WO1990006134A1 - Anticorps humains specifiques de plaquettes - Google Patents

Anticorps humains specifiques de plaquettes Download PDF

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Publication number
WO1990006134A1
WO1990006134A1 PCT/US1989/005418 US8905418W WO9006134A1 WO 1990006134 A1 WO1990006134 A1 WO 1990006134A1 US 8905418 W US8905418 W US 8905418W WO 9006134 A1 WO9006134 A1 WO 9006134A1
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WO
WIPO (PCT)
Prior art keywords
antibody
fragment
specific
human
platelet
Prior art date
Application number
PCT/US1989/005418
Other languages
English (en)
Inventor
Herbert Lazarus
Barry S. Coller
Original Assignee
Centocor, 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
Application filed by Centocor, Inc. filed Critical Centocor, Inc.
Publication of WO1990006134A1 publication Critical patent/WO1990006134A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
    • C07K16/2848—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily against integrin beta3-subunit-containing molecules, e.g. CD41, CD51, CD61
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1027—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against receptors, cell-surface antigens or cell-surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Platelet aggregation is an essential event in the formation of blood clots. Under normal circumstances, blood clots serve to prevent the escape of blood cells from the vascular system. However, during certain disease states (e.g., myocardial infarction), clots can restrict or totally prevent blood flow, resulting in cellular necrosis.
  • certain disease states e.g., myocardial infarction
  • Heart attack patients are typically treated with thrombolytic agents such as tissue plasminogen activator or streptokinase, which dissolve the fibrin component of clots.
  • thrombolytic agents such as tissue plasminogen activator or streptokinase, which dissolve the fibrin component of clots.
  • a major complication associated with fibrinolysis is reocclusion based on platelet aggregation which can result in further heart damage. Since glycoprotein
  • Ilb/IIIa (GPIIb/IIIa) receptors are known to be responsible for platelet aggregation, reagents that block these receptors are expected to reduce or prevent reocclusion following thrombolytic therapy and to accelerate the rate of thrombolysis.
  • a r ⁇ urine monoclonal antibody designated 7E3, that inhibits platelet aggregation and appears useful in the treatment of human thrombotic diseases is described in published European Patent Application Nos. 205,207 and 206,532.
  • Murine antibodies have characteristics that may severely limit their use in human therapy. They are foreign proteins, which may elicit immune reactions that reduce or destroy their therapeutic efficacy and/or evoke allergic or hypersensitivity reactions in patients. The need for readministration of such therapeutic modalities in thromboembolic disorders increases the likelihood of these types of immune reactions.
  • This invention pertains to human platelet-specific monoclonal antibodies.
  • the antibodies are specific for the GPIIb/IIIa receptor, or other platelet components. These antibodies bind to platelets, and can block platelet aggregation, and thus, are useful as antithrombotic agents, and to prevent or reduce reocclusion following thrombolysis.
  • Human platelet-specific antibodies minimize some of the problems often associated with the immunogenicity of antibodies composed of nonhuman protein.
  • the present invention relates to human platelet- specific monoclonal antibodies.
  • the antibodies are comprised entirely of human protein. These antibodies target platelet components, such as the GPIIb/IIIa receptor. The antibodies bind to platelets and thereby prevent platelet aggregation and thrombus formation.
  • the human antibodies invention are specific for platelet surface components. Preferred are specific for platelet GP Ilb/IIIa receptors; they bind to the
  • GPIIb/IIIa receptor block ligand binding to the GPIIb/IIIa receptor complex.
  • the preferred antibodies are specific for the complexed form of GPIIb/IIIa receptor.
  • antibodies can be also specific for either the GPIIb or GPIIIa components.
  • antibodies specific for other platelet antigens can also be employed.
  • human antibodies that bind to platelet granule membrane protein GMP-140 can be used.
  • platelet- specific antibodies can be prepared by obtaining lymphoid cells from an individual who produces antibody against a platelet antigen.
  • the lymphoid cells are fused to immortalizing cells to produce continuous hybrid cell lines.
  • Hybrid cells producing antibody against the desired platelet antigen are selected and cloned.
  • human monoclonal antibody specific for GPIIb/IIIa can be prepared as follows.
  • GPIIb/IIIa is normally on all human platelets, humans are 'tolerant' to this heterodimer and do not mount an antibody response to it. Certain rare individuals (e.g. individuals with Glanzmann's throm- basthenia) do not express this complex on their platelets. Individuals who lack GPIIb/IIIa may mount an antibody response when exposed to GPIIb/IIIa. Such exposure would be likely to occur during the course of transfusions that include blood platelets. Transfusion might be employed for a variety of medically justified reasons. In the case of Glanzmann patients it would be used to treat hemorrhages caused by the inability of their defective (i.e. GPIIb/IIIa lacking) platelets to aggregate properly. Following transfusions such individuals would be expected to respond immuno- logically to the GPIIb/IIIa complex just as they would to any 'foreign' protein. They would mount a B cell
  • a hybridor ⁇ a capable of secreting human monoclonal antibody specific to the human GPIIb/III complex can be made from B cells from such patients.
  • An individual is identified who has a serum antibody titer to GPIIb/IIIa. Such an individual might be one who lacks the heterodimer as in Glanzmann's thrombasthenia. This individual after having been exposed to normal
  • transfusion would be expected to develop an antibody response.
  • a normal individual might be exposed to GPIIb/IIIa in an immunogenic fashion. This might take the form of repeated transfusions wherein some of the material might become partially denatured and hence more immunogenic or it might occur through the binding of a drug or other substance to the platelets causing modification of surface molecules and eliciting an antibody response.
  • individuals with autoimmune disease such as idiopathic thrombocytopenic purpura might be suitable sources of antigen specific B lymphocytes.
  • B lymphocytes are obtained from the individual in the form of, for example, spleen, lymph nodes or peripheral blood obtained by venipuncture or pheresis.
  • the lymphoid cells can be enriched by use of a one step gradient such as Ficoll-Hypaque.
  • the recovered cells can be washed to thoroughly remove the gradient material which may be toxic.
  • Unwanted or undesirable cell populations such as suppressor cells (CD8 ) or B cells making an unwanted isotype such as IgM are removed. This may be accomplished by complement mediated lysis, cell sorting using flow cytometry or affinity purification such as 'panning'.
  • the B cells Prior to fusion, the B cells can be stimulated with antigen, lymphokines and/or other mitogenic substances or substances that will induce the B cells to synthesize and secrete antibody.
  • the appropriately stimulated cells are then fused using polyethylene glycol or other fusogenic agents or devices.
  • the fusion partner is a cell or hybrid of B cell lineage capable of supporting the synthesis and secretion of human antibodies.
  • the immortalizing cell line is a tumor cell, which endows the hybridoma with the ability to grow permanently in culture. This ensures a stable culture of antibody-producing hybridoma cells which can produce monoclonal antibodies in a continuous supply.
  • the immortalizing cell may be a plasmacytoma cell, such as a myeloma cell.
  • the myeloma cell can be human, non-human, or a heteromyeloma.
  • Suitable human immortalizing cell lines include the HMMA2.11, HF2 cell line, and the U-266.
  • a heteromyeloma is a myeloma hybrid formed by the fusion of cells of two different species. See Oestberg, U.S. Patent 4,634,664.
  • the cell fusions are accomplished by standard procedures. See, Kohler and Milstein, Natrure (London),256:495-497 (1975); Olsson and Kaplan, Proc. Natl. Acad.Sci USA 77:5429 (1980).
  • the hybridomas are then screened for production of antibodies reactive with platelets or platelet component such as the GPIIb/IIIa receptor.
  • the screening can be accomplished by an enzyme immunoassay.
  • purified GPIIb/IIIa can be bound to a solid phase.
  • the solid phase can then be contacted with hybridoma supernatant and antibody binding to the GPIIb/IIIa- solid phase can be evaluated with enzyme-conjugated anti-human antibody.
  • Hybridomas that secrete reactive antibodies are cloned.
  • Another method of forming the antibody-producing cells is by viral or oncogenic transformation.
  • human B-lymphocyte which produced a plate- specific antibody may be infected and transformed with a virus, such as the Epstein-Barr virus, to give an immortal antibody-producing cell.
  • a virus such as the Epstein-Barr virus
  • B-lymphocyte may be transformed by a transforming gene or gene product.
  • Monoclonal antibodies are generally produced In large quantities by culturing hybridomas that produce anti-platelet antibody in vitro and isolating the secreted monoclonal antibodies from the cell culture medium.
  • the human platelet-specific antibodies of this invention are useful as antithrombotic therapeutic agents.
  • the antibodies (or fragments thereof) can be used to inhibit platelet aggregation and thrombus formation.
  • the antibodies can be used in any situation where thrombus formation or reformation is to be prevented.
  • the antibody alone can be used to prevent clotting in post- angioplas ty treatment, pulmonary embolism, deep vein thrombosis and coronary bypass surgery.
  • the antibody can also be administered in conjunction which a thrombolytic agent, such as t i s sue plasminogen activator, streptokinase, single chain streptokinase, acyl-plasminogen-streptokinase activator complex, urokinase or the mutant variants of tissue plasminogen activator, streptokinase and urokinase, to prevent or reduce reocculusion that can occur after thrombolysis, and to accelerate clot lysis.
  • the antibody or fragment can be administered before, along with, or subsequent to administration of the thrombolytic agent, in an amount sufficient to prevent platelet aggregation, which can result in reocclusion.
  • the antibody is given parenterally, preferably intravenously, in a pharma- ceutically acceptable vehicle such as sterile saline.
  • a pharma- ceutically acceptable vehicle such as sterile saline.
  • the antibody could be given multiple times or by a controlled release mechanism (e.g., by a polymer or patch delivery system).
  • the platelet-specific human antibody of this invention is also useful for thrombus imaging.
  • antibody fragments are generally preferred.
  • Antibody fragments such as Fab, Fab' and F(ab')2 can be produced by standard procedures.
  • the fragments can be labeled directly, or through a coupled chelating agent such as diethylenetr iaminepentaacetic acid, with radio- isotopes such as 1 3 1 Iodine , 125 I odine , 9 9m Technetium or
  • radioimmunoscintigraphic agents Indium to produce radioimmunoscintigraphic agents.
  • the radiolabeled antibody is administered to a patient suspected of having thrombus.
  • the signal generated by the label is detected by a photoscanning device such as a gamma camera.
  • the detected signal is then converted to an image of the thrombus. The image makes it possible to locate the thrombus in vivo and to devise an appropriate therapeutic strategy.
  • the donor was lymphopheresed using a Fenwal CS3000
  • the cells were collected in an acid-citrate dextrose anticoagulant. A total of 125ml containing 1.6x10 9 cells were obtained. A white cell differential analysis showed 93% lymphocytes.
  • the cells were diluted 1:3 in Hanks' Balanced Salt Solution (HBSS) and layered over Ficoll-Paque. The cells recovered from the interface were washed two times in HBSS. Recovery by Coulter count was 1.5x10 9 .
  • HBSS Hanks' Balanced Salt Solution
  • the cells were pooled into 4 groups (which were processed separately throughout the remainder of the experiment) and each pool was placed in a 75cm 2 tissue culture flask which had been pre-coated with 50 ⁇ g/ml of goat anti-human IgM and 50 ⁇ g/ml of mouse monoclonal anti-CD8 antibodies for 2hrs at 4°C. The cells were allowed to adhere to the antibody coated plates for 45 minutes with occasional gentle agitation at 4oC. At the end of this 'panning' step 1.0x10 9 cells (Coulter count) were recovered by gently removing the non-adherent cells.
  • the cells were washed with HBSS and each group was seeded at 2x10 6 cells/ml in 30ml in 75cm 2 tissue culture flasks (4 flasks/group, a total of 16 flasks).
  • Each 500ml of medium ('modified' alpha MEM) was supplemented with Eagle's nonessential amino acids (100x, 5ml), sodium pyruvate (100mM, 5ml), glutamine (200mM, 5ml), fetal bovine serum (100ml), gentamycin (50mg/ml; 2.5ml), Pokeweed Mitogen (Gibco, 0.25ml), and GPIIb/IIIa adsorbed to fumed silica (final concentration of
  • GPIIb/IIIa l ⁇ g/ml
  • the cells were incubated for 4 days at 37°C in a humidified atmosphere of 5% CO 2 in air.
  • the stimulated lymphocytes were fused with the human myeloma analogue HMMA 2.11tg/o.
  • the lymphocytes in each group were mixed with an equivalent number (1x10 9 ) of HMMA cells.
  • the cells were washed 2 times in HBSS, pH 7.8 and the resulting pellets were very slowly resuspended in 1.5ml of polyethylene glycol (PEG)

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Biochemistry (AREA)

Abstract

On décrit des fragments humains d'immunoglobulines et des fragments humains d'immunoglobulines monoclonales qui sont spécifiques contre les plaquettes de sang. Lesdites immunoglobulines, ou fragments de celles-ci, sont de préférence spécifiques contre le récepteur de glycoprotéine IIb/IIIa dans sa forme complexée. Ces anticorps bloquent la liaison de ligand au récepteur, empêchant ainsi l'agrégation plaquettaire impliquée dans la formation de thrombi. Ces immunoglobulines sont utiles dans la thérapie anti-thrombotique,s eules ou en combinaison avec des agents thrombolytiques, ainsi que dans l'imagerie scintigraphique de thrombi.
PCT/US1989/005418 1988-12-01 1989-11-29 Anticorps humains specifiques de plaquettes WO1990006134A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US27880588A 1988-12-01 1988-12-01
US278,805 1988-12-01

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WO1990006134A1 true WO1990006134A1 (fr) 1990-06-14

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992010520A1 (fr) * 1990-12-12 1992-06-25 The Blood Center Research Foundation Anticorps monoclonal op-g2 et procede d'utilisation
US5196403A (en) * 1989-01-27 1993-03-23 Biogen, Inc. Method of inhibiting platelet activation
EP0557535A1 (fr) * 1991-09-17 1993-09-01 Teijin Limited ANTICORPS MONOCLONAL HUMAIN CONTRE LA GLYCOPROTEINE IIb/IIIa
US5242810A (en) * 1990-12-07 1993-09-07 Biogen, Inc. Bifunctional inhibitors of thrombin and platelet activation
WO1998055619A1 (fr) * 1997-06-06 1998-12-10 Asat Ag Applied Science & Technology Anticorps recombines anti-gpiib/iiia
WO2004069875A2 (fr) * 2003-02-06 2004-08-19 University Of Bradford Immunoglobuline
EP1539236A2 (fr) * 2002-07-03 2005-06-15 The Trustees of The University of Pennsylvania Compositions, procedes et kits ayant trait a des auto-anticorps antiplaquettaires et leurs inhibiteurs

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0205270A2 (fr) * 1985-06-07 1986-12-17 The Research Foundation Of State University Of New York Anticorps monoclonal antiplaquettaire marqué pour la visualisation de caillots sanguins in vivo
EP0206533A2 (fr) * 1985-06-14 1986-12-30 The Research Foundation Of State University Of New York Fragment d'anticorps monoclonal inhibant les plaquettes
EP0206532A2 (fr) * 1985-06-07 1986-12-30 The Research Foundation Of State University Of New York Anticorps monoclonal bloquant le fibrinogène

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0205270A2 (fr) * 1985-06-07 1986-12-17 The Research Foundation Of State University Of New York Anticorps monoclonal antiplaquettaire marqué pour la visualisation de caillots sanguins in vivo
EP0206532A2 (fr) * 1985-06-07 1986-12-30 The Research Foundation Of State University Of New York Anticorps monoclonal bloquant le fibrinogène
EP0206533A2 (fr) * 1985-06-14 1986-12-30 The Research Foundation Of State University Of New York Fragment d'anticorps monoclonal inhibant les plaquettes

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Blood, Vol. 70, No. 1, July 1987 D.J. Nugent et al: "A human monoclonal autoantibody recognizes a neoantigen on glycoprotein IIIA expressed on stored and activated platelets ", *
British Medical Bulletin, Vol. 40, No. 3, 1984 K. Sikora: "Human monoclonal antibodies ", *
British Medical Journal, Vol. 293, December 1986 A.M. Peters et al: "Imaging thrombus with radiolabelled monoclonal antibody to platelets ", *
J. Clin. Invest., Vol. 81, April 1988 T. Y. Herman et al: "Monoclonal antibody against the platelet glycoprotein (GP) IIb/IIIa receptor prevents coronary artery reocclusion after reperfusion with recombinant tissue-type plasminogen activat", *
J. Clin. Invest., Vol. 81, January 1988 S.R. Hanson et al: "Effects of monoclonal antibodies against the platelet glycoprotein IIb/IIIa complex on thrombosis and hemostasis in the baboon ", *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5196403A (en) * 1989-01-27 1993-03-23 Biogen, Inc. Method of inhibiting platelet activation
US5242810A (en) * 1990-12-07 1993-09-07 Biogen, Inc. Bifunctional inhibitors of thrombin and platelet activation
WO1992010520A1 (fr) * 1990-12-12 1992-06-25 The Blood Center Research Foundation Anticorps monoclonal op-g2 et procede d'utilisation
EP0557535A1 (fr) * 1991-09-17 1993-09-01 Teijin Limited ANTICORPS MONOCLONAL HUMAIN CONTRE LA GLYCOPROTEINE IIb/IIIa
EP0557535A4 (fr) * 1991-09-17 1994-02-16 Teijin Limited
WO1998055619A1 (fr) * 1997-06-06 1998-12-10 Asat Ag Applied Science & Technology Anticorps recombines anti-gpiib/iiia
US6790938B1 (en) 1997-06-06 2004-09-14 Asat Ag Applied Science & Technology Anti-GPIIb/IIIa recombinant antibodies
EP1539236A2 (fr) * 2002-07-03 2005-06-15 The Trustees of The University of Pennsylvania Compositions, procedes et kits ayant trait a des auto-anticorps antiplaquettaires et leurs inhibiteurs
EP1539236A4 (fr) * 2002-07-03 2007-07-18 Univ Pennsylvania Compositions, procedes et kits ayant trait a des auto-anticorps antiplaquettaires et leurs inhibiteurs
WO2004069875A2 (fr) * 2003-02-06 2004-08-19 University Of Bradford Immunoglobuline
WO2004069875A3 (fr) * 2003-02-06 2005-04-07 Univ Bradford Immunoglobuline
JP2007527201A (ja) * 2003-02-06 2007-09-27 ユニバーシティ・オブ・ブラッドフォード 抗インテグリン免疫グロブリン

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Publication number Publication date
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