WO2007033369A2 - Evaluation du risque de thrombose vasculaire cerebrale par mesure de c4d sur les plaquettes - Google Patents

Evaluation du risque de thrombose vasculaire cerebrale par mesure de c4d sur les plaquettes Download PDF

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Publication number
WO2007033369A2
WO2007033369A2 PCT/US2006/036007 US2006036007W WO2007033369A2 WO 2007033369 A2 WO2007033369 A2 WO 2007033369A2 US 2006036007 W US2006036007 W US 2006036007W WO 2007033369 A2 WO2007033369 A2 WO 2007033369A2
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individual
level
antibody
platelets
cerebrovascular thrombosis
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PCT/US2006/036007
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English (en)
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WO2007033369A3 (fr
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Joseph M. Ahearn
Susan M. Manzi
Amy Kao
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University Of Pittsburgh
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Publication of WO2007033369A3 publication Critical patent/WO2007033369A3/fr

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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
    • G01N33/564—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
    • G01N2800/22—Haematology
    • G01N2800/226—Thrombotic disorders, i.e. thrombo-embolism irrespective of location/organ involved, e.g. renal vein thrombosis, venous thrombosis

Definitions

  • this invention provides a method for assessing risk of cerebrovascular thrombosis in an individual. This method comprises the following steps: first, determining the platelet surface level of a complement pathway component C4d in the individual, and second, comparing the level of C4d of the individual with a standard control. In the event an increase in the level of C4d from the standard control is detected, an increased risk of cerebrovascular thrombosis is then indicated in this individual.
  • the level of C4d is determined using an antibody that specifically binds C4d.
  • the C4d antibody is labeled, e.g., with a fluorescent moiety, which allows detection of the antibody by flow cytometry.
  • the individual being tested has no clinical symptoms of cerebrovascular thrombosis; or the individual might have previously suffered from cerebrovascular thrombosis.
  • this invention provides a method for diagnosing or monitoring cerebrovascular thrombosis in an individual.
  • This method comprises the following steps: first, determining the platelet surface level of a complement pathway component C4d in the individual, and second, comparing the level of C4d of the individual with a standard control. In the case an increase in the level of C4d from the standard control is detected, it is indicated that the individual is suffering from the condition of cerebrovascular thrombosis or a worsening of the condition.
  • the level of C4d is determined using an antibody that specifically binds C4d.
  • the C4d antibody is labeled, e.g., with a fluorescent moiety, which allows detection of the antibody by flow cytometry.
  • the individual being tested already has one or more clinical symptoms of cerebrovascular thrombosis.
  • this invention provides a computer readable medium for predicting, diagnosing, or monitoring cerebravascular thrombosis in an individual.
  • This computer readable medium comprises: (a) code for receiving data corresponding to a level of the complement pathway component C4d on the surface of platelets from an individual; (b) code for retrieving a standard control; and (c) code for comparing the data in (a) with the standard control in (b).
  • FIG 1 illustrates the levels of C4d detected on platelet surface in 19 stroke patients and in normal healthy control subjects. The C4d levels are indicated by indirect immunofluorescence.
  • ischemic stroke a type of stroke characterized by damage to the brain cells due to insufficient blood flow and oxygen supply.
  • TIA transient ischemic attack
  • the clinical symptoms of cerebrovascular thrombosis include, but are not limited to, weakness or paralysis on one side of the body; a partial or complete loss of voluntary movement and/or sensation in a leg and/or arm; speech problems and weak muscles of the face, which can cause drooling; numbness or tingling in the leg, arm, or face; impaired balance, vision, and swallowing functions; difficulty breathing and even unconsciousness.
  • the "complement pathway” or “complement system” refers to a complex network of more than 30 functionally linked proteins that interact in a highly regulated manner to provide many of the effector functions of humoral immunity and inflammation, thereby serving as the major defense mechanism against bacterial and fungal infections.
  • This system of proteins acts against invasion by foreign organisms via three distinct pathways: the classical pathway (in the presence of antibody), the alternative pathway (in the absence of antibody), and the lectin pathway. Once activated, the proteins within each pathway form a cascade involving sequential self-assembly into multimolecular complexes that perform various functions intended to eradicate the foreign antigens that initiated the response.
  • the complement pathway see, e.g., Sim and Tsiftsoglou, Biochem. Soc. Trans. 32:21-27 (2004).
  • the classical pathway is usually triggered by an antibody bound to a foreign particle. It consists of several components that are specific to the classical pathway and designated Cl, C4, C2. Sequentially, binding of CIq to an antigen-antibody complex results in activation of CIr and CIs (both are serine proteases), and activated CIs cleaves C4 and C2 into, respectively, C4a and C4b and C2a and C2b. Fragments C4b and C2a assemble to form C4b2a, which cleaves protein C3 into C3a and C3b, which completes activation of the classical pathway. Fragments C4b and C3b are subject to further degradation by Factor I.
  • This factor cleaves C4b to generate C4d and also cleaves C3b, to generate iC3b followed by C3d.
  • activation of the classical pathway of complement can lead to deposition of a number of fragments, such as C4d, iC3b, and C3d, on immune complexes or other target surfaces.
  • targets include cells circulating in the blood, e.g., lymphocytes and other white blood cells, erythrocytes, and platelets.
  • Components of the complement pathway include proteins Cl, C4, C2, C3, and fragments thereof, e.g., CIq, CIr, CIs, C4a, C4b, C2a, C2b, C4b2a, C3a, C3b, C4c, C4d, iC3b, C3d, C3i, C3dg. Also included are C5, C5b, C6, C7, C8, C9, Clinh, MASP2, CRl, DAF, MCP, CD59, C3aR, C5aR, CIqR, CR2, CR3, and CR4, as well as other complement pathway components, receptors and ligands not listed specifically herein.
  • the platelet surface level of a complement pathway component As used herein, "the platelet surface level of a complement pathway component
  • C4d refers to the amount of C4d found on the surface of a predetermined number of platelets obtained from an individual person.
  • a "standard control" as used herein refers to a platelet surface C4d level used as a comparison basis in practicing a method of the present invention. Such a standard control should reasonably indicate the level of platelet surface C4d in an average individual who is not suffering from or at risk of developing cerebrovascular thrombosis, and is not suffering from or at risk of any other diseases or conditions that tend to elevate platelet surface C4d level.
  • a standard control reflects the platelet surface C4d level from a healthy individual with medical background, as well as in age, gender, ethnicity, etc., comparable to the individual whose platelet surface C4d level is being tested.
  • An increase in the level of C4d from the standard control refers to a positive change in value from the standard control. Such an increase is usually at least 50%.
  • the increased level of C4d is preferably at least 2-fold, more preferably at least 5-fold, and most preferably at least 10-fold of the control level.
  • an "antibody” refers to a glycoprotein of the immunoglobulin family or a polypeptide comprising fragments of an immunoglobulin that is capable of noncovalently, reversibly, and in a specific manner binding a corresponding antigen.
  • the typical antibody structural unit is a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light” (about 25 kD) and one "heavy" chain (about 50-70 kD), connected through a disulfide bond.
  • the recognized immunoglobulin genes include the /c, ⁇ , a, 7, ⁇ , e, and ⁇ constant region genes, as well as the myriad immunoglobulin variable region genes.
  • Light chains are classified as either K or ⁇ Heavy chains are classified as ⁇ , ⁇ , a, ⁇ , or e, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD, and IgE, respectively.
  • the N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
  • the terms variable light chain (V L ) and variable heavy chain (V H ) refer to these regions of light and heavy chains respectively.
  • antibody includes both monoclonal and polyclonal antibodies, and encompasses antibodies raised in vivo, e.g., produced by an animal upon immunization by an antigen, and antibodies generated in vitro, e.g., generated by hybridomas.
  • antibodies that specifically recognize the same antigen, e.g., a pathogenic organism are regarded as "one antibody,” regardless of whether they actually bind to the same or to separate antigenic epitopes of the antigen.
  • any technique known in the art can be used (see, e.g., Kohler & Milstein, Nature 256:495-497, 1975; Kozbor et al, Immunology Today 4:72, 1983; Cole et al, Monoclonal Antibodies and Cancer Therapy, pp. 77-96. Alan R. Liss, Inc., 1985).
  • Techniques for the production of single chain antibodies can be adapted to produce antibodies to polypeptides of this invention.
  • transgenic mice, or other organisms such as other mammals may be used to express humanized antibodies.
  • phage display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens (see, e.g., McCafferty et al., supra; Marks et al, Biotechnology, 10:779-783, 1992).
  • the specified antibodies bind to a particular protein at least two times the background and more typically more than 10 to 100 times background. Specific binding to an antibody under such conditions requires an antibody that is selected for its specificity for a particular protein.
  • polyclonal antibodies raised to a component of the complement pathway or to a surface marker of platelets can be selected to obtain only those polyclonal antibodies that are specifically immunoreactive with the component of the complement pathway or the platelet surface marker and not with other proteins. This selection may be achieved by subtracting out antibodies that cross-react with other molecules.
  • a variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein.
  • solid-phase ELISA immunoassays are routinely used to select antibodies specifically immunoreactive with a protein ⁇ see, e.g., Harlow & Lane, Antibodies, A Laboratory Manual (1988) for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity) .
  • the present invention provides a novel method for expediently assessing a person's risk for a future episode of cerebrovascular thrombosis, a type of stroke caused by the blockage of a blood vessel in the brain.
  • a patient's blood sample is taken and the level of platelet surface C4d, a component of the complement system, is measured.
  • This C4d level is then compared with an established standard control, which reflects the average amount of platelet surface C4d found in a healthy person not at risk of cerebrovascular thrombosis or other conditions that tend to elevate C4d level on the platelets.
  • An increase in the C4d level indicates a heighten risk for an individual to suffer from cerebrovascular thrombosis.
  • the platelet surface C4d levels can also be used to diagnose cerebrovascular thrombosis or monitor the condition of cerebrovascular thrombosis in a patient, where a higher-than-normal C4d level indicates that presence of cerebrovascular thrombosis or a worsening of the condition in a patient.
  • the present invention involves conducting assays on platelets obtained from an individual to determine the level of C4d, a complement pathway component, deposited on the surface of platelets. The C4d level of is then used to predict, diagnose, or monitor cerebrovascular thrombosis in the individual.
  • the procedure of determining platelet surface C4d level begins with acquisition of a blood sample from a patient.
  • patient blood samples are treated with EDTA (ethylenediaminetetraacetate) to inhibit complement activation, and can be maintained at room temperature or under cold conditions.
  • Assays are run preferably within 24 hours from sample collection.
  • Isolation of platelets can also be achieved by an affinity-based method.
  • a platelet surface marker e.g., CD42b
  • a solid support such as a Sepharose column
  • platelets can be recovered from the solid support.
  • FACS fluorescence activated cell sorting
  • a molecule of interest can be specific for a type of cell or for particular cell state.
  • the molecule of interest can be fluorescently labeled directly by binding to a fluorescent dye, or by binding to a second molecule, which has been fluorescently labeled, e.g., an antibody, lectin, or aptamer that has been fluorescently labeled and that specifically binds to the molecule of interest.
  • platelet specific markers can by used to distinguish platelets from other components of the blood such as red or white blood cells in a blood sample.
  • Isolation of platelets also refers to gating techniques used to assay platelets during flow cytometric analysis.
  • a labeled marker specific for platelets e.g., a labeled anti-CD42b monoclonal antibody
  • a second labeled marker e.g., a labeled anti-C4d antibody
  • platelet surface C4d level is determined to predict, diagnose, or monitor the progression of cerebrovascular thrombosis in individuals.
  • the platelets are isolated or detected using platelet-specific antibodies e.g., anti-CD42b antibodies.
  • determination of the level of platelet surface C4d may be achieved by a number of methods including flow cytometry, ELISA using purified platelet preparations, and radioimmunoassay.
  • the determination of the platelet surface C4d level is made using flow cytometric methods, with measurements taken by direct or indirect immunofluorescence using polyclonal or monoclonal antibodies specific for C4d.
  • MFC mean fluorescence channel
  • Kits for conducting the assays for predicting, diagnosing, or monitoring of cerebrovascular thrombosis in a patient are a part of this invention.
  • the kits may comprise any of the various reagents needed to perform the methods described herein.
  • a kit adapted for the immunofluorescence assays generally comprises a conjugate of a monoclonal antibody specific for C4d with a first fluorescent moiety, and preferably also a conjugate of a monoclonal antibody specific for a platelet surface marker ⁇ e.g., CD42b) with a second, different fluorescent moiety.
  • the kits can comprise instructional material for the user and such other material as may be needed in carrying out assays of this type, for example, buffers, radiolabeled antibodies, colorimeter reagents, etc.
  • CD42b monoclonal antibodies specific for CD42b are available from commercial suppliers such as BIODESIGN International (Saco, ME) and Yorkshire Bioscience (United Kingdom).
  • Anti-C4d antibodies are available from Quidel Corp. (San Diego, CA) and are generally described in Rogers, J., N. Cooper, et al. PNAS 89:10016- 10020 (1992); Schwab, C. et a!.. Brain. Res. 707(2):196 (1996); Gemmell, C. J. Biomed. Mater. Res. 37:474-480 (1997); and, Stoltzner, S.E., et al. Am. J. Path. 156:489-499 (2000).
  • Diagnosis of a patient with cerebrovascular thrombosis or with an increased risk of developing cerebrovascular thrombosis is carried out by comparing the level of platelet surface C4d in this patient with a base value or standard control for the quantity of C4d that is typically present on the surface platelets in normal individuals. In normal individuals, the level of C4d on the surface of platelets is very low to not detectable.
  • the MFC of C4d on platelet surface of healthy individuals ranged from -1.17 to 0.87 (mean -0.39). In contrast, the MFC of platelet surface C4d in two patients suffering from cerebrovascular thrombosis was observed to be 6.00 and 16.53.
  • a particular feature of the methods of this invention is to indicate or reflect the progress of cerebrovascular thrombosis that has occurred in a patient during the preceding several weeks or even several months. It is possible, using the claimed methods, to identify the worsening of cerebrovascular thrombosis that has previously occurred, or to predict a subsequent occurrence of cerebrovascular thrombosis based on the persistence of elevated level of C4d deposited on the surface of platelets.
  • the determination of platelet surface C4d level, and the diagnostic and monitoring methods described above can be carried out manually, but often are conveniently carried out using an automated system and/or equipment, in which the blood sample is analyzed automatically to make the necessary determination or determinations, and the comparison with a standard control or reference value is performed automatically, using computer software appropriate to that purpose.
  • the invention comprises a method for predicting, diagnosing, or monitoring cerebrovascular thrombosis in an individual comprising (a) automatically determining, in a blood sample from the individual containing platelets, the level of C4d deposited on surfaces of platelets in the sample, and (b) automatically comparing the platelet surface C4d level with a standard control or reference value that reflects the average C4d level found on a normal, healthy individual's platelets.
  • the invention comprises a method for predicting, diagnosing, or monitoring cerebrovascular thrombosis in an individual comprising (a) automatically determining, in a blood sample from the individual containing platelets, the level of C4d deposited on surface of platelets in the sample, and (b) automatically comparing C4d level with a standard control indicating the average C4d level found on a normal, healthy individual's platelets.
  • Computer software, or computer-readable media for use in the methods of this invention includes a computer readable medium, which comprises:
  • more than one standard controls may be stored in a memory associated with a digital computer. After data corresponding to the level of platelet surface C4d are obtained (e.g., from an appropriate analytical instrument), the digital computer may compare the C4d level with one or more appropriate standard controls. After this comparison takes place, the digital computer can automatically determine if the data corresponding to the C4d level is associated with cerebrovascular thrombosis.
  • more than one C4d levels may be stored in a memory associated with a digital computer.
  • the platelet surface C4d level from a particular individual may be measured at different points in time for the purpose of monitoring the progress of cerebrovascular thrombosis.
  • the digital computer can compare the C4d levels with the appropriate standard control(s), and/or with the platelet C4d levels recorded at previous time points. After this comparison takes place, the digital computer can automatically determine if the data corresponding to the C4d levels indicate an improvement or deterioration of cerebrovascular thrombosis in the patient.
  • one aspect of the invention may be embodied by computer code that is executed by a digital computer.
  • the digital computer may be a micro, mini, or large frame computer using any standard or specialized operating system such as a WindowsTM based operating system.
  • the code may be stored on any suitable computer readable media. Examples of computer readable media include magnetic, electronic, or optical disks, tapes, sticks, chips, etc.
  • the code may also be written by those of ordinary skill in the art and in any suitable computer programming language including, C, C++, etc.
  • Example 1 Measuring Platelet Surface C4d Level in Healthy Individuals—Establishing Standard Controls
  • C4d was not detected on the surface of platelets in each of the twenty-five healthy individuals.
  • Samples of 1 mL of EDTA-anticoagulated peripheral blood were taken from each individual and used as a source of platelets. The platelets were washed and resuspended in FACS buffer. Levels of C4d and CD42b were measured by two color indirect immunofluorescence using monoclonal antibodies specific for C4d and CD42b, respectively, Levels of C4d and CD42b were quantified by flow cytometry using a FACSCalibur cytometer (Becton Dickinson, Franklin Lakes, NJ). The platelets were identified by forward and side scatter and CD42b- fiuorescence, and the mean fluorescence channel (MFC) was determined for C4d as well as for CD42b.
  • MFC mean fluorescence channel
  • blood was drawn into 4 cc Vacutainer tubes containing 7.2 mg EDTA as an anticoagulant (Becton Dickinson), and processed within two hours.
  • Whole blood was diluted 1/10 in phosphate buffered saline (PBS). 10 ⁇ l aliquots of the diluted blood were immufluorescently labeled for flow cytometry with 0.
  • PBS phosphate buffered saline
  • Platelets were electronically gated by forward scatter properties and expression of CD42b, a platelet-specific marker. Nonspecific binding of immunoglobulins to platelets was determined by performing identical assays in parallel using the isotype control antibody MOPC21. Specific binding of anti-C4d and anti-CD42b were determined by subtracting the MFC obtained with MOPC21 from the MFC obtained with anti-C4d and anti- CD42b, respectively.
  • Example 2 Increased Platelet C4d Levels in Cerebrovascular Thrombosis Patients
  • This example describes assays detecting higher-than-normal platelet surface C4d levels in patients suffering from cerebrovascular thrombosis.
  • platelet surface C4d level is an indicator of risk for premature cerebrovascular thrombosis in an individual and can serve as a biomarker for diagnosing cerebrovascular thrombosis or monitoring response to stroke therapy in patients already demonstrating one or more symptoms of a thrombotic stroke.

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Abstract

Test d'évaluation pratique, économique et réactif pour l'évaluation du risque d'accident thrombotique chez un sujet ; plus précisément, il a été établi que les personnes à risque dans le domaine de la thrombose vasculaire cérébrale présentaient un dépôt élevé de C4d sur leurs plaquettes.
PCT/US2006/036007 2005-09-14 2006-09-14 Evaluation du risque de thrombose vasculaire cerebrale par mesure de c4d sur les plaquettes WO2007033369A2 (fr)

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US71752505P 2005-09-14 2005-09-14
US60/717,525 2005-09-14
US52005406A 2006-09-11 2006-09-11
US11/520,054 2006-09-11

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5976540A (en) * 1993-05-17 1999-11-02 T Cell Sciences, Inc. Compositions comprising complement related proteins and carbohydrates, and methods for producing and using said compositions
US6312693B1 (en) * 1998-02-19 2001-11-06 Alejandro A. Aruffo Antibodies against human CD40
US20020081293A1 (en) * 1998-02-20 2002-06-27 Tanox, Inc., Delaware Corporation Inhibitors of complement activation
US20020192758A1 (en) * 2000-08-01 2002-12-19 Welcher Andrew A. C3b/C4b complement receptor-like molecules and uses thereof
US20040077934A1 (en) * 1999-07-06 2004-04-22 Intercure Ltd. Interventive-diagnostic device
US20050130230A1 (en) * 2003-09-23 2005-06-16 Antoni Davalos Cellular fibronectin as a diagnostic marker in stroke and methods of use thereof

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5976540A (en) * 1993-05-17 1999-11-02 T Cell Sciences, Inc. Compositions comprising complement related proteins and carbohydrates, and methods for producing and using said compositions
US6312693B1 (en) * 1998-02-19 2001-11-06 Alejandro A. Aruffo Antibodies against human CD40
US6413514B1 (en) * 1998-02-19 2002-07-02 Bristol-Myers Squibb Company Methods of using antibodies against human CD40
US20020081293A1 (en) * 1998-02-20 2002-06-27 Tanox, Inc., Delaware Corporation Inhibitors of complement activation
US20040077934A1 (en) * 1999-07-06 2004-04-22 Intercure Ltd. Interventive-diagnostic device
US20020192758A1 (en) * 2000-08-01 2002-12-19 Welcher Andrew A. C3b/C4b complement receptor-like molecules and uses thereof
US20050130230A1 (en) * 2003-09-23 2005-06-16 Antoni Davalos Cellular fibronectin as a diagnostic marker in stroke and methods of use thereof

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