP-HPLC or WAX, preferably as determined by WAX-HPLC.
- the polypeptide dimer contains less than 6%, 4%, 3%, 2%, 1%, 0.5%, 0.2%, or even 0.1% of galactose- alpha- 1,3- galactose, relative to the total amount of glycans, either by mass or on a molar basis.
- the gpl30 proteins are sialylated. This has the advantage of increasing the half-life of polypeptides of the invention.
- Each chain of the polypeptide dimer contains 10 N- glycosylation sites; nine N-glycosylation sites are located in the gpl30 portion and one N-glycosylation site is located in the Fc portion.
- the polypeptide therefore contains a total of 20 glycosylation sites.
- a mean of at least 52% or at least 54% of glycans on the polypeptide include a sialic acid residue, such as a mean from 52-65% (e.g., as measured by WAX- HPLC, NP-HPLC or WAX, preferably as determined by WAX-HPLC).
- the gpl30 protein has an approximate molecular weight of 220 kDa; each 93 kDa having an additional ⁇ 20 kDa molecular weight derived from 10 N-glycosylation chains.
- sgp 130 proteins described herein are for use in parenteral administration, such as intravenous infusion or subcutaneous injection.
- suitable formulations include those comprising a surfactant, particularly a nonionic surfactant such as a polysorbate surfactant (e.g., polysorbate 20).
- Formulations can also include buffering agents and sugars.
- An exemplary buffering agent is histidine.
- An exemplary sugar is sucrose.
- a suitable formulation could include polysorbate 20 (e.g., 0.01-1 mg/mL, 0.02-0.5 mg/mL, 0.05-0.2 mg/mL), histidine (e.g., 0.5 mM-250 mM, 1-100 mM, 5-50 mM, 10-20 mM) and sucrose (e.g., 10-1000 mM, 20-500 mM, 100-300 mM, 150- 250 mM).
- the sgp 130 proteins described herein are typically administered at doses of 60 mg to 1 g, preferably 150 mg to 600 mg. In some embodiments the sgl30 proteins are administered at doses of between 500 to 700 mg.
- the dosing frequency is typically once every 7-28 days, preferably every 7-14 days. In preferred embodiments, the dose occurs weekly (once every 7 days) or biweekly (once every 14 days).
- a dose refers to a single dosing episode, whether the dose is a unit dosage form or multiple unit dosage forms taken together (e.g., receiving two or more injections, administration of an IV infusion over several minutes or hours). Suitable dosage regimes and frequencies are described in WO2016/087941, which is hereby incorporated by reference.
- the disclosure provides the use of at least one biomarker for predicting a response to treatment with an sgp 130 protein, as disclosed herein, in an individual suffering from inflammatory bowel disease, said biomarker selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC.
- said biomarker selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP,
- NCBI National Center for Biotechnology Information
- the disclosure further provides methods for identifying an individual suffering from inflammatory bowel disease that will likely respond to treatment with an sgp 130 protein as well as methods for predicting sgp 130 protein treatment response.
- the methods comprise measuring the blood expression levels of one or more biomarkers selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC.
- individuals that are identified as likely treatment responders are administered one or more subsequent doses of the sgp 130 protein.
- the methods comprise measuring the blood expression levels of one or more biomarkers from an individual to whom the sgp 130 protein was administered.
- the methods described herein comprise measuring the blood expression levels of one or more biomarkers from an individual prior to sgp 130 protein administration as well as post- administration. As described herein, a reduction in the blood expression levels of at least one biomarker as disclosed herein indicates that the individual is likely to respond to sgp 130 protein treatment.
- the expression level of at least two, at least five, preferably at least 10, at least 15, or all 30 of the biomarkers is determined. As demonstrated in the examples, a reduction of blood expression levels is indicative of response. As will be clear to a skilled person, the blood expression levels of all biomarkers need not be reduced in order to classify an individual as likely benefiting from treatment. In some embodiments, having a reduced blood expression level of at least one of said biomarkers is sufficient for predicting treatment benefit. In some embodiments, having a reduced blood expression level of at least two, at least five, at least 10, at least 15, or all 30 biomarkers indicates likelihood of treatment benefit.
- the biomarker is selected from AC005392.2, AL035661.1, ANXA3, CD177, CYSTM1, FCGR1A, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, S100A12, S100A9, SLC1A3, SOCS3, and TESC.
- having a reduced blood expression level of at least two, at least five, at least 10, at least 15, or all 24 of said biomarkers indicates likelihood of treatment benefit.
- blood expression levels and “blood sample” refers to the biomarker expression level from whole blood as well as from samples comprising red blood cells (e.g., peripheral blood mononuclear cells (PBMC)) and/or blood plasma.
- red blood cells e.g., peripheral blood mononuclear cells (PBMC)
- PBMC peripheral blood mononuclear cells
- Biomarker expression levels can be determined by measuring the level of nucleic acid or protein expression.
- nucleic acid or protein is purified from the sample and gene expression is measured by nucleic acid or protein expression analysis.
- the level of protein expression can be determined by any method known in the art including ELISAs, immunocytochemistry, flow cytometry, Western blotting, proteomic, and mass spectrometry.
- nucleic acid expression levels are determined.
- the level of nucleic acid expression may be determined by any method known in the art including RT-PCR, quantitative PCR, Northern blotting, gene sequencing, in particular RNA sequencing, and gene expression profiling techniques.
- Representative methods for sequencing- based gene expression analysis include Serial Analysis of Gene Expression (SAGE), and gene expression analysis by massively parallel signature sequencing (MPSS).
- biomarker expression levels are assessed using RNA sequencing (RNAseq).
- the nucleic acid is RNA, such as mRNA.
- RNA such as mRNA.
- the level of RNA expression determined may be detected directly or it may be determined indirectly, for example, by first generating cDNA and/or by amplifying the RNA/cDNA.
- the level of expression need not be an absolute value but may rather be a normalized expression value or a relative value.
- the levels of expression can be normalized against housekeeping or reference gene expression.
- blood expression levels of the one or more biomarkers obtained from an individual after receiving at least one dose of sgp 130 protein are compared to the blood expression levels obtained from said individual prior to sgp 130 protein administration (i.e., at baseline).
- post-treatment levels are obtained between 2 to 60 days after the individual received a dose of sgp 130 protein.
- post-treatment levels are obtained between 7-28 days after the individual received a dose of sgp 130 protein.
- post-treatment levels are obtained between 7 to 21 days after the individual received a dose of sgp 130 protein.
- post-treatment levels are obtained between 13 to 15 days after the individual received a dose of sgp 130 protein. More preferably, post-treatment levels are obtained 14 days after the individual received a dose of sgp 130 protein. In some embodiments, post-treatment levels are obtained between 2 to 60 days after the individual received a first dose of sgp 130 protein. In some embodiments, post- treatment levels are obtained between 7-28 days after the individual received a first dose of sgp 130 protein. In some embodiments, post-treatment levels are obtained between 7 to 21 days after the individual received a first dose of sgp 130 protein. Preferably, post-treatment levels are obtained between 13 to 15 days after the individual received a first dose of sgp 130 protein. More preferably, post-treatment levels are obtained 14 days after the individual received a first dose of sgp 130 protein.
- the strength of the correlation between the expression level of a differentially-expressed gene and treatment response may be determined by a statistical test of significance. For example, a chi square test may be used to assign a chi square value to each differentially-expressed marker, indicating the strength of the correlation of the expression of that marker to treatment benefit.
- the method described in Anders and Huber 2010 is used for determining significant reductions in expression from RNAseq data (Genome Biology 11:R106).
- the examples demonstrate that a reduction in blood expression levels of one or more biomarkers as disclosed herein after at least one dose of sgp 130 protein administration is indicative of treatment benefit.
- reduced blood expression levels are predictive of clinical remission and/or endoscopic remission.
- the ability to predict a positive response to treatment (e.g., clinical remission) early in the treatment schedule (e.g., after only the first treatment dose) is useful for determining further treatment options.
- the disclosure provides methods of treatment and the use of an sgp 130 protein in a method of treatment which identifies individuals to be treated based on the reduction of blood expression levels of the biomarkers disclosed herein after initial sgp 130 protein treatment(s).
- the individual to be treated is a human.
- the disclosure provides an sgp 130 protein for use in treating an individual for inflammatory bowel disease, where the individual having reduced blood expression levels of one or more biomarkers selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC at 7-28 days, preferably 7-21 days, and even more preferably 14 days after receiving a dose, preferably first dose, of the sgp 130 protein, receives a second dose of the sgp 130 protein
- the disclosure provides a method for treating an inflammatory bowel disease in an individual, said method comprising administering at least a first dose of an sgp 130 protein, and administering a further dose of the sgp 130 polypeptide dimer if said individual has reduced blood expression levels of one or more biomarkers selected from
- Preferred sgp 130 proteins, dosages, and frequency regimes are as disclosed further herein.
- said treatment methods and uses may comprise comparing the blood expression levels of the one or more biomarkers obtained from an individual after receiving at least one dose of sgp 130 protein to the blood expression levels obtained from said individual prior to sgp 130 protein treatment.
- said treatment methods and uses further comprise measuring blood expression levels of the one or more biomarkers as disclosed further herein.
- the disclosure provides methods comprising
- sgp 130 protein - measuring blood expression levels of one or more biomarkers selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD 177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4- 1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC,
- biomarkers selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD 177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16,
- the methods further comprise measuring blood expression levels of the one or more biomarkers at baseline (i.e., prior to sgp 130 treatment).
- treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
- treatment may be administered after one or more symptoms have developed.
- treatment may be administered in the absence of symptoms.
- treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
- the treatments described herein result in clinical remission or endoscopic remission.
- endoscopic remission is based on the assessment of the size of ulcers, the ulcerated surface, the affected surface, and narrowings in five colon segments (terminal ileum, right colon, transverse colon, left colon, and rectum).
- An exemplary scoring system for CD is as follows.
- to comprise and its conjugations is used in its nondimiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded.
- verb “to consist” may be replaced by “to consist essentially of’ meaning that a compound or adjunct compound as defined herein may comprise additional component(s) than the ones specifically identified, said additional component(s) not altering the unique characteristic of the invention.
- an element means one element or more than one element.
- Table 3 Patient demographic data at baseline
- the two-centre, exploratory, open label, investigator-initiated trial investigated gene expression changes and mechanistic aspects of olamkicept efficacy as well as clinical response and remission at week 14 (proportions of patients achieving clinical remission, measured by clinical disease parameters for UC [ Mayo Score ⁇ 2, bleeding 0 and endoscopy ⁇ 1] and CD [CDAI ⁇ 150]).
- Olamkicept was administered at one dose level (600 mg) as intravenous (i.v.) infusions every 2 weeks for 12 weeks (i.e. 7 infusions in total).
- clinical disease activity including endoscopy was assessed at baseline and weeks 2, 6 and 14.
- RNA-Seq high-throughput RNA sequencing
- Differentially expressed genes were identified by comparing expression profiles throughout the course of treatment, whether by grouping or not the patients into specific categories (e.g. patients under clinical remission). Data sets were tested as intention-to-treat and per-protocol.
- the DESeq2 R package Love et al. 2014, Genome Biol. 15:550
- the impulseeDE2 R package Frischer et al. 2018, Nucleic Acids Res. 46:ell9
- DESeq2 was used for executing pairwise comparisons between baseline and time points after treatment
- ImpulseDE2 was used to identify genes with transient differential expression in the longitudinal dataset. Both statistical tools are based on a negative binomial distribution model with dispersion trend smoothing.
- the normalized reads counts per sample were determined by estimating size factors to control for library size, followed by a log2 transformation of the raw count data using DESeq2.
- ENSG ENSEMBL gene identification number
- Gene name abbreviation according to the National Center of Biotechnology Information (NCBI) Gene database
- sequence identifier according to NCBI GenBank
- log2-FC log2 fold change
- Padj adjusted p value of fold change at 2, 6 or 14 weeks compared to baseline gene expression.
- Table 4 Means and standard deviations of normalized expression levels of genetic sequences selectively and significantly downregulated in peripheral blood cells of IBD patients in response to treatment with olamkicept
- NCBI National Center of Biotechnology Information
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Abstract
The present invention relates to an sgp130 protein, exemplified by olamkicept, for use 5 in treating individuals for inflammatory bowel diseases (IBD). In particular, the invention provides a panel of gene expression biomarkers that predict response in patients with inflammatory bowel disease after a single administration of as sgp130 protein, such as olamkicept.
Description
Title: BLOOD GENE EXPRESSION BIOMARKERS TO PREDICT RESPONSE
IN PATIENTS WITH INFLAMMATORY BOWEL DISEASES
FIELD
The present invention relates to an sgp 130 protein, exemplified by olamkicept, for use in treating individuals for inflammatory bowel diseases (IBD). In particular, the invention provides a panel of gene expression biomarkers that predict response in patients with inflammatory bowel disease after a single administration of as sgp 130 protein, such as olamkicept.
BACKGROUND
Inflammatory bowel diseases (IBD) comprise the main forms Crohn's disease (CD) and ulcerative colitis (UC), which are chronic incurable inflammatory diseases of the gastrointestinal tract. The therapy of IBD has been greatly improved by the introduction of specific therapies directed against single molecular targets. The first targeted therapies that were introduced and are still most widely used in clinical practice are monoclonal antibodies directed against the cytokine tumor necrosis factor-alpha (TNF), i.e. infliximab, adalimumab and golimumab, meanwhile complemented by generics. Later introductions into clinical management of IBD include anti-adhesion molecules (vedolizumab), anti-interleukin- 12/-23 antibodies (ustekinumab) and Janus kinase inhibitors (tofacitinib). Although the use of targeted therapies has greatly improved disease-related mortality and helped to reduce cases of severe uncontrolled disease, therapeutic long-term success is still small. With less than 20% of the exposed patient population remaining in clinical and endoscopic remission under any of these therapies, significant numbers of patients progress towards disease-related complications (development of fistulae, stenotic disease and colitis-associated carcinoma) and long-term comorbidities of chronic inflammation (cardiovascular and metabolic diseases). The economic burden of IBD is large considering the rather small patient population (up to 0.5% of the general population in Western countries).
The high number of patients failing on targeted therapies creates a large unmet need for biomarkers to identify patient populations that will enter clinical remission in response to a targeted therapy in an early stage of treatment, not only in order to adapt dose intensification or target changes as early as possible to minimize the progression of the disease, but also to spare patients and health systems unnecessary and very expensive therapies. However, the search for appropriate biomarkers is complicated by the increasing number of available targeted therapies, making it difficult to differentiate between drug-specific and response-specific signatures. Currently, no established biomarker on the transcriptome level (blood or intestinal mucosa) is validated for early response or remission prediction, although a variety of markers have been identified in previous studies.
Biomarkers may be classified as, e.g., prognostic or predictive. A prognostic biomarker provides information regarding likely patient outcome irrespective of treatment. In contrast, a predictive biomarker indicates the likely benefit of treatment. In many instances, predictive biomarkers are measured before treatment (i.e., at baseline) and provide information on the probability of response to treatment. Another type of predictive biomarkers are those identified whose expression changes dynamically over time and which are identified from the differential expression of genes between baseline and early time points after therapy induction.
Due to the introduction of anti-TNF agents as the first targeted therapy in IBD, most biomarkers have been identified in the context of anti-TNF treatment, but there are also emerging serum biomarkers for other biologies (Noor et al. 2020, Lancet Gastroenterol. Hepatol. 5:80; Gisbert & Chaparro 2020, J. Crohns Colitis, doi: 10.1093/ecco-jcc/jjz195).
Interleukin-6 (IL-6) is a pleiotropic cytokine which is produced by haematopoietic and non-haematopoietic cells in response to infection and tissue damage and is involved in the pathophysiology of IBD (Garbers et al. 2018, Nat. Rev. Drug Discov. 17:395). IL-6 exerts its multiple functions through two main signaling pathways, which both require signal transduction by a pre-formed dimer of the transmembrane co-receptor gp!30 (Scheller et al. 2014, Semin. Immunol. 26:2). In classic signaling, IL-6 uses the
membrane-bound IL-6 receptor (IL-6R), which is mainly expressed by hepatocytes and leukocytes. In the trans-signaling pathway, circulating soluble IL-6R (sIL-6R) produced by proteolytic cleavage or alternative splicing recruits IL-6 to form IL-6/sIL- 6R complexes, which could activate the ubiquitously expressed gpl30 on nearly any body cell (Garbers et al. 2018, Nat. Rev. Drug Discov. 17:395). Such ubiquitous trans- signaling is physiologically prevented by an excess of soluble gpl30 isoforms (sgp 130) acting as a buffer in the blood (Jostock et al. 2001, Eur. J. Biochem. 268:160). While classic IL-6 signaling has many physiological and anti-infectious functions, excessive trans-signaling is seen in many chronic inflammatory conditions. An increased rate of opportunistic and severe infections is observed with the anti-IL-6R antibody tocilizumab (Rose-John et al. 2017, Nat. Rev. Rheumatol. 13:399). Another potential limitation of complete IL-6 inhibition is the potential increase in triglycerides and LDL cholesterol (Garbers et al. 2018, Nat. Rev. Drug Discov. 17:395). Specific trans- signaling inhibition instead of blocking IL-6 or its receptor by sgp 130 proteins has therefore been proposed to treat chronic inflammation without the negative effect of systemic immunosuppression and other side effects (Rose-John et al. 2017, Nat. Rev. Rheumatol. 13:399; Garbers et al. 2018, Nat. Rev. Drug Discov. 17:395).
The selective IL-6/sIL-6R complex trap olamkicept consists of two sgp 130 domains fused to the crystallisable fragment of human immunoglobulin G1 (EP1148065B1; Jostock et al. 2001, Eur. J. Biochem. 268:160). Olamkicept (optimized sgp 130Fc; W02008000516) was efficacious in a large series of animal models (Rose- John et al. 2017, Nat. Rev. Rheumatol. 13:399; Garbers et al. 2018, Nat. Rev. Drug Discov. 17:395), successfully passed Phase I trials without safety issues and a Phase Ila mechanistic trial in IBD (EudraCT 2016-000205-36), and presently undergoes full Phase IIb clinical development in UC (NCT03235752). So far, no biomarkers for the prediction of clinical response or remission after administration of any sgp 130 protein have been published. For the reasons stated above, it would highly desirable to find easily accessible biomarkers in peripheral blood that predict remission in olamkicept- treated patients already after a single administration of olamkicept.
SUMMARY OF THE INVENTION
The disclosure provides the following preferred embodiments. However, the invention is not limited to these embodiments.
In one embodiment the disclosure provides one or more biomarkers for predicting a response to treatment with an sgp 130 protein in an individual suffering from inflammatory bowel disease, said biomarker selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, S0CS3, and TESC.
In one embodiment the disclosure provides a method of identifying an individual suffering from inflammatory bowel disease that will likely respond to treatment with an sgp 130 protein, comprising measuring, from an individual to whom sgp 130 protein was administered, blood expression levels of one or more biomarkers selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD 177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4- 1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC, wherein a decrease of blood expression levels of the at least one or more biomarkers identifies the individual as likely to respond to said treatment.
In one embodiment the disclosure provides an in-vitro method of identifying receptivity to sgp 130 comprising measuring expression levels of one or more biomarkers selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC in a blood sample, wherein the blood sample is obtained from a subject to whom an initial dose of sgp 130 protein was administered, preferably wherein expression levels of two or more of the biomarkers are selected. In one embodiment the disclosure provides an in-vitro method of measuring expression levels of one or more biomarkers, preferably
two or more biomarkers, selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, S0CS3, and TESC in a blood sample, wherein the blood sample is obtained from a subject to whom an initial dose of sgp 130 protein was administered. In one embodiment the disclosure provides an in-vitro method of predicting response to sgp 130, preferably for predicting clinical remission in response to sgp 130, in an individual comprising measuring blood expression levels of one or more biomarkers, preferably two or more biomarkers, selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC, wherein the blood expression levels are measured 7-28 days after administration of the sgp 130 protein.
Preferably, the blood expression levels of the one or more biomarkers are measured 7- 28 days, preferably 7-21 days, more preferably 7-14 days, and even more preferably 14 days after administration of the sgp 130 protein. Preferably, the blood expression levels of the one or more biomarkers are determined by RNA -sequencing.
Preferably, the response to treatment is clinical remission. Preferably, the response to treatment is endoscopic remission.
In one embodiment the disclosure provides an sgp 130 protein for use in treating inflammatory bowel disease in an individual, where the individual, having reduced blood expression levels of one or more biomarkers selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC at 7-28 days, preferably 7-21 days, and even more preferably 14 days after receiving a first dose of the sgp 130 protein, receives at least a second dose of the sgp 130 protein.
In one embodiment the disclosure provides a method for treating an inflammatory bowel disease in an individual, said method comprising administering at least a first dose of an sgp 130 protein to an individual in need thereof, and administering a further dose of the sgp 130 polypeptide dimer if said individual has reduced blood expression levels of one or more biomarkers selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC, preferably wherein the method further comprises measuring blood expression levels of the one or more biomarkers.
In preferred embodiments of the disclosure, the blood expression levels of the one or more biomarkers are measured 7-28 days, preferably 7-21 days, more preferably 7- 14 days, and even more preferably 14 days after administration of the first dose of the sgp 130 protein. In preferred embodiments of the disclosure, the sgp 130 protein is administered to the individual every 7-28 days, preferably every 7-14 days. In preferred embodiments of the disclosure, the administered doses of sgp 130 protein are 60 mg tol g, preferably 150 mg to 600 mg. In preferred embodiments of the disclosure, the inflammatory bowel disease is ulcerative colitis. In preferred embodiments of the disclosure, the inflammatory bowel disease is Crohn's disease. In preferred embodiments of the disclosure, the inflammatory bowel disease is mild to moderate. In preferred embodiments of the disclosure, the inflammatory bowel disease is moderate to severe. In preferred embodiments of the disclosure, the sgp 130 protein is a polypeptide dimer comprising two monomers, each monomer having at least 90% sequence identity to SEQ ID NO: 1, wherein the monomers comprise the gpl30 D6 domain comprising the amino acids at positions 585-595 of SEQ ID NO:1, an Fc domain hinge region comprising the amino acids at positions 609-612 of SEQ ID NO:1, and the monomers do not comprise a linker between the gp 130 part and the Fc domain.
In some embodiments, the expression of at least two biomarkers, at least three biomarkers, or at least four biomarkers is determined. In preferred embodiments of the disclosure, the biomarker is selected from AC005392.2, AL035661.1, ANXA3, CD177, CYSTM1, FCGR1A, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24,
IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, S100A12, S100A9, SLC1A3, S0CS3, and TESC. In preferred embodiments of the disclosure, the biomarker is selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, and TESC.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: Exemplary differential regulation of secreted frizzled-related protein-2 (SFRP2) gene expression in peripheral blood of patients with inflammatory bowel diseases (IBD), depending on whether or not the patients achieved clinical remission in response to treatment with olamkicept.
DETAILED DESCRIPTION OF THE DISCLOSED EMBODIMENTS
The disclosure provides biomarkers for predicting response to treatment with an sgp 130 protein. Treatment with sgp 130 proteins is known in the art and is also encompassed in some aspects of the invention.
In particular, the biomarkers are useful for predicting response in an individual suffering from inflammatory bowel disease. Inflammatory bowel disease (IBD), such as Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammation occurring in the gut of susceptible individuals that is believed to be independent of a specific pathogen. Alterations in the epithelial mucosal barrier with increased intestinal permeability lead to an enhanced exposure of the mucosal immune system to luminal antigens, which causes an inappropriate activation of the intestinal immune system in patients.
The sgp 130 proteins described herein inhibit excessive IL-6 trans-signalling by selectively targeting and neutralizing IL-6/sIL-6R complexes and are therefore considered to only inhibit IL-6 trans-signalling in the desired therapeutic concentrations, leaving classic signalling and its many physiological functions, as well as its acute inflammatory defence mechanisms, intact. Currently, sgp 130 proteins like olamkicept are found to have an efficacy similar to global IL 6 blockade, e.g., by the
anti-IL-6R antibody tocilizumab or the anti-IL-6 antibody sirukumab, but with significantly fewer side effects, especially without general immunosuppression.
The sgp 130 proteins described herein preferably comprise gpl30-Fc monomers, such as olamkicept, having the sequence corresponding to SEQ ID NO:1. In certain embodiments, these gpl30-Fc monomers form gpl30-Fc polypeptide dimers. Such gpl30-Fc polypeptide dimers as described herein comprise polypeptides having at least 90%, 95%, 97%, 98%, 99% or 99.5% sequence identity to SEQ ID NO: 1. Preferably, the polypeptide comprises the gpl30 D6 domain (in particular the amino acid residues TFTTPKFAQGE: amino acid positions 585-595 of SEQ ID NO:1), the amino acid residues AEGA in the Fc domain hinge region (amino acid positions 609- 612 of SEQ ID NO:1) and does not comprise a linker between the gpl30 part and the Fc domain. In a preferred embodiment, the disclosure provides a polypeptide dimer comprising two monomers having an amino acid sequence at least 90% sequence identify to SEQ ID NO: 1, wherein the amino acid sequence comprises the gpl30 D6 domain, AEGA in the Fc domain hinge region, and there is no linker present between the gpl30 part and the Fc domain. Preferably, the dimers comprise two monomers of SEQ ID NO: 1 linked by a disulfide bridge. Preferably, the dimers comprise two monomers of SEQ ID NO: 2 linked by a disulfide bridge. In some embodiments, the invention provides compositions comprising a plurality of sgp 130 proteins described herein (e.g., a plurality of polypeptide monomers and/or polypeptide dimers described herein).
Methods for preparing sgp 130 proteins, as well as sgp 130 polypeptide dimers, are well-known in the art and are described for example in WO 2016/089206, which is hereby incorporated by reference. In an exemplary embodiment, the DNA encoding the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2 may be cloned into the vector such that the signal peptide is linked in-frame to the amino terminus of the amino acid sequence of the antibody chain. The vector may be introduced (e.g. transfected) into a host cell a mammalian cell such as a Chinese hamster ovary (CHO) cell. The transfected cells are cultured to express the dimer. The cells and culture media may then be collected and polypeptide dimers are purified, e.g., by
chromatography column steps (e.g., MAbSelect Sure, SP Sepharose, Capto Q). The dimer can also be concentrated and/or treated with viral reduction/ inactivation steps.
When used as a treatment, it is desirable for the gpl30 proteins to be substantially free of galactose-alpha-l,3-galactose moieties, as these are associated with an immunogenic response. In preferred embodiments, the polypeptide dimer contains no greater than 6 % of galactose-alpha-l,3-galactose per mole polypeptide. Preferably, the polypeptide dimer contains no greater than 4 mole %, 3 mole %, 2 mole %, 1 mole %, 0.5 mole %, 0.2 mole %, 0.1 mole % or even an undetectable level of galactose- alpha- 1,3- galactose (e.g., as measured by WAX-HPLC, NP-HPLC or WAX, preferably as determined by WAX-HPLC). In other embodiments, the polypeptide dimer contains less than 6%, 4%, 3%, 2%, 1%, 0.5%, 0.2%, or even 0.1% of galactose- alpha- 1,3- galactose, relative to the total amount of glycans, either by mass or on a molar basis.
It is also desirable for the gpl30 proteins to be sialylated. This has the advantage of increasing the half-life of polypeptides of the invention. Each chain of the polypeptide dimer contains 10 N- glycosylation sites; nine N-glycosylation sites are located in the gpl30 portion and one N-glycosylation site is located in the Fc portion. The polypeptide therefore contains a total of 20 glycosylation sites. In certain embodiments, a mean of at least 52% or at least 54% of glycans on the polypeptide include a sialic acid residue, such as a mean from 52-65% (e.g., as measured by WAX- HPLC, NP-HPLC or WAX, preferably as determined by WAX-HPLC). Preferably, the gpl30 protein has an approximate molecular weight of 220 kDa; each 93 kDa having an additional ~20 kDa molecular weight derived from 10 N-glycosylation chains.
The sgp 130 proteins described herein are for use in parenteral administration, such as intravenous infusion or subcutaneous injection. Suitable formulations include those comprising a surfactant, particularly a nonionic surfactant such as a polysorbate surfactant (e.g., polysorbate 20). Formulations can also include buffering agents and sugars. An exemplary buffering agent is histidine. An exemplary sugar is sucrose. Thus, a suitable formulation could include polysorbate 20 (e.g., 0.01-1 mg/mL, 0.02-0.5 mg/mL, 0.05-0.2 mg/mL), histidine (e.g., 0.5 mM-250 mM, 1-100 mM, 5-50 mM, 10-20 mM) and sucrose (e.g., 10-1000 mM, 20-500 mM, 100-300 mM, 150- 250 mM).
The sgp 130 proteins described herein are typically administered at doses of 60 mg to 1 g, preferably 150 mg to 600 mg. In some embodiments the sgl30 proteins are administered at doses of between 500 to 700 mg. The dosing frequency is typically once every 7-28 days, preferably every 7-14 days. In preferred embodiments, the dose occurs weekly (once every 7 days) or biweekly (once every 14 days). A dose refers to a single dosing episode, whether the dose is a unit dosage form or multiple unit dosage forms taken together (e.g., receiving two or more injections, administration of an IV infusion over several minutes or hours). Suitable dosage regimes and frequencies are described in WO2016/087941, which is hereby incorporated by reference.
As discussed in Example 1, gene expression biomarkers correlating with gpl30 protein treatment were identified. Accordingly, the disclosure provides the use of at least one biomarker for predicting a response to treatment with an sgp 130 protein, as disclosed herein, in an individual suffering from inflammatory bowel disease, said biomarker selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC.
The gene name abbreviations used in the present disclosure and defined in Table 1 below correspond to the those used in the Gene database of the National Center for Biotechnology Information (NCBI; Bethesda, MD, USA), and the sequence identifiers are from the NCBI GenBank database.
The disclosure further provides methods for identifying an individual suffering from inflammatory bowel disease that will likely respond to treatment with an sgp 130 protein as well as methods for predicting sgp 130 protein treatment response. The methods comprise measuring the blood expression levels of one or more biomarkers selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC. In some embodiments, individuals that are identified as likely treatment responders are administered one or more subsequent doses of the sgp 130 protein.
In particular, the methods comprise measuring the blood expression levels of one or more biomarkers from an individual to whom the sgp 130 protein was administered. In some embodiments, the methods described herein comprise measuring the blood expression levels of one or more biomarkers from an individual prior to sgp 130 protein administration as well as post- administration. As described herein, a reduction in the blood expression levels of at least one biomarker as disclosed herein indicates that the individual is likely to respond to sgp 130 protein treatment.
In some embodiments, the expression level of at least two, at least five, preferably at least 10, at least 15, or all 30 of the biomarkers is determined. As demonstrated in the examples, a reduction of blood expression levels is indicative of response. As will be clear to a skilled person, the blood expression levels of all biomarkers need not be reduced in order to classify an individual as likely benefiting from treatment. In some embodiments, having a reduced blood expression level of at least one of said biomarkers is sufficient for predicting treatment benefit. In some embodiments, having a reduced blood expression level of at least two, at least five, at least 10, at least 15, or all 30 biomarkers indicates likelihood of treatment benefit.
In preferred embodiments, the biomarker is selected from AC005392.2, AL035661.1, ANXA3, CD177, CYSTM1, FCGR1A, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, S100A12, S100A9, SLC1A3, SOCS3, and TESC. In some embodiments, having a reduced blood expression level of at least two, at least five, at least 10, at least 15, or all 24 of said biomarkers indicates likelihood of treatment benefit.
As used herein, the term “blood expression levels” and “blood sample” refers to the biomarker expression level from whole blood as well as from samples comprising red blood cells (e.g., peripheral blood mononuclear cells (PBMC)) and/or blood plasma.
Biomarker expression levels can be determined by measuring the level of nucleic acid or protein expression. In some embodiments, nucleic acid or protein is purified from the sample and gene expression is measured by nucleic acid or protein expression analysis. The level of protein expression can be determined by any method known in
the art including ELISAs, immunocytochemistry, flow cytometry, Western blotting, proteomic, and mass spectrometry.
Preferably, nucleic acid expression levels are determined. The level of nucleic acid expression may be determined by any method known in the art including RT-PCR, quantitative PCR, Northern blotting, gene sequencing, in particular RNA sequencing, and gene expression profiling techniques. Representative methods for sequencing- based gene expression analysis include Serial Analysis of Gene Expression (SAGE), and gene expression analysis by massively parallel signature sequencing (MPSS). Preferably, biomarker expression levels are assessed using RNA sequencing (RNAseq).
Preferably, the nucleic acid is RNA, such as mRNA. As is understood by a skilled person, the level of RNA expression determined may be detected directly or it may be determined indirectly, for example, by first generating cDNA and/or by amplifying the RNA/cDNA.
The level of expression need not be an absolute value but may rather be a normalized expression value or a relative value. For example, the levels of expression can be normalized against housekeeping or reference gene expression.
In an exemplary embodiment, blood expression levels of the one or more biomarkers obtained from an individual after receiving at least one dose of sgp 130 protein (herein referred to as “post-treatment/post-administration” levels) are compared to the blood expression levels obtained from said individual prior to sgp 130 protein administration (i.e., at baseline). In some embodiments, post-treatment levels are obtained between 2 to 60 days after the individual received a dose of sgp 130 protein. In some embodiments, post-treatment levels are obtained between 7-28 days after the individual received a dose of sgp 130 protein. In some embodiments, post-treatment levels are obtained between 7 to 21 days after the individual received a dose of sgp 130 protein. Preferably, post-treatment levels are obtained between 13 to 15 days after the individual received a dose of sgp 130 protein. More preferably, post-treatment levels are obtained 14 days after the individual received a dose of sgp 130 protein.
In some embodiments, post-treatment levels are obtained between 2 to 60 days after the individual received a first dose of sgp 130 protein. In some embodiments, post- treatment levels are obtained between 7-28 days after the individual received a first dose of sgp 130 protein. In some embodiments, post-treatment levels are obtained between 7 to 21 days after the individual received a first dose of sgp 130 protein. Preferably, post-treatment levels are obtained between 13 to 15 days after the individual received a first dose of sgp 130 protein. More preferably, post-treatment levels are obtained 14 days after the individual received a first dose of sgp 130 protein.
It is within the purview of one skilled in the art to determine whether the expression level in post-treatment differs, or is reduced, “significantly” from baseline. The strength of the correlation between the expression level of a differentially-expressed gene and treatment response may be determined by a statistical test of significance. For example, a chi square test may be used to assign a chi square value to each differentially-expressed marker, indicating the strength of the correlation of the expression of that marker to treatment benefit. In some embodiments, the method described in Anders and Huber 2010 is used for determining significant reductions in expression from RNAseq data (Genome Biology 11:R106).
As described herein, the examples demonstrate that a reduction in blood expression levels of one or more biomarkers as disclosed herein after at least one dose of sgp 130 protein administration is indicative of treatment benefit. In particular, reduced blood expression levels are predictive of clinical remission and/or endoscopic remission. As will be appreciated by the skilled practitioner, the ability to predict a positive response to treatment (e.g., clinical remission) early in the treatment schedule (e.g., after only the first treatment dose) is useful for determining further treatment options. Accordingly, the disclosure provides methods of treatment and the use of an sgp 130 protein in a method of treatment which identifies individuals to be treated based on the reduction of blood expression levels of the biomarkers disclosed herein after initial sgp 130 protein treatment(s). Preferably, the individual to be treated is a human.
In an aspect, the disclosure provides an sgp 130 protein for use in treating an individual for inflammatory bowel disease, where the individual having reduced blood expression levels of one or more biomarkers selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC at 7-28 days, preferably 7-21 days, and even more preferably 14 days after receiving a dose, preferably first dose, of the sgp 130 protein, receives a second dose of the sgp 130 protein.
In an aspect, the disclosure provides a method for treating an inflammatory bowel disease in an individual, said method comprising administering at least a first dose of an sgp 130 protein, and administering a further dose of the sgp 130 polypeptide dimer if said individual has reduced blood expression levels of one or more biomarkers selected from
AC005392.2, AL035661.1, ANKRD22, ANXA3, CD 177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4- 1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC.
Preferred sgp 130 proteins, dosages, and frequency regimes are as disclosed further herein.
In some embodiments, said treatment methods and uses may comprise comparing the blood expression levels of the one or more biomarkers obtained from an individual after receiving at least one dose of sgp 130 protein to the blood expression levels obtained from said individual prior to sgp 130 protein treatment.
In some embodiments, said treatment methods and uses further comprise measuring blood expression levels of the one or more biomarkers as disclosed further herein. For example, the disclosure provides methods comprising
- administering at least a first dose of an sgp 130 protein to an individual in need thereof,
- measuring blood expression levels of one or more biomarkers selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD 177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4- 1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC,
- administering a further dose of the sgp 130 protein to the individual, if the blood expression levels from the one or more biomarkers is reduced as compared to the blood expression levels at baseline. In some embodiments, the methods further comprise measuring blood expression levels of the one or more biomarkers at baseline (i.e., prior to sgp 130 treatment).
As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. In preferred embodiments, the treatments described herein result in clinical remission or endoscopic remission.
In some embodiments, endoscopic remission is based on the assessment of the size of ulcers, the ulcerated surface, the affected surface, and narrowings in five colon segments (terminal ileum, right colon, transverse colon, left colon, and rectum). An exemplary scoring system for CD is as follows.
As used herein, "to comprise" and its conjugations is used in its nondimiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. In addition the verb “to consist” may be replaced by “to consist essentially of’ meaning that a compound or adjunct compound as defined herein may comprise additional component(s) than the ones specifically identified, said additional component(s) not altering the unique characteristic of the invention.
The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.
All patent and literature references cited in the present specification are hereby incorporated by reference in their entirety.
The invention is further explained in the following examples. These examples do not limit the scope of the invention, but merely serve to clarify the invention.
EXAMPLES
Example 1
In a 14-week, open label, systems biology- driven Phase Ila trial (EudraCT 2016- 000205-36), 16 patients with active IBD were treated with olamkicept to assess efficacy, safety and the molecular mechanism of IL-6 trans-signalling blockade. In total, 44% of all patients (UC, 55%, 5/9; CD, 28%, 2/7) achieved clinical response and 20% (UC, 22%, 2/9; CD, 14%, 1/7) achieved clinical remission. Gene expression biomarkers of remission induced by olamkicept were identified in peripheral blood cells.
Methods
Patients
Patients were aged 21 to 66 years and had moderately to severely active UC (Mayo score max. 11 and endoscopic sub-score ≥2) or ileocolonic CD (Crohn's disease activity
index [CDAI] 220-500; simple endoscopic score for CD [SES-CD] >7), immunologically active inflammation (C-reactive protein [CRP] ≥5 mg/L), had failed conventional therapies, and had received no more than 2 prior biologies (limited to anti-TNFs and/or vedolizumab). Patient demographic data at baseline are summarized in Table 3.
Table 3: Patient demographic data at baseline
The two-centre, exploratory, open label, investigator-initiated trial investigated gene expression changes and mechanistic aspects of olamkicept efficacy as well as clinical response and remission at week 14 (proportions of patients achieving clinical remission, measured by clinical disease parameters for UC [Mayo Score ≤ 2, bleeding 0 and endoscopy ≤1] and CD [CDAI <150]). Olamkicept was administered at one dose level (600 mg) as intravenous (i.v.) infusions every 2 weeks for 12 weeks (i.e. 7 infusions in total). In addition to multiple biosampling, clinical disease activity (including endoscopy) was assessed at baseline and weeks 2, 6 and 14. All endoscopies were videotaped and independently rated, and clinical disease activity was evaluated using the endoscopic Mayo score (UC) or SES-CD (CD). A continuous paper diary was dispensed to the patients to be used for the reporting of daily stool frequency and rectal bleeding (blood in stool). Patients were instructed on the use of the diary, and the diary review occurred with every clinical visit.
RNA sequencing
Whole blood samples were collected for 16 patients as a longitudinal dataset from which the RNA for high-throughput RNA sequencing (RNA-Seq) was isolated. The samples were gathered at baseline (0 h), 2 weeks, 6 weeks and 14 weeks after the first olamkicept infusion. Whole RNA libraries were prepared using TruSeq RNA Library Prep technology (Illumina) and, in total, 104 blood and 105 biopsy samples were sequenced using HiSeq 3000 and HiSeq 4000 (Illumina), respectively. Both data sets were paired end reads of 75 bp (2x75bp). Gene expression for each patient throughout the course of treatment was systematically accessed. An in-house RNA-Seq pipeline was used to map and align the sequenced data (https://github.com/nf-core/rnaseq).
The pipeline output indicated all sequenced samples mapped well to GRCh38 Homo sapiens genome (Genome Reference Consortium Human Build 38 and GenBank Assembly ID: GCA_000001405.27), with the total of reads per sample aligning on average 70.87% to reference genome for the blood samples. The dataset included female and male patients, but only females achieved clinical remission. Nevertheless, there is no reason to believe that response to olamkicept therapy is affected by gender. In order to avoid potential biases in the differential expression analyses, we decided to remove all reads that mapped to Y chromosome genes.
Analysis
Differentially expressed genes were identified by comparing expression profiles throughout the course of treatment, whether by grouping or not the patients into specific categories (e.g. patients under clinical remission). Data sets were tested as intention-to-treat and per-protocol. To identify differentially expressed genes, the DESeq2 R package (Love et al. 2014, Genome Biol. 15:550) and the ImpulseDE2 R package (Fischer et al. 2018, Nucleic Acids Res. 46:ell9) were used. DESeq2 was used for executing pairwise comparisons between baseline and time points after treatment, while ImpulseDE2 was used to identify genes with transient differential expression in the longitudinal dataset. Both statistical tools are based on a negative binomial distribution model with dispersion trend smoothing. The normalized reads counts per sample were determined by estimating size factors to control for library size, followed by a log2 transformation of the raw count data using DESeq2.
Results and Discussion
In total, 44% of all patients (UC, 55%, 5/9; CD, 28%, 2/7) achieved clinical response and 20% (UC, 22%, 2/9; CD, 14%, 1/7) achieved clinical remission. A panel of 30 genetic sequences selectively and significantly downregulated in peripheral blood cells of IBD patients achieving clinical remission in response to olamkicept was identified (ordered by fold change in Table 3). For statistical analyses, the 3 patients entering remission (2 patients with UC and 1 with CD) were pooled. When the data from remitting and non-remitting patients are compared either pooled (IBD) or separated by disease (CD vs. UC), it is obvious that similar changes are observed in most genetic sequences in both CD and UC (Table 4; same order as in in Table 3). Not surprisingly, many proteins encoded by the marker genes are expressed by immune cells or relevant to immune responses. One example for a gene that is strongly and clearly diffentially regulated in remitters vs. non-remitters after a single administration of olamkicept is secreted frizzled-related protein-2 (SFRP2) (Fig. 1).
Table 3: Mean fold changes in expression of genetic sequences selectively and significantly downregulated in peripheral blood cells of IBD patients achieving clinical remission in response to treatment with olamkicept
ENSG, ENSEMBL gene identification number; Gene name abbreviation according to the National Center of Biotechnology Information (NCBI) Gene database; sequence identifier according to NCBI GenBank; log2-FC, log2 fold change; Padj, adjusted p value of fold change at 2, 6 or 14 weeks compared to baseline gene expression.
Table 4: Means and standard deviations of normalized expression levels of genetic sequences selectively and significantly downregulated in peripheral blood cells of IBD patients in response to treatment with olamkicept
BL, baseline; CD, Crohn's disease; Gene, gene name abbreviation according to the National Center of Biotechnology Information (NCBI) Gene database or gene sequence identifier according to NCBI GenBank; IBD, inflammatory bowel diseases (Crohn's disease and ulcerative colitis combined); NA, not applicable; NR, non-remitting patients; R, remitting patients; Rem., remission; SD, standard deviation; UC, ulcerative colitis; w, weeks.
SEQUENCE LISTING
SEQ ID NO: 1
Glu Leu Leu Asp Pro Cys Gly Tyr Ile Ser Pro Glu Ser Pro Val Val 1 5 10 15 Gln Leu His Ser Asn Phe Thr Ala Val Cys Val Leu Lys Glu Lys Cys
20 25 30
Met Asp Tyr Phe His Val Asn Ala Asn Tyr Ile Val Trp Lys Thr Asn
35 40 45
His Phe Thr Ile Pro Lys Glu Gln Tyr Thr Ile Ile Asn Arg Thr Ala
50 55 60
Ser Ser Val Thr Phe Thr Asp Ile Ala Ser Leu Asn Ile Gln Leu Thr
65 70 75 80
Cys Asn Ile Leu Thr Phe Gly Gln Leu Glu Gln Asn Val Tyr Gly Ile 85 90 95
Thr Ile Ile Ser Gly Leu Pro Pro Glu Lys Pro Lys Asn Leu Ser Cys
100 105 110 Ile Val Asn Glu Gly Lys Lys Met Arg Cys Glu Trp Asp Gly Gly Arg
115 120 125
Glu Thr His Leu Glu Thr Asn Phe Thr Leu Lys Ser Glu Trp Ala Thr
130 135 140
His Lys Phe Ala Asp Cys Lys Ala Lys Arg Asp Thr Pro Thr Ser Cys 145 150 155 160
Thr Val Asp Tyr Ser Thr Val Tyr Phe Val Asn Ile Glu Val Trp Val 165 170 175
Glu Ala Glu Asn Ala Leu Gly Lys Val Thr Ser Asp His Ile Asn Phe
180 185 190
Asp Pro Val Tyr Lys Val Lys Pro Asn Pro Pro His Asn Leu Ser Val 195 200 205 Ile Asn Ser Glu Glu Leu Ser Ser Ile Leu Lys Leu Thr Trp Thr Asn
210 215 220
Pro Ser Ile Lys Ser Val Ile Ile Leu Lys Tyr Asn Ile Gln Tyr Arg 225 230 235 240
Thr Lys Asp Ala Ser Thr Trp Ser Gln Ile Pro Pro Glu Asp Thr Ala 245 250 255
Ser Thr Arg Ser Ser Phe Thr Val Gln Asp Leu Lys Pro Phe Thr Glu
260 265 270
Tyr Val Phe Arg Ile Arg Cys Met Lys Glu Asp Gly Lys Gly Tyr Trp
275 280 285
Ser Asp Trp Ser Glu Glu Ala Ser Gly Ile Thr Tyr Glu Asp Arg Pro
290 295 300
Ser Lys Ala Pro Ser Phe Trp Tyr Lys Ile Asp Pro Ser His Thr Gln 305 310 315 320 Gly Tyr Arg Thr Val Gln Leu Val Trp Lys Thr Leu Pro Pro Phe Glu
325 330 335
Ala Asn Gly Lys Ile Leu Asp Tyr Glu Val Thr Leu Thr Arg Trp Lys
340 345 350
Ser His Leu Gln Asn Tyr Thr Val Asn Ala Thr Lys Leu Thr Val Asn
355 360 365
Leu Thr Asn Asp Arg Tyr Leu Ala Thr Leu Thr Val Arg Asn Leu Val
370 375 380
Gly Lys Ser Asp Ala Ala Val Leu Thr Ile Pro Ala Cys Asp Phe Gln 385 390 395 400 Ala Thr His Pro Val Met Asp Leu Lys Ala Phe Pro Lys Asp Asn Met
405 410 415
Leu Trp Val Glu Trp Thr Thr Pro Arg Glu Ser Val Lys Lys Tyr Ile
420 425 430
Leu Glu Trp Cys Val Leu Ser Asp Lys Ala Pro Cys Ile Thr Asp Trp
435 440 445 Gln Gln Glu Asp Gly Thr Val His Arg Thr Tyr Leu Arg Gly Asn Leu
450 455 460
Ala Glu Ser Lys Cys Tyr Leu Ile Thr Val Thr Pro Val Tyr Ala Asp 465 470 475 480 Gly Pro Gly Ser Pro Glu Ser Ile Lys Ala Tyr Leu Lys Gln Ala Pro
485 490 495
Pro Ser Lys Gly Pro Thr Val Arg Thr Lys Lys Val Gly Lys Asn Glu
500 505 510
Ala Val Leu Glu Trp Asp Gln Leu Pro Val Asp Val Gln Asn Gly Phe
515 520 525 Ile Arg Asn Tyr Thr Ile Phe Tyr Arg Thr Ile Ile Gly Asn Glu Thr
530 535 540
Ala Val Asn Val Asp Ser Ser His Thr Glu Tyr Thr Leu Ser Ser Leu
545 550 555 560
Thr Ser Asp Thr Leu Tyr Met Val Arg Met Ala Ala Tyr Thr Asp Glu 565 570 575
Gly Gly Lys Asp Gly Pro Glu Phe Thr Phe Thr Thr Pro Lys Phe Ala
580 585 590 Gln Gly Glu Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
595 600 605
Ala Glu Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
610 615 620
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
625 630 635 640 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
645 650 655 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
660 665 670
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
675 680 685
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
690 695 700
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
705 710 715 720
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
725 730 735 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
740 745 750
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
755 760 765
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
770 775 780
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
785 790 795 800
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
805 810 815
Ser Leu Ser Pro Gly Lys
820
SEQ ID NO: 2
Met Leu Thr Leu Gln Thr Trp Leu Val Gln Ala Leu Phe Ile Phe Leu 1 5 10 15
Thr Thr Glu Ser Thr Gly Glu Leu Leu Asp Pro Cys Gly Tyr Ile Ser
20 25 30
Pro Glu Ser Pro Val Val Gln Leu His Ser Asn Phe Thr Ala Val Cys
35 40 45
Val Leu Lys Glu Lys Cys Met Asp Tyr Phe His Val Asn Ala Asn Tyr 50 55 60 Ile Val Trp Lys Thr Asn His Phe Thr Ile Pro Lys Glu Gln Tyr Thr 65 70 75 80 Ile Ile Asn Arg Thr Ala Ser Ser Val Thr Phe Thr Asp Ile Ala Ser 85 90 95
Leu Asn Ile Gln Leu Thr Cys Asn Ile Leu Thr Phe Gly Gln Leu Glu
100 105 110 Gln Asn Val Tyr Gly Ile Thr Ile Ile Ser Gly Leu Pro Pro Glu Lys
115 120 125
Pro Lys Asn Leu Ser Cys Ile Val Asn Glu Gly Lys Lys Met Arg Cys
130 135 140
Glu Trp Asp Gly Gly Arg Glu Thr His Leu Glu Thr Asn Phe Thr Leu 145 150 155 160
Lys Ser Glu Trp Ala Thr His Lys Phe Ala Asp Cys Lys Ala Lys Arg 165 170 175
Asp Thr Pro Thr Ser Cys Thr Val Asp Tyr Ser Thr Val Tyr Phe Val
180 185 190
Asn Ile Glu Val Trp Val Glu Ala Glu Asn Ala Leu Gly Lys Val Thr
195 200 205
Ser Asp His Ile Asn Phe Asp Pro Val Tyr Lys Val Lys Pro Asn Pro
210 215 220
Pro His Asn Leu Ser Val Ile Asn Ser Glu Glu Leu Ser Ser Ile Leu
225 230 235 240
Lys Leu Thr Trp Thr Asn Pro Ser Ile Lys Ser Val Ile Ile Leu Lys
245 250 255
Tyr Asn Ile Gln Tyr Arg Thr Lys Asp Ala Ser Thr Trp Ser Gln Ile
260 265 270
Pro Pro Glu Asp Thr Ala Ser Thr Arg Ser Ser Phe Thr Val Gln Asp 275 280 285
Leu Lys Pro Phe Thr Glu Tyr Val Phe Arg Ile Arg Cys Met Lys Glu
290 295 300
Asp Gly Lys Gly Tyr Trp Ser Asp Trp Ser Glu Glu Ala Ser Gly Ile 305 310 315 320
Thr Tyr Glu Asp Arg Pro Ser Lys Ala Pro Ser Phe Trp Tyr Lys Ile 325 330 335
Asp Pro Ser His Thr Gln Gly Tyr Arg Thr Val Gln Leu Val Trp Lys
340 345 350
Thr Leu Pro Pro Phe Glu Ala Asn Gly Lys Ile Leu Asp Tyr Glu Val
355 360 365
Thr Leu Thr Arg Trp Lys Ser His Leu Gln Asn Tyr Thr Val Asn Ala 370 375 380
Thr Lys Leu Thr Val Asn Leu Thr Asn Asp Arg Tyr Leu Ala Thr Leu 385 390 395 400
Thr Val Arg Asn Leu Val Gly Lys Ser Asp Ala Ala Val Leu Thr Ile
405 410 415
Pro Ala Cys Asp Phe Gln Ala Thr His Pro Val Met Asp Leu Lys Ala
420 425 430
Phe Pro Lys Asp Asn Met Leu Trp Val Glu Trp Thr Thr Pro Arg Glu 435 440 445
Ser Val Lys Lys Tyr Ile Leu Glu Trp Cys Val Leu Ser Asp Lys Ala
450 455 460
Pro Cys Ile Thr Asp Trp Gln Gln Glu Asp Gly Thr Val His Arg Thr 465 470 475 480
Tyr Leu Arg Gly Asn Leu Ala Glu Ser Lys Cys Tyr Leu Ile Thr Val
485 490 495
Thr Pro Val Tyr Ala Asp Gly Pro Gly Ser Pro Glu Ser Ile Lys Ala
500 505 510
Tyr Leu Lys Gln Ala Pro Pro Ser Lys Gly Pro Thr Val Arg Thr Lys
515 520 525
Lys Val Gly Lys Asn Glu Ala Val Leu Glu Trp Asp Gln Leu Pro Val
530 535 540
Asp Val Gln Asn Gly Phe Ile Arg Asn Tyr Thr Ile Phe Tyr Arg Thr 545 550 555 560 Ile Ile Gly Asn Glu Thr Ala Val Asn Val Asp Ser Ser His Thr Glu
565 570 575
Tyr Thr Leu Ser Ser Leu Thr Ser Asp Thr Leu Tyr Met Val Arg Met
580 585 590
Ala Ala Tyr Thr Asp Glu Gly Gly Lys Asp Gly Pro Glu Phe Thr Phe
595 600 605
Thr Thr Pro Lys Phe Ala Gln Gly Glu Asp Lys Thr His Thr Cys Pro
610 615 620
Pro Cys Pro Ala Pro Glu Ala Glu Gly Ala Pro Ser Val Phe Leu Phe 625 630 635 640 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
645 650 655
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
660 665 670
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
675 680 685
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
690 695 700 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 705 710 715 720 Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
725 730 735
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
740 745 750
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
755 760 765
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
770 775 780
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 785 790 795 800
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
805 810 815
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
820 825 830 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
835 840
Claims
1. Use of a biomarker for predicting a response to treatment with an sgp 130 protein in an individual suffering from inflammatory bowel disease, said biomarker selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2- 24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, S0CS3, and TESC.
2. A method of identifying an individual suffering from inflammatory bowel disease that will likely respond to treatment with an sgp 130 protein, comprising measuring blood expression levels of one or more biomarkers selected from
AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC, from an individual to whom an sgp 130 protein was administered, wherein a decrease of blood expression levels of the at least one or more biomarkers identifies the individual as likely to respond to said treatment.
3. An in-vitro method of identifying receptivity to sgp 130 comprising measuring expression levels of one or more biomarkers selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC in a blood sample, wherein the blood sample is obtained from a subject to whom an initial dose of sgp 130 protein was administered, preferably wherein expression levels of two or more of the biomarkers are selected.
4. An in-vitro method of measuring expression levels of one or more biomarkers, preferably two or more biomarkers, selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14,
GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, S0CS3, and TESC in a blood sample, wherein the blood sample is obtained from a subject to whom an initial dose of sgp 130 protein was administered.
5. An in-vitro method of predicting response to sgp 130, preferably for predicting clinical remission in response to sgp 130, in an individual comprising measuring blood expression levels of one or more biomarkers, preferably two or more biomarkers, selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC, wherein the blood expression levels are measured 7-28 days after administration of the sgp 130 protein.
6. The method or use of any one of the preceding claims, wherein expression levels are determined by RNA-sequencing.
7. The method or use of any one of the preceding claims, wherein blood expression levels of the one or more biomarkers are measured 7-28 days, preferably 7-21 days, more preferably 7-14 days, and even more preferably 14 days after administration of the sgp 130 protein.
8. The method or use of any one of the preceding claims, wherein the response to treatment is clinical remission or wherein the response to treatment is endoscopic remission.
9. An sgp 130 protein for use in treating inflammatory bowel disease in an individual, where the individual, having reduced blood expression levels of one or more biomarkers selected from
AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16,
IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, S0CS3, and TESC at 7-28 days, preferably 7-21 days, and even more preferably 14 days after receiving a first dose of the sgp 130 protein, receives at least a second dose of the sgp 130 protein.
10. The sgp 130 protein for use according to claim 9, wherein the blood expression levels of the one or more biomarkers are measured 7-28 days, preferably 7-21 days, more preferably 7-14 days, and even more preferably 14 days after administration of the first dose of the sgp 130 protein.
11. The sgp 130 protein for use according to claim 9 or 10, wherein the sgp 130 protein is administered to the individual every 7-28 days, preferably every 7-14 days.
12. The method or sgp 130 protein for use of any one of claims 2-11, wherein the administered doses of sgp 130 protein are 60 mg tol g, preferably 150 mg to 600 mg.
13. The use, method or sgp 130 protein for use of any one of the preceding claims, wherein the inflammatory bowel disease is ulcerative colitis.
14. The use, method or sgp 130 protein for use of any one of the preceding claims, wherein the inflammatory bowel disease is Crohn's disease.
15. The use, method or sgp 130 protein for use of any one of the preceding claims, wherein the inflammatory bowel disease is mild to moderate or wherein the inflammatory bowel disease is moderate to severe.
16. The use, method or sgp 130 protein for use of any one of the preceding claims, wherein the sgp 130 protein is a polypeptide dimer comprising two monomers, each monomer having at least 90% sequence identity to SEQ ID NO: 1, wherein the monomers comprise the gpl30 D6 domain that comprises the amino acids at positions 585-595 of SEQ ID NO:1, an Fc domain hinge region comprising the amino acids at positions 609-612 of SEQ ID NO:1, and the monomers do not comprise a linker between the gpl30 part and the Fc domain.
17. The use, method or sgp 130 protein for use of any one of the preceding claims, wherein at least two biomarkers, at least three biomarkers, or at least four biomarkers are selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC.
18. The use, method or sgp 130 protein for use of any one of the preceding claims, wherein the biomarker is selected from AC005392.2, AL035661.1, ANXA3, CD 177, CYSTM1, FCGR1A, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, S100A12, S100A9, SLC1A3, SOCS3, and TESC or wherein the biomarker is selected from AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, and TESC. .
19 A method for treating an inflammatory bowel disease in an individual, said method comprising administering at least a first dose of an sgp 130 protein to an individual in need thereof, and administering a further dose of the sgp 130 protein if said individual has reduced blood expression levels of one or more biomarkers selected from
AC005392.2, AL035661.1, ANKRD22, ANXA3, CD177, CYSTM1, FCGR1A, FCGR1B, FCGR1CP, GALNT14, GYG1, HP, IGHG2, IGKV1-12, IGKV1-16, IGKV2-24, IGKV4-1, IGLV2-11, IGLV5-45, IGLV7-43, MCEMP1, MRC2, PDZK1IP1, PLSCR1, S100A12, S100A9, SFRP2, SLC1A3, SOCS3, and TESC, preferably wherein the method further comprises measuring blood expression levels of the one or more biomarkers.
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