WO1998022821A1 - DETECTION D'ANTICORPS DE RECEPTEUR GPIIa/IIIb DEPENDANT D'ANTAGONISTES - Google Patents

DETECTION D'ANTICORPS DE RECEPTEUR GPIIa/IIIb DEPENDANT D'ANTAGONISTES Download PDF

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Publication number
WO1998022821A1
WO1998022821A1 PCT/US1997/020954 US9720954W WO9822821A1 WO 1998022821 A1 WO1998022821 A1 WO 1998022821A1 US 9720954 W US9720954 W US 9720954W WO 9822821 A1 WO9822821 A1 WO 9822821A1
Authority
WO
WIPO (PCT)
Prior art keywords
gpiib
iiia receptor
labeled
complex
iiia
Prior art date
Application number
PCT/US1997/020954
Other languages
English (en)
Inventor
Bohumil Bednar
Robert J. Gould
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9702822.9A external-priority patent/GB9702822D0/en
Priority claimed from GBGB9705856.4A external-priority patent/GB9705856D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to CA002271684A priority Critical patent/CA2271684A1/fr
Priority to JP52378398A priority patent/JP2001504584A/ja
Priority to EP97947553A priority patent/EP0939900A4/fr
Publication of WO1998022821A1 publication Critical patent/WO1998022821A1/fr

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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
    • G01N33/86—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood coagulating time or factors, or their receptors
    • 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
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70546—Integrin superfamily, e.g. VLAs, leuCAM, GPIIb/GPIIIa, LPAM

Definitions

  • Drug-induced thrombocytopenia contributes to morbitity and, occasionally, mortality in patients treated with a wide range of medications (Karpatkin, Am. J. Med. Sci. 262:68 (1971)). More than 100 different medications have been implicated in drug-induced thrombocytopenia, including heparin, quinine, quinidine and sulfonamide antibiotics (Shulman et al. Hemostasis and Thrombosis (ed 2) Philadelphia, PA, Lippincott (1987) p.452, and Kracke et al. JAMA 122: 168 (1943).
  • the present invention is a means for identifying, in a patient, the presence of one or more antibodies in GP Hb/IHa receptor (fibrinogen receptor) antagonist-induced thrombocytopenia which recognize GPIIb/IIIa receptor:GPIIb/IIIa receptor antagonist complexes formed with purified platelets or purified GPIIb/IIIa receptor and a selected GPIIb/IIIa receptor antagonist. Identification of such antibodies identifies the patient as being at risk to development of thrombocytopenia resulting from administration to the patient of the selected GP Ilb IIIa receptor antagonist.
  • GP Hb/IHa receptor fibrinogen receptor
  • the invention is a method for identifying a patient at risk to developing fibrinogen receptor antagonist-induced thrombocytopenia resulting from treatment of the patient with a selected fibrinogen receptor antagonist, which comprises reacting patient plasma with a GPIIb/IIIa receptor: GPIIb/HIa receptor antagonist complex to form a first reaction product, reacting the first reaction product with a secondary anti-human detectable antibody to form a second reaction product, and detecting in the second reaction product the level of binding between the secondary anti- human detectable antibody and the GPIIb/IIIa receptor: GPIIb/IIIa receptor antagonist complex.
  • GPIIb/IIIa receptor antagonist complex indicates the presence of interaction between the GPIIb/ ⁇ ia recepto ⁇ GPIIb ⁇ Ha receptor antagonist complex and a patient plasma antibody. The presence of such interaction identifies the patient as at risk to developing thrombocytopenia following treatment with the selected fibrinogen receptor antagonist.
  • the patient at risk is one who is receiving treatment to inhibit thrombosis by administration of a selected fibrinogen receptor antagonist which inhibits the binding of fibrinogen to the GPIIb/IIIa receptor.
  • the objective of the method is to determine whether the patient's plasma contains an antibody to the GPIIb/IIIa receptor:GPIIb/IIIa receptor antagonist complex formed when the selected fibrinogen receptor antagonist binds to the GPIIb/IIIa receptor.
  • the GPIIb/IIIa receptor:GPIIb/IlIa receptor antagonist complex may be prepared for purposes of the method by coating commercially available GPIIb/IIIa platelet receptors, including but not limited to those on platelets or purified platelets, and GPIIb/IIIa platelet receptors and purified GPIIb/IIIa platelet receptors, with a selected fibrinogen receptor antagonist to form a GPIIb/IIIa receptor: GPIIb/IIIa receptor antagonist complex.
  • the method for identifying a patient at risk comprises incubating patient plasma with a GPIIb/IIIa receptor:GPIIb/IIIa receptor antagonist complex to form a GPIIb/IIIa receptor:GPIIb/IIIa receptor antagonist:plasma antibody complex, incubating the GPIIb/IIIa receptor: GPIIb/IIIa receptor antagonist ⁇ lasma antibody complex with a secondary anti-human detectable antibody to form a GPIIb/IIIa receptor:GPIIb/ ⁇ ia receptor antagonist ⁇ lasma antibody:secondary anti- human detectable antibody complex, and detecting the presence of the secondary anti-human detectable antibody in the GPIIb/IIIa receptor:GPIIb/ ⁇ ia receptor antagonisCplasma antibody:secondary anti- human detectable antibody complex.
  • the GPIIb/IIIa receptor:GP ⁇ b/ ⁇ ia receptor antagonist complex is incubated with the patient's plasma.
  • Patient plasma which contains antagonist-dependent antibodies will induce formation of a GPIIb/IIIa receptor:GPIIb/IIIa receptor antagonist ⁇ lasma antibody complex.
  • Plasma which does not contain antagonist-dependent antibodies will not form a GPIIb/IIIa receptor: GPIIb/IIIa receptor antagonisCplasma antibody complex after this incubation step.
  • the material formed following the incubation step is washed to remove substances which do not associate with the formed GPIIb/IIIa receptor:GPIIb/IIIa receptor antagonist ⁇ lasma antibody complex.
  • the material formed following the above-described incubation step is then incubated with a secondary anti-human detectable antibody (e.g. antihuman IgG, antihuman IgM, antihuman IgA, associated with a detectable marker such as a fluorescent label or an enzyme (e.g. horseradish peroxidase, which induces a detectable reaction when exposed to a substrate that is acted upon by the enzyme)).
  • a secondary anti-human detectable antibody e.g. antihuman IgG, antihuman IgM, antihuman IgA, associated with a detectable marker such as a fluorescent label or an enzyme (e.g. horseradish peroxidase, which induces a detectable reaction when exposed to a substrate that is acted upon by the enzyme)
  • a GPIIb/IIIa receptor:GPIIb/ ⁇ ia receptor antagonist ⁇ lasma antibody complex forms following addition of the patient's plasma, then the secondary anti-human detectable antibody will complex with the GPIIb/ ⁇ ia recepto ⁇ GP ⁇ b/IIIa receptor antagonist:plasma antibody complex, and will not be washed away during a washing step. If a GPIIb/IIIa receptor: GPIIb IIIa receptor antagonist:plasma antibody complex does not form following addition of the patient's plasma, then the secondary antibody will not complex with the GPIIb/ ⁇ ia receptor: GPIIb/IIIa receptor antagonist complex, and will be washed away during a subsequent washing step.
  • Detection of the presence of the GPIIb/IIIa receptor:GPIIb/IIIa receptor antagonist:plasma antibody secondary anti-human detectable antibody complex is an indication that the patient does have antagonist-dependent antibodies reactive with platelets and that the patient is at risk to developing thrombocytopenia following consumption of the selected fibrinogen receptor antagonist.
  • the absence of the GPIIb/IIIa receptor: GPIIb/IIIa receptor antagonis plasma antibody:secondary anti-human detectable antibody complex indicates that the GPIIb/IIIa recepto ⁇ GPIIb/IIIa receptor antagonist:plasma antibody complex did not form, and that the patient is not at risk to developing fibrinogen receptor antagonist induced thrombocytopenia.
  • the secondary anti-human detectable antibody is, for example, a fluorescence-labeled F(ab')2 anti-IgG, fluorescence-labeled F(ab')2 anti-IgM, fluorescence-labeled F(ab')2 anti- IgA, enzyme labeled IgG, enzyme labeled IgM, or enzyme labled IgA.
  • the fluorescence-labeled F(ab')2 anti-IgG, fluorescence-labeled F(ab')2 anti- IgM, fluorescence-labeled F(ab')2 anti-IgA antibodies may be suitably labeled with flourescein.
  • the enzyme labeled IgG, enzyme labeled IgM, and enzyme labled IgA antibodies may be suitably labeled with an enzyme such as horseradish peroxidase.
  • the invention also is a method for identifying a patient not at risk to developing fibrinogen receptor antagonist-induced thrombocytopenia which comprises reacting patient plasma with a GPIIb/IIIa receptor:GPIIb/ ⁇ ia receptor antagonist complex to form a first reaction product, reacting the first reaction product with a secondary antihuman detectable antibody to form a second reaction product, washing substances from the second reaction product which do not complex with the GPIIb/IIIa receptor:GPIIb IIIa receptor antagonist complex to form a washed second reaction product, and detecting the absence of the secondary anti-human detectable antibody in the washed second reaction product.
  • the selected GP Ilb/IIIa receptor antagonist suitable for the methods of the invention is any antagonist which is useful for inhibiting fibrinogen binding to the GP Ub/IIIa platelet receptor. Such antagonists are well known in the art
  • Antagonists for the GP Ub/IIIa receptor have been described in, for example, United States Patents 5,470,849, 5,463,01 1, 5,455,243, 5,451,578, 5,446,056, 5,441 ,952, 5,422,249, 5,416,099, 5,405,854, 5,397,791, 5,393,760, 5,389,631 , 5,380,713, 5,374,622, 5,358,956, 5,344,783, 5,340,798, 5,338,7235,334,596, 5,321 ,034, 5,318,899 (e.g.
  • Mpr is mercapto propionyl
  • 5,312,923, 5,294,616, 5,292,756 e.g.
  • EP 505 868 e.g. ((l-(2-((4 (aminoiminomethyl)benzoyl)amino)-3-(4-hydroxyphenyl)-l-oxopropyl)-4- piperidinyl)oxy)-(S)-acetic acid
  • WO 931 1152 e.g.
  • GP Ilb/IIIa antagonist treatment and method for identifying a patient at risk to developing GP Ilb/ ⁇ ia antagonist-induced thrombocytopenia A patient with acute coronary ischemic syndromes receives coronary revascularization with angioplasty. Aspirin is administered in a dose of 325 mg at least two hours before angioplasty, and daily thereafter. Heparin is given intravenously in an initial bolus dose of 10,000 to 12,000 units followed by incremental bolus doses of up to 3000 units at 15-minute intervals, but no more than 20,000 units is given during the procedure.
  • the goal is to keep the activated clotting time between 300 and 350 seconds during the operation. Heparin is continued by constant infusion for at least 12 hours to maintain the activated partial-thromboplastin time at 1.5 to 2.5 times the control value. Aspirin is required at discharge in a dose of 325 mg per day.
  • the patient is scheduled to receive an oral tablet containing 15 mg of the fibrinogen receptor gp Ilb/IHa antagonist 2(S)-[(p- Toluenesulfonyl)amino]-3-[[[5,6,7,8-tetrahydro-4-oxo-5-[2-(piperidin-4- yl)ethyl]-4H-pyrazolo-[l ,5-a][l,4]diazepin-2-yl]carbonyl]-amino]propionic acid (compound 1-1). described in WO 94/18981.
  • the patient Prior to initiation of treatment with compound ⁇ , the patient is screened to determine whether the patient is at risk to developing thrombocytopenia induced by compound 1-1.
  • a plasma sample is drawn from the patient and incubated with a GPIIb/IIIa receptorxompound 1-1 complex to bind antagonist-dependent plasma antibodies to the complex and form a GPIIb/ ⁇ ia receptorxompound l-l :plasma antibody complex.
  • the GPIIb/IIIa receptorxompound l-l :plasma antibody complex is incubated with horseradish peroxidase anti-human IgG to form a GPIIb/IIIa receptorxompound l-l :plasma antibody :horseradish peroxidase anti- human IgG complex.
  • the presence of the horseradish peroxidase antihuman IgG in the GPIIb/IIIa receptorxompound l-l :plasma antibody:horseradish peroxidase anti-human IgG complex is detected by observing a horseradish peroxidase-induced enzyme reaction, which confirms the presence of plasma antibodies associated with a thrombocytopenic reaction to the GPIIb/IIIa receptorxompound 1 -1 complex.
  • the patient is determined to be at risk to developing antagonist-induced thrombocytopenia.
  • a patient with acute coronary ischemic syndromes receives coronary revascularization with angioplasty.
  • Aspirin is administered in a dose of 325 mg at least two hours before angioplasty, and daily thereafter.
  • Heparin is given intravenously in an initial bolus dose of 10,000 to 12,000 units followed by incremental bolus doses of up to 3000 units at 15-minute intervals, but no more than 20,000 units is given during the procedure.
  • the goal is to keep the activated clotting time between 300 and 350 seconds during the operation.
  • Heparin is continued by constant infusion for at least 12 hours to maintain the activated partial-thromboplastin time at 1.5 to 2.5 times the control value.
  • Aspirin is required at discharge in a dose of 325 mg per day.
  • the patient is scheduled to receive an oral tablet containing 15 mg of the fibrinogen receptor gp Ilb/IIIa antagonist 2(S)-[(p- Toluenesulfonyl)amino]-3-[[[5,6,7,8-tetrahydro-4-oxo-5-[2-(piperidin-4- yl)ethyl]-4H-pyrazolo-[l ,5-a][l ,4]diazepin-2-yl]carbonyl]-amino]propionic acid (compound 1-1). described in WO 94/18981.
  • the patient Prior to initiation of treatment with compound LJL, the patient is screened to determine whether the patient is at risk to developing thrombocytopenia induced by compound 1-1.
  • a plasma sample is drawn from the patient and incubated with a GPIIb/IIIa receptorxompound 1-1 complex to attempt to bind antagonist- dependent plasma antibodies to the complex and form a GPIIb/IIIa receptorxompound l-l :plasma antibody complex.
  • a GPIIb/IIIa receptorxompound 1-1 complex is incubated with horseradish peroxidase anti-human IgG. Since no plasma antibody complex formed, the horseradish peroxidase anti-human IgG does not associate with the
  • GPIIb/ ⁇ ia receptorxompound 1-1 complex The horseradish peroxidase anti-human IgG is washed away because it does not complex with the GPIIb/IIIa receptorxompound 1-1 complex. Exposure of the GPIIb/ ⁇ ia receptorxompound 1-1 complex to conditions that would identify the presence of the horseradish peroxidase anti -human IgG indicate that no enzyme is present and that the patient plasma does not have plasma antibodies associated with compound 1-1 -induced thrombocytopenia, and that the patient is not at risk to developing thrombocytopenia.

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Abstract

La présente invention concerne un procédé d'identification chez un patient du risque de développement d'une thrombocytopénie induite par un antagoniste du récepteur du fibrinogène. Le procédé consiste à incuber le plasma du patient avec un complexe récepteur GPIIb/IIIa: antagoniste du récepteur GPIIb/IIIa pour former un complexe récepteur GPIIb/IIIa: antagoniste du récepteur GPIIb/IIIa: anticorps du plasma; à incuber le complexe récepteur GPIIb/IIIa: antagoniste du récepteur GPIIb/IIIa: anticorps du plasma avec un anticorps détectable anti-humain secondaire pour former un complexe récepteur GPIIb/IIIa: antagoniste du récepteur GPIIb/IIIa: anticorps du plasma: anticorps détectable anti-humain secondaire; et à détecter la présence de l'anticorps détectable anti-humain secondaire dans le complexe récepteur GPIIb/IIIa: antagoniste de récepteur GPIIb/IIIa: anticorps du plasma: anticorps détectable anti-humain secondaire.
PCT/US1997/020954 1996-11-21 1997-11-17 DETECTION D'ANTICORPS DE RECEPTEUR GPIIa/IIIb DEPENDANT D'ANTAGONISTES WO1998022821A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002271684A CA2271684A1 (fr) 1996-11-21 1997-11-17 Detection d'anticorps de recepteur gpiia/iiib dependant d'antagonistes
JP52378398A JP2001504584A (ja) 1996-11-21 1997-11-17 拮抗薬依存性ＧＰＩＩｂ／ＩＩＩａレセプタ抗体の検出
EP97947553A EP0939900A4 (fr) 1996-11-21 1997-11-17 DETECTION D'ANTICORPS DE RECEPTEUR GPIIb/IIIa DEPENDANT D'ANTAGONISTES

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US3166196P 1996-11-21 1996-11-21
US60/031,661 1996-11-21
US3546197P 1997-01-14 1997-01-14
US60/035,461 1997-01-14
GBGB9702822.9A GB9702822D0 (en) 1997-02-12 1997-02-12 Anticoagulant test
GBGB9705856.4A GB9705856D0 (en) 1997-03-21 1997-03-21 Anticoagulant test
GB9702822.9 1997-03-21
GB9705856.4 1997-03-21

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WO1998022821A1 true WO1998022821A1 (fr) 1998-05-28

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EP (1) EP0939900A4 (fr)
JP (1) JP2001504584A (fr)
CA (1) CA2271684A1 (fr)
WO (1) WO1998022821A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999038014A1 (fr) * 1998-01-27 1999-07-29 Du Pont Pharmaceuticals Company Evaluation du risque de developpement d'affections liees a un antagoniste/agoniste de l'integrine
WO2000043793A1 (fr) * 1999-01-26 2000-07-27 Du Pont Pharmaceuticals Company PROCEDE A FACS PERMETTANT LA DETECTION D'ACTIVATEURS DEPENDANTS DE L'INHIBITEUR GPIIb/IIIa DANS DES ECHANTILLONS DE PLASMA

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5318899A (en) * 1989-06-16 1994-06-07 Cor Therapeutics, Inc. Platelet aggregation inhibitors
WO1995008116A1 (fr) * 1993-09-15 1995-03-23 The Blood Center Of Southeastern Wisconsin, Inc. Procede de detection de la cytopenie induite par un anticorps dependant de medicaments, qui se lie aux cellules sanguines

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4717654A (en) * 1984-06-19 1988-01-05 Akzo N.V. Process for solid phase platelet antibody assay
FR2665769B1 (fr) * 1990-08-09 1994-04-29 Serbio Determination des thrombopenies notamment induites par l'heparine au moyen du facteur plaquettaire 4.

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5318899A (en) * 1989-06-16 1994-06-07 Cor Therapeutics, Inc. Platelet aggregation inhibitors
WO1995008116A1 (fr) * 1993-09-15 1995-03-23 The Blood Center Of Southeastern Wisconsin, Inc. Procede de detection de la cytopenie induite par un anticorps dependant de medicaments, qui se lie aux cellules sanguines
US5585243A (en) * 1993-09-15 1996-12-17 The Blood Center Of Southeastern Wisconsin, Inc. Method of detecting cytopenia that is mediated by drug-dependent antibody binding to blood cells

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0939900A4 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999038014A1 (fr) * 1998-01-27 1999-07-29 Du Pont Pharmaceuticals Company Evaluation du risque de developpement d'affections liees a un antagoniste/agoniste de l'integrine
US6623981B2 (en) 1998-01-27 2003-09-23 Bristol-Myers Squibb Company Detection of patients at risk for developing integrin antagonist/agonist mediated disease states
WO2000043793A1 (fr) * 1999-01-26 2000-07-27 Du Pont Pharmaceuticals Company PROCEDE A FACS PERMETTANT LA DETECTION D'ACTIVATEURS DEPENDANTS DE L'INHIBITEUR GPIIb/IIIa DANS DES ECHANTILLONS DE PLASMA

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Publication number Publication date
CA2271684A1 (fr) 1998-05-28
JP2001504584A (ja) 2001-04-03
EP0939900A4 (fr) 2003-01-08
EP0939900A1 (fr) 1999-09-08

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