WO2018041989A1 - Procédés de diagnostic et de traitement de la maladie coeliaque réfractaire de type 2 - Google Patents

Procédés de diagnostic et de traitement de la maladie coeliaque réfractaire de type 2 Download PDF

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WO2018041989A1
WO2018041989A1 PCT/EP2017/071944 EP2017071944W WO2018041989A1 WO 2018041989 A1 WO2018041989 A1 WO 2018041989A1 EP 2017071944 W EP2017071944 W EP 2017071944W WO 2018041989 A1 WO2018041989 A1 WO 2018041989A1
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residue
patient
mutation
rcdii
stat3
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PCT/EP2017/071944
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Nadine CERF-BENSUSSAN
Bertrand MERESSE
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INSERM (Institut National de la Santé et de la Recherche Médicale)
Université Paris Descartes
Assistance Publique-Hôpitaux De Paris (Aphp)
Fondation Imagine
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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
    • 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
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • 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
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • 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
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention relates to methods diagnosing and treating refractory celiac disease type 2.
  • Celiac disease also known as celiac sprue
  • celiac sprue is a quite common autoimmune disease having genetic, immunological and environmental components.
  • gliadins and glutenins present in wheat, or to similar proteins (prolamines) soluble in alcohol contained in barley, rye, spelt, kamut and other minor cereals, collectively called gluten.
  • gluten proteins
  • Refractory celiac disease affects patients who have failed to heal after 6-12 months of strict gluten-free diet (GFD) and when other causes of symptoms (including overt lymphoma) have been ruled out. It may also occur in patients who had previously responded to GFD.
  • RCD may be categorized as RCDI (when IEL remain polyclonal and display a normal T mainly CD8+ immunophenotype) and RCDII (characterized by an expansion of clonal innate- like IEL with intracellular but no surface CD3, often referred as aberrant immunophenotype).
  • RCDI patients usually respond to therapeutic agents such as corticosteroids and immunosuppressive drugs.
  • RCDII is now considered as an intraepithelial lymphoma and is associated with serious complications including severe malnutrition, dissemination and/or further transformation into high-grade enteropathy-associated T-cell lymphoma (EATL) with very severe prognosis in approximately 40% of cases.
  • TTL enteropathy-associated T-cell lymphoma
  • RCD is a diagnosis of exclusion, it is supported by objective findings in laboratory and histological studies. The availability of novel tests for detection of abnormal (clonal) intraepithelial lymphocytes in the intestine is needed to facilitate the confirmation of RCDII.
  • the present invention relates to methods for diagnosis and treatment of refractory celiac disease type 2.
  • the present invention is defined by the claims.
  • the inventors demonstrate that in a subset of celiac patients, intraepithelial lymphocytes with intracellular expression of CD3 (iCD3+ innate IEL) with gain-of-function JAKl or STAT3 mutations display enhanced response to IL-15 and acquire a selective advantage that favors clonal expansion and transformation into lymphoma. Accordingly, detecting such gain-of- function mutations offers a novel method for diagnosing refractory celiac disease type 2.
  • the first object of the present invention thus relates to a method for diagnosing refractory celiac disease type 2 (RCDII) in a patient comprising detecting the presence of at least one gain- of-function JAKl or STAT3 mutation in sample obtained from the patient and concluding that the patient suffers from refractory celiac disease type 2 when the mutation is detected.
  • RCDII refractory celiac disease type 2
  • JAKl has its general meaning in the art and refers to Janus kinase 1 which is encoded by JAKl gene (Gene ID: 3716). JAKl is also known as JTK3; JAKl A; or JAK1B.
  • JAKl is a protein tyrosine kinase of the JAK (Janus protein tyrosine kinase) family highly expressed in immune cells where it is essential for signaling by members of the IL-2 receptor family (IL-2R, IL-4R, IL-7R, IL-9R, IL-15R and IL-21R), the IL-4 receptor family (IL-4R, IL-13R), the gpl30 receptor family and class II cytokine receptors.
  • Exemplary human nucleic acid and amino acid sequences are represented by the NCBI reference sequences NM_001320923.1 and NP_001307852.1 respectively.
  • STAT3 has its general meaning in the art and refers to signal transducer and activator of transcription 3, which is encoded by STAT3 gene (Gene ID: 6774). STAT3 is also known as APRF; HIES; ADMIO; and ADMIOl . Exemplary human nucleic acid and amino acid sequences are represented by the NCBI reference sequences NM_139276.2 and NP_644805.1 respectively.
  • gain-of-function mutation refers to a mutation that is associated with an increase of the gene or gene product activity.
  • An increase of activity can be due to an increase in transcription and/or processing of the RNA, an increase in translation, stability, transport, or activity of the gene product, or any combination thereof.
  • normal activity of a gene or gene product is increased from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 up to 100%.
  • the gain-of-function JAKl mutation is G1097D/C/V/A, which indicates the substitution of the glycine (G) residue at position 1097 by an aspartic acid (D), a cysteine (C), a valine (V) or an alanine (A) residue.
  • the gain-of function STAT3 mutation is D661V/Y/H, which indicates the substitution of the aspartic acid (D) residue at position 661 by a valine (V), a tyrosine (Y) or a histidine (H) residue.
  • the sample is a biopsy sample.
  • the sample is a mucosal tissue sample.
  • mucosal tissue sample means any sample derived from the intestine of the patient, which comprises mucosal and lymphoid cells.
  • the mucosal tissue sample is obtained for the purpose of diagnosis of in vitro evaluation.
  • the mucosal tissue sample results from an endoscopic biopsy performed in the intestine of the subject. Said endoscopic biopsies may be taken from various areas of the intestine.
  • the mucosal tissue sample is isolated from an inflamed mucosa of the patient's intestine.
  • the presence of the mutation is determined by detection assays known those skilled in the art, such as protein or peptide detection methods and/or molecular biological detection, including but not limited to targeted next generation sequencing, Sanger sequencing, RNA- sequencing, PCR, qRT-PCR, Northern, Southern or Western blots, chip arrays and antibody assays.
  • detection assays known those skilled in the art, such as protein or peptide detection methods and/or molecular biological detection, including but not limited to targeted next generation sequencing, Sanger sequencing, RNA- sequencing, PCR, qRT-PCR, Northern, Southern or Western blots, chip arrays and antibody assays.
  • the presence of the mutation is determined by targeted next generation sequencing.
  • mutations are detected from RNA or DNA isolated from the sample, preferably after amplification.
  • the isolated RNA may be subjected to coupled reverse transcription and amplification, such as reverse transcription and amplification by polymerase chain reaction (RT-PCR) using oligonucleotide primers that are specific for a mutated site or that enable amplification of a region containing the mutated site.
  • RT-PCR polymerase chain reaction
  • conditions for primer annealing may be chosen to ensure specific reverse transcription (where appropriate) and amplification so that the appearance of an amplification product be a diagnostic of the presence of a particular mutation.
  • RNA may be reversely transcribed and amplified, or DNA may be amplified, after which a mutated site may be detected in the amplified sequence by hybridization with a suitable probe or by direct sequencing, or any other appropriate method known in the art.
  • a cDNA obtained from RNA may be cloned and sequenced to identify a mutation.
  • numerous strategies for genotype analysis are available (Antonarakis et al, 1989; Cooper et al, 1991 ; Grompe, 1993). Briefly, the nucleic acid molecule may be tested for the presence or absence of a restriction site. When a base substitution mutation creates or abolishes the recognition site of a restriction enzyme, this allows a simple direct PCR test for the mutation.
  • Further strategies include, but are not limited to, direct sequencing, restriction fragment length polymorphism (RFLP) analysis, hybridization with allele-specific oligonucleotides (ASO) that are short synthetic probes which hybridize only to a perfectly matched sequence under suitably stringent hybridization conditions, allele-specific PCR, PCR using mutagenic primers, ligase-PCR, HOT cleavage, denaturing gradient gel electrophoresis (DGGE), temperature denaturing gradient gel electrophoresis (TGGE), single-stranded conformational polymorphism (SSCP) and denaturing high performance liquid chromatography (Kuklin et al, 1997).
  • RFLP restriction fragment length polymorphism
  • ASO allele-specific oligonucleotides
  • DGGE denaturing gradient gel electrophoresis
  • TGGE temperature denaturing gradient gel electrophoresis
  • SSCP single-stranded conformational polymorphism
  • Direct sequencing may be accomplished by any method, including without limitation chemical sequencing using the Maxam-Gilbert method, enzymatic sequencing, using the Sanger method, mass spectrometry sequencing, sequencing using a chip-based technology and real-time quantitative PCR.
  • DNA will initially be subjected to amplification by PCR using a specific set of primers.
  • RCA rolling circle amplification
  • InvaderTMassay oligonucleotide ligation assay
  • OLA may be used for revealing base substitution mutations.
  • oligonucleotides are constructed that hybridize to adjacent sequences in the target nucleic acid, with the join sited at the position of the mutation.
  • DNA ligase will covalently join the two oligonucleotides only if they are perfectly hybridized. Therefore, useful nucleic acid molecules, in particular oligonucleotide probes or primers, according to the present invention include those, which specifically hybridize at regions where the mutations are located.
  • Oligonucleotide probes or primers may contain at least 10, 15, 20 or 30 nucleotides. Their length may be shorter than 400, 300, 200 or 100 nucleotides.
  • the mutation is detected by direct RNA sequencing.
  • Direct RNA sequencing technology Helicos Biosciences Corporation, Cambridge, MA
  • transcriptome profiling using single-molecule direct RNA sequencing are described by Ozsolak et al. (Nature 461(7265 :814-818 (2009)) and Ozsolak and Milos (Methods Mol Biol 733:51-61 (2011)).
  • True Single Molecule and Direct RNA Sequencing technologies are further described in U.S. Patent Publication Nos. 2008/0081330, 2009/0163366, 2008/0213770, 2010/0184045, 2010/0173363, 2010/0227321, 2008/0213770, and 2008/0103058 as well as U.S. Patent Nos.
  • the mutation is detected by RNA-seq.
  • the methods for performing RNA-seq are known and complete descriptions of the general methods can be found in Wang, Z., M. Gerstein, and M. Snyder, RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet, 2009. 10(1): p. 57-63, and Mortazavi, A., et al, Mapping and quantifying mammalian transcriptomes by RNA-Seq (Nature Methods, 2008. 5(7): p. 621-628).
  • the mutation may be also detected at a protein level (e.g.
  • a biological sample such as a tissue biopsy may be exposed to antibodies specific for a mutated form of the protein of interest (JAK1 or STAT3) i.e. antibodies that are capable of distinguishing between the mutated form of and the wild-type protein, to determine the presence or absence of the mutation.
  • the antibodies may be monoclonal or polyclonal antibodies, single chain or double chain, or portions of an immunoglobulin molecule, including those portions known in the art as antigen binding fragments Fab, Fab', F(ab')2 and F(v). They can also be immunoconjugated, e.g. with a toxin, or labelled antibodies.
  • polyclonal antibodies may be used, monoclonal antibodies are preferred for they are more reproducible in the long run. Procedures for raising "polyclonal antibodies" are also well known.
  • binding agents other than antibodies may be used for the purpose of the invention.
  • aptamers which are a class of molecules that represent an alternative to antibodies in terms of molecular recognition.
  • Aptamers are oligonucleotide or oligopeptide sequences with the capacity to recognize virtually any class of target molecules with high affinity and specificity.
  • Such ligands may be isolated through Systematic Evolution of Ligands by Exponential enrichment (SELEX) of a random sequence library. Flow cytometry and immunohistochemistry are preferred methods for detecting the presence of the mutation.
  • the diagnostic method of the present invention is thus particularly suitable for determining whether the patient suffering from refractory celiac disease type 2 (RCDII) has or is at risk of having an enteropathy-associated T-cell lymphoma (EATL), since the detection of the gain-of- function mutation indicates that the patient has or is at risk of having an enteropathy- associated T-cell lymphoma.
  • RCDII refractory celiac disease type 2
  • EATL enteropathy-associated T-cell lymphoma
  • the diagnostic method of the present invention is also particularly suitable for the detection of JAK1 or STAT3 gain-of-function mutations in RCDII patients, which will confirm diagnosis and indicate the risk of already suffering from or potentially developing an EATL.
  • the second object of the present invention relates to a method of treating refractory celiac disease type 2 in a patient in need thereof comprising administering to the patient a therapeutically effective amount of an IL-15 antagonist.
  • the method of the present invention comprises detecting at least one gain-of-function of the present invention and administering to the patient the therapeutically effective amount of an IL-15 antagonist.
  • the third object of the present invention relates to a method of treating refractory celiac disease type 2 in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a JAK/STAT inhibitor.
  • the method of the present invention comprises detecting at least one gain-of-function of the present invention and administering to the patient the therapeutically effective amount of a JAK/STAT inhibitor.
  • treatment refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including the treatment of patients at risk of contracting the disease or suspected to have contracted the disease as well as patients who are already sick or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset, reduce the severity or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond a point to be expected in the absence of such treatment.
  • a therapeutic regimen addresses the pattern of treatment of a disease, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the term “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would during a maintenance- regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during disease treatment, e.g. to keep the patient in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g. administering a drug at a regular intervals, e.g. weekly, monthly, yearly, etc.) or intermittent therapy (e.g. interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria (e.g. pain, disease manifestation, etc.)).
  • the therapeutic method of the present invention is particularly suitable for preventing enteropathy-associated T-cell lymphoma in a patient diagnosed with refractory celiac disease type 2 (RCDII), by the method of the present invention.
  • RCDII refractory celiac disease type 2
  • IL-15 has its general meaning in the art and refers to interleukin 15, which is encoded by IL15 gene (Gene ID: 3600).
  • IL-15 is a cytokine that regulates T and natural killer cell activation and proliferation.
  • IL-15 and IL-2 share many biological activities.
  • IL-15 induces the activation of kinases of the JAK family and followed by subsequent phosphorylation and activation of transcription factors such as STAT3, STAT5 and STAT6.
  • Exemplary human nucleic acid and amino acid sequences are represented by the NCBI reference sequences NM_000585.4 and NP 000576.1 respectively.
  • IL-15 antagonist refers to any compound or composition that specifically antagonizes the biological activity of IL-15, i.e.by preventing IL-15 from signal- transduction through the IL-15 receptor complex.
  • the term IL-15 -specific antagonist thus includes, inter alia, compounds and compositions that block or downregulate the production, modification, transport, or secretion of IL-15 or IL-15 receptor subunits, compounds and compositions that interfere with the interaction between IL-15 and subunits of the IL-15 receptor complex, and compounds and compositions that interfere with IL-15 signaling events.
  • Antagonists according to the invention include muteins of mature or native IL-15 wherein the IL-15 has been substituted at one or more amino acid residues or regions that play a role in binding to the ⁇ or ⁇ subunits of the IL- 15 receptor complex. Typically, such muteins are created by additions, deletions or substitutions at or near key positions.
  • Antagonists include those muteins wherein at least one of the critical amino acids E64, 168 and N65 have been replaced by a charged group (D, E or K) or by an oppositely charged group (K).
  • the IL-15 antagonist is an IL-15 mutant polypeptide having the amino acid sequence as indicated in SEQ ID NO: l wherein the leucine residue at position 45 is substituted by an aspartic acid residue, the asparagine residue at position 65 is substituted by a lysine residue and the leucine residue at position 69 is substituted by an arginine residue.
  • the IL-15 antagonist is an immunoadhesin.
  • the term "immunoadhesin” designates antibody-like molecules, which combine the binding specificity of the IL-15 mutant polypeptide of the invention with the effector functions of immunoglobulin constant domains.
  • the immunoglobulin constant domain sequence in the immunoadhesin may be obtained from any immunoglobulin, such as IgGl, IgG2, IgG3 or IgG4 subtypes, IgA (including IgAl and IgA2), IgE, IgD or IgM.
  • the immunoglobulin sequence typically, but not necessarily, is an immunoglobulin constant domain (Fc region). Immunoadhesins can possess many of the valuable chemical and biological properties of human antibodies.
  • immunoadhesins can be constructed from a human protein sequence with a desired specificity linked to an appropriate human immunoglobulin hinge and constant domain (Fc) sequence, the binding specificity of interest can be achieved using entirely human components. Such immunoadhesins are minimally immunogenic to the patient and are safe for chronic or repeated use. The artisan skilled in the art can easily select the most appropriate Fc domain (Chan AC, Carter PJ. Therapeutic antibodies for autoimmunity and inflammation. Nat Rev Immunol. 2010 May;10(5):301-16. doi: 10.1038/nri2761. Review.).
  • the Fc region includes or not a mutation that inhibits complement fixation and/or Fc receptor binding (Zheng et al, Transplantation. 2006 Jan 15;81(1): 109-16).
  • SEQ ID NO : 1 IL- 15 (Homo sapiens)
  • the IL-15 antagonist is selected from monoclonal antibodies that immunoreact with mature IL-15 and prevents signal transduction through the IL-15 receptor complex.
  • Antagonists according to the invention also include IL-15 antisense nucleic acids, IL- 15 ribozymes, small molecules targeting IL-15, IL-15 receptor antibodies, IL-15 receptor antisense nucleic acids, IL-15 receptor ribozymes and small molecules targeting the IL-15 receptor.
  • antibody thus refers to any antibody- like molecule that has an antigen binding region, and this term includes antibody fragments that comprise an antigen binding domain such as Fab', Fab, F(ab')2, single domain antibodies (DABs), TandAbs dimer, Fv, scFv (single chain Fv), dsFv, ds-scFv, Fd, linear antibodies, minibodies, diabodies, bispecific antibody fragments, bibody, tribody (scFv-Fab fusions, bispecific or trispecific, respectively), sc-diabody, kappa(lamda) bodies (scFv-CL fusions), BiTE (Bispecific T-cell Engager, scFv-scFv tandems to attract T cells), DVD-Ig (dual variable domain antibody; bispecific format), SIP (small immunoprotein; a kind of minibody), SMIP ("small modular immunopharmaceutical”), scF
  • Antibodies can be fragmented using conventional techniques. For example, F(ab')2 fragments can be generated by treating the antibody with pepsin. The resulting F(ab')2 fragment can be treated to reduce disulfide bridges to produce Fab' fragments. Papain digestion can lead to the formation of Fab fragments.
  • Fab, Fab' and F(ab')2, scFv, Fv, dsFv, Fd, dAbs, TandAbs, ds-scFv, dimers, minibodies, diabodies, bispecific antibody fragments and other fragments can also be synthesized by recombinant techniques or can be chemically synthesized. Techniques for producing antibody fragments are well known and described in the art. For example, Beckman et al. (2006), Holliger & Hudson (2005), Le Gall et al. (2004), Reff & Heard (2001), Reiter et al. (1996) and Young et al. (1995) further describe and enable the production of effective antibody fragments.
  • the antibody of the present invention is a single chain antibody.
  • single domain antibody has its general meaning in the art and refers to the single heavy chain variable domain of antibodies of the type that can be found in Camelid mammals, which are naturally devoid of light chains. Such single domain antibodies are also called “nanobodies®”.
  • single domain antibodies are also called “nanobodies®”.
  • (single) domain antibodies reference is also made to the prior art cited above as well as to EP 0 368 684, Ward et al. (Nature 1989 Oct 12; 341 (6242): 544-6), Holt et al.
  • the antibody is a humanized antibody. In some embodiments, the antibody is a fully human antibody. In some embodiments, the antibody comprises human heavy chain constant region sequences but will induce antibody dependent cellular cytotoxicity (ADCC). In some embodiments, the antibody of the present invention does not comprise an Fc domain capable of substantially binding to a FcgRIIIA (CD 16) polypeptide. In some embodiments, the antibody of the present invention lacks an Fc domain (e.g. lacks a CH2 and/or CH3 domain) or comprises an Fc domain of IgG2 or IgG4 isotype.
  • the antibody of the present invention consists of or comprises a Fab, Fab', Fab'-SH, F (ab') 2, Fv, a diabody, single- chain antibody fragment or a multispecific antibody with multiple different antibody fragments.
  • the antibody of the present invention is not linked to a toxic moiety.
  • one or more amino acids selected from amino acid residues can be replaced with different amino acid residues such that an antibody with altered C2q binding and/or reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in further detail in U.S. Patent Nos. 6,194,551 by ldusogie et al.
  • IL-15 antagonists include IL-15 antisense nucleic acids, IL-15 ribozymes, small molecules targeting IL-15, IL-15 receptor antibodies, IL-15 receptor antisense nucleic acids, IL-15 receptor ribozymes as well as small molecules targeting the IL-15 receptor.
  • JAK inhibitor is intended to describe compounds inhibiting the activity or expression of at least JAKl and/or JAK2. JAK inhibitors down-regulate the quantity or activity of JAK molecules.
  • the JAK inhibitor is a JAK2 inhibitor.
  • the JAK inhibitor is a JAKl inhibitor.
  • the JAK inhibitor can also inhibit other members of the JAK family (i.e., JAK3 or TYK2).
  • the JAK inhibitor is selective.
  • the compound binds to or inhibits a JAKl and/or JAK2 with greater affinity or potency compared to at least one other JAK (e.g., JAK2, JAK3 and/or TYK2).
  • the JAK inhibitor is selective for JAKl and JAK2 over JAK3 and TYK2.
  • the compounds of the invention are selective inhibitors of JAKl over JAK2, JAK3 and TYK2.
  • Selectivity can be at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 50-fold, at least about 100-fold, at least about 200-fold, at least about 500-fold or at least about 1000-fold. Selectivity can be measured by routine methods in the art. In some embodiments, selectivity can be measured by the Km of each enzyme. In some embodiments, selectivity of compounds for JAKl and/or JAK2 can be determined by the cellular ATP concentration.
  • JAK inhibitors are well known in the art.
  • JAK inhibitors include phenylaminopyrimidine compounds (WO2009/029998), substituted tricyclic heteroaryl compounds (WO2008/079965), cyclopentyl-propanenitrile compounds (WO2008/157208 and WO2008/157207), indazole derivative compounds (WO2008/114812), substituted ammo- thiophene carboxylic acid amide compounds (WO2008/156726), naphthyridine derivative compounds (WO2008/112217), quinoxaline derivative compounds (WO2008/148867), pyrrolopyrimidine derivative compounds (WO2008/119792), purinone and imidazopyridinone derivative compounds (WO2008/060301 ), 2,4-pyrimidinediamine derivative compounds (WO2008/118823), deazapurine compounds (WO2007/117494) and tricyclic heteroaryl compounds (WO2008/079521).
  • JAK inhibitors include compounds disclosed in the following publications: US2004/176601, US2004/038992, US2007/135466, US2004/ 102455, WO2009/054941, US2007/134259, US2004/265963, US2008/194603, US2007/207995, US2008/260754, US2006/063756, US2008/261973, US2007/142402, US2005/159385, US2006/293361, US2004/205835, WO2008/148867, US2008/207613, US2008/279867, US2004/09799, US2002/055514, US2003/236244, US2004/097504, US2004/147507, US2004/ 176271, US2006/217379, US2008/092199, US2007/043063, US2008/021013, US2004/ 152625, WO2008/079521, US2009/186815, US2007/203142, WO2008/144011, US2006/270694 and US2001/044442.
  • JAK inhibitors further include compounds disclosed in the following publications: WO2003/011285, WO2007/145957, WO2008/156726, WO2009/035575, WO2009/054941, and WO2009/075830. JAK inhibitors further include compounds disclosed in the following patent applications: US Serial Nos. 61/137475 and 61/134338.
  • JAK inhibitors include AG490, AUB-6-96, AZ960, AZD1480, baricitinib (LY3009104, INCB28050), BMS-911543, CEP-701, CMP6, CP352,664, CP690,550, CYT- 387, INCB20, Jak2-IA, lestaurtinib (CEP-701), LS104, LY2784544, NS018, pacritinib (SB1518), Pyridone 6, ruxolitinib (INCB018424), SB1518, TG101209, TG101348 (SAR302503), TG101348, tofacitinib (CP-690,550), WHI-PI 54, WP1066, XL019, and XLOI 9.
  • Ruxolitinib (JakafiTM, INCBO 18424; (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile) is a potent, orally available, selective inhibitor of both JAK1 and JAK2 of the JAK-STAT signaling pathway.
  • CYT387 is an inhibitor of Janus kinases JAK1 and JAK2, acting as an ATP competitor with IC50 values of 11 and 18 nM, respectively.
  • TG101348 (SAR302503) is an orally available inhibitor of JAK2.
  • AZD1480 is an orally bioavailable inhibitor of JAK2 with potential antineoplastic activity. JAK2 inhibitor AZD 1480 inhibits JAK2 activation, leading to the inhibition of the JAK/STAT signaling including activation of STAT3.
  • Lestaurtinib CEP-701 is a tyrosine kinase inhibitor structurally related to staurosporine. Tofacitinib (Xeljanz®, tasocitinib or CP-690,550) is a known inhibitor of JAK1 and JAK3.
  • Tofacitinib is used to inhibit JAK/STAT signaling and is used for treatment of rheumatoid arthritis.
  • Pacritinib (SB 1815) is an orally bioavailable inhibitor of JAK2 and the JAK2 mutant JAK2V617F . Pacritinib competes with JAK2 for ATP binding, which may result in inhibition of JAK2 activation, inhibition of the JAK/STAT signaling pathway, and therefore caspase-dependent apoptosis.
  • XLOI 9 is an orally bioavailable inhibitor of JAK2. XLOI 9 inhibits the activation of JAK2 as well as the mutated form JAK2V617F.
  • NS018 is a potent JAK2 inhibitor with some inhibition of Src-family kinases. NS018 has been shown to be highly active against JAK2 with a 50% inhibition (IC50) of ⁇ 1 nM, and had 30- to 50-fold greater selectivity for JAK2 over other JAK-family kinases.
  • the JAK inhibitor is an inhibitor of expression of at least one
  • JAK gene e.g. antisense nucleic acids, ribozymes, siRNA.
  • terapéuticaally effective amount describes the amount of the active agent (e.g. IL-15 antagonist or JAK inhibitor) sufficient for treating or reducing the symptoms at reasonable benefit/risk-ratio applicable to any medical treatment. It will be understood that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the nature of the disorder being treated and its severity, the activity of the specific compound employed, the specific composition employed, the age, body weight, general health status, sex and diet of the subject, the time and route of administration, the compounds rate of clearance, the duration of the treatment, drugs used in combination with the active ingredients and other factors well known in the medical arts.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
  • the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject being treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, typically from 1 mg to about 100 mg of the active ingredient.
  • An effective amount of the drug is usually supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • the active agent e.g. IL-15 antagonist or JAK inhibitor
  • pharmaceutically acceptable excipients such as biodegradable polymers
  • pharmaceutically acceptable excipients such as biodegradable polymers
  • pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • the carrier can also be a solvent or dispersion medium containing for example water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof as well as vegetables oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • the active ingredients of the invention can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports.
  • Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
  • TCRD, TCRG and TCRB rearrangements were assessed on 100 ng DNA from duodenal biopsies by multiplex polymerase chain reaction (PCR) as described in BIOMED-2 Concerted Action protocols (van Dongen et al, 2003). See also supplemental experimental procedures.
  • PCR multiplex polymerase chain reaction
  • NGS targeted sequencing of a custom-made panel of 80 oncogenes was performed on exonic fragments enriched from genomic DNA and analyzed using in-house Poly Web software, as described in supplementary methods.
  • CD103 + lymphomas which develop within the gut epithelium as a massive expansion of clonal surface(s)CD3 " intracellular(i)CD3 + intra epithelial lymphocytes (IEL) that selectively respond to IL-15 and develop NK-like cytotoxicity against epithelial cells (Cellier et al, 1998; Malamut et al, 2010; Mention et al, 2003).
  • IEL intra epithelial lymphocytes
  • RCDII clonal or type II refractory CD
  • TCR rearrangements were characterized in intestinal biopsies from 28 patients and in IL-15- dependent sCD3 " iCD3 + IEL lines derived from 14 of these 28 biopsies to ascertain that clonal TCR rearrangements were present in sCD3 " iCD3 + IEL.
  • multiplex PCR and CDR3 sequencing demonstrated incomplete or non- functional TCRG, D and B rearrangements.
  • In-frame rearrangements of both TCRG and TCRD genes were detected in 8/28 cases (28.5%), of which one (#20) also had an in-frame TCRB but no TCRA rearrangement.
  • RCDII IEL depend for their survival and growth on IL-15, a cytokine which is up-regulated in the gut epithelium in CD (Mention et al, 2003).
  • iCD3 + innate IEL remain a minor subset of IEL in most patients with active CD, calling into question the mechanism(s) that drive(s) the selective expansion of clonal iCD3 + innate IEL in RCDII.
  • clonal RCDII IEL have acquired somatic mutation(s) which selectively increase(s) their responsiveness to IL-15.
  • next generation sequencing targeting a panel of 80 oncogenes mutated in human lymphoid malignancies showed G1097D/C/V/A mutations in JAK1 kinase domain and D661V/Y mutations in STAT3 SH2 domain in duodenal biopsies and RCDII IEL lines from 7 and 2 out of 12 RCDII patients respectively. Mutations were absent in polyclonal autologous T-IEL lines, indicating their somatic acquisition by malignant cells.
  • CD defines patients with proven CD (HLA-DQ27anti-TG2 + ). Out of the 7 patients indicated as CD, 3 had uncomplicated CD responsive to gluten free diet while 4 had developed EATL at time of diagnosis of CD but had no evidence of RCDII in duodenal biopsies.
  • RCD defines patients with CD refractory to gluten free diet for over 6 months. 6 CD patients were classified as type I RCD (RCDI) based on normal IEL phenotype by immunohistochemistry and flow cytometry and lack of detectable clonality in biopsies.
  • RCDII type II RCD
  • EATL extraopathy-associated lymphomas
  • EATL is defined as overt lymphoma and characterized by medium to large-sized cells with evidence of abnormal cytological features and expression of CD30 and of the proliferation marker KI67. Diagnosis can be obvious in case of massive infiltration but more difficult in some cases limited to small number of CD30 + KI67 + large cells.
  • EATL is used to indicate biopsies containing evidence of overt lymphoma. EATL was diagnosed in 9 patients classified as CD (see above) and in 17 patients classified as RCDII. In 3 CD and in 14 RCDII, detection of mutations was performed in biopsies containing EATL and on duodenal biopsies without evidence of EATL. In 6 patients with CD and in 3 patients with RCDII, mutations were only studied in EATL-containing biopsies.
  • Targeted sequencing of exon-enriched fragments was performed on genomic DNA extracted from frozen biopsies using a custom-made panel designed by the laboratory of Biological Hematology to sequence exons from 112 oncogenes. This panel includes most of the 80 oncogenes analyzed in the initial study. Exon capture, library building and MI sequencing were performed in the laboratory of Biological Hematology.
  • the first part of data sequence analysis was performed by Paris Descartes University / Institut IMAGINE's Bioinformatics core facilities). Paired-end sequences were mapped on the human genome reference (NCBI build37/hgl9 version) using the Burrows- Wheeler Aligner. Downstream processing was carried out with the Genome Analysis Toolkit (GATK), SAMtools, and Picard, according documented best practices
  • At least one JAK1 mutation was detected in 24 out of 50 (48%) duodenal biopsies classified as RCDII without EATL. 22 were in position 1097 (92%), with the G residue replaced by diverse aminoacids.
  • One patient displayed a distinct SI 0431 GOF mutation located in the activating loop of the tyrosine kinase domain of JAK1. This mutation does not seem to be described in human cancer but was in vitro selected in BaF3 cells as conferring cytokine independent growth. It was associated with constitutive STAT5 activation. In 1/23 patients, the JAK1 mutation was a large deletion difficult to interpret. Three patients with the JAK1 1097 mutation had additional mutations.
  • duodenal biopsies obtained from 3 uncomplicated CD and from 6 RCD1. Mutations were also absent in the duodenal biopsies from 4 patients who developed an EATL diagnosed at the same time as CD. The lack of detectable mutation is coherent with the lack of evidence of RCDII IEL and of clonality in the duodenal biopsies.
  • JAKl mutations in position 1097 are observed in 44% of RCDII and 50 % of EATL complicating RCDII or arising in CD patients without evidence of RCDII.
  • Other JAKl mutations can occur but are in most cases associated with JAKl 097 mutations
  • JAKl 097 mutation is not one of the hot spot mutation reported for JAKl in Cosmic.
  • Cosmic only reports this mutation in one case of HTLVl + leukemia out of 426 cases studied.
  • Analysis of the literature indicates that JAKl mutations are present in lymphoid neoplasms with a frequency between 2% and 6% (up to 18% in report in adult T leukemias) but reported mutations were never in 1097 (except in the article reported in Cosmic).
  • JAKl mutations in position 1097 seem only recurrent in anaplastic T cell lymphomas. In one study (Crescenzo et al Cancer Cell 2015) JAKl mutations were noted in 8% of cases with 10/13 cases with 1097 mutations).
  • anaplastic T cell lymphomas which arise in tissues, share mechanisms of oncogenesis with lymphomas complicating CD.
  • a recent article emphasizes their dependency on cytokines signalling.
  • the cellular origin of anaplastic T lymphoma is unclear. We do not exclude that some of them derive from innate-like lymphocytes and we intend to test this hypothesis by using appropriate markers.
  • TNGS was performed in 4 cases considered as typical RCDII. Patients only differed from "classical "RCDII” by the T phenotype of IEL. In 3 patients, clonal IEL were gamma delta T cells with one case containing 2 STAT3 mutations and 1 case containing the 1097 JAKl mutation. In the 4 th patient, IEL were TCRalpha beta T cells lacking CD4 and CD8, all Vbeta20+. They contained the 1097 JAKl mutation.
  • TNGS was performed in 12 cases of small intestinal T cell lymphoma, including
  • JAKl 1097 mutation is an interesting marker.
  • Table 1 Prevalence of JAK1/STAT3 mutations in biopsies from patients with celiac disase (CD) or refractory celiac disase type I (RCDI) or type II (RCDII) complicated or not with enteropathy associagted T cell lymphoma (EATL)
  • RCDII+EATL biopsies containing EATL and arising in RCDII.
  • samples of RCDII away from EATL were not available in the 9 RCDII with EATL and mutations in JAKland/ or STAT3, at least one of the mutation was present in RCDII biopsies away from EATL
  • CD duodenal biopsies from 3 uncomplicated CD and CD complicated with EATL but without evidence of RCDII
  • IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis. J Clin Invest 120, 2131-2143.
  • Interleukin 15 a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology 125, 730-745.

Abstract

La présente invention concerne des procédés de diagnostic et de traitement de la maladie coeliaque réfractaire de type 2 (RCDII). Les inventeurs ont démontré que dans un sous-ensemble de patients atteints d'une maladie coeliaque, les lymphocytes intraépithéliaux présentant une expression intracellulaire de CD3 (iCD3 + IEL inné) et des mutations de gain de fonction de JAKl ou de STAT3 présentent une réponse augmentée à l'IL-15 et acquièrent un avantage sélectif qui favorise l'expansion clonale et la transformation en lymphome. En particulier, la présente invention concerne ainsi un procédé de diagnostic de RCDII chez un patient comprenant la présence détectée d'au moins une mutation de gain de fonction de JAKl ou de STAT3 dans un échantillon obtenu à partir du patient et entraînant la conclusion selon laquelle le patient souffre de RCDII lorsque la mutation est détectée.
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