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WO2013045672A1 - Procédé pour prédire l'aptitude d'un patient à répondre à un traitement à base d'antagoniste d'il-6 - Google Patents

Procédé pour prédire l'aptitude d'un patient à répondre à un traitement à base d'antagoniste d'il-6 Download PDF

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Publication number
WO2013045672A1
WO2013045672A1 PCT/EP2012/069279 EP2012069279W WO2013045672A1 WO 2013045672 A1 WO2013045672 A1 WO 2013045672A1 EP 2012069279 W EP2012069279 W EP 2012069279W WO 2013045672 A1 WO2013045672 A1 WO 2013045672A1
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Prior art keywords
monocytes
patient
antagonist
treatment
classical
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Ceased
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PCT/EP2012/069279
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English (en)
Inventor
Pascale LOUIS-PLENCE
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Institut National de la Sante et de la Recherche Medicale INSERM
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Institut National de la Sante et de la Recherche Medicale INSERM
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Publication of WO2013045672A1 publication Critical patent/WO2013045672A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G01N33/5047—Cells of the immune system
    • G01N33/5055—Cells of the immune system involving macrophages
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/10—Musculoskeletal or connective tissue disorders
    • G01N2800/101—Diffuse connective tissue disease, e.g. Sjögren, Wegener's granulomatosis
    • G01N2800/102—Arthritis; Rheumatoid arthritis, i.e. inflammation of peripheral joints

Definitions

  • the present invention relates to a method for predicting the responsiveness of a patient to a treatment with an IL-6 antagonist such as tocilizumab.
  • RA Rheumatoid arthritis
  • the synovium the inner lining of synovial joints, is abnormal.
  • There is infiltration of acute inflammatory cells in the synovium which undergoes hypertrophy, resulting in effusion of the joint.
  • Hyperplastic synovium may also lead to erosion of the adjacent cartilage and bone, causing joint destruction.
  • the end result is joint inflammation, effusion, joint and adjacent ligament destruction, joint deformity and, finally, loss of function.
  • RA The pathogenesis of RA is complex and has not been fully defined.
  • cytokines including interleukin IL-6, IL-15, IL-17, and tumor necrosis factor, have been implicated in causing joint and systemic inflammation (Tamer, et al, Nat. Clin. Pract. Rheumatol, 3:336-45 (2007)). Accordingly targeting one of these cytokines has been proposes as a potential therapeutic strategy of RA (Choy, et al, N. Engl. J. Med., 344:907-16 (2001)).
  • the present invention relates to a method for predicting the responsiveness of a patient to a treatment with an IL-6 antagonist, said method comprising measuring in a blood sample obtained from said patient the level of at least one subpopulation of blood monocytes selected from the group consisting of classical monocytes, intermediate monocytes and non classical patrolling monocytes.
  • the present invention relates to a method for predicting the responsiveness of a patient to a treatment with an IL-6 antagonist, said method comprising measuring in a blood sample obtained from said patient the level of at least one subpopulation of blood monocytes selected from the group consisting of classical monocytes, intermediate monocytes and non classical patrolling monocytes.
  • the term "IL-6 antagonist” refers to any compound that prevents, inhibits, or lessens the effect(s) of IL-6 signalling.
  • the IL-6 antagonist according to the invention is an anti-IL-6 antibody or an anti-IL-6 receptor antibody.
  • An "anti-IL-6 antibody” is an antibody that specifically binds an IL-6 polypeptide.
  • An “anti-IL-6-receptor antibody” is an antibody that specifically binds the extracellular domain of an IL-6 receptor polypeptide.
  • the IL-6 antagonist according to the invention is tocilizumab.
  • patient refers to any subject (preferably human) afflicted with a disease likely to benefit from a treatment with an IL-6 antagonist.
  • the method of the invention is particularly useful to predict the response to a treatment by a IL-6 antagonist, preferably tocilizumab, in a patient affected with rheumatoid arthritis.
  • a IL-6 antagonist preferably tocilizumab
  • the rheumatoid arthritis can be moderate or active.
  • 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 a clinically significant relief in the disease when treated with the IL-6 antagonist.
  • a preferred responder group of patients that provides for the control values is a group that shows a decrease of DAS28 >1.2 after three months of treatment with the IL-6 antagonist, preferably tocilizumab.
  • the method is performed before the treatment of the patient with the IL-6 antagonist.
  • the blood sample is a serum sample. More preferably, the blood sample is a sample obtained from the blood of the patient that contains the non-adherent cell fraction, and more preferably the monocyte fraction.
  • blood monocyte has its general meaning in the art and refers to a large mononuclear phagocyte of the peripheral blood. Monocytes vary considerably, ranging in size from 10 to 30 ⁇ in diameter.
  • the nucleus to cytoplasm ratio ranges from 2: 1 to 1 : 1.
  • the nucleus is often band shaped (horseshoe), or reniform (kindey-shaped). It may fold over on top of itself, thus showing brainlike convolutions. No nucleoli are visible.
  • the chromatin pattern is fine, and arranged in skein-like strands. The cytoplasm is abundant and appears blue gray with many fine azurophilic granules, giving a ground glass appearance in Giemsa staining.
  • human blood monocytes can be distinguished from other blood cell types by the expression of specific surface markers.
  • Human blood monocyte are contained within CD115+ cells or DR+ cells that do not express B cell (CD 19-), T cell (CD2-), NK cell (NKp46-) or granulocyte marker (CD 15-).
  • the main surface markers of human monocyte cells are therefore: CDl lb, CDl lc, CD33 and CD115.
  • monocyte cells Upon contact with sensitive target cells, monocyte cells also produce a number of cytokines, including IFNs, TNF, GM-CSF, G-CSF, M-CSF, and IL-1.
  • Human blood monocytes can be divided in three subpopulations: classical monocytes, intermediate monocytes and non classical patrolling monocytes (Cros J, Cagnard N, Woollard K, Patey N, Zhang SY, Senechal B, Puel A, Biswas SK, Moshous D, Picard C, Jais JP, D'Cruz D, Casanova JL, Trouillet C, Geissmann F. Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity. 2010 Sep 24;33(3):375-86. Epub 2010 Sep 9.).
  • classical monocytes has its general meaning in the art and refers to by the CD 14+ blood monocytes subpopulation that can include a subpopulation of cells with higher expression of CD 16 and HLA-DR corresponding to activated monocytes.
  • classical monocytes are CD14 ++ CD16 CD33 ++ HLA-DR + monocytes with a subpopulation CD 16 + HLA-DR high .
  • intermediate monocytes has its general meaning in the art and refers to the CD14+ blood monocytes subpopulation having a higher expression of CD 16+ than the classical monocytes.
  • intermediate monocytes are CD14 ++ CD16 ++ monocytes.
  • non classical patrolling monocytes has its general meaning in the art and refers to subpopulation of monocytes with a lower expression of CD 14.
  • non classical patrolling monocytes are CD 14 dim CD 16 ++ HLA-DR +++ .
  • said subpopulation of monocytes may be easily isolated and quantified in the blood sample obtained from the patient by detecting the presence of specific surface markers ("positive selection") and/or by detecting the absence of specific surface markers ("negative selection”).
  • Specific surface markers e.g. monocyte surface
  • negative selection Standard methods for detecting the presence or absence of specific surface marker at cell surface (e.g. monocyte surface) are well known in the art.
  • cells of the blood sample are contacting with a set of binding partners specific for surface markers.
  • binding partner directed against a surface marker refers to any molecule (natural or not) that is able to bind said surface marker with high affinity.
  • the binding partners may be antibodies that may be polyclonal or monoclonal, preferably monoclonal. In another embodiment, the binding partners may be a set of aptamers.
  • Polyclonal antibodies of the invention or a fragment thereof can be raised according to known methods by administering the appropriate antigen or epitope to a host animal selected, e.g., from pigs, cows, horses, rabbits, goats, sheep, and mice, among others.
  • Various adjuvants known in the art can be used to enhance antibody production.
  • antibodies useful in practicing the invention can be polyclonal, monoclonal antibodies are preferred.
  • Monoclonal antibodies of the invention or a fragment thereof can be prepared and isolated using any technique that provides for the production of antibody molecules by continuous cell lines in culture. Techniques for production and isolation include but are not limited to the hybridoma technique originally; the human B-cell hybridoma technique; and the EBV- hybridoma technique.
  • the binding partners may be aptamers.
  • Aptamers are a class of molecule that represents an alternative to antibodies in term 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, as described in Tuerk C. 1997.
  • the random sequence library is obtainable by combinatorial chemical synthesis of DNA. In this library, each member is a linear oligomer, eventually chemically modified, of a unique sequence. Possible modifications, uses and advantages of this class of molecules have been reviewed in Jayasena S.D., 1999.
  • Peptide aptamers consist of conformationally constrained antibody variable regions displayed by a platform protein, such as E. coli Thioredoxin A that are selected from combinatorial libraries by two hybrid methods.
  • binding partners of the invention such as antibodies or aptamers may be labelled with a detectable molecule or substance, such as preferentially a fluorescent molecule, or a radioactive molecule or any others labels known in the art.
  • Labels are known in the art that generally provide (either directly or indirectly) a signal.
  • the term "labelled", with regard to the antibody or aptamer, is intended to encompass direct labelling of the antibody or aptamer by coupling (i.e., physically linking) a detectable substance, such as a fluorophore [e.g. fluorescein isothiocyanate (FITC) or phycoerythrin (PE) or Indocyanine (Cy5)]) or a radioactive agent to the antibody or aptamer, as well as indirect labelling of the probe or antibody by reactivity with a detectable substance.
  • FITC fluorescein isothiocyanate
  • PE phycoerythrin
  • Indocyanine Cy5
  • An antibody or aptamer of the invention may be labelled with a radioactive molecule by any method known in the art.
  • radioactive molecules include but are not limited radioactive atom for scintigraphic studies such as 1123, 1124, Inl 11, Rel86, Rel88.
  • the antibodies against a surface marker are already conjugated to a fluorophore (e.g. FITC-conjugated and/or PE-conjugated).
  • a fluorophore e.g. FITC-conjugated and/or PE-conjugated.
  • the aforementioned assays may involve the binding of the binding partners (ie. antibodies or aptamers) to a solid surface.
  • the solid surfaces may be beads, such as activated beads, magnetically responsive beads.
  • Beads may be made of different materials, including but not limited to glass, plastic, polystyrene, and acrylic.
  • the beads are preferably fluorescently labelled.
  • fluorescent beads are those contained in TruCount(TM) tubes, available from Becton Dickinson Biosciences, (San Jose, California).
  • methods of flow cytometry are preferred methods for isolating and quantifying the subpopulation of monocytes in the blood sample.
  • Said methods are well known in the art.
  • fluorescence activated cell sorting FACS
  • a FACS method such as described in Example here below may be used.
  • the level a subpopulation of monocytes could be expressed in percentage of the total population of monocytes contained in the blood sample of the patient.
  • the levels of the three subopopulation of monocytes are determined in the blood sample obtained from the patient.
  • the method of the invention may further comprise a step of comparing the level of the subpopulation of monocytes with reference values obtained from responder and non- responder group of patients, wherein detecting differential in the level between the biological sample and the reference values is indicative whether the patient will be a responder or not to the treatment with the IL-6 antagonist.
  • a lower level of classical monocytes, associated with higher levels for intermediate monocytes and non classical patrolling monocytes are indicative that the patient will not respond to the treatment.
  • the patients may be prescribed with said IL-6 antagonist.
  • kits for performing the methods the present invention comprising means for measuring the level of the subpopulation of monocytes.
  • the kit may include a set of binding partners as above described. In a particular embodiment, the binding partners are labelled as above described.
  • the kit may also contain other suitably packaged reagents and materials needed for the particular detection protocol, including solid supports, if applicable, and standards.
  • FIGURES are a diagrammatic representation of FIGURES.
  • Figure 1 shows the DAS of the patients (responders and non responders)
  • Figure 2 shows the CRP of the patients (responders and non responders)
  • Figure 3 shows the 3 subpopulations of monocytes
  • Figure 4 shows the monitoring of the monitoring of the three subpopulations of monocytes
  • Patients 19 patients with severe and active Rheumatoid Arthritis fulfilling the revised criteria from ACR, refractory to methotrexate or anti-TNF therapies were recruited. Patients are 20 to 80 years old with only 3 male include in the study. The presence of at least one susceptible allele (HLA-DRB1 *01 or DRB1 *04) is 84% in the non responders versus 73% in the responders. Patients were treated with 8mg/kg of tocilizumab monthly. Peripheral blood was recovered for each patient at day 0, as well as 1 and 3 month after informed consents. Patients were classified in 2 groups according to the clinical response
  • the antibodies used for the staining of monocytes are the following: FITC-conjugated CD64, PE-conjugated CD33, PE-conjugated CD314, PerCP-Cy5.5- conjugated HLA-DR, PE-Cy7-conjugated CD56, PE-Cy7-conjugated CD14, CD32 APC- conjugated CD32, APC-H7 conjugated CD4, APC-H7 conjugated CD 16, V450-conjugated CD3 and V500-conjugated CD45. Staining was performed on whole blood. The data were acquired on a FACS Canto II (3 fixed alignment lasers, 405,488 and 635 nm) and analyzed using DIVA software.
  • the viable population was gated according to FSC and SSC, excluding the doublets.
  • the monocytes were gated based on the SSC and CD45 staining.
  • the 3 populations of monocytes were defined according to the intensities of CD 14 and CD 16 staining ( Figure 3):
  • a third population with a lower expression of CD 14 called the Non-classical patrolling monocytes.

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Abstract

La présente invention concerne un procédé permettant de prédire l'aptitude d'un patient à répondre à un traitement à base d'antagoniste d'IL-6. Ce procédé implique de mesurer, dans un échantillon de sang prélevé chez ledit patient, le niveau d'au moins une sous-population de monocytes à choisir dans le groupe comprenant les monocytes classiques, les monocytes intermédiaires, et les monocytes patrouilleurs non classiques.
PCT/EP2012/069279 2011-09-30 2012-09-28 Procédé pour prédire l'aptitude d'un patient à répondre à un traitement à base d'antagoniste d'il-6 Ceased WO2013045672A1 (fr)

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US201161541158P 2011-09-30 2011-09-30
US61/541,158 2011-09-30

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019053244A1 (fr) * 2017-09-15 2019-03-21 Universität Zürich Biomarqueurs pour la thérapie par inhibiteur de point de contrôle de sensibilité

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008156867A1 (fr) * 2007-06-21 2008-12-24 The Board Of Trustees Of The Leland Stanford Junior University Marqueurs biologiques pour le diagnostic d'une maladie auto-immune
WO2011154139A2 (fr) * 2010-06-07 2011-12-15 Roche Diagnostics Gmbh Marqueurs d'expression génique pour la prédiction d'une réponse à un traitement par un médicament anticorps monoclonal inhibant le récepteur de l'interleukine-6
WO2012041332A2 (fr) * 2010-10-01 2012-04-05 Rigshospitalet Variations génétiques du gène du récepteur d'interleukine-6 permettant de prédire la réponse de patients au traitement basé sur des inhibiteurs dudit récepteur d'interleukine-6

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008156867A1 (fr) * 2007-06-21 2008-12-24 The Board Of Trustees Of The Leland Stanford Junior University Marqueurs biologiques pour le diagnostic d'une maladie auto-immune
WO2011154139A2 (fr) * 2010-06-07 2011-12-15 Roche Diagnostics Gmbh Marqueurs d'expression génique pour la prédiction d'une réponse à un traitement par un médicament anticorps monoclonal inhibant le récepteur de l'interleukine-6
WO2012041332A2 (fr) * 2010-10-01 2012-04-05 Rigshospitalet Variations génétiques du gène du récepteur d'interleukine-6 permettant de prédire la réponse de patients au traitement basé sur des inhibiteurs dudit récepteur d'interleukine-6

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
CHOY ET AL., N. ENGL. J. MED., vol. 344, 2001, pages 907 - 16
CROS J; CAGNARD N; WOOLLARD K; PATEY N; ZHANG SY; SENECHAL B; PUEL A; BISWAS SK; MOSHOUS D; PICARD C: "Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors", IMMUNITY, vol. 33, no. 3, 9 September 2010 (2010-09-09), pages 375 - 86
KAMISHIMA TAMOTSU ET AL: "Monitoring anti-interleukin 6 receptor antibody treatment for rheumatoid arthritis by quantitative magnetic resonance imaging of the hand and power Doppler ultrasonography of the finger.", SKELETAL RADIOLOGY JUN 2011, vol. 40, no. 6, June 2011 (2011-06-01), pages 745 - 755, XP002687177, ISSN: 1432-2161 *
KAWADA Y ET AL: "Predicting effectiveness of anti-interleukin-6 receptor antibody e.g. tocilizumab against rheumatism and other IL-6 associated diseases e.g. cachexia, involves measuring expression level of specific human gene or its complement", WPI / THOMSON,, vol. 2009, no. 47, 30 April 2009 (2009-04-30), XP002661658 *
SMOLEN ET AL., LANCET, vol. 371, 2008, pages 987 - 97
TAMER ET AL., NAT. CLIN. PRACT. RHEUMATOL., vol. 3, 2007, pages 336 - 45
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", ARTHRITIS RHEUM, vol. 39, 1996, pages 34 - 40

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019053244A1 (fr) * 2017-09-15 2019-03-21 Universität Zürich Biomarqueurs pour la thérapie par inhibiteur de point de contrôle de sensibilité

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