US20150160226A1 - Method, reagents, and kits for detecting minimal residual disease - Google Patents

Method, reagents, and kits for detecting minimal residual disease Download PDF

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US20150160226A1
US20150160226A1 US14/407,268 US201314407268A US2015160226A1 US 20150160226 A1 US20150160226 A1 US 20150160226A1 US 201314407268 A US201314407268 A US 201314407268A US 2015160226 A1 US2015160226 A1 US 2015160226A1
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antibodies
markers
cells
conjugated
reagent composition
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Jacobus Johannes Maria van Dongen
Jose Alberto Orfao De Matos Correia E Vale
Juan Alejandro Flores Montero
Julia Maria Almeida Parra
Vincent Henricus Johnnes Van der Velden
Sebastian Bottcher
Anthonie Willem Langerak
Ester Mejstrikova
Tomasz Szczepanski
Matthias Ritgen
Paulo Jorge Monteiro Da Silva Lucio
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Erasmus University Medical Center
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Priority to US14/407,268 priority Critical patent/US20150160226A1/en
Assigned to ERASMUS UNIVERSITY MEDICAL CENTER ROTTERDAM reassignment ERASMUS UNIVERSITY MEDICAL CENTER ROTTERDAM ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MEJSTRIKOVA, ESTER, RITGEN, Matthias, BOTTCHER, SEBASTIAN, VAN DER VELDEN, VINCENT HENRICUS JOHANNES, PARRA, JULIA MARIA ALMEIDA, Szczepanski, Tomasz, DA SILVA LUCIO, PAULO JORGE MONTEIRO, E VALE, JOSE ALBERTO ORFAO DE MATOS CORREIA, LANGERAK, ANTHONIE WILLEM, MONTERO, JUAN ALEJANDRO FLORES, VAN DONGEN, JACOBUS JOHANNES MARIA
Assigned to ERASMUS UNIVERSITY MEDICAL CENTER ROTTERDAM reassignment ERASMUS UNIVERSITY MEDICAL CENTER ROTTERDAM CORRECTIVE ASSIGNMENT TO CORRECT THE INVENTORS' NAMES PREVIOUSLY RECORDED AT REEL: 035606 FRAME: 0212. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Assignors: MEJSTRIKOVA, ESTER, RITGEN, Matthias, BOTTCHER, SEBASTIAN, VAN DER VELDEN, VINCENT HENRICUS JOHANNES, Almeida Parra, Julia Maria, Szczepanski, Tomasz, FLORES MONTERO, Juan Alejandro, LANGERAK, ANTHONIE WILLEM, Monteiro Da Silva Lucio, Paulo Jorge, ORFAO DE MATOS CORREIA E VALE, JOSE ALBERTO, VAN DONGEN, JACOBUS JOHANNES MARIA
Publication of US20150160226A1 publication Critical patent/US20150160226A1/en
Priority to US15/812,384 priority patent/US10874710B2/en
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    • G01N33/57484—
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A61K38/1716—Amyloid plaque core protein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/025—Enterobacteriales, e.g. Enterobacter
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/09—Lactobacillales, e.g. aerococcus, enterococcus, lactobacillus, lactococcus, streptococcus
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/14—Optical investigation techniques, e.g. flow cytometry
    • 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
    • G01N33/575—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57505—Immunoassay; Biospecific binding assay; Materials therefor for cancer of the blood, e.g. leukaemia
    • 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
    • G01N33/575—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/5758—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N2015/1006—Investigating individual particles for cytology

Definitions

  • the invention relates to the field of cancer diagnosis, more specifically to means and method for the monitoring of disease development during and after treatment or for the detection of minimal disseminated disease.
  • Cytostatic or cytotoxic treatment induces remission in the majority of patients with lymphoid malignancies. Nevertheless many of these patients relapse.
  • the current cytostatic or cytotoxic treatment protocols are not capable of killing all malignant cells in these relapsing patients, although they reached so-called complete remission according to cytomorphological criteria. Since the detection limit of cytomorphological techniques is not lower than 1-5% malignant cells, it is obvious that such techniques can only provide superficial information about the effectiveness of treatment, up to 10 10 tumor cells still potentially remaining in the body
  • MRD minimal residual disease
  • this new approach is not anymore limited to individual patients, but is applicable to every patient of a specific disease category, such B-cell precursor acute lymphoblastic leukemia (BCP-ALL), B-cell chronic lymphocytic leukemia (B-CLL) and multiple myeloma (MM).
  • BCP-ALL B-cell precursor acute lymphoblastic leukemia
  • B-CLL B-cell chronic lymphocytic leukemia
  • MM multiple myeloma
  • One or two ⁇ 8-color combinations per patient will allow careful MRD monitoring with sensitivities of at least 10 ⁇ 4 .
  • the provided 10-color and 12-color antibody combinations can even better discriminate between normal cells and their malignant counterparts, thereby allowing for MRD detection with sensitivities down to 10 ⁇ 5 .
  • BCP-ALL B-cell precursor acute lymphoblastic leukemia
  • B-cell chronic lymphocytic leukemia B-CLL
  • MM multiple myeloma
  • PCD plasma cell disorders
  • the invention provides unique reagent compositions for flow cytometric detection of MRD, comprising a combination of at least eight distinct fluorochrome-conjugated antibodies.
  • the reagent compositions are of use for detecting MRD in patients with BCP-ALL, B-CLL or MM/PCD.
  • the composition comprises monoclonal antibodies against a given CD antigen.
  • CD stands for cluster designation and is a nomenclature for the identification of specific cell surface antigens or intracellular antigens defined by monoclonal antibodies.
  • the invention provides a reagent composition for flow cytometric detection of BCP-ALL cells in a human subject, comprising a panel of at least eight distinct fluorochrome-conjugated antibodies.
  • the BCP-ALL panel comprises antibodies against the four “core markers” CD10, CD19, CD20, CD34 and CD45.
  • the panel further comprises one or more antibodies selected from the group of antibodies against CD38, CD81, CyIg ⁇ , and deoxynucleotidyl transferase (NuTdT).
  • the panel further comprises one or more sets of antibodies selected from (a) set of antibodies against CD66c and CD123; (b) set of antibodies against CD304 and CD73; and (c) set of antibodies against SmIg ⁇ and SmIg ⁇ , wherein the antibodies within each set are conjugated to the same fluorochrome.
  • the BCP-ALL panel comprises antibodies against CD 10, CD 19, CD20, CD34, CD45, one or more antibodies selected from the group of antibodies against CD38, CD81, CyIg ⁇ , NuTdT, and two or more sets of antibodies selected from (a) set of antibodies against CD66c and CD123; (b) set of antibodies against CD304 and CD73; and (c) set of antibodies against SmIg ⁇ and SmIg ⁇ , wherein the antibodies within each set are conjugated to the same fluorochrome.
  • a reagent composition comprises distinct fluorochrome-conjugated antibodies directed against one of the following combinations of markers:
  • it comprises distinct fluorochrome-conjugated antibodies directed against the markers CD20, CD45, CD81, NuTdT, CD34, CD19, CD10 and CD38, and one or more sets of antibodies selected from (a) set of antibodies against CD66c and CD123; (b) set of antibodies against CD304 and CD73; and (c) set of antibodies against SmIg ⁇ and SmIg ⁇ , wherein the antibodies within each set are conjugated to the same fluorochrome. See for instance the 10-color tube in Panel 1B comprising antibodies against the markers CD20, CD45, CD81, NuTdT, CD66c, CD123, CD304, CD73, CD34, CD19, CD10 and CD38.
  • the composition comprises a combination of fluorochrome-conjugated antibodies directed against the markers CD20, CD45, CD81, NuTdT, CD66c, CD123, CD304, CD73, SmIg ⁇ , SmIg ⁇ , CyIg ⁇ , CD34, CD19, CD10 and CD38, wherein the antibodies against each of the sets CD66c/CD123, CD304/CD73 and SmIg ⁇ /SmIg ⁇ are conjugated to the same fluorochrome. See for instance the 12-color tube in panel 1C.
  • Suitable fluorochromes for conjugating antibodies for use in the present invention against the recited markers are known in the art. As will be understood, the fluorochromes used within a reagent composition should be distinguishable from each other by flow cytometry. The fluorochromes are preferably selected for brightness, limited spectral overlap and limited need for compensation, stability, etc (see: Kalina et al. Leukemia 2012: 26: 1986-2010).
  • the following panel of fluorochromes is of particular use in a BCP-ALL reagent composition according to the invention: (1) pacific blue (PacB), brilliant violet 421 (BV421) or Horizon V450, (2) pacific orange (PacO), Horizon V500 (HV500), BV510, Khrome orange (KO) or OC515, (3) fluorescein isothiocyanate (FITC) or Alexa488, (4) phycoerythrin (PE), (5) peridinin chlorophyl protein/cyanine 5.5 (PerCP-Cy5.5), PerCP or PE-TexasRed, (6) phycoerythrin/cyanine7 (PE-Cy7), (7) allophycocyanine (APC) or Alexa647, and (8) allophycocyanine/hilite 7 (APC-H7), APC-Cy7, Alexa680, APC-A750, APC-C750 or Alexa700.
  • PacB pacific blue
  • the present inventors observed that very good results can be obtained if the following fluorochromes are chosen: Pacific Blue, brilliant violet 421 or Horizon V450, PacO or Horizon V500, FITC, PE, PerCP-Cy5.5, PE-Cy7, APC, and APC-H7 or APC-A750 or APC-C750.
  • the invention provides for a reagent composition shown in Table 1, panel 1A, panel 1B or panel 1C.
  • reagent compositions for MRD detection in BCP-ALL . . . Panel 1A Marker Composition of 8-color BCP-ALL MRD panels of the invention tube PacB PacO FITC PE PerCPCy5.5 PECy7 APC APCC750 1 CD20 CD45 CD81 CD66c and CD34 CD19 CD10 CD38 CD123 2 CD20 CD45 CD81 CD304 and CD34 CD19 CD10 CD38 CD73 2 CD20 CD45 NuTdT SmIg ⁇ and CyIg ⁇ CD19 CD34 CD10 SmIg ⁇ Panel 1B.
  • Marker Composition of 10-color BCP-ALL MRD panel of the invention F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 CD20 CD45 CD81 NuTdT CD66c and CD304 and CD34 CD19 CD10 CD38 CD123 CD73 Panel 1C.
  • Marker Composition of 12-color BCP-ALL MRD panel of the invention F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 CD20 CD45 CD81 NuTdT CD66c CD304 SmIg ⁇ CyIg ⁇ CD34 CD19 CD10 CD38 and and CD123 CD73 SmIg ⁇
  • the invention provides a reagent composition for flow cytometric detection of B-cell chronic lymphocytic leukemia (B-CLL) in a human subject, comprising a panel of at least eight distinct fluorochrome-conjugated antibodies, the panel comprising at least antibodies against the seven “core markers” CD5, CD27, CD79b, CD3, CD200, CD81 and CD19. It was found that CD22 and/or Receptor tyrosine kinase-like orphan receptor 1 (ROR1) can be used as valuable additional marker(s). Very good results were obtained in combination with the markers CD43 and CD38.
  • B-CLL B-cell chronic lymphocytic leukemia
  • Preferred marker combinations for detecting B-CLL are as follows:
  • the following panel of fluorochromes is of particular use in a CLL reagent composition according to the invention: (1) pacific blue (PacB), brilliant violet 421 (BV421) or Horizon V450, (2) pacific orange (PacO), Horizon V500 (HV500), BV510, Khrome orange (KO) or OC515, (3) fluorescein isothiocyanate (FITC) or Alexa488, (4) phycoerythrin (PE), (5) peridinin chlorophyl protein/cyanine 5.5 (PerCP-Cy5.5), PerCP or PE-TexasRed, (6) phycoerythrin/cyanine7 (PE-Cy7), (7) allophycocyanine (APC) or Alexa647, and (8) allophycocyanine/hilite 7 (APC-H7), APC-Cy7, Alexa680, APC-A750, APC-C750 or Alexa700.
  • PacB pacific blue
  • fluorochromes are chosen: Pacific Blue, brilliant violet 421 or Horizon V450, PacO or Horizon V500, FITC, PE, PerCP-Cy5.5, PE-Cy7, APC, and APC-H7 or APC-A750 or APC-C750.
  • the invention provides for a reagent composition shown in Table 2.
  • compositions for MRD detection in B-CLL Panel 2A Composition of 8-color CLL MRD panel BV421 BV510 FITC PE PerCPCy5.5 PECy7 APC APCC750 CD27 CD3 CD79b CD5 CD22 CD19 CD200 CD81 CD5 CD3 CD79b ROR1 CD27 CD19 CD200 CD81 Panel 2B. Composition of 10-color CLL MRD tube F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 CD27 CD3 CD79b ROR1 CD5 CD22 CD19 CD20 CD200 CD81 Panel 2C. Composition of 12-olor CLL MRD tube F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 CD27 CD3 CD79b ROR1 CD5 CD22 CD19 C20 CD200 CD43 CD81 CD38
  • MM/PCD Flow Cytometric MRD Detection in Multiple Myeloma/Plasma Cell Disease
  • a still further aspect of the invention relates to a reagent composition for detecting MM or PCD cells.
  • the panel comprises antibodies against the four “core markers” CD138, CD38, CD56 and CD19, supplemented with at least four additional markers selected from the group consisting of CD27, CD117, CD81, CD229, CD45, CyIg ⁇ and CyIg ⁇ .
  • CD45 is a preferred fifth marker, preferably in combination with CD27, CD 117 and CD81 or CD229, CyIg ⁇ and CyIg ⁇ .
  • reagent composition with distinct fluorochrome-conjugated antibodies against either one of the following panels of markers:
  • a reagent composition for flow cytometric detection of MM or PCD in a human subject comprising a panel of at least eight distinct fluorochrome-conjugated antibodies, the panel comprising at least antibodies against the core markers CD138, CD38, CD56 and CD19, supplemented with at least four additional markers selected from the group consisting of CD27, CD117, CD81, CD229, CD45, CyIg ⁇ and CyIg ⁇ .
  • CD45 is the fifth marker, more preferably in combination with the markers CD27, CD 117 and CD81, or in combination with the markers CD229, CyIg ⁇ and CyIg ⁇ .
  • Preferred reagent compositions comprise distinct fluorochrome-conjugated antibodies directed against one of the following combinations of markers:
  • the following panel of fluorochromes is of particular use in a MM/PCD reagent composition according to the invention: (1) pacific blue (PacB), brilliant violet 421 (BV421) or Horizon V450, (2) pacific orange (PacO), Horizon V500 (HV500), BV510, Khrome orange (KO) or OC515, (3) fluorescein isothiocyanate (FITC) or Alexa488, (4) phycoerythrin (PE), (5) peridinin chlorophyl protein/cyanine 5.5 (PerCP-Cy5.5), PerCP or PE-TexasRed, (6) phycoerythrin/cyanine7 (PE-Cy7), (7) allophycocyanine (APC) or Alexa647, and (8) allophycocyanine/hilite 7 (APC-H7), APC-Cy7, Alexa680, APC-A750, APC-C750 or Alexa700.
  • PacB pacific blue
  • fluorochromes are chosen: Pacific Blue, brilliant violet 421 or Horizon V450, PacO or Horizon V500, FITC, PE, PerCP-Cy5.5, PE-Cy7, APC, and APC-H7 or APC-A750 or APC-C750.
  • compositions for MRD detection in MM/PCD Panel 3A Composition of PCD MRD panel PacB or APCH7 or BV421 HV500 APCA750 or or or Tube HV450 PacO FITC PE PerCPCy5.5 PECy7 APC APCC750 1 CD45 CD138 CD38 CD56 CD27 CD19 CD117 CD81 2 CD45 CD138 CD38 CD56 CD229 CD19 CyIg ⁇ CyIg ⁇ 3 CD138 CD27 CD38 CD56 CD45 CD19 CD117 CD81 4 CD138 CD27 CD38 CD56 CD229 CD19 CyIg ⁇ CyIg ⁇ 5 CD138 CD27 CD38 CD56 CD45 CD19 CyIg ⁇ CyIg ⁇ Panel 3B.
  • a further aspect of the invention relates to a diagnostic kit for detecting MRD, in particular BCP-ALL MRD, CLL MRD or MM/PCD MRD comprising one or more of the reagent compositions described herein above, optionally together with instructions for use, buffer, and/or control samples (see: Kalina et al. Leukemia 2012: 26: 1986-2010).
  • a BCP-ALL kit comprising one or more reagent compositions of Table 1.
  • a CLL kit comprising one or more reagent compositions of Table 2.
  • a PCD kit comprising one or more reagent compositions of Table 3.
  • the invention also relates to a method for flow cytometric detection of MRD, comprising the steps of providing a biological sample from a human subject and contacting at least a portion (aliquot) of the sample with a reagent composition provided herein.
  • a biological sample from a human subject
  • a reagent composition provided herein.
  • Any type of sample known or suspected to contain leukocytes may be used directly, or after lysing non-nucleated red cells, or after density centrifugation, or after cell sorting procedures.
  • the sample is peripheral blood, bone marrow, tissue sample such as lymph nodes, adenoid, spleen, or liver, or other type of body fluid such as cerebrospinal fluid, vitreous fluid, synovial fluid, pleural effusions or ascitis. Peripheral blood or bone marrow is preferred.
  • the analysis in step (iv) involves multivariate analysis, preferably principal component analysis (PCA), wherein each marker has added value in the distinction process via the principal component analysis.
  • PCA principal component analysis
  • APS view is used employing for example Infinicyt software, or multidimensional scaling (MDS) analysis.
  • PCA is a mathematical procedure that uses an orthogonal transformation to convert a set of observations of possibly correlated variables into a set of values of uncorrelated variables called principal components.
  • the number of principal components is less than or equal to the number of original variables.
  • This transformation is defined in such a way that the first principal component has as high a variance as possible (that is, accounts for as much of the variability in the data as possible), and each succeeding component in turn has the highest variance possible under the constraint that it be orthogonal to (uncorrelated with) the preceding components.
  • Principal components are guaranteed to be independent only if the data set is jointly normally distributed.
  • PCA is sensitive to the relative scaling of the original variables.
  • KLT discrete Karhunen-Loéve transform
  • POD proper orthogonal decomposition
  • MDS any other type of well-established multivariate analysis, can be used (see: Pedreira et al. Trends Biotechnol 2013).
  • MRD minimal residual disease
  • BCP-ALL reagent composition preferably a composition selected from any one of panels 1A, 1B or 1C;
  • MRD minimal residual disease
  • CLL reagent composition preferably a composition selected from any one of panels 2A, 2B or 2C;
  • MRD minimal residual disease
  • MM/PCD reagent composition preferably a composition selected from any one of panels 3A, 3B or 3C;
  • FIG. 1 Typical example of how to use the CD19 and CD45 identification markers in combination with SSC (Panel A to C) for the distinction between BCP cells and other nucleated cells in a bone marrow sample from a BCP-ALL patient during therapy.
  • SSC Session Control System
  • light grey events correspond to non-B cells in the sample, while dark grey events are mature B-cells and black events BCP cells.
  • APS1 multivariate analysis representation
  • both mature B cells and BCP cells are clearly separated from all other events based on all informative parameters (e.g. CD19, CD45, SSC).
  • FIG. 2 Illustrating example of how to use immunophenotypic characterization markers CD10, CD20, CD34, CD66c/CD123, and CD38 in combination with SSC for the distinction between BCP-ALL cells and normal residual B-cells in a bone marrow sample from a BCP-ALL patient during therapy (Panels A to D). Only bone marrow B-cells are displayed, after gated/selected as described in FIG. 1 . In each plot, black dots correspond to BCP-ALL cells in the sample, while grey dots are normal B-cells.
  • BCP-ALL cells Compared to normal B-cells, BCP-ALL cells show overexpression of CD81 (Panel D), CD10 (Panels A and D), and CD66c/CD123 (Panel C).
  • APS1 principal component 1 versus principal component 2 representation based on all immunophenotypic markers and scatter characteristics evaluated (Panel E)
  • normal residual B-cells grey
  • black normal residual B-cells
  • FIG. 3 Illustrating example of how to use the CD19 and CD3 identification markers in combination with SSC (Panels A to C) for the distinction between mature B-cells and other nucleated cells in a peripheral blood sample from a CLL patient.
  • grey events correspond to non-B-cells in the sample, while black events are total peripheral blood B-cells.
  • APS1 multivariate analysis representation
  • principal component 1 vs. principal component 2
  • B-cells are clearly separated from all other events based on all informative parameters (e.g. CD19, CD3, SSC).
  • FIG. 4 Illustrating example of how to use immunophenotypic characterization markers CD27, CD5, CD22, CD200 and CD79b (panels A to C) for the distinction between CLL cells and normal mature B-cells in a peripheral blood sample from a CLL patient. Only peripheral blood B-cells are displayed, after gated/selected as described in FIG. 3 . In each plot, black dots correspond to CLL cells in the sample, while grey dots are normal peripheral blood B-cells. Compared to normal B-cells, CLL cells show underexpression of CD22 (Panel B) and CD79b (Panel C) together with overexpression of CD200 (Panel B) and CD5 (Panels A and C).
  • FIG. 5 Illustrating example of how to use the CD38 and CD138 identification markers in combination with SSC (Panel A to C) for the distinction between plasma cells and other nucleated cells in a bone marrow sample of an MM patient after therapy.
  • grey dots correspond to non-plasma cells in the sample, while black dots are total bone marrow plasma cells.
  • APS 1 multivariate analysis representation
  • principal component 1 vs. principal component 2
  • plasma cells black dots
  • FIG. 6 Illustrating example of how to use immunophenotypic characterization markers CD81, CD19, CD45, CD56, CD27, CD117 and CD38, in combination with SSC (Panels A to D) for the distinction between myeloma/malignant plasma cells and normal residual plasma cells in a bone marrow sample of an MM patient after therapy. Only bone marrow plasma cells are displayed, after gated/selected as described in FIG. 5 . In each plot, black dots correspond to myeloma/clonal plasma cells in the sample, while grey dots are normal residual bone marrow plasma cells.
  • myeloma/clonal plasma cells show underexpression of CD81, CD19, CD45, CD27 and CD38 together with higher SSC and overexpression of CD56 and CD117.
  • APS1 principal component 1 vs. principal component 2 representation
  • the power of the EuroFlow approach disclosed herein is based on the combination of sets of markers and the usage of multivariate analyses for both the identification of normal cells (e.g. normal precursor B-cells, normal B-lymphocytes and normal plasma cells) and the distinction between normal/reactive cells vs. clonal/malignant cells.
  • normal cells e.g. normal precursor B-cells, normal B-lymphocytes and normal plasma cells
  • Such a strategy was used to evaluate the selected combinations of most discriminating markers in multiple sequential rounds of experimental testing. Because of this the final proposed antibody combinations became extremely strong when used in combination with the principal component analysis, specifically with the automated population separation (APS) tool of the Infinicyt software, so that the added (independent) value of each marker is used in a single step of analysis.
  • APS automated population separation
  • Pre-gating using the CD19 marker is essential for identifying a pure B-cell population.
  • BCP normal B-cell precursors
  • CD45-negativity or weak positivity can be used to discriminate BCP from CD45-positive mature B-cells.
  • CD19 might be replaced by CD22.
  • SSC sideward light scatter
  • FSC forward light scatter
  • markers like CD10, CD20, CD38 and CD34, which are used for discriminating BCP-ALL cells from normal BCP cells (see below), may also contribute to the gating of the total BCP cell population (e.g. CD34+, CD10+, CD20 ⁇ to dim, CD38+).
  • Pre-gating using this marker combination is essential for identifying a pure B-cell population, and removing T-cell/B-cell doublets.
  • These markers may be used in combination also with sideward light scatter (SSC) or forward light scatter (FSC) or both FSC and SSC to identify B-cells in peripheral blood or bone marrow or other types of samples (e.g. tissue biopsy, spinal fluid).
  • SSC sideward light scatter
  • FSC forward light scatter
  • both CD5 and CD27 may be used.
  • any combination of the three markers in any fluorochrome position works; also it is possible to use any combinations of two of the three markers or in a subset of cases (not all) even one of the three markers alone. Preferable combinations are order as follows: 1) CD138/CD38/CD229; 2) CD138/CD38, 3) CD138/CD229; 4) CD38/CD229; 5) CD138; 6) CD38); 7) CD229. Note that any of these markers individually and in combination may be used in combination also with sideward light scatter (SSC) or forward light scatter (FSC) or both FSC and SSC to identify plasma cells in the bone marrow or other types of samples (e.g. peripheral blood, tissue biopsy, spinal fluid).
  • SSC sideward light scatter
  • FSC forward light scatter

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US11571457B2 (en) 2012-06-14 2023-02-07 Erasmus University Medical Center Rotterdam Methods, reagents and kits for detecting minimal residual disease
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