EP0804484A1 - Antigene polypeptidsequenz von faktor viii, fragmenten und/oder epitope davon - Google Patents

Antigene polypeptidsequenz von faktor viii, fragmenten und/oder epitope davon

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Publication number
EP0804484A1
EP0804484A1 EP95927598A EP95927598A EP0804484A1 EP 0804484 A1 EP0804484 A1 EP 0804484A1 EP 95927598 A EP95927598 A EP 95927598A EP 95927598 A EP95927598 A EP 95927598A EP 0804484 A1 EP0804484 A1 EP 0804484A1
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EP
European Patent Office
Prior art keywords
epitope
sequence
asp
factor viii
glu
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
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EP95927598A
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English (en)
French (fr)
Inventor
Ruth Laub
Mario Di Giambattista
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CAF - DCF cvba - scrl
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Croix-Rouge de Belgique
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Publication of EP0804484A1 publication Critical patent/EP0804484A1/de
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/745—Blood coagulation or fibrinolysis factors
    • C07K14/755—Factors VIII, e.g. factor VIII C (AHF), factor VIII Ag (VWF)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to the antigenic polypeptide sequence of factor VIII, fragments, epitopes thereof and the strong parts of these epitopes, the inhibitors directed against this sequence, its fragments, its epitopes and / or the strong parts of these epitopes. , as well as the anti-inhibitors directed against said inhibitors.
  • the present invention also relates to a pharmaceutical composition and a diagnostic device comprising the above-mentioned molecules.
  • FVIII is a glycoprotein cofactor for plasma coagulation and acts on the activation of factor X (FX).
  • FX factor X
  • the characterization of FVIII and its mechanism of action is made more difficult by its low concentration in plasma, size heterogeneity, and its extreme sensitivity to enzymatic degradation.
  • FVIII is such a complex protein that, although the gene sequence has been known since 1984 (Verhar et al., Nature 312, pp. 317-342 (1984)), the complete structure of plasma FVIII has not yet been established. (almost 50% of the protein has only been sequenced) as well as the precise structure of the carbohydrates.
  • the DNA sequence has been accepted as defining the primary sequence of FVIII (rare exception to guidelines prescribed by the FDA for therapeutic products derived from biotechnology).
  • FVIII farnesoid protein
  • hepatocytes The cDNA of FVIII has also been expressed in transgenic sheep (Halter et al., 1993).
  • CDNA codes for a polypeptide of 2351 amino acids including the signal peptide of 19 amino acids cleaved in the endoplasmic reticulum.
  • Post-translational modifications take place in the Golgi apparatus: glycosylation of serines and threonmes and addition of sulphate ions to tyrosine residues.
  • the protein After maturation, the protein is then secreted in the plasma, in the form of 2 chains 210 kDa (there 1648 residues) and 80 Da (from 1649 to 2332 residues) united by a divalent ion, and the lightest of which is associated non-covalently to von Willebrand Factor (vWf) by its N-terminal end (1 molecule vWf per molecule of FVIII).
  • vWf von Willebrand Factor
  • the FVIII is made up of three structural domains A, B and C (Kaufman RJ, 1992; Bihoreau et al., 1992) organized in Al: A2: B: A3: C1: C2 ( Figure 1). Domains A have more than 40% homology and are also homologous to ceruloplasmin. There is also 30% homology between the A domain of factor V and FVIII. Domain C intervenes twice and would be able to bind glycoconjugates and phospholipids with negative net charge (Kemball-Cook and Barrowcliffe (1992); Fay, PJ, 1993)). It presents a homology with lectins capable of binding to negatively charged phospholipids.
  • Domain C2 which represents more than 40% of the mass of FVIII, has no known specific activity but could play a subtle role in the regulation of FVIII by protecting it, for example, from the action of thro bine. It has no known homology with other proteins.
  • the bond of the two chains is non-covalent and results via a bond of a divalent metal ion (Me ++) between the residues responsible for the domains Al and A3.
  • a divalent metal ion Me ++
  • a mactivation phase is observed probably following prolonged contact with thrombin and dissociation of the 50 kDa fragments. and 45 kDa.
  • FVIIIa is also inactivated by activated protein C (APC) after proteolysis of the heavy chain. This mactivation is accelerated if the FVIIIa is fixed on a phospholipic surface.
  • antigenic determinants consist of fragments 351 - 365 (domain Al - heavy chain), 713 - 740 (domain A2), 1670 - 1684 (domain A3 - light chain) (NH2 terminal of the light chain) or 2303 - 2332 ( domain C2 - light chain) (Foster C, (1990)), the fragments 701 - 750 (Ware et al. (1989)), 1673 - 1689 (Leyte et al. (1989)), 330 - 472, 1694-1782 (EP-0 202 853), 322 - 740 and 2170 - 2322 (Scandella et al. (1992)).
  • the antibodies recognize these various sites, respectively interfere with the activation of FVIII, the binding of vWf or the binding of phospholipids.
  • Other antibodies which are not inhibitors of conventional in vitro activity tests, can act on the action of FVIII with the other constituents of the coagulation cascade by binding to sites on the molecule which are very far from the active sites. These, thus modified, can interfere with the natural folding of FVIII, altering some of its properties ("allosteric model").
  • mapping experiments use peptides synthesized by fragments of FVIII genes cloned into E coii, and allowing only an approximate idea of the location of the antigenic determinants recognized by these monoclonals. Indeed, the size of the identified fragments ranges from 30 to 100 amino acids.
  • the antigenic regions coincide with the hydrophilic character of these regions: the more the oligopeptide sequence is exposed to the external medium (located on the surface), the more this part will be likely to be recognized in an immunization reaction.
  • the hydrophobic parts generally located inside the protein, are considered to be not very antigenic.
  • IL-2 (Triulzi et al., 1990).
  • FVIII 0.5 to 10 U / mg proteins
  • Activated factor VIII obtained by recombinant DNA, has also been used as an alternative coagulation pathway in patients with inhibitors (Ingerslev et al. (1991)).
  • IVIG polyvalent intravenous immunoglobulins
  • the present invention aims to obtain an antigenic polypeptide sequence of factor VIII, fragments and epitopes thereof, intended to improve the diagnosis and / or therapy of immune disorders, in particular those induced by FVIII inhibitors, the inhibitors of the binding of FVIII to von Willebrand factor (vWf) and / or to membrane phospholipids (PL).
  • FVIII inhibitors the inhibitors of the binding of FVIII to von Willebrand factor (vWf) and / or to membrane phospholipids (PL).
  • Another object of the invention is to obtain inhibitors having immunoaffinity with this antigenic polypeptide sequence, its fragments and / or its epitopes, also intended to improve the diagnosis and / or the therapy. immune disorders.
  • FIG. 1 schematically represents the polypeptide sequence of factor VIII.
  • FIG. 2 represents the hydrophilicity graph of the A3 sequence of factor VIII renumbered from 1 to
  • FIG. 3 represents the flexibility graph of this A3 sequence of factor VIII.
  • FIG. 4 represents the accessibility graph of this A3 sequence of factor VIII.
  • FIG. 5 represents the general graph showing the sum of the values defined in graphs 2 to 4.
  • FIG. 6 represents the detection of anti-factor VIII antibodies in the sera of mice by an ELISA test. Characteristic elements of the invention.
  • the present invention relates to the antigenic polypeptide sequence of factor VIII and / or fragments thereof, as described by Verhar et al. (Nature, vol. 312, p 339 (1984)).
  • factor VIII polypeptide sequence means the natural human or animal sequence, optionally glycosylated, obtained by purification of plasma pools, in particular Cohn fraction I, by synthesis and / or genetic engineering (that is to say also say a possibly deleted sequence of the portions not involved in the blood coagulation mechanism) of factor VIII.
  • the present invention relates in particular to the factor VIII antigenic polypeptide sequence lacking fragments Alanine 322 - Serine 750, Leucme 1655 - Arginine 1689, Lysine 1694 - Prolme 1782 and Aspartic Acid 2170 - Tyrcsme 2332.
  • the present invention relates in particular to the antigenic polypeptide sequences A1, A2, A3, and C (Cl and C2) of factor VIII.
  • amino acids will be represented by their three-letter abbreviation or by the symbol of a single letter as identified in the table below.
  • a first embodiment of the invention relates to the A3 antigenic polypeptide sequence of factor VIII, fragments and / or epitopes thereof.
  • Said sequence is between Glutamic Acid 1649 and Asparagine 2019, preferably between Arginine 1652 and Arginine 1917 or between Arginine 1803 and Arginine 1917, of the polypeptide sequence of factor VIII such as published by Verhar et al. (Nature, vol. 312, p 339 (1984)) and Toole et al. (Nature, vol. 312, pp. 342-347 (1984)).
  • the fragments of said sequence are between Arg ine 1652 and Arginme 1696, preferably between Arginine 1652 and Argmine 1689, between Threonine 1739 and Aspartic Acid 1831 or between Acid Glutamic 1885 and Arginine 1917.
  • the invention also relates to the sequence epitopes of these fragments, in particular:
  • Threonine 1739 and Tyrosine 1748 defined by the following sequence:
  • SEQ ID NO: 7 Glu Thr Lys Ser Trp Tyr Phe 1 5
  • said sequence, its specific fragments and its epitopes exhibit an antigenic characteristic illustrated by FIGS. 2 to 5 appended.
  • Another preferred embodiment of the invention relates to the A1 antigenic polypeptide sequence of factor VIII, fragments and / or epitopes thereof.
  • the fragments of said sequence are between Alanine 108 and Methionine 355, preferably between Alanine 108 and Glutamine 228.
  • the invention also relates to the sequence epitopes of these fragments, in particular: - the epitope between Alanine 108 and Val e 128 defined by the following sequence: SEQ ID NO: 10:
  • Another preferred embodiment of the invention relates to the A2 antigenic polypeptide sequence of factor VIII, fragments and / or epitopes thereof.
  • the fragments of said sequence are between the Aspartic Acid 403 and the Aspartic Acid 725, preferably between the Histidme 693 and the Aspartic Acid 725.
  • the invention also relates to the epitopes of the sequence of these fragments, in particular: the epitope comprised between Aspartic Acid 403 and Lysine 425 defined by the following sequence:
  • Glycine 701 defined by the following sequence: SEQ ID NO: 16:
  • a final preferred embodiment of the invention relates to the factor VIII antigenic polypeptide sequence C, fragments and / or epitopes thereof.
  • the fragments of said sequence are between Lysine 2085 and Lysine 2249, preferably between Lysine 2085 and Glycine 2121.
  • the invention also relates to the epitopes of the sequence of these fragments, in particular: - the epitope between Lysine 2085 and Phenylalanine 2093 defined by the following sequence:
  • the epitope comprised between Aspartic Acid 2108 and Glycine 2121 defined by the following sequence:
  • the invention also relates to the strong parts of said epitopes or of said fragments, that is to say the sequence portions of said epitopes comprising the amino acids Tyrosine and Histidme, which unexpectedly exhibit a particularly high affinity towards factor VIII inhibitors.
  • these strong parts comprise said amino acid Tyrosine or Histidine linked to at least two other identical or different amino acids.
  • sequences, these fragments and these epitopes, in particular the strong parts of the epitopes or of the fragments, are characterized in a particularly advantageous manner by a high hydrophilicity as described by Parker, Guo and Hodges (Biochemistry 25, pp 5425-5432 (1986) ), significant flexibility as described by Karplus and Schultz (Naturwissenschaften 72, p 212 (1985)) and significant accessibility as described by Janin (Nature 277, pp 491-492 (1979)) (see Figures 2 to 5) .
  • said polypeptide sequence, its fragments, its epitopes and / or these strong parts of said fragments or said epitopes are also independently immunogenic (that is to say that they are immunogenic even without being complexed with a large protein such as BSA, hemocyanin, ...), and preferably exhibit immunoaffinity with factor VIII inhibitors, such as anti-factor VIII antibodies and / or exhibit immunoaffinity for T and / or B lymphocyte receptors .
  • sequences are therefore characterized by a high immunogenicity with respect to monoclonal and polyclonal antibodies.
  • the peptides Asp 1681 - Arg 1696 and Asp 327 - Met 355 were synthesized to demonstrate anti-factor VIII antibodies in the sera of mice by an ELISA test.
  • the present invention also relates to conformational epitopes comprising at least two different fragments of said sequence, at least two epitopes of sequence and / or at least two strong parts of said epitopes or said different fragments according to the invention and identified above. of two or several different portions of a polypeptide sequence located close to each other during the folding of the protein into its tertiary or quaternary structure.
  • epitopes are likely to be "recognized” (that is to say to have an immunoaffinity), preferably simultaneously, with inhibitors of factor VIII, in particular B lymphocytes (via the major locus of histoco patibility
  • said sequence, said fragments, said epitopes and / or the strong parts of said epitopes or said fragments are complexed with a carrier protein or a carrier peptide, such as BSA or hemocyanin, so as to form a complex having a stronger immunogenicity.
  • Another aspect of the present invention relates to a factor VIII inhibitor having immunoaffinity with the antigenic polypeptide sequence according to the present invention, with fragments, epitopes thereof, strong parts of said epitopes or said fragments and / or the complex. according to the invention.
  • inhibitor is intended to mean any biological molecule or cell intervening with and / or against factor VIII, and capable of creating immune disorders.
  • an inhibitor can be a monoclonal or polyclonal antibody (gamma globulin) or an anti-factor VIII antibody fragment (such as the hypervariable Fab portion of said antibody), which inactivates said factor VIII and / or which inhibits the binding of factor VIII to von Willebrand factor and / or to membrane phospholipids.
  • said inhibitors are synthesized by a "chimeric" animal comprising a human immune system such as a SCID-hu mouse producing human antibodies.
  • SCID severe combined immunodeficient mice are mice with a deficiency in functional B and T lymphocytes due to a dysfunction in the recombination of the genes responsible for antigenic receptors.
  • the immune systems of SCID mice can be reconstituted with human immunocompetent cells from fetal organs or peripheral blood (Mosler et al. (1988) •
  • Peripheral blood lymphocytes are taken from several types of donors: non-hemophiliac volunteers, hemophiliacs lacking inhibitors detectable by conventional methods, hemophiliacs with a high rate inhibitors as well as donors producing auto ⁇ antibodies.
  • This model is used in two types of work.
  • mice is obtained with cells from a single donor, and after checking the reproducibility of the system, the antigenicity of several preparations of factor VIII can be compared.
  • B cells are cultured cloned in the presence or not of anti-CD40, from the spleen of mice producing anti-factor VIII, or else transformed in the presence of the EBV virus.
  • Anti-CD40 antibodies recognize a membrane antigen and activate B cells in the presence of a line of fibroblasts (Banchereau et al. (1991)). It is therefore possible to envisage the use of these immunodominant epitopes as a possible target of immunotherapy.
  • MHC class I and class II markers carried by the clones of B lymphocytes makes it possible to analyze the immune response of anti-factor VIII at the genetic level, and thus to follow the recognition by specific T cells. This is also a great method to see if there is a risk factor associated with this condition.
  • BALB / C mice chosen for the preparation of anti-factor VIII mAbs are injected three times beforehand, 2 weeks apart with a solution of recombinant factor VIII (rFVIII).
  • This type of preparation has the advantage of containing a factor VIII of high purity at a high concentration with a minimum of contaminating proteins.
  • SP207 mouse myeloma
  • the selection of hybridomas producing anti-factor VIII antibodies are carried out by the ELISA technique using polystyrene plates on which rFVIII has previously been insolubilized.
  • Supernatants of hybridomas containing anti-factor VIII antibodies are cloned by the limiting dilution technique, then cultured in vitro.
  • the antibodies are purified by chromatography from these supernatants.
  • the quantification, the determination of the light chain (k or 1) and the subclass (IgGl, IgG2a, IgG2b, IgG3) of anti-factor VIII mAbs are carried out by the ELISA technique.
  • the determination of the epitopes recognized on the factor VIII molecule is carried out by the immunoblot technique with native factor VIII solutions or after enzymatic cleavage with thrombin.
  • the capacity of the anti-factor VIII mAbs produced to inhibit function is evaluated, for each of these, by a coagulation method (Bethesda method) (Kasper et al.
  • the cell lines producing human monoclonal anti-factor VIII antibodies are derived from human B lymphocytes taken from the abdominal cavity of SCID mice immunized with different batches of factor VIII after reconstitution of the animal immune system with human lymphocytes.
  • the B lymphocytes are cultured in the presence of fibroblastic cells expressing a receptor for the Fc portion of the immunoglobulins to which a monoclonal anti-CD40 antibody is attached.
  • These cells activated by the polymerization of the CD40 receptor, are then infected and immortalized by the Epstein-Barr virus (Kozbor, (1981)).
  • the cell lines producing the desired antibodies can then be subcloned.
  • Another aspect of the invention relates to an anti ⁇ inhibitor characterized in that it is directed against said factor VIII inhibitor previously described.
  • anti-inhibitor directed against the factor VIII inhibitor means any biological molecule and / or cell capable of interfering with said inhibitor so as to ensure its inactivation.
  • such an anti-inhibitor is an antibody (monoclonal or polyclonal), or a fragment of anti-idiotypic anti-factor VIII antibody.
  • these anti-inhibitors directed against factor VIII inhibitors are synthesized by a "chimeric" animal exhibiting a human immune system such as a SCID-hu mouse. Only mice which produce less than 10 ⁇ g / ml of residual immunoglobulins are used for the experiments.
  • the model is developed using peripheral white blood cells from volunteers immunized against tetanus.
  • Reconstitution is carried out with a single i.p. from 15 to 20,106 mononuclear cells of human origin. These cells are obtained after centrifugation in a Ficoll-Hypaque gradient of peripheral blood (approximately 200 ml). Twelve to twenty mice can be reconstructed from a single donor. The production of human immunoglobulins is measured as a function of time.
  • Anti-idiotypic anti-factor VIII antibodies are purified from a starting plasma pool, which is made up of voluntary donations from at least 7200 donors to increase the probability of finding anti-idiotypic antibodies, by immunoaffinity by means of human anti-factor VIII antibodies covalently attached to a Sepharose column or by an Fc part to a protein G column. After fractionation, by the Cohn-Oncley method, two rich Fr II and Fr III fractions in IgG are obtained. They will serve as a starting preparation for the purification of anti-idiotypic antibodies. These monoclonal antibodies will be obtained from B cells collected from hemophiliac patients. These cells have previously proliferated in SCID mice and have been transformed into secreting cell cultures by the EBV virus.
  • the idiotype specific to human antibodies is analyzed by sequencing the variable part of the molecule. These data "are of extreme importance, because they are of great utility .. both in the diagnosis and the regulation of the production of anti-factor VIII.
  • Anti-factor VIII antibodies prepared from a pool of gamma globulins can advantageously replace the autologous source.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an element chosen from the group consisting of said factor VIII antigenic polypeptide sequence, fragments, epitopes thereof and / or strong parts of said epitopes or said fragments, a a factor VIII inhibitor directed against them, an anti-inhibitor directed against said inhibitor, and / or a mixture of them.
  • a diagnostic and / or purification device such as a diagnostic kit or a chromatography column (as described by Ezzedine et al. (1993)), comprising an element chosen from group consisting of the antigenic polypeptide sequence according to the invention, fragments, epitopes thereof and / or the strong parts of said epitopes or said fragments, the complex according to the invention, an inhibitor directed against them, an anti-inhibitor directed against said inhibitor, and / or a mixture thereof.
  • the purification device can therefore consist of a chromatography column as described by Ezzedine et al. (1993), comprising the factor VIII sequence, fragments, epitopes thereof and / or the strong parts of said fragments or epitopes attached to the solid phase of the chromatography column.
  • a physiological liquid (such as serum) from a patient comprising inhibitors of factor VIII is then passed over this chromatography column, said inhibitors (for example antibodies) binding specifically to said factor VIII, said fragments. said epitopes or said strong parts.
  • a final aspect of the invention relates to the use of the pharmaceutical composition according to the invention, for the preparation of a medicament intended for the prevention and / or treatment of immune disorders, in particular those induced by factor VIII inhibitors , von Willebrand factor VIII binding inhibitors (vWF) and / or inhibitors of factor VIII binding to membrane phospholipids.
  • anti-inhibitors anti-idiotypic anti-factor VIII antibodies
  • vWF von Willebrand factor VIII binding inhibitors

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EP95927598A 1994-07-14 1995-07-14 Antigene polypeptidsequenz von faktor viii, fragmenten und/oder epitope davon Withdrawn EP0804484A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
BE9400666A BE1008491A3 (fr) 1994-07-14 1994-07-14 Sequence polypeptidique antigenique du facteur viii, fragments et/ou epitopes de celle-ci.
BE9400666 1994-07-14
PCT/BE1995/000068 WO1996002572A2 (fr) 1994-07-14 1995-07-14 Sequence polypeptidique antigenique du facteur viii, fragments et/ou epitopes de celle-ci

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EP0804484A1 true EP0804484A1 (de) 1997-11-05

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US (1) US6866848B2 (de)
EP (1) EP0804484A1 (de)
JP (2) JPH10506610A (de)
BE (1) BE1008491A3 (de)
CA (1) CA2195126A1 (de)
WO (1) WO1996002572A2 (de)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020068303A1 (en) 1994-07-14 2002-06-06 Ruth Laub Antigenic polypeptide sequences of factor VIII, and fragments and/or epitopes of these sequences
JPH11507664A (ja) * 1995-06-12 1999-07-06 ステイヒテイング・セントラール・ラボラトリウム・バン・デ・ブレドトランスフシーデイーンスト・バン・ヘト・ネーデルランドセ・ロデ・クルイス 第ｖｉｉｉ因子由来の第ｉｘ因子結合ペプチド及び血液凝固のインヒビターとしてのそれらの使用
EP0885394B1 (de) * 1996-03-08 2000-08-16 Octapharma AG Verfahren zur eignungsprüfung von faktor viii-haltigen proteinfraktionen
FR2830865B1 (fr) 2001-10-17 2004-10-22 Centre Nat Rech Scient Leurres peptidiques pour la preparation de medicaments destines a la prevention ou au traitement des pathologies auto-immunes, ou des troubles lies a l'apparition d'anticorps diriges contre des proteines exogenes
EP1495052B9 (de) * 2002-04-18 2009-12-16 MERCK PATENT GmbH Modifizierter faktor viii
US7632921B2 (en) * 2004-11-12 2009-12-15 Bayer Healthcare Llc Site-directed modification of FVIII
CA2632714A1 (en) 2005-12-07 2007-06-14 Technische Universitaet Muenchen Small peptidic and peptido-mimetic affinity ligands for factor viii and factor viii-like proteins
FR2913020B1 (fr) * 2007-02-23 2012-11-23 Biomethodes Nouveaux facteurs viii pour le traitement des hemophiles de type a
ES2610356T3 (es) 2009-02-03 2017-04-27 Amunix Operating Inc. Polipéptidos recombinantes extendidos y composiciones que comprenden los mismos

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0317279A2 (de) * 1987-11-17 1989-05-24 Scripps Clinic And Research Foundation Peptide für die Verwendung zur Reinigung von Faktor-VIII

Family Cites Families (2)

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Publication number Priority date Publication date Assignee Title
US4649132A (en) * 1983-03-31 1987-03-10 Scripps Clinic And Research Foundation Treatment of Factor VIII inhibitors
US4965199A (en) * 1984-04-20 1990-10-23 Genentech, Inc. Preparation of functional human factor VIII in mammalian cells using methotrexate based selection

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0317279A2 (de) * 1987-11-17 1989-05-24 Scripps Clinic And Research Foundation Peptide für die Verwendung zur Reinigung von Faktor-VIII

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE MEDLINE NLM2119526; FOSTER P.A. ET AL: "A synthetic factor VIII peptide of eight amino acid residues (1677-1684) contains the binding region of an anti-factor VIII antibody which inhibits the binding of factor VIII to von Willebrand factor" *
SHIMA M ET AL: "Localization of the binding site for a factor VIII activity neutralizing antibody to amino acid residues Asp1663-Ser1669.", THE JOURNAL OF BIOLOGICAL CHEMISTRY 25 JUL 1988 LNKD- PUBMED:2455712, vol. 263, no. 21, 25 July 1988 (1988-07-25), pages 10198 - 10203, ISSN: 0021-9258 *

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WO1996002572A3 (fr) 1997-02-13
JPH10506610A (ja) 1998-06-30
CA2195126A1 (fr) 1996-02-01
JP2006316062A (ja) 2006-11-24
WO1996002572A2 (fr) 1996-02-01
US20030147900A1 (en) 2003-08-07
US6866848B2 (en) 2005-03-15

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