WO2013162458A1 - Utilisation de ro52 comme marqueur prédictif pour l'évolution d'une tumeur immuno-dérivée - Google Patents

Utilisation de ro52 comme marqueur prédictif pour l'évolution d'une tumeur immuno-dérivée Download PDF

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Publication number
WO2013162458A1
WO2013162458A1 PCT/SE2013/050454 SE2013050454W WO2013162458A1 WO 2013162458 A1 WO2013162458 A1 WO 2013162458A1 SE 2013050454 W SE2013050454 W SE 2013050454W WO 2013162458 A1 WO2013162458 A1 WO 2013162458A1
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expression
patient
set value
lymphoma
derived tumor
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PCT/SE2013/050454
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English (en)
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Marie WAHREN HERLENIUS
Susanna BRAUNER
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Wahren Herlenius Marie
Brauner Susanna
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    • 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
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention relates generally to immune derived tumors. More specifically, the invention relates to prognostic factors of survival of patients with hematopoetic cell derived tumors, preferentially lymphoid tumors including, but not limited to, lymphoma, leukemia and myeloma.
  • Diffuse Large B-cell lymphoma (DLBCL) is the most common form of adult lymphoma, accounting for approximately 30% of all non-Hodgkin lymphoma cases.
  • the annual incidence in the US is 25,000 persons, and has increased during the last decades.
  • the prognosis is highly variable, indicating heterogenic features of the disease.
  • progress has been made in sub-classification of diffuse large B-cell lymphomas. Alizadeh and colleagues (Alizadeh, et al.
  • a primary objective of the present invention is to use Ro52 as a prognostic marker for immune derived tumor outcome.
  • An objective of the present invention is to use monoclonal antibodies binding different epitopes of Ro52 to measure the expression of Ro52 in immune derived tumors.
  • An objective of the present invention is to use the expression levels of Ro52 for identifying patients who are likely to benefit from IFN-alpha treatment.
  • the present invention provides a method for obtaining prognostic information of a patient, determined to have an immune derived tumor, comprising analysing the expression of Ro52 in a sample from said patient, where expression of Ro52 above or below a set value indicates a patient's survival prognosis.
  • an expression of Ro52 at or below a set value indicates a shorter overall survival than expression of Ro52 above said set value.
  • the present invention provides a method for identifying whether a patient, determined to have an immune derived tumor, will benefit from IFN-alpha treatment, comprising analysing the expression of Ro52 in a sample from said patient, where expression of Ro52 below a set value indicates that the patient will benefit from the IFN-alpha treatment.
  • the sample from said patient is a biopsy and said set value is defined by immunohistochemistry as a certain percentage or a certain level of stained sections of the immune derived tumor.
  • the set value is 30-50 %, more preferably about 40%, or level 1 on a scale ranging from 0 to 3, where 0 indicates no expression and 3 indicates strong expression.
  • the immune derived tumor is selected from a group comprising a diffuse large B-cell lymphoma (DLBCL), MALT lymphoma, Burkitt lymphoma, nodular Hodgkin's lymphoma, Hodgkin's lymphoma, T cell lymphoma, Mantle cell lymphoma, immunocytoma and chronic
  • CLL lymphocytic leukemia
  • the set value is defined by flow cytometry.
  • the set value is defined by PCR.
  • the expression is measured using monoclonal antibodies binding to Ro52.
  • the monoclonal antibodies are selected from the group comprising the clones 7.8C7, 7.12E11, 7.5F5, 7.3D10, 7.9D3, 7.2H4, 7.8H4, 7.1F2, 7.2F4, 7.3E2 and 7.7F9.
  • the present invention provides a use of monoclonal antibodies binding to Ro52 by analysing the expression of Ro52 in a sample from a patient, for obtaining prognostic information of a patient, determined to have an immune derived tumor, where expression of Ro52 above or below a set value indicates a patient's survival prognosis.
  • the present invention provides a use of monoclonal antibodies binding to Ro52 for analysing the expression of Ro52 in a sample from a patient, for identifying whether a patient, determined to have an immune derived tumor, will benefit from IFN-alpha treatment, where expression of Ro52 below a set value indicates that the patient will benefit from the IFN-alpha treatment.
  • the monoclonal antibodies binding to Ro52 are selected from the group comprising the clones 7.8C7, 7.12E11, 7.5F5, 7.3D10, 7.9D3, 7.2H4, 7.8H4, 7.1F2, 7.2F4, 7.3E2 and 7.7F9.
  • the present invention provides a kit for obtaining prognostic information of a patient, determined to have an immune derived tumor, comprising monoclonal antibodies binding to Ro52, for analysing the expression of Ro52, and written instructions for comparing the analysed expression of Ro52 to a set value of Ro52 expression, which is correlated to the patient's survival prognosis and/or benefit from IFN-alpha treatment.
  • the set value is 30-50 %, more preferably about 40%, or level 1 on a scale ranging from 0 to 3, where 0 indicates no expression and 3 indicates strong expression.
  • Figure 1 is a graph showing the correlation between the expression of
  • scoring used is a computerized scoring, based on computer-assisted image
  • Figure 2 is a graph showing the correlation between the expression of
  • scoring used is a manual scoring with a scale ranging from 0 to 3, where 0
  • Figure 3 shows pictures of stained lymphoma biopsies scored according to the manual scoring system.
  • Figure 4 shows the correlation between manual and computerized score.
  • Figure 5 is a graph showing that there is no correlation between
  • Figure 6 (a)-(h) include eight graphs showing the correlation between
  • CLL lymphocytic leukemia
  • Ro52 (TRIM21) was first described as an autoantigen in rheumatic diseases.
  • the intracellular Ro52 protein is mainly expressed in cells of hematopoietic origin, and has been shown to be a RING-dependent E3 ligase involved in ubiquitination.
  • the Ro52 gene is located in a locus with suggested tumor suppressor activity on the short arm of chromosome 11 (l lpl5.5).
  • immune derived tumor tissue is a highly prognostic marker for both overall survival and progression- free survival in immune derived tumors, which are tumors derived from any hematopoietic cells, including but not limited to lymphoma, leukemia and myeloma, such as for example diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma, Follicular B cell lymphoma, Hodgkin lymphoma, Nodular Hodgkin lymphoma, Immunocytoma, Chronic lymphocytic leukemia (CLL), Mucosa associated lymphoid tissue (MALT) lymphoma, Mantle cell lymphoma, undifferentiated B cell lymphoma, plasmacytoma, Peripheral T cell lymphoma, multiple myeloma, as well as glial cell tumors.
  • lymphoma leukemia and myeloma
  • LLBCL diffuse large B-cell lymphoma
  • Ro52 expression levels have not previously been associated with prediction of survival in immune derived tumor development.
  • the prognostic outcome of this marker is independent of Ann Arbor and international prognostic index (IPI) classification as well as germinal center formation. Therefore, the analysis of Ro52 expression gives an added value in prognostic considerations in immune derived tumor diagnostic procedures.
  • IPI Ann Arbor and international prognostic index
  • the inventors have found out that there is a highly significant correlation of Ro52 expression in immune derived tumors and survival, following a previously unknown relationship where expression over or below a certain set value indicates the outcome of the tumor.
  • Type 1 and 2 interferons upregulate Ro52 expression
  • treatment with type 1 interferon (IFN-alpha) is a second-line consideration for therapy in specific lymphoma subsets.
  • Patients with Ro52 expression below the set value in their tumors, are individuals that will benefit the most from IFN-alpha treatment, since IFN-alpha may re-establish Ro52 expression and the control of proliferation and apoptosis.
  • a biomarker for selecting patients for IFN-alpha treatment is important not only to pinpoint patients that would benefit the most from the treatment, but also to avoid treatment of other patients especially considering the adverse effects of the drug.
  • a manual scoring system based on visual analysis of samples from patients
  • a computerized scoring system based on computer-assisted image analysis of samples from patients.
  • the option of using a manual scoring system may be a useful alternative in a clinical setting since not all clinics have access to an image analyser.
  • the scoring value is defined as a percentage of area stained.
  • stained sections obtained from the immune derived tumor, or a biopsy from an immune derived tumor are analysed visually and the estimated percentage of area stained is used as the scoring value.
  • stained sections may be scored by using a scale, ranging for example from 0 to 3, where 0 indicates no expression of Ro52 and 3 indicates strong expression of Ro52.
  • a scale ranging for example from 0 to 3, where 0 indicates no expression of Ro52 and 3 indicates strong expression of Ro52.
  • level 0 corresponds to a low percentage of area stained, e.g. 0-25 %
  • level 1 corresponds to a somewhat higher percentage of area stained, e.g. 25-50 %
  • level 2 corresponds to an even higher percentage of area stained, e.g. 50-75 %
  • level 3 corresponds to the highest percentage of area stained, e.g. 75-100 %.
  • Figure 3 shows pictures of stained lymphoma biopsies scored according to the manual system.
  • the inventors have used Cox-regression analysis and ROC curves to define set values that are used to divide patients into groups below or above the set value. These patient groups have different prognosis in terms of survival. Patients in which Ro52 expression in the tumor is below the set value have a poor prognosis, while patients in which Ro52 expression in the tumour is above the set value have a good prognosis.
  • patients are divided into expression groups, below or above the set value. These certain expression levels are highly prognostic markers for survival of immune derived tumor patients.
  • the set value or set expression level is defined as about 30-50 %, more preferably about 40 %, of area stained, according to either the computerized scoring system or the manual scoring system, or level 1 or less according to the manual scoring system, .
  • level 1 corresponds to about 30-50 %, more preferably about 40 %, of area stained.
  • the specific expression level is important when using Ro52 as a predictive biomarker for immune derived tumor outcome.
  • This invention shows for the first time that a specific level of expression of Ro52 in immune derived tumor tissue is a highly prognostic marker for both overall survival and progression-free survival in immune derived tumors. Further, we show that the prognostic outcome of this marker is independent of Ann Arbor and IPI classification as well as germinal center formation, suggesting that analysis of Ro52 expression gives an added value to current tools in prognostic considerations in immune derived tumor diagnostic procedures.
  • the present invention relates to the use of monoclonal antibodies, prepared as known in the art (see for example Strandberg et al. Interferon-alpha induces up-regulation and nuclear translocation of the Ro52 autoantigen as detected by a panel of novel Ro52- specific monoclonal antibodies. J Clin Immunol 2008 May 28(3): 220-31) binding different epitopes of Ro52 and their use to measure the expression of Ro52, including, but not limited to, clones 7.8C7, 7.12E11, 7.5F5, 7.3D10, 7.9D3, 7.2H4, 7.8H4, 7.1F2, 7.2F4, 7.3E2 and 7.7F9.
  • Ro52 may be analysed according to methods known in the art.
  • the Ro52 monoclonal antibodies can be used to visualize Ro52 protein expression in fixed, sectioned tissue (immunohistochemistry), or in flow cytometry of single cells.
  • Ro52 expression can also be measured at the mRNA level in polymerase chain reaction (PCR).
  • Lymphoma and leukemia biopsies were re-assessed and classified by the 2001 WHO classification (IARC Press 2001). Patients fulfilling diagnosis of a rheumatic disease and lymphoma and where a sufficient biopsy and clinical data could be obtained were included in the present study. In total 127 patients with RA or SLE and DLBCL were included. In addition, 74 patients with DLBCL without any concomitant inflammatory disease diagnosed at the Department of Pathology at Uppsala University Hospital between 1984
  • lymphoma nodular Hodgkin's lymphoma, Hodgkin's lymphoma, T cell
  • lymphoma Mantle cell lymphoma, immunocytoma or chronic lymphocytic
  • CLL leukemia
  • Tissue microarray blocks were constructed as previously described (Lofstrom, J
  • Sections were analyzed in a Polyvar II light microscope (Rei chert- Jung, Vienna, Austria) using a xlO magnification. Semi-quantitative scoring was performed in a blinded manner by two independent investigators, using a score with a scale ranging from 0, indicating no expression, to 3, indicating strong expression, with 1 and 2 indicating intermediate steps in between. The mean value of the two core biopsies was used for analysis. Further, computer-assisted image analysis of whole core biopsies was performed using the Quantimet 600 image analyzer (Leica) in which the stained area divided by total area is calculated. The specific set value was 40% or >1 if using the manual score based on ROC curve analysis and sections having ⁇ 40% of area stained or 0-1 when using the manual score were considered to have an expression below the set value.
  • Single cell suspensions were prepared from peripheral blood and cells blocked in Fc blockTM (BD Biosciences) for 30 min before staining by fluorophore-conjugated antibodies.
  • Fc blockTM BD Biosciences
  • For intracellular Ro52 staining cells were first stained for surface lymphoid cell markers followed by fixation and permeabilization and subsequent intracellular Ro52 staining. Cells were analyzed on a flow cytometer.
  • AAACC ATGT AGTTG-3 ' AAACC ATGT AGTTG-3 ' .
  • ROC curves are first constructed and the chosen value verified by Cox-regression analysis.
  • the cut off of 40% and 1 respectively were confirmed further by performing a proportional hazards regression (Cox regression) (p ⁇ 0.0001). Mann- Whitney U tests was used when comparing two groups. Correlation was analyzed using logistic regression. Survival was calculated using the Kaplan-Meier method. P-values less than 0.05 were considered significant.
  • Prism graph pad 5 was used for all statistical analyses, except for the Cox regressions, which were calculated using R version 2.14.0.
  • Sections of lymphoma biopsies were stained with two anti-Ro52 antibodies (clones 7.8C7 and 7.12E11) binding different epitopes of the protein.
  • the antibodies yielded similar results (data not shown), confirming that the staining was specific for Ro52 and no or low cross-reactivity to other proteins.
  • the overall survival (OS) in patients with Ro52-expressing DLBCL lymphomas below the set value is significantly shorter than to those expressing above this level.
  • Median survival in the group with expression below the set value was 8 months and 21 months in the group with expression above the set value respectively (p ⁇ 0.0001), Figure la.
  • Median PFS was 1 month and 34 months in the groups below and above the set value for Ro52 expression in lymphomas respectively ( Figure lb).
  • MALT lymphoma Burkitt lymphoma, nodular Hodgkin's lymphoma, Hodgkin's lymphoma, T cell lymphoma, Mantle cell lymphoma, immunocytoma and chronic lymphocytic leukemia (CLL) are examplified in Figure 6.
  • DLBCL are commonly classified into germinal center positive and negative, with longer OS observed in GC positive lymphomas (Alizadeh, Nature, 2000).
  • OS remains similar when stratified by GC status.
  • Ro52 is a survival marker independent of GC status and both Ann Arbor and IPI staging.

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Abstract

La présente invention concerne des facteurs de pronostic de survie de patients souffrant de tumeurs dérivées des cellules hématopoïétiques, préférentiellement de tumeurs lymphoïdes, y compris mais de manière non exhaustive le lymphome, la leucémie et le myélome. La présente invention concerne un procédé permettant d'obtenir des informations de pronostic sur un patient présentant une tumeur immuno-dérivée, et comprenant l'analyse de l'expression de Ro52, sachant qu'une expression de Ro52 au-dessus ou au-dessous d'une valeur fixée spécifique indique un pronostic de survie du patient.
PCT/SE2013/050454 2012-04-24 2013-04-24 Utilisation de ro52 comme marqueur prédictif pour l'évolution d'une tumeur immuno-dérivée WO2013162458A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012012693A2 (fr) * 2010-07-23 2012-01-26 President And Fellows Of Harvard College Procédés de détection de signatures de maladies ou pathologies dans des liquides biologiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012012693A2 (fr) * 2010-07-23 2012-01-26 President And Fellows Of Harvard College Procédés de détection de signatures de maladies ou pathologies dans des liquides biologiques

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ISABELLE, M.: "Short-term and long-term outcome of anti-Jo1- positive patients with anti-Ro52 antibody", SEMINARS IN ARTHRITIS AND RHEUMATISM, vol. 41, no. 6, June 2012 (2012-06-01), pages 890 - 899 *
KUBOSHIMA, M. ET AL.: "Presence of serum tripartite motif- containing 21 antibodies in patients with esophageal squamous cell carcinoma", CANCER SCIENCE, vol. 97, no. 5, March 2006 (2006-03-01), pages 380 - 386 *
LYONS, R. ET AL.: "Marginal Zone lymphoma with autoantibodies to Ro52 in Sjogrens Syndrome", CLINICAL IMMUNOLOGY, vol. 115, 2005, pages S3 - S282 *
STRANDBERG L ET AL.: "Interferon-alpha induces up-regulation and nuclear translocation of the Ro52 autoantigen as detected by a panel of novel Ro52-specific monoclonal antibodies", J CLIN IMMUNOL., vol. 28, no. 3, May 2008 (2008-05-01), pages 220 - 31 *

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