WO2017125402A1 - Procédés de prédiction de la réactivité à un médicament chez des patients souffrant de maladies inflammatoires auto-immunes - Google Patents

Procédés de prédiction de la réactivité à un médicament chez des patients souffrant de maladies inflammatoires auto-immunes Download PDF

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WO2017125402A1
WO2017125402A1 PCT/EP2017/050928 EP2017050928W WO2017125402A1 WO 2017125402 A1 WO2017125402 A1 WO 2017125402A1 EP 2017050928 W EP2017050928 W EP 2017050928W WO 2017125402 A1 WO2017125402 A1 WO 2017125402A1
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syndrome
disease
autoimmune
chronic
patient
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PCT/EP2017/050928
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Thierry Lequerre
Olivier Vittecoq
Céline DERAMBURE
Manuela GOZARIU LE BARS
Robert Martin Townsend
Sean Eugène CONNOLLY
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INSERM (Institut National de la Santé et de la Recherche Médicale)
Université de Rouen
Centre Hospitalier Universitaire De Rouen
Bristol-Myers Squibb Company
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Publication of WO2017125402A1 publication Critical patent/WO2017125402A1/fr

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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
    • 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
    • C12Q2600/158—Expression markers

Definitions

  • the present invention relates to methods of predicting drug responsiveness of patients suffering from autoimmune inflammatory diseases.
  • rheumatoid arthritis is the most common form of inflammatory rheumatism involving small joints which are the seat for swelling and pain with structural damage, responsible for functional disabilities if no treatment is proposed.
  • treatment should aim at reaching a target, such as remission or low disease activity in all patients, suppressing systemic and joint inflammation as soon as possible (1-3).
  • methotrexate MTX
  • MTX methotrexate
  • MTX leads to low disease activity states in 25-50% of patients with early RA and to remission states in only 10- 20% of RA patients at 6-12 months (4). Advancement over the last few decades of our understanding of RA pathophysiology has led to the development of new treatments designed to act against a precise therapeutic target.
  • TNFa tumor necrosis factor-alpha
  • ILl-Ra interleukin-1 -receptor antagonist
  • CTLA4-Ig T-lymphocyte activation
  • ABA abatacept
  • mAb monoclonal antibody binding to CD20 expressed on B cells
  • IL-6R tocilizumab
  • RA is a syndrome grouping several entities with different pathophysiological mechanisms, with a spectrum ranging from the most 'inflammatory' forms, susceptible of responding to immunotherapies directed against proinflammatory cytokines (anti-TNFa, anti-IL6, etc), to the most 'autoimmune' forms, able to respond better to anti-cellular therapies (rituximab and ABA). Nevertheless, prescription of conventional treatments, and that of biologies agents, remains highly empirical (1-3).
  • the present invention relates to methods of predicting drug responsiveness of patients suffering from autoimmune inflammatory diseases.
  • the present invention is defined by the claims. DETAILED DESCRIPTION OF THE INVENTION:
  • RA rheumatoid arthritis
  • the inventors aimed to identify a gene expression profile predictive of abatacept response in rheumatoid arthritis. From a first subset of 36 RA patients, a combination including 87 transcripts found by microarray study was able to separate almost perfectly responders and non-responders to abatacept. Next, an independent subset of 32 RA patients allowed the inventors to validate a minimal signature with only 4 genes by qRT-PCR. This latter signature classified 81% of RA patients with 75% sensitivity, 85% specificity and 85% negative predictive value.
  • ETC electron transport chain
  • abatacept is CTLA4 molecule that interrupts the T-cell co-stimulatory signal mediated through the CD28-CD80/CD86 pathway
  • the gene signature identified by the inventor could thus be suitable for predicting whether patients suffering from and autoimmune inflammatory disease could achieve a response with those type of drugs.
  • a first object of the present invention relates to a method for predicting whether a patient suffering from an autoimmune inflammatory disease will achieve a response with an agent that interrupts the T-cell co-stimulatory signal mediated through the CD28-CD80/CD86 pathway comprising i) determining the expression level of at least one gene selected from the group consisting of RNASE3, BLOC1S1, COX6A1 and PTRH2 ii) comparing the expression level determined at step i) with a predetermined reference value and iii) concluding that there is probability that the patient will achieve a response when the level determined at step i) is lower than the predetermined reference value or concluding that there is probability that the patient will not achieve a response when the level determined at step i) is higher than the predetermined reference value.
  • the patient suffers from an autoimmune inflammatory disease selected from the group consisting of arthritis, rheumatoid arthritis, acute arthritis, chronic rheumatoid arthritis, gouty arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, vertebral arthritis, and juvenile-onset rheumatoid arthritis, osteoarthritis, arthritis chronica progrediente, arthritis deformans, polyarthritis chronica primaria, reactive arthritis, and ankylosing spondylitis), inflammatory hyperproliferative skin diseases, psoriasis such as plaque psoriasis, gutatte psoriasis, pustular psoriasis, and psoriasis of the nails, dermatitis including contact dermatitis, chronic contact dermatitis, allergic dermatitis, allergic contact dermatitis, dermatitis herpetiformis,
  • the term “response” or “responsiveness” refers to an improvement in at least one relevant clinical parameter as compared to an untreated patient diagnosed with the same pathology (e.g., the same type, stage, degree and/or classification of the pathology), or as compared to the clinical parameters of the same patient prior to interferon treatment.
  • the term “non responder” refers to a patient not experiencing an improvement in at least one of the clinical parameter and is diagnosed with the same condition as an untreated patient diagnosed with the same pathology (e.g., the same type, stage, degree and/or classification of the pathology), or experiencing the clinical parameters of the same patient prior to the treatment.
  • the response is associated with a decrease in the disease activity which can be determined by any conventional method well known in the art.
  • the disease activity can be measured according to the standards recognized in the art.
  • the "Disease Activity Score” (DAS) is a measure of the activity of rheumatoid arthritis. In Europe the DAS is the recognized standard in research and clinical practice. The following parameters are included in the calculation (Van Gestel AM, Prevoo MLL, van't Hof MA, et al. Development and validation of the European League against Rheumatism response criteria for rheumatoid arthritis.
  • a "responder patient” refers to a patient who shows or will show a clinically significant relief in the disease when treated with the treatment.
  • the response is defined as follows according to the EULAR response criteria:
  • predicting whether a patient will achieve a response refers to the determination of the likelihood that the patient will respond either favorably or unfavorably to the treatment.
  • prediction relates to an individual assessment of any parameter that can be useful in determining the evolution of a patient.
  • the prediction of the clinical response to the treatment although preferred to be, need not be correct for 100% of the patients to be diagnosed or evaluated. The term, however, requires that a statistically significant portion of patients can be identified as having an increased probability of having a positive response.
  • Whether a patient is statistically significant can be determined without further ado by the person skilled in the art using various well known statistic evaluation tools, e.g., determination of confidence intervals, p-value determination, Student's t-test, Mann- Whitney test, etc. Details are found in Dowdy and Wearden, Statistics for Research, John Wiley & Sons, New York 1983.
  • Preferred confidence intervals are at least 50%, at least 60%>, at least 70%>, at least 80%>, at least 90%> at least 95%.
  • the p-values are, preferably, 0.2, 0.1 or 0.05.
  • blood sample means any blood sample derived from the patient that contains nucleic.
  • Peripheral blood is preferred, and mononuclear cells (PBMCs) are the preferred cells.
  • PBMC peripheral blood mononuclear cells
  • unfractionated PBMC refers to whole PBMC, i.e. to a population of white blood cells having a round nucleus, which has not been enriched for a given sub-population.
  • these cells can be extracted from whole blood using Ficoll, a hydrophilic polysaccharide that separates layers of blood, with the PBMC forming a cell ring under a layer of plasma.
  • PBMC can be extracted from whole blood using a hypotonic lysis which will preferentially lyse red blood cells. Such procedures are known to the expert in the art.
  • the template nucleic acid need not be purified. Nucleic acids may be extracted from a sample by routine techniques such as those described in Diagnostic Molecular Microbiology: Principles and Applications (Persing et al. (eds), 1993, American Society for Microbiology, Washington D.C.). According to the invention the blood sample is obtained from the patient prior to the treatment.
  • the name of each of the genes of interest refers to the internationally recognised name of the corresponding gene, as found in internationally recognised gene sequences and protein sequences databases, including in the database from the HUGO Gene Nomenclature Committee, that is available notably at the following Internet address : http://www.gene.ucl.ac.uk/nomenclature/index.html.
  • the name of each of the various biological markers of interest may also refer to the internationally recognised name of the corresponding gene, as found in the internationally recognised gene sequences and protein sequences database Genbank. Through these internationally recognised sequence databases, the nucleic acid and the amino acid sequences corresponding to each of the biological marker of interest described herein may be retrieved by the one skilled in the art.
  • Table B genes of the present invention.
  • the expression of at least 1, 2, 3, 4, or more genes are determined in the blood sample obtained from the patient.
  • the method of the present invention comprises determining the expression levels of R ASE3, BLOC IS 1, COX6A1 and PTRH2 are determined in the blood sample obtained from the patient.
  • the nucleic acid sample used for detecting the target sequence may be a DNA sample or an R A sample. The latter may be preliminarily converted into cDNA before proceeding with said detection.
  • PCR polymerase chain reaction
  • Primers useful in the present invention include oligonucleotides capable of acting as a point of initiation of nucleic acid synthesis within the target nucleic acid sequence.
  • a primer can be purified from a restriction digest by conventional methods, or it can be produced synthetically. If the template nucleic acid is double-stranded (e.g. DNA), it is necessary to separate the two strands before it can be used as a template in PCR.
  • Strand separation can be accomplished by any suitable denaturing method including physical, chemical or enzymatic means.
  • One method of separating the nucleic acid strands involves heating the nucleic acid until it is predominately denatured (e.g., greater than 50%, 60%, 70%>, 80%), 90%o or 95%) denatured).
  • the heating conditions necessary for denaturing template nucleic acid will depend, e.g., on the buffer salt concentration and the length and nucleotide composition of the nucleic acids being denatured, but typically range from about 90°C to about 105°C for a time depending on features of the reaction such as temperature and the nucleic acid length.
  • Denaturation is typically performed for about 30 sec to 4 min (e.g., 1 min to 2 min 30 sec, or 1.5 min). If the double-stranded template nucleic acid is denatured by heat, the reaction mixture is allowed to cool to a temperature that promotes annealing of each primer to its target sequence on the target nucleic acid sequence.
  • the temperature for annealing is usually from about 35°C to about 65°C (e.g., about 40°C to about 60°C; about 45°C to about 50°C).
  • Annealing times can be from about 10 sec to about 1 min (e.g., about 20 sec to about 50 sec; about 30 sec to about 40 sec).
  • the reaction mixture is then adjusted to a temperature at which the activity of the polymerase is promoted or optimized, i.e., a temperature sufficient for extension to occur from the annealed primer to generate products complementary to the template nucleic acid.
  • the temperature should be sufficient to synthesize an extension product from each primer that is annealed to a nucleic acid template, but should not be so high as to denature an extension product from its complementary template (e.g., the temperature for extension generally ranges from about 40°C to about 80°C (e.g., about 50°C to about 70°C; about 60°C).
  • Extension times can be from about 10 sec to about 5 min (e.g., about 30 sec to about 4 min; about 1 min to about 3 min; about 1 min 30 sec to about 2 min).
  • thermostable polymerase refers to a polymerase enzyme that is heat stable, i.e., the enzyme catalyzes the formation of primer extension products complementary to a template and does not irreversibly denature when subjected to the elevated temperatures for the time necessary to effect denaturation of double-stranded template nucleic acids. Generally, the synthesis is initiated at the 3 ' end of each primer and proceeds in the 5' to 3' direction along the template strand. Thermostable polymerases have been isolated from Thermus fiavus, T. ruber, T. thermophilus, T. aquaticus, T. lacteus, T.
  • polymerase is a Taq polymerase (i.e. Thermus aquaticus polymerase).
  • the primers are combined with PCR reagents under reaction conditions that induce primer extension.
  • chain extension reactions generally include 50 mM KC1, 10 mM Tris-HCl (pH 8.3), 15 mM MgC12, 0.001% (w/v) gelatin, 0.5-1.0 ⁇ g denatured template DNA, 50 pmoles of each oligonucleotide primer, 2.5 U of Taq polymerase, and 10% DMSO.
  • the reactions usually contain 150 to 320 ⁇ each of dATP, dCTP, dTTP, dGTP, or one or more analogs thereof.
  • Quantitative PCR is typically carried out in a thermal cycler with the capacity to illuminate each sample with a beam of light of a specified wavelength and detect the fluorescence emitted by the excited fluorophore.
  • the thermal cycler is also able to rapidly heat and chill samples, thereby taking advantage of the physicochemical properties of the nucleic acids and thermal polymerase.
  • amplicon i.e. amplified target nucleic acid sequence
  • a measurable signal has to be generated, which is proportional to the amount of amplified product.
  • All current detection systems use fluorescent technologies. Some of them are non-specific techniques, and consequently only allow the detection of one target at a time. Alternatively, specific detection chemistries can distinguish between non- specific amplification and target amplification. These specific techniques can be used to multiplex the assay, i.e. detecting several different targets in the same assay. For example, SYBR® Green I probes, High Resolution Melting probes, TaqMan® probes, LNA® probes and Molecular Beacon probes can be suitable.
  • TaqMan® probes are the most widely used type of probes. They were developed by Roche (Basel, Switzerland) and ABI (Foster City, USA) from an assay that originally used a radio-labelled probe (Holland et al. 1991), which consisted of a single- stranded probe sequence that was complementary to one of the strands of the amplicon. A fluorophore is attached to the 5 ' end of the probe and a quencher to the 3' end. The fluorophore is excited by the machine and passes its energy, via FRET (Fluorescence Resonance Energy Transfer) to the quencher. Traditionally, the FRET pair has been conjugated to FAM as the fluorophore and TAMRA as the quencher.
  • FRET Fluorescence Resonance Energy Transfer
  • FAM does not fluoresce as it passes its energy onto TAMRA.
  • TAMRA fluorescence is detected at a different wavelength to FAM, the background level of FAM is low.
  • the probe binds to the amplicon during each annealing step of the PCR.
  • the Taq polymerase extends from the primer which is bound to the amplicon, it displaces the 5 ' end of the probe, which is then degraded by the 5 '-3' exonuclease activity of the Taq polymerase. Cleavage continues until the remaining probe melts off the amplicon. This process releases the fluorophore and quencher into solution, spatially separating them (compared to when they were held together by the probe). This leads to an irreversible increase in fluorescence from the FAM and a decrease in the TAMRA.
  • the predetermined reference value is a threshold value or a cutoff value.
  • a “threshold value” or “cut-off value” can be determined experimentally, empirically, or theoretically.
  • a threshold value can also be arbitrarily selected based upon the existing experimental and/or clinical conditions, as would be recognized by a person of ordinary skilled in the art. For example, retrospective measurement of expression level of the gene in properly banked historical patient samples may be used in establishing the predetermined reference value. The threshold value has to be determined in order to obtain the optimal sensitivity and specificity according to the function of the test and the benefit/risk balance (clinical consequences of false positive and false negative).
  • the optimal sensitivity and specificity can be determined using a Receiver Operating Characteristic (ROC) curve based on experimental data.
  • ROC Receiver Operating Characteristic
  • the full name of ROC curve is receiver operator characteristic curve, which is also known as receiver operation characteristic curve. It is mainly used for clinical biochemical diagnostic tests.
  • ROC curve is a comprehensive indicator that reflects the continuous variables of true positive rate (sensitivity) and false positive rate (1 -specificity). It reveals the relationship between sensitivity and specificity with the image composition method.
  • a series of different cut-off values are set as continuous variables to calculate a series of sensitivity and specificity values. Then sensitivity is used as the vertical coordinate and specificity is used as the horizontal coordinate to draw a curve. The higher the area under the curve (AUC), the higher the accuracy of diagnosis.
  • AUC area under the curve
  • the point closest to the far upper left of the coordinate diagram is a critical point having both high sensitivity and high specificity values.
  • the AUC value of the ROC curve is between 1.0 and 0.5. When AUO0.5, the diagnostic result gets better and better as AUC approaches 1. When AUC is between 0.5 and 0.7, the accuracy is low. When AUC is between 0.7 and 0.9, the accuracy is moderate.
  • a score which is composite of said expression levels may be calculated and compared with a predetermined reference value, wherein when the score is higher than the predetermined reference value it is concluded that the patient will achieve a response.
  • the term "agent that interrupts the T-cell co-stimulatory signal mediated through the CD28-CD80/CD86 pathway” refers to any molecule that e.g. binds with CD80, CD86, or CD28 providing inhibition of CD28 co-stimulation in the T cells of the patient.
  • CD28 is a molecule expressed on T cells that provides co-stimulatory signals needed for T cell activation.
  • CD28 is the receptor for CD80 (B7.1) and CD86 (B7.2).
  • the agent of the present invention aims at inhibiting naive T-cell activation, thus having the potential to selectively inhibit T-cell response to specific antigens instead of broad immunosuppression.
  • the agent of the present invention is a small organic molecule, a recombinant polypeptide or an antibody (e.g. an antibody having specificity for CD28, C80 or CD86).
  • the agent that interrupts the T-cell co-stimulatory signal mediated through the CD28-CD80/CD86 pathway is a CTLA-4 molecule.
  • CTLA4 has its general meaning in the art and refers to the cytotoxic T-lymphocyte-associated antigen 4.
  • CTLA4 which is also known as CD 152, is a protein involved in the regulation of the immune system.
  • Naturally occurring CTLA4 is described in U.S. Pat. Nos. 5,434,131 , 5,844,095, and 5,851 ,795.
  • An exemplary human amino acid sequence is represented by SEQ ID NO: l .
  • Natural CTLA4 proteins are encoded by the CTLA4 gene.
  • CTLA4 is a cell surface protein, having an N-terminal extracellular domain, a transmembrane domain, and a C-terminal cytoplasmic domain.
  • the extracellular domain binds to and/or interferes with target antigens, such as CD80 and CD86, serves as nature natural break of T cell stimulation.
  • target antigens such as CD80 and CD86
  • the extracellular domain of the CTLA4 molecule begins with methionine at position +1 and ends at aspartic acid at position +124.
  • SEQ ID NO: l CTLA-4_homo sapiens
  • CTLA4 molecule refers to a molecule comprising a cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) extracellular domain.
  • the extracellular domain of CTLA4 comprises a portion of the CTLA4 protein that recognizes and binds to at least one B7 (CD80/86) antigen such as a B7 antigen expressed on B cells and on antigen presenting cells (APCs).
  • the extracellular domain may also include fragments or derivatives of CTLA4 that bind a B7 antigen.
  • the CTLA4 extracellular domain can also recognize and bind CD 80 and/or CD86.
  • the extracellular domain may also include fragments or derivatives of CTLA4 that bind a binds CD80 and/or CD86.
  • the CTLA4 molecule of the present invention is a recombinant fusion protein, where a fusion protein is defined as one or more amino acid sequences joined together using methods well known in the art.
  • the CTLA4 molecule contains at least a portion of an immunoglobulin, such as the Fc portion of an immunoglobulin.
  • immunoglobulin such as the Fc portion of an immunoglobulin.
  • Conventionally said type of fusion proteins are designated "immunoadhesin".
  • the immunoglobulin constant domain sequence in the immunoadhesin may be obtained from any immunoglobulin, such as IgG-1, IgG-2, IgG-3, or IgG-4 subtypes, IgA (including IgA-1 and IgA-2), IgE, IgD or IgM.
  • the immunoglobulin sequence is an immunoglobulin constant domain (Fc region).
  • Immunoadhesins can possess many of the valuable chemical and biological properties of human antibodies. Since 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.
  • 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).
  • the Fc region is a native sequence Fc region.
  • the Fc region is a variant Fc region.
  • the Fc region is a functional Fc region.
  • the term "Fc region” is used to define a C-terminal region of an immunoglobulin heavy chain, including native sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof.
  • the adhesion portion and the immunoglobulin sequence portion of the immunoadhesin are linked by a minimal linker.
  • the CTLA4 molecule is abatacept.
  • Abatacept is a soluble fusion protein that consists of the extracellular domain of human CTLA-4 linked to the modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin Gl (IgG 1 ).
  • Abatacept is produced by recombinant DNAtechnology in a mammalian cell expression system. The apparent molecular weight of abatacept is 92 kilodaltons.
  • Abatacept was developed by Bristol-Myers Squibb and is disclosed, for example, in U.S. Pat. 5,851 ,795, U.S. Pat. 7,455,835, and EP1962886.
  • the amino acid sequence of abatacept is represented by SEQ ID NO:2.
  • SEQ ID NO:2 Abatacept
  • the CTLA molecule is belatacept that is the result of altering two amino acids in the CD80/86 binding portion of the abatacept compound (L104E and A29Y). This slight change in chemistry resulted in a 10-fold increase in the ability to inhibit T-cell activation when compared in vitro.
  • Belatacept (L104EA29YIg) is the first biologic agent approved for primary maintenance immunosuppression, selectively blocking the CD28 co-stimulation pathway to prevent T-cell activation (Larsen, CP. et al, Am. J. Transplant., 5:443-453 (2005)).
  • the amino acid sequence of belatacept is represented by SEQ ID NO:3.
  • the CTLA4 molecule is MAXY-4, which is also a protein derived from abatacept but having increased binding to CTLA4 targets, ant that is currently in preclinical development by Perseid Therapeutics, LLC and Astellas Pharma, Inc. for treatment of autoimmune diseases and transplant rejection.
  • the agent of the present invention is administered in combination with another drug.
  • the agent may be administered in combination with methotrexate.
  • methotrexate is synonymous with "MTX" and means a molecule that includes, in part, a 2,4-diamino substituted pterine ring moiety linked at the 6 position to the amino group of a p-aminobenzoyl moiety, the p-aminobenzoyl moiety having a methylated amino group and linked to a glutamic acid moiety through an amide bond.
  • Methotrexate functions as an inhibitor of dihydrofolate reductase (DHFR), decreasing the production of tetrahydro folate (THF) from dihydrofolate (DHF).
  • DHFR dihydrofolate reductase
  • THF tetrahydro folate
  • DHF dihydrofolate
  • methotrexate indirectly inhibits purine and thymidine synthesis and amino acid interconversion.
  • Methotrexate also exhibits anti-proliferative activity through inhibition of thymidylate synthesis, which is required for production of DNA (Calvert, Semin. Oncol. 26:3- 10 (1999)).
  • a further object of the present invention relates to a method of treating an inflammatory autoimmune disease in a patient in need thereof comprising i) predicting whether the patient will achieve a response with an agent that interrupts the T-cell co- stimulatory signal mediated through the CD28-CD80/CD86 pathway ii) and administering the agent when it is concluded that there is probability that the patient will achieve a response.
  • treatment refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill 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 patient having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a patient beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “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 administer the drug 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 treatment of an illness, 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.]).
  • TNFa-blocking agent a biological agent which is capable of neutralizing the effects of TNFa.
  • Said agent is a preferentially a protein such as a soluble TNFa receptor, e.g. Pegsunercept, or an antibody.
  • the TBA is a monoclonal antibody.
  • the TBA is selected in the group consisting of Etanercept (Enbrel®), Infliximab (Remicade®), Adalimumab (Humira®), Certolizumab pegol (Cimzia®), and golimumab (Simponi®).
  • the patient is adminitsed with another anti-inflammatory biological drug.
  • anti- inflammatory biological drug it is herein meant a biological agent (typically a recombinant protein, including recombinant antibodies) with anti- inflammatory properties.
  • IL-IRa such as anakinra or IL- 6R such as tocilizumab
  • This also notably includes the following biological agents (preferably recombinant proteins, including recombinant antibodies).
  • the patient can also be administered with an agent capable of depleting the B cells such as anti-CD20 antibodies (e.g. rituximab (Rituxan®)).
  • the agents of the present invention are administered to the patient in the form of pharmaceutical compositions.
  • the pharmaceutical composition as provided herewith may include a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington's Pharmaceutical-Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof.
  • any conventional carrier medium is incompatible with the compounds of provided herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention.
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogenfree water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium
  • the compounds described herein including pharmaceutically acceptable carriers can be delivered to a patient using a wide variety of routes or modes of administration. Suitable routes of administration include, but are not limited to, inhalation, transdermal, oral, rectal, transmucosal, intestinal and parenteral administration, including intramuscular, subcutaneous and intravenous injections.
  • routes of administration include, but are not limited to, inhalation, transdermal, oral, rectal, transmucosal, intestinal and parenteral administration, including intramuscular, subcutaneous and intravenous injections.
  • Figure 1 Ancillary study design from the APPRAISE trial. Of 104 RA patients enrolled in the APPRAISE trial, 68 were included in our ancillary study after discarding patients with missing data or poor quality R A samples. Among them, two subsets of RA patients -one for discovery and one for validation- were designated. The first step of this ancillary study was to identify clinical parameters to predict MTX/ABA response. The second step was to identify gene combination able to predict MTX ABA response. To perform that, a first subset of 36 RA patients was used to identify clinical parameters or genes combination to predict drug responsiveness. Next, the second subset including 32 RA patients was used to validate these clinical parameters or genes combination.
  • Figure 2 Incapacity of clinical and biological parameters to predict methotrexate/abatacept response. Two independent statistical methods were performed to identify parameters to predict drug responsiveness with subset 1. Next, the prediction efficiency of these parameters was checked with subset 2.
  • B In subset 1, linear discriminant analysis was performed to balance each parameter by coefficient of linear discriminant analysis calculation. In subset 2, these data allowed good classification 13 out of 19 R and 6 out of 13 NR. A total of 13 patients out of 32 were misclassified.
  • APPRAISE NCT00767325
  • NCT00767325 including initially 104 RA patients was a 24-weeks, Phase Illb, open- label, multicentre, single-arm study conducted at 21 sites across Europe (Denmark, France, Germany, Hungary, Italy, Norway, Spain and the UK) (25).
  • Eligible patients were >18 years of age, had American College of Rheumatology (ACR)-defined RA according to the 1987 classification criteria for at least 6 months (47), and on MTX (>15 mg/week) for at least 3 months prior to baseline, with a stable MTX dose for at least 28 days before baseline (except in cases of intolerance to MTX).
  • Patients were required to have active disease, defined by a baseline DAS28(CRP) score of >3.2 or tender and swollen joint counts of >6 and a CRP level greater than the upper limit of normal.
  • IV infusions of ABA All patients received intravenous (IV) infusions of ABA at a weight-titered dose of 10 mg/kg at baseline (day 1), and at weeks 2, 4, 8, 12, 16, 20 and 24, in addition to stable doses of concomitant MTX (>15 mg/week). MTX dose increases were not permitted, and dose decreases were allowed only in cases of intolerance. Oral corticosteroid use (stable dose of ⁇ 10 mg prednisone/day) was permitted during the study. For this study, 5 ml of whole blood were collected in PAXgene RNA tube (PreAnalytiX, Qiagen) just before the first infusion and 6 months later and stored at -80°C until use.
  • PAXgene RNA tube PreAnalytiX, Qiagen
  • the response to MTX/ ABA was evaluated at 6 months with the EULAR response criteria based on DAS28(CRP) (48). These patients were classified according to their response as R (good responders from EULAR criteria) or NR (moderate responders and no responders from EULAR criteria) (48). The study was approved by the Institutional Review Board/Independent Ethics Committee (IRB/IEC) and local ethics committees, and was conducted in accordance with the ethical principles underlying the European Union Directive 2001/20/EC and the United States Code of Federal Regulations on Good Clinical Practice, as defined by the International Conference on Harmonisation. All patients provided written informed consent.
  • IRS Institutional Review Board/Independent Ethics Committee
  • RNAs from whole blood were extracted with PAXgene blood RNA kit according to the manufacturer's recommendations (Qiagen PreAnalytiX GmbH, Courtaboeuf, France) and stored at -80°C until use.
  • Total RNA from 10 healthy donors (5 women and 5 men) were pooled and were used as an internal standard reference. The quality and quantity of isolated mRNAs were assessed using the 2100 Bioanalyzer (Agilent Technologies, Santa Clara, California, USA) and the Nanodrop (Thermo Scientific, Wilmington, USA). Only RNA samples with a minimal RNA integrity number of 7 were used for subsequent experiments.
  • RNA samples were labeled by Cyanine-5 and co-hybridized with a Cyanine-3 labeled RNA control pool according to the manufacturer's instructions (Low Input QuickAmp Labeling Kit, Agilent Technologies). Briefly, 100 ng of RNAs were labeled with cyanine-5 CTP (RA patients) or cyanine-3 CTP (control pool). Co-hybridization was performed at 65°C for 17 hours using a hybridization kit (Agilent Technologies).
  • microarrays were scanned with a 5 ⁇ pixel size using the DNA Microarray Scanner GB (Agilent Technologies). Image analysis and extraction of raw and normalized signal intensities (Lowess) were performed with Feature Extraction Software 10.5.1.1 (Agilent Technologies). The data were in agreement with the Minimum Information About a Microarray Experiment guidelines and were deposited in the National Center for Biotechnology Information's Gene Expression Omnibus. The data are accessible using the following accession number: GSE68215. Nonuniform spots and saturated spots or spots with intensities below the background were not taken into account. Only spots, which passed these quality controls on 100% of arrays, were selected for further analysis. Hierarchical clustering was performed with Pearson coefficient metric and complete linkage to build the transcripts and sample dendrograms.
  • cDNA was synthesized from 1 ⁇ g RNA samples using random primers and M-MLV enzyme (InvitrogenTM, Carlsbad, USA). qRT-PCR was performed using a Lightcycler as instructed by the manufacturer (RocheTM, Meylan, France). qRT-PCR reactions for each sample were performed in duplicate using SYBR-Green (RocheTM, Meylan, France) and values were normalized using geometric mean of three control genes (18S, ACTB, B2M) defined by geNorm algorithm (49).
  • Sequences of primers used for qRT-PCR were: BLOC1S1 forward, 5 '-AAGC AGACAGGCCAGTGGAT-3 ' ; BLOC1S1 reverse, 5 ' -C AGTGC AGTGGC AATGGTG-3 ' ; RNASE3 forward, 5'- C AGGAGCC AC AGCTC AGAGA-3 ' ; RNASE3 reverse, 5'- GAGCCCTCCACACCCATAAG-3'; COX6A1 forward, 5'--
  • Comparisons of clinical and biological data between R and NR at baseline were performed using Student's t-test for continuous variables. Comparisons of R or NR before and after treatment were performed with paired t-test. Identification of clinical parameters able to predict MTX/ABA responsiveness was performed with two different multivariate analyses: i) a logistic regression model with variable selection using Bayesian information criterion (BIC); ii) a linear discriminant analysis (LDA) which estimates a coefficient for each variable.
  • BIC Bayesian information criterion
  • LDA linear discriminant analysis
  • SEA GeneSpring Single Experiment Analysis
  • Table 1 provides demographic and clinical information for these 68 RA patients at baseline and after 6 months of treatment.
  • Table 1 Clinical and biological parameters of RA patients. Clinical and biological variables were collected before treatment and 6 months later. Response to methotrexate/abatacept was assessed by disease activity score 28 (DAS28) calculated with C reactive protein (CRP) at 6 months of treatment. Patients are categorized as indicated in material and methods. Values of parameters are expressed as mean ⁇ standard error of the mean. Stars indicate significant comparisons between responders (R) and non-responders (NR) at baseline (* p ⁇ 0.05; ** p ⁇ 0.01). Dollars indicate significant comparisons in responders between baseline and 6 months ($$$ p ⁇ 0.001). Pounds indicate significant comparisons in non-responders between baseline and 6 months (££ p ⁇ 0.01 ; ££££ p ⁇ 0.001). All other comparisons are not significant. P values were determined by Student's t-test or paired t-test according to the comparisons. VAS: visual analog scale.
  • Clinical and biological parameters not associated with MTX/ABA responsiveness Identification of clinical and/or biological parameters as predictors of responsiveness was performed by two different multivariate statistical approaches such as logistic regression and linear discriminant analysis.
  • subset 1 the cRNA from 17 R and 19 NR were co-hybridized with a cRNA internal reference from 10 healthy subjects on whole human genome microarrays, by two color technology. After elimination of spikes and flagged probes, 19,620 probes were detected in all samples. From these 19,620 transcripts, we next identified 87 transcripts with statistically significant variation between R and NR according to a t-test with correction for multiple testing [false discovery rate (FDR), Benjamini Hochberg correction]. These transcripts are listed in Table 2 (69 transcripts are referenced with a Ref Seq accession number while 18 probes were unknown) (Table 2). Table 2: List of transcripts differentially expressed in MTX/ABA responders (R) vs non-responders (NR).
  • RNASE3 ribonuclease RNase A family
  • 3 NM_002935 ribonuclease RNase A family
  • RNASE2 liver, eosinophil-derived
  • NM_002934 ribonuclease, RNase A family, 2
  • RNASE2 liver, eosinophil-derived
  • LSM LSM1 U6 small nuclear RNA
  • CTBP1 antisense RNA 2 (head
  • TBP TBP-associated factor
  • This procedure identified six misclassified patients and indicated that this set of 4 transcripts provides 75% sensitivity, 85% specificity, and 85% negative predictive value and 75% positive predictive value for identification of future R and NR to MTX/ABA.
  • TNFa blocking agents such as etanercept or adalimumab, both associated with MTX.
  • ETC pathway includes 104 proteins split up into five complexes of electron transport chain, embedded in the inner membrane of mitochondria.
  • the dysregulation of these transcripts could be linked to the more elevated CRP observed in NR compared to R at baseline (Table 1). Correlations between each significant transcript level from ETC pathway (NDUFA6, NDUFA4, UQCRQ, ATP5J, COX7A2, COX7B, COX6A1) and CRP or DAS28(CRP) were performed to discard a CRP or disease activity effect on the gene expression levels from this signature linked to a supposedly more pronounced mitochondrial activity in the inflammatory state.
  • transcriptomic approach based on the whole genome allowed to identify a signature able to separate R from NR to several drugs (infliximab, tocilizumab, rituximab) used in RA (19-24).
  • ABA only one study has previously measured the type-I interferon- regulated transcripts from peripheral blood mononuclear cells in RA patients independently of response to ABA (30).
  • This signature included 87 genes variously involved in ETC, proteasome, interferon, RNA processes, etc. This combination of 87 genes is also specific to ABA since it was not able to predict TNFa blocking agent response.
  • this signature is the optimized combination of genes able to predict drug responsiveness with good accuracy, since it correctly predicted the future response in 81% of RA patients (75% sensitivity, 85% specificity, and 85% negative predictive value and 75% positive predictive value) prior to treatment (Fig.4).
  • Each gene taken separately was unable to predict drug responsiveness (data not shown) but all genes together predicted MTX ABA responsiveness with good accuracy.
  • RNAselll gene codes for the RNAselll enzyme which specifically cleaves double-stranded RNA and is involved in the processing of ribosomal RNA precursors of some mRNAs (31).
  • BLOC1S1 Biogenesis of lysosomal organelles complex-1, subunit 1 codes for the protein BLOC1 S1, also known as GCN5L1, is an essential component of the mitochondrial acetyltransferase machinery, and modulates mitochondrial respiration via acetylation of ETC proteins (32).
  • COX6A1 codes for the mitochondrial protein cytochrome c oxidase subunit 6A1 (COX6A1) located in the complex IV. This is the last enzyme in the mitochondrial ETC which drives ATP synthesis (33).
  • PTRH2 codes for the peptidyl-tRNA hydrolase 2 which is a mitochondrial protein released from the mitochondria to the cytoplasm during apoptosis.
  • ETC is a series of 5 complexes anchored to the inner membrane of mitochondria that transfer electrons via redox reactions that drives ATP synthesis generating reactive oxygen species (ROS) and subsequent oxidative stress (34). Redox balance in mitochondria is a critical component in T cell activation and proliferation (35). The production of ROS by the ETC complex III conducts to large amount of ATP to enhance activity of proliferating T cell after TCR cross-linking (36-39).
  • RASSF5 which was significantly up-regulated in R compared to NR.
  • RASSF5 also known as RAPL, is the effector of Rapl . Rapl plays a central role in T cell response through TCR and costimulation signals. Indeed, a model was drawn in which inactivation of Rapl plays a central role in establishing oxidative stress and can influence the T cell response in RA (40, 41). So, since RASSF5 was upregulated in future R, we could speculate that Rapl is overexpressed suggesting low level of ROS and subsequent less T cell activation and proliferation in R.
  • CACNA2D4 member of the alpha-2/delta subunit family from the voltage-dependent calcium channel complex
  • CALM2 calcium sensor and signal transducer by binding calcium
  • T cells Mitochondria and T cell activation. Nat Rev Immunol 13, 224 (2013).
  • CTLA-4IG suppresses reactive oxygen species by preventing synovial adherent cell- induced inactivation of Rapl, a Ras family GTPASE mediator of oxidative stress in rheumatoid arthritis T cells. Arthritis Rheum 54, 3135-3143 (2006).

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Abstract

La présente invention concerne des procédés de prédiction de la réactivité à un médicament chez les patients souffrant de maladies inflammatoires auto-immunes. En particulier, la présente invention concerne un procédé de prédiction du fait qu'un patient souffrant d'une maladie inflammatoire auto-immune atteindra une réponse à un agent qui interrompt le signal de co-stimulation des cellules T à médiation à travers la voie CD28-CD80/CD86 comprenant i) la détermination du niveau d'expression d'au moins un gène sélectionné dans le groupe constitué de l'ARNASE3, de BLOC1S1, de COX6A1 et de PTRH2 ii) la comparaison du niveau d'expression déterminé dans l'étape i) à une valeur de référence prédéterminée et iii) la conclusion qu'il existe une probabilité que le patient obtiendra une réponse lorsque le niveau déterminé à l'étape i) est inférieur à la valeur de référence prédéterminée ou la conclusion qu'il existe une probabilité que le patient n'atteindra pas une réponse lorsque le niveau déterminé à l'étape i) est supérieur à la valeur de référence prédéterminée.
PCT/EP2017/050928 2016-01-19 2017-01-18 Procédés de prédiction de la réactivité à un médicament chez des patients souffrant de maladies inflammatoires auto-immunes WO2017125402A1 (fr)

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CN110923310A (zh) * 2019-12-24 2020-03-27 广州市妇女儿童医疗中心 用于指导肾病综合征cyp3a5表达型患儿使用他克莫司的多态性位点
WO2020116567A1 (fr) * 2018-12-07 2020-06-11 株式会社Ｄｎａチップ研究所 Procédé de prédiction de l'efficacité d'un médicament contre la polyarthrite rhumatoïde et biomarqueur utilisé dans le cadre dudit procédé
NL2030973A (en) * 2021-08-04 2023-02-15 Hangzhou Zheda Dixun Biological Gene Eng Co Ltd Primer set for detection of expression of human eosinophil cationic protein (ecp) mrna and kit
CN117031044A (zh) * 2023-10-07 2023-11-10 首都医科大学附属北京天坛医院 一种预测卒中相关性肺炎的生物标志物和试剂盒及诊断设备
EP4290237A1 (fr) * 2022-06-10 2023-12-13 Biohope Scientific Solutions for Human Health SL Procede de determination de la reponse au methrotrexate (mtx) chez un sujet humain diagnostique d'une arthrite rhumatoide
JP7514458B2 (ja) 2018-12-07 2024-07-11 株式会社Ｄｎａチップ研究所 関節リウマチ治療薬の奏効を予測する方法及びそれに用いるバイオマーカー

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EP3901264A4 (fr) * 2018-12-07 2023-03-15 DNA Chip Research Inc. Procédé de prédiction de l'efficacité d'un médicament contre la polyarthrite rhumatoïde et biomarqueur utilisé dans le cadre dudit procédé
JP7514458B2 (ja) 2018-12-07 2024-07-11 株式会社Ｄｎａチップ研究所 関節リウマチ治療薬の奏効を予測する方法及びそれに用いるバイオマーカー
CN110904219A (zh) * 2019-12-24 2020-03-24 广州市妇女儿童医疗中心 Myh9及ctla4基因多态性位点在指导肾病综合征患儿使用他克莫司中的应用
CN110923310A (zh) * 2019-12-24 2020-03-27 广州市妇女儿童医疗中心 用于指导肾病综合征cyp3a5表达型患儿使用他克莫司的多态性位点
CN110923310B (zh) * 2019-12-24 2023-04-18 广州市妇女儿童医疗中心 用于指导肾病综合征cyp3a5表达型患儿使用他克莫司的多态性位点
CN110904219B (zh) * 2019-12-24 2023-04-18 广州市妇女儿童医疗中心 Myh9及ctla4基因多态性位点在指导肾病综合征患儿使用他克莫司中的应用
NL2030973A (en) * 2021-08-04 2023-02-15 Hangzhou Zheda Dixun Biological Gene Eng Co Ltd Primer set for detection of expression of human eosinophil cationic protein (ecp) mrna and kit
EP4290237A1 (fr) * 2022-06-10 2023-12-13 Biohope Scientific Solutions for Human Health SL Procede de determination de la reponse au methrotrexate (mtx) chez un sujet humain diagnostique d'une arthrite rhumatoide
WO2023237767A1 (fr) * 2022-06-10 2023-12-14 Biohope Scientific Solutions For Human Health, S.L Procédé de détermination de la réponse au méthotrexate (mtx) chez un sujet humain diagnostiqué avec la polyarthrite rhumatoïde
CN117031044A (zh) * 2023-10-07 2023-11-10 首都医科大学附属北京天坛医院 一种预测卒中相关性肺炎的生物标志物和试剂盒及诊断设备
CN117031044B (zh) * 2023-10-07 2024-01-02 首都医科大学附属北京天坛医院 一种预测卒中相关性肺炎的生物标志物和试剂盒及诊断设备

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