WO2008151847A1 - Peptides de liaison aux autoanticorps et leur utilisation pour le traitement de maladies vasculaires - Google Patents

Peptides de liaison aux autoanticorps et leur utilisation pour le traitement de maladies vasculaires Download PDF

Info

Publication number
WO2008151847A1
WO2008151847A1 PCT/EP2008/005044 EP2008005044W WO2008151847A1 WO 2008151847 A1 WO2008151847 A1 WO 2008151847A1 EP 2008005044 W EP2008005044 W EP 2008005044W WO 2008151847 A1 WO2008151847 A1 WO 2008151847A1
Authority
WO
WIPO (PCT)
Prior art keywords
peptide
peptides
occlusion
receptor
nucleic acid
Prior art date
Application number
PCT/EP2008/005044
Other languages
English (en)
Inventor
Gerd Wallukat
Thomas Harrer
Dandel Michael
Original Assignee
Max-Delbrück-Centrum für Molekulare Medizin
Deutsches Herzzentrum Berlin
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 Max-Delbrück-Centrum für Molekulare Medizin, Deutsches Herzzentrum Berlin filed Critical Max-Delbrück-Centrum für Molekulare Medizin
Publication of WO2008151847A1 publication Critical patent/WO2008151847A1/fr

Links

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
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4713—Autoimmune diseases, e.g. Insulin-dependent diabetes mellitus, multiple sclerosis, rheumathoid arthritis, systemic lupus erythematosus; Autoantigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/62—DNA sequences coding for fusion proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/40—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/50—Fusion polypeptide containing protease site

Definitions

  • the invention relates to peptides, nucleic acids encoding for such peptides and the use of the peptides and nucleic acids in detection and treatment of diseases relating to the group of vascular diseases.
  • the invention relates more specifically to peptides being epitopes for antibodies and nucleic acid molecules encoding peptides which interact with autoantibodies associated with vascular diseases to the peptides themselves, to a pharmaceutical composition comprising said nucleic acid molecules and peptides, and to the use of said peptides - especially in apheresis - for the treatment of vascular diseases.
  • antibodies An important regulatory mechanism enabling the organism to cope successfully with microorganisms, and parasites is to provide cellular and humoral substances, such as antibodies.
  • the function of antibodies is based on the capability of dis- tinguishing between "foreign” and "self. That is, the organism itself produces antibodies which are designed in such a way that endogenous structures such as tissues or organs are not attacked, but bind to bacteria, parasites or other exogenic components, thus initiating or supporting immunological reactions.
  • somatic hypermutations of antibody-producing B cells occur during T cell-dependent immune response.
  • Such mutations selectively involve immunoglobulin genes, being essential to the formation of precursor cells of antibody-forming cells with high affinity. It should be noted in this context that such mutation is a normal and essentially non- pathogenic process. However, mutations may also give rise to the formation of highly affine autoantibodies, thus doing damage to the organism.
  • Autoantibodies are closely associated with the development of autoimmune diseases or causally responsible for such diseases.
  • Antibody-mediated autoimmune diseases also include diseases such as rheumatism or lupus erythematosus. Numerous autoimmune diseases, being highly inconvenient to affected persons, relate to important biochemical cycles in the organism.
  • the object of the present invention is to provide means and methods for the treatment of autoantibody related diseases, especially vascular diseases.
  • the present invention is based on the discovery that in patients suffering from coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma are autoantibodies present binding to the Endothelin-I-Receptor (ETA). For coronary arterial occlusion, angina pectoris and Raynaud syndrome / scleroderma are additionally autoantibod- ies present binding the Protease-Activated-Receptor (PAR) 1 , 2 and/or 3. Finally, patients suffering from pulmonary hypertension or occlusion of peripheral arterial vessels the ⁇ 1-Adrenergic-Receptor is bound by autoantibodies.
  • ETA Endothelin-I-Receptor
  • PAR Protease-Activated-Receptor
  • the present invention provides a peptide as part of an epitope binding to an autoantibody, whereas the peptide comprises at least one of the following amino acid sequences
  • Such a peptide is able to bind to the ETA.
  • a peptide of the present in- vention comprises whether the amino acid sequences chosen from the group APEDET 1 WKEPAP or PPDERF, or from the group ITTCHDVL, LNITTCHD or PALNITTC.
  • Such peptides are able to bind additionally the PAR 1 , 2 or 3 or the ⁇ 1- Adrenergic-Receptor.
  • the invention provides a peptide characterized by an epitope for autoantibodies directed against endothelin-l receptor, protease-activated receptor 1 , 2 or 3 and/or ⁇ 1 -adrenergic receptor.
  • a peptide according to the present invention is characterized in that is selected from the group consisting of: a) a peptide comprising at least one of the amino acid sequences mentioned above; b) a peptide consisting of an amino acid sequence having sufficient homology to be functionally analogous to an amino acid sequence in accordance with a);
  • Such peptides are further characterized in that the amino acid sequence specified under b) has at least 40% homology to any of the amino acid sequences specified under a). Especially an amino acid sequence specified under b) has at least 60%, preferably 70%, more preferably 80%, especially preferably 90% homology to any of the amino acid sequences specified under a).
  • Another objective of the present invention is the use of the peptides of the invention as medical active substances. This includes the us of the peptides for preparation of a medicament for the treatment of patients suffering from coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma. As previously mentioned the peptides bind specifically to autoantibodies occurring in patients suffering from the listed diseases.
  • peptides of the invention are intended for being immobilized and/or fixed to magnetic, paramagnetic and/or non magnetic nanoparticles or being bound to a solid phase.
  • the present invention includes peptides that are inear and branched as well as in cyclic form, whereas the peptide ring closure is effected through disulfide bridging when two cysteines are present, or through amide cyclization, which is optionally effected through side chains, through the C and N termini or through a combination of these three possibilities. Additionally chemical modifications of the peptides are intended like additional amino groups, amides, acetyl groups, biotin groups, markers, spacers and/or linkers.
  • a further objective of the present invention is an isolated nucleic acid molecule selected from the group comprising: a) a nucleic acid molecule comprising a nucleotide sequence which encodes at least one peptide selected from the group consisting of peptides of claim 1 , 2 or 3;
  • nucleic acid molecule which undergoes hybridization with a nucleotide sequence of a) or b) under stringent conditions
  • nucleic acid molecule comprising a nucleotide sequence having sufficient homology to be functionally analogous to a nucleotide sequence of a), b) or c);
  • nucleic acid molecule of a nucleotide sequence of a) through e) which is modified by deletions, additions, substitutions, transloca- tions, inversions and/or insertions and functionally analogous to a nucleotide sequence of a) through e).
  • the invention involves the surprising teaching that the nucleic acid molecules of the invention, as well as the peptides encoded by same, can be used for diagnosis and therapy of vascular diseases like coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma.
  • the biological structures, preferably peptides, encoded by said nucleic acid molecules can be used in various forms in the prophylaxis, diagnosis, therapy, follow-up and/or aftercare of diseases like coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma.
  • the nucleic acid molecule which has sufficient homology to be functionally analogous to the nucleic acid sequence in accordance with a), b) and/or c) has at least 40% homology.
  • the term "to be functionally analogous to the above-mentioned nucleotide se- quences or to the sequences hybridizing with said nucleotide sequences" means that the homologues exhibit a behavior in diseases of coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma., such that reliable and effective use thereof is possible in diagnosis and/or therapy of such diseases or pathogenic conditions as- sociated with said diseases.
  • Functionally analogous sequences in the meaning of the invention are all those sequences which can be identified as equally effective by a person skilled in the art, using routine tests.
  • the nucleic acid molecule has at least 60%, preferably 70%, more preferably 80%, especially preferably 90% homology to the nucleic acid molecule in accordance with d).
  • the nucleic acid molecule is a genomic DNA, a cDNA and/or an RNA.
  • the invention also relates to a vector comprising a nucleic acid molecule of the invention and, in addition, to a host cell comprising said vector.
  • the invention also relates to a peptide encoded by a nucleic acid molecule of the invention and by the preferred functionally analogous nucleic acid molecules.
  • the peptide of the invention can be used in the diagnosis and/or therapy of diseases associated with vascular diseases. More specifically, the peptides of the invention are bound by autoantibodies in patients suffering from coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma.
  • the invention relates to all peptides encoded by the nucleic acid molecules of the invention, preferably those having at least 60%, preferably 70%, more preferably 80%, especially preferably 90% homology to the nucleic acid molecule in accordance with d).
  • said functionally analogous nucleic acid molecules can be modified by deletion, addition, substitution, translocation, inversion and/or insertion in such a way that the peptides encoded by same interact with autoantibodies associated with coronary arterial occlusion, angina pectoris, pulmonary hy- pertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma.
  • the peptides (as a substance, molecule or a mixture of substances) of the invention would not be selected in a way so as to completely represent the naturally occurring human endothelin-l receptor, protease activated receptors 1 and 2 and/or ⁇ 1 -adrenergic receptor.
  • endothelin-1 receptor, protease-activated receptor 1 , 2 or 3 and ⁇ 1 -adrenergic receptor or parts thereof as specific ligands for removing significant portions of the immunoglobulin from plasma taken from a patient, suffering from coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma.
  • Ligands or specific ligands in the context of the invention are means which interact specifically with immunoglobulins, preferred autoantibodies, more preferred autoantibodies directed against endothelin-1 receptor, protease-activated receptor 1 , 2 or 3 and ⁇ 1 -adrenergic receptor, most preferred against the second extracellular loop of said receptors.
  • the ligands or specific ligands consist of the peptides of the invention.
  • the invention relates to the use of a specific ligand for human immunoglobulin in the manufacture of a column having said ligand coupled thereto for the treatment of a patient suffering from coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma, said treatment comprising passing plasma of the patient over the column under conditions which effect the binding of said specific ligand to immunoglobulin in the patient's plasma, thereby removing a significant portion of the immunoglobulin from the patient's plasma and reinfusing the plasma to the patient.
  • the term "significant portion" is directed to an amount of autoantibodies whose removal from the plasma leads to an improvement of the patient's condition or to the non-appearance of a further aggravation.
  • This improvement of the patient's condition relates to at least one of the aspects of coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma, known to a person skilled in the art.
  • the specific ligand is the endothelin-l receptor, protease activated receptors 1 and 2 and/or ⁇ 1 -adrenergic receptor or the peptides of the invention.
  • the invention also encompasses the use of a specific ligand in the manufacture of a column for extracorporal removal of autoantibodies directed against coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma structures by removing immonglobu- lins of any or all classes and subclasses, for the treatment of coronary arterial occlu- sion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma.
  • Such removal can be accomplished by using any specific ligands for human immunoglobulin coupled to the IA column.
  • Such ligands include polyclonal and monoclonal anti-human immunoglobulin antibodies, fragments of such antibodies (FAB1 , FAB2), recombinant antibodies or pro- teins, synthesized peptides, Protein A and Protein G.
  • Another aspect of the invention is therefore also the essentially unspecific removal of immunoglobulins from plasma taken from a patient suffering from coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arte- rial vessels, Raynaud syndrome and scleroderma and reinfusing said plasma to the patient.
  • the reinfused plasma may also contain those immunoglobulins which induce a positive effect in the context of the patient's immune system.
  • the invention also encompasses the use of more specific ligands in the manufac- ture of a column for extracorporal removal of autoantibodies which are directed against the second loop of the endothelin-l receptor, second loop of protease activated receptors 1 and 2 and/or second loop of ⁇ 1 -adrenergic receptor.
  • the peptides in the meaning of the invention can be designed in such a way and may include such a number of additional amino acids, spacers or other structures that they are suitable for interaction with the antibodies, and preferably in such a way that they represent an epitope for the latter.
  • the peptides of the invention are not restricted to the sequences MLNATSK, SKFMEFY, EQHKTCM, MLNATSKSKFMEFY, APEDET, WKEPAP 1 PPDERF, ITTCHDVL, LNITTCHD or PALNITTC, but rather, the peptides are preferably antibody epitopes essentially including the above-mentioned or functionally analogous sequences, so that they represent and characterize the epitope in such a way that the antibodies would undergo specific interaction with them. Therefore, under particular conditions the terms "epitope” and "peptide” may also be used synonymously.
  • a second way of generating peptide sequences starting from the peptides of invention is the subtitutional analysis (MoI. Diversity 2004, 8, 281-290; J. of Immunol. Methods 2002, 267, 37-51).
  • the substitutional analysis is carried out by systematical replacement of each amino acid by all amino acids/building blocks of your interest.
  • the activity of these peptides/constructs shows the ability of those substitutions.
  • the resulting sequences could have improved properties i.e. higher stability and/or lower hydrophicity).
  • Another method to generate peptide structure anologues is the synthesis of retro- inverso peptides.
  • This sequence is the retro-inverso sequence of a peptide of the invention, in which several amino ac- ids were replaced by other amino acids with similar properties.
  • the small letters indicate D-amino acids.
  • Glycine (G) doesn't exist in two different D- or L-structures.
  • peptides, peptide fragments or structures comprising peptides generated using the methods mentioned above - starting from the peptides of the invention - are peptides of the invention, provided they accomplish the object of the invention and, in particular, interact with the pathogenic autoantibodies.
  • these autoantibodies - via dimerization - can be agonistic autoantibodies activating receptors.
  • the peptide sequences can be a natural component of the s second loop of the endothelin-l receptor, second loop of protease activated receptors 1 and 2 and/or second loop of ⁇ 1 -adrenergic receptor.
  • the autoantibodies specifically interact with the second loop of the endothelin-l receptor, second loop of protease activated receptors 1 and 2 and/or second loop of ⁇ 1 -adrenergic receptor.
  • the invention also relates to the surprising teaching that the major epitope of the autoantibodies associated with diseases like coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma are peptides having the amino acid sequences of claim 1.
  • the autoantibodies can be antibodies acting as agonistic autoantibodies, i.e., these autoantibodies are capable of activating the corresponding receptors by binding thereto.
  • various diseases or pathogenic changes can be induced and/or accompanied. For example, it is possible that activation of receptors modulates the production of messenger molecules.
  • the autoantibodies may also damage receptors of cells which are responsible for essentially normal blood flow in limbs.
  • the function of attacking and damaging the corresponding target by chronic stressing - usually observed with antibodies - is the predominant one in non-agonistic autoantibodies. However, this does not exclude activation or deactivation of the receptors.
  • the peptide additionally comprises amino groups, amides, acetyl groups, biotin groups, markers, spacers and/or linkers.
  • the peptide can be used with advantage in various fields of diagnosis and therapy of autoimmune diseases like coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial ves- sels, Raynaud syndrome and scleroderma.
  • autoimmune diseases like coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial ves- sels, Raynaud syndrome and scleroderma.
  • Various ways of modifying peptides for various applications are well-known to those skilled in the art. If, for example, the peptides are envisaged to be administered as a drug, the structure of the peptides has to be changed in an specific fashion, as is well-known to those skilled in the art.
  • the peptides may also be bound to the supporting material of an affinity column in order to be used in the purification of body fluids, especially blood; binding of the peptides to a matrix requires specific structural modifications of the peptides of the invention, and such modifications are also well-known to those skilled in the art or can be determined using routine tests.
  • amino acids are representing gene encoded peptides with similar properties as well as retro-inverso peptides with D-amino acids (small letters) with similar properties, available by biochemical or chemical peptide synthesis.
  • amino acids have analogous phys- icochemical properties so that these amino acids advantageously can be replaced by each other.
  • these include the group of nonpolar (hydrophobic) amino acids (a) glycine, alanine, valine, leucine and/or isoleucine; or the hydroxy amino acids (b) serine, threonine and/or tyrosine, the amides of amino dicarboxylic acids (c) asparagine and glutamine, the amino dicarboxylic acids (d) aspartic acid and glutamic acid; the basic amino acids (e) lysine, arginine and/or ornithine as well as the group of aromatic amino acids (f) phenylalanine, tyrosine and/or tryptophan.
  • nonpolar amino acids a) glycine, alanine, valine, leucine and/or isoleucine
  • hydroxy amino acids b) serine, threonine and/or ty
  • Another aspect is the replacement of amino acids by structural similar amino acids.
  • this is the case in the group with a ⁇ -functional group (g) cysteine, methionine, serine, ⁇ - aminobutyric acid and selenocysteine as well as the turn- inducing group (h) praline, 1-amino-2-carboxy cyclohexane, pipecolic acid and an ortho-aminobenzoic acid.
  • Amino acids within one and the same group (a-h) can be replaced with one another.
  • peptide sequences will have a sufficient homology to be an analogous to an amino acid sequence of the peptides of the in- vention.
  • the amino acids can be replaced by modified amino acids or specific enantiomers.
  • the peptide comprises a linker and/or a spacer selected from the group comprising ⁇ -aminocarboxylic acids as well as homo- and heterooligomers thereof, ⁇ , ⁇ -aminocarboxylic acids and branched homo- or hete- rooligomers thereof, other aliphatic and/or aromatic amino acids, as well as linear and branched homo- or heterooligomers (peptides); amino-oligoalkoxyalkylamines; maleinimidocarboxylic acid derivatives; oligomers of alkylamines; 4-alkylphenyl derivatives; 4-oligoalkoxyphenyl or 4-oligoalkoxyphenoxy derivatives; 4- oligoalkylmercaptophenyl or 4-oligoalkylmercaptophenoxy derivatives; 4- oligoalkylaminophenyl or 4-oligoalkylaminophenoxy derivatives; (oligoalkylbenzyl)- phenyl or 4-(oligoalkyl
  • GLN- Cys(Maleinimidopropionic acid)-TYAN The following sequence is an example: GLN- Cys(Maleinimidopropionic acid)-TYAN.
  • a peptide of the invention several amino acids were replaced by other with similar properties as described above.
  • the SH group of the cysteine reacts with the double bound of the maleinimide group to form a covalent bound to a linker molecule. This linkage is could couple to another molecule or a solid phase.
  • solid phases for affinity chromatography or solid phase extraction constisting of organic, inorganic, synthetic polymers or of mixed polymers, preferably cross-linked agarose, cellulose, silica gel, polyamide and polyvinyl alcohols, which are optionally chemically activated, with peptides of the inven- tion immobilized on the surface of the solid phase.
  • the peptides are bound to the solid support phase preferably covalently or by adsorption.
  • the peptides are distanced from the support surface by linkers/spacers.
  • the invention relates to a method for the adsorption of immunoglobulins to a solid phase, wherein the peptides of the invention are bound to a solid phase usual in affinity chromatography or to mobile solid phases, and the immunoglobulin- containing samples to be adsorbed are contacted, in particular, with the solid phases of the invention.
  • the method for the adsorption of immunoglobulins is performed on a solid phase, wherein the peptides of the invention are bound to a solid phase usual in affinity chromatography or to mobile solid phases, and the immunoglobulin- containing samples to be adsorbed are anticoagulant-treated human blood plasma or human whole blood and are contacted with the solid phases of the invention.
  • the method of the invention is suitable, in particular, for the adsorption of immunoglobulins from immunoglobulin-containing samples which contain auto-antibodies related to autoimmune diseases, especially rheumatoid diseases, multiple sclerosis, myasthenia gravis and other auto-antibody-mediated diseases.
  • the method of the invention is advantageously performed with a device of the invention for removing immunoglobulins from immunoglobulin-containing samples on solid phases, wherein the device contains a solid phase of the invention, and means for the entry of immunoglobulin-containing samples are provided.
  • the invention also relates to the use of the peptides of the invention, the solid phases of the invention and the devices of the invention for removing immunoglobulins from immunoglobulin-containing samples.
  • the peptide is selected from the group comprising:
  • a peptide comprising an amino acid sequence having sufficient homology to be functionally analogous to an amino acid sequence in accordance with a); c) a peptide of an amino acid sequence a) or b) which is modified by deletions, additions, substitutions, translocations, inversions and/or insertions and functionally analogous to an amino acid sequence in accordance with a) or b).
  • the coupling could result by a direct bond to amino acids of the sequences or by an indirect bond to amino acids of the sequences using a linker or spacer.
  • the peptide is used or employed as a therapeutic active substance.
  • use as a therapeutic active substance means use of the peptide in the entire field of medicine.
  • the peptide is bound by specific antibodies of patients with coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma, especially by autoantibodies.
  • autoantibody-peptide complexes will form which, for example, undergo precipitation or exhibit specific reaction behavior in a way so as to allow elimination or reduction of the autoantibodies.
  • the peptide in another preferred embodiment of the invention is immobilized.
  • immobilization is understood to involve various methods and techniques to fix the peptides on specific carriers, e.g. of WO 99/56126 or WO 02/26292.
  • immobilization can serve to stabilize the peptides so that their activity would not be reduced or adversely modified by biological, chemical or physical exposure, especially during storage or in single-batch use.
  • Immobilization of the peptides allows repeated use under technical or clinical routine conditions; furthermore, a sample - preferably blood components - can be reacted with at least one of the peptides of the invention in a continuous fashion.
  • this can be achieved by means of various immobilization techniques, with binding of the peptides to other peptides or molecules or to a carrier proceeding in such a way that the three-dimensional structure - particularly in the active center mediat- ing the interaction with the autoantibodies - of the corresponding molecules, especially of said peptides, would not be changed.
  • immobilization techniques with binding of the peptides to other peptides or molecules or to a carrier proceeding in such a way that the three-dimensional structure - particularly in the active center mediat- ing the interaction with the autoantibodies - of the corresponding molecules, especially of said peptides, would not be changed.
  • there is no loss in specificity to the autoantibodies of the patient as a result of such immobilization.
  • three basic methods can be used for immobilization:
  • crosslinking in crosslinking, the peptides are fixed to one another without adversely affecting their activity. Advantageously, they are no longer soluble as a result of such crosslinking.
  • binding to a carrier proceeds via adsorption, ionic binding or covalent binding, for example. Such binding may also take place inside microbial cells or liposomes or other membranous, closed or open structures.
  • the peptides are not adversely affected by such fixing. For example, multiple or continuous use of carrier-bound peptides is possible with advantage in clinics in diagnosis or therapy.
  • inclusion in the meaning of the invention especially is inclusion in a semipermeable membrane in the form of gels, fibrils or fibers.
  • encapsulated peptides are separated from the surrounding sample solution by a semipermeable membrane in such a way that interaction with the autoantibodies or fragments thereof still is possible.
  • Immobilization such as adsorption on an inert or electrically charged inorganic or organic carrier.
  • such carriers can be porous gels, aluminum oxide, bentonite, agarose, starch, nylon or polyacrylamide.
  • Immobilization proceeds via physical binding forces, frequently involving hydrophobic interactions and ionic binding.
  • such methods are easy to handle, having little influence on the conformation of the peptides.
  • binding can be improved as a result of electrostatic binding forces between the charged groups of the peptides and the carrier, e.g. by using ion exchangers such as Sephadex.
  • the carriers may have reactive groups forming homopolar bonds with amino acid side chains.
  • Suit- able functional side chain groups in peptides are carboxy, hydroxy and hydrosulfide groups and especially the terminal amino groups of lysines.
  • Aromatic groups offer the possibility of diazo coupling.
  • the surface of microscopic porous glass particles can be activated by treatment with silanes and subsequently coated with peptides.
  • hydroxy groups of natural polymers can be activated with bromo- cyanogen and subsequently coupled with peptides.
  • a large number of peptides can undergo direct covalent binding with polyacrylamide resins.
  • Inclusion in three-dimensional networks involves inclusion of the peptides in ionotropic gels or other structures well-known to those skilled in the art. More specifically, the pores of the matrix are such in nature that the peptides are retained, allowing interaction with the target molecules.
  • crosslinking the peptides are converted into polymer aggregates by crosslinking with bifunctional agents.
  • Such structures are gelatinous, easily deformable and, in particular, suitable for use in various reactors. By adding other inactive components such as gelatin in crosslinking, advantageous improvement of mechanical and binding properties is possible.
  • microencapsulation the reaction volume of the peptides is restricted by means of membranes. For example, microencapsulation can be carried out in the form of an interfacial polymerization.
  • the peptides are made insoluble and thus reusable.
  • immobilized peptides are all those peptides being in a condition that allows reuse thereof. Restricting the mobility and solubility of the peptides by chemical, biological or physical means advantageously results in lower process cost, particularly when eliminating autoantibodies from blood components.
  • the peptide is bound to a solid phase. Binding the peptide to the solid phase may proceed via a spacer. All those chemical compounds can be used as spacers which have the structural and functional preconditions suitable for the function of a spacer, provided they do not modify the binding behavior in such a way that binding of the autoantibody with the peptide would be adversely affected.
  • the invention also relates to recognition molecules directed against the agonistic autoantibodies which interact with the peptides of the invention.
  • These agonistic autoantibodies are directed against the endothelin-l receptor, protease activated receptors 1 and 2 and/or ⁇ 1 -adrenergic receptor.
  • the interaction or reaction or binding of the autoantibody is a specific antigen-antibody-interaction.
  • the recognition molecules are antibodies, antisense constructs and/or chelating agents and/or aptamers or Spiegelmers.
  • the recognition molecules of the invention can be antibodies directed against the autoantibodies inducing e.g.
  • aptamers are nucleic acid structure that can bind to a target molecule conceptually similar to an antibody that recognizes an antigen (Ellington & Szostak, 1990). Based on the SELEX (Systematic Evolution of Ligands by Exponential enrichment) process (Tuerk & Gold, 1990), aptamers can be identified from huge combinatorial nucleic acids libraries of up to > 1015 different sequences.
  • the sequences in the library are comprised of a central randomized region flanked by fixed sequences that permit amplification by polymerase chain reactions (PCR).
  • the library size depends on the length of the random portion of the molecule, creating a diverse universe of mole- cules ready for screening.
  • the aptamers capable of binding to a target are then selected by incubating the libraries with the immobilized target, washing extensively, then eluting the bound aptamer. After amplification by PCR, these binding molecules are re-selected, eluted and amplified. By repeating this procedure multiple times, and eluting bound aptamers under progressively more stringent conditions, the molecules with greatest affinity and specificity are selected.
  • Aptamers have binding characteristics similar to peptides or antibodies, with affinities in the low nanomolar to the picomolar range.
  • aptamers demonstrate circulating half-lives in vivo in the order of minutes. This situation can be addressed by attaching large inert molecules to aptamers (e.g. polyethylene glycol) to reduce their elimination via the kidney and increase their presence in the circulation.
  • aptamers as natural nucleic acid polymers, are prone to rapid degradation by nucleases that are present in all tissues in the body. To overcome this latter problem, methods of creating nuclease-resistant molecules that retained the binding capabilities of aptamers needed to be created.
  • Spiegelmers should not be confused with antisense RNAs in that they do not directly interfere with protein synthesis of their target molecules. They are designed to bind specifically to extracellular molecules, either a receptor or its ligand, similar to the behavior of a monoclonal antibody, aptamer or peptide. However, recent findings demonstrate that Spiegelmers are capable of entering cells and interfering with intracellular processes as well. Finally, Spiegelmers appear to be non-immunogenic, even under the most inductive conditions for antibody formation in rabbits. This situation is of critical importance if Spiegelmer therapy is to be used repeatedly to treat chronic diseases.
  • RNAi-pharmaceuticals for blocking the plasma cells which produce the agonistic autoantibodies directed against the endothelin-l receptor, protease activated receptors 1 and 2 and/or ⁇ 1 -adrenergic receptor.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the inventive nucleic acid molecules, vectors, host cells, peptides and/or recognition molecules, optionally together with a pharmaceutically tolerable carrier.
  • the pharmaceutical composition can be used as a drug.
  • endogenous peptide- degrading structures e.g. serum proteases
  • the drugs are administered directly to the patient; in ex vivo neutralization, the blood is conducted out of the body e.g. via a loop, e.g. in the form of a tube circulation, subsequently contacted with the drug and, following neutralization of the autoantibodies, resupplied into the organism, i.e., the patient.
  • a loop e.g. in the form of a tube circulation
  • the drug is administered directly to the patient; in ex vivo neutralization, the blood is conducted out of the body e.g. via a loop, e.g. in the form of a tube circulation, subsequently contacted with the drug and, following neutralization of the autoantibodies, resupplied into the organism, i.e., the patient.
  • drugs in the meaning of the invention are compositions for therapeutic and prophylactic purposes, as well as pharmaceutical compositions usable as diagnostic agents.
  • drugs or pharmaceutical compositions - used in a synonymous fashion herein - are substances and formulations of substances intended to cure, alleviate or avoid diseases, illness, physical defects or pathological affection by application on or in the human body.
  • medical adjuvants are sub- stances used as active ingredients in the production of drugs.
  • Pharmaceutical- technical adjuvants serve to suitably formulate the drug or pharmaceutical composition and, if required during the production process only, can even be removed thereafter, or they can be part of the pharmaceutical composition as pharmaceutically tolerable carriers. Examples of pharmaceutically tolerable carriers will be given below.
  • Drug formulation or formulation of the pharmaceutical composition is optionally effected in combination with a pharmaceutically tolerable carrier and/or diluent.
  • Suitable pharmaceutically tolerable carriers are well-known to those skilled in the art and comprise e.g. phosphate-buffered saline, water, emulsions such as oil/water emulsions, various types of detergents, sterile solutions, and so forth.
  • Drugs or pharmaceutical compositions comprising such carriers can be formulated by means of well-known conventional methods. These drugs or pharmaceutical compositions can be administered to an individual at a suitable dose, e.g. in a range of from 0,01 ⁇ g to 10 g of peptides per day and patient. Doses of from 1 ⁇ g to 1 g are preferred. Preferred is administration of doses as small in number and as low as possible, preferably a single dose.
  • Administration can be effected on various routes, e.g. intravenous, intraperitoneal, intrarectal, intragastrointestinal, intranodal, intramuscular, local, but also subcutaneous, intradermal or on the skin or via mucosa.
  • Administration of nucleic acids encoding the peptide of the invention can also be effected in the form of a gene therapy, e.g. via viral vectors.
  • the kind of dosage and route of administration can be determined by the attending physician of clinical factors. As is familiar to those skilled in the art, the kind of dosage will depend on various factors such as size, body surface, age, sex, or general health condition of the patient, but also on the particular agent being administered, the time period and type of administration, and on other medications possibly administered in parallel. Those skilled in the art will also be familiar with the fact that the concentration of autoantibodies can be diagnosed first, using the peptides of the invention, in order to determine the required concentration of drug.
  • compositions or drugs comprise a pharmacological substance which includes one or more peptides or recognition molecules of the invention, or/and nucleic acid molecules encoding same, in a suitable solution or administration form.
  • Administration thereof can be effected either alone or together with appropriate adjuvants described in connection with drugs or pharmaceutical compositions, or in combination with one or more adjuvants, e.g.
  • the pharmaceutical composition or drug can also be a combination of two or more of the inventive pharmaceutical compositions or drugs, as well as a combination with other drugs, such as antibody therapies, chemotherapies or radiothera- pies, suitably administered or applied at the same time or separately in time.
  • the production of the drugs or pharmaceutical compositions proceeds of per se known methods.
  • the invention also relates to a kit comprising the nucleic acid molecule, the vector, the host cell, the peptide and/or the recognition molecule, optionally together with instructions or information as to the pharmaceutical provision or the procedure of therapeutical treatment.
  • the information can be an instruction leaflet or other medium providing the user with information in which therapeutical procedure the above-mentioned substances should be used.
  • the instruction leaflet includes detailed and/or important information about the therapeutical treatment.
  • the information need not necessarily be in the form of an instruction leaflet, and the information may also be imparted via the Internet.
  • the invention also relates to an apparatus for chromatography, which includes the peptides of the invention.
  • the peptides are bound to a solid phase or an apparatus which catches from blood or plasma extracellular loop 2 peptides of the human ⁇ 2 receptor or antibody binding peptido mimetica fixed to nanoparticles, magnetic or paramagnetic particles or microspheres of cellulosis and other polymeric matrix molecules.
  • the peptides are bound to a solid phase within the chromatography system.
  • anti-human immunoglobulin coupled columns are used for the removal of immunoglobulin from the plasma or blood of a patient suffering from coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma.
  • coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma is caused by antibodies, especially by autoantibodies
  • the treatment of coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma may also be effected by providing columns which remove antibodies or autoantibodies irrespectively from their specificity from the plasma or blood of a patient suffering from coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma.
  • the antibodies or autoantibodies which are not associ- ated with coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma can be reinfused to the patient.
  • the apparatus of the invention (this may be an apparatus which fea- tures a specific ligand for human immunoglobulins, for example endothelin-l receptor, protease activated receptors 1 and 2 and/or ⁇ 1 -adrenergic receptor or the second loops of the receptors) can be used to eliminate the autoantibodies from fluids of a patient or to neutralize the autoantibodies.
  • This method is known to those skilled in the art under the term of immunoadsorption and/or plasma apheresis ther- apy.
  • immunoglobulins are removed from the blood or serum of a coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma patient.
  • this immunoadsorption treatment can be con- ducted in a stationary and ambulant fashion.
  • the apparatus particularly the so-called adsorber, is part of an extracorporeal blood circulation.
  • blood is taken continuously or discontinuously from a patient's major vessel, particularly from an arm vein, and separated into single components, such as cellular and humoral components, using filtration or centrifugation.
  • one essential blood component obtained in this fashion is blood plasma.
  • the blood plasma can be passed through the apparatus of the invention and, following adsorption of the autoantibodies, returned into the patient, particularly through another vein of arms or legs, together with previously separated blood com- ponents, especially cellular components.
  • the specific ligand for the human immunoglobulin or the peptides are immobilized on a Sepha- rose matrix.
  • the matrix can be placed in a container having a volume of e.g. 10 to 400 ml. Thereafter, the blood plasma of the patient can be passed over the matrix where the autoantibodies will be bound, thus allowing elimination thereof from the blood plasma.
  • the invention also relates to a method for the treatment of coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial ves- sels, Raynaud syndrome and scleroderma by binding and/or removing autoantibodies by means of peptides or specific ligands for human immunoglobulin/auto- immunoglobulin of the invention bound to a solid phase.
  • the autoantibodies are directed against human endothelin-l receptor, protease activated receptors 1 and 2 and/or ⁇ 1- adrenergic receptor.
  • the invention also relates to the use of the nucleic acid molecules of the invention, the host cells of the invention, the vector of the invention, the peptides of the invention, the recognition molecules of the invention, the pharmaceutical composition of the invention, the kit of the invention and the apparatus of the invention in the pro- phylaxis, diagnosis, therapy, follow-up and/or aftercare of coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma.
  • the invention also relates to the use of the nucleic acid molecules of the invention, the host cells of the invention, the vector of the invention, the peptides of the invention, the recognition molecules of the invention, the pharmaceutical composition of the invention, the kit of the invention and the apparatus of the invention in the production of a drug for the treatment of coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syn- drome and scleroderma.
  • the coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma are a primary open angle coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma (POAG), a normal tension coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma (NTG), an acute angle-closure coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of pe- ripheral arterial vessels, Raynaud syndrome and scleroderma, a primary congenital coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma and/or a secondary coronary arterial occlusion, POAG),
  • Acute angle-closure coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma is characterized by an acute rise in the intraocular pressure. This occurs in susceptible eyes when the pupil dilates and blocks the flow of fluid through it, leading to the peripheral iris blocking the trabecular meshwork.
  • Acute angle-closure coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma can cause pain and reduced visual acuity (blurred vision), and may lead to irreversible visual loss within a short time. This is an ocular emergency requiring immediate treatment. Many people with coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma experience halos around bright lights as well as the loss of sight characterized by the disease.
  • secondary coronary arterial occlusion occurs as a complication of various medical conditions such as eye surgery, advanced cataracts, eye injuries, some eye tumors, uveitis, diabetes or use of corticosteroid drugs.
  • the invention also relates to the use of a specific ligand for human immunoglobulin or the inventive peptides and nucleic acids or host cells, the pharmaceutical composition of the invention, the kit of the invention and/or the apparatus of the invention in drug screening.
  • drug screening may comprise the identification of substances, particularly peptides, proteins, carbohydrates and/or lipids, which inter- act with autoantibodies directed against the endothelin-l receptor, protease activated receptors 1 and 2 and/or of ⁇ 1 -adrenergic receptor.
  • Interaction can be binding to said peptides, but also activation or inhibition of or by peptides.
  • a drug can be e.g. a structure binding to the autoantibodies or - in another embodiment of the invention - to the peptide structures in the body of a patient, and consequently to the loops, thus competing with the autoantibodies for a binding site.
  • the invention also relates to a method for the treatment of an autoimmune disease by binding and/or removal of autoantibodies by means of the inventive peptides bound to a solid phase.
  • the autoantibodies are bound, complexed and/or neutral- ized on the solid phase by means of the peptides bound to the solid phase.
  • autoantibodies directed against endo- thelin-l receptor, protease activated receptors 1 and 2 and/or ⁇ 1 -adrenergic receptor are bound, complexed and/or neutralized by means of the above-mentioned inven- tive materials and products, apparatus, particularly the chromatography apparatus, and peptides.
  • the peptides can be used in the detection of autoantibodies in serums of patients, using an ELISA or other immunological detection methods well-known to those skilled in the art.
  • the separated autoantibodies are detected using igG subtype-specific labelled antibodies.
  • the antibodies are detected using particularly IgG ⁇ subtype-specific labelled antibodies.
  • the invention relates also to the use of a specific ligand for human immunoglobulins in the manufacture of a column coupled to said ligand for the treatment of a patient suffering from coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma, said treatment comprising passing plasma of the patient, over the column under conditions which effect the binding of said specific ligand to immunoglobulin in the pa- tient's plasma, thereby removing a significant portion of the immunoglobulin from the patient's plasma, and reinfusing the plasma to the patient.
  • the invention relates also to the treatment of a patient suffering from coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma, said treatment comprising the steps of: (a) providing a column coupled to a specific ligand for human immunoglobulin,
  • the treatment of a patient is characterized in that the specific ligand is selected from the group consisting of polyclonal anti-human immunoglobulin antibodies, monoclonal anti-human immunoglobulin antibodies, a fragment of such antibodies, recombinant molecules of the antibody idiotype, synthesized peptides, Protein A and Protein G.
  • the specific ligand is selected from the group consisting of polyclonal anti-human immunoglobulin antibodies, monoclonal anti-human immunoglobulin antibodies, a fragment of such antibodies, recombinant molecules of the antibody idiotype, synthesized peptides, Protein A and Protein G.
  • the specific ligand recognizes antibodies directed against endothelin-l receptor, protease activated receptors 1 and 2 and/or ⁇ 1 -adrenergic receptor.
  • the specific ligand is an antigen-mimicking molecule selected from the group consisting of polyclonal and monoclonal antiidiotypic antibodies, fragments of such antibodies, and synthesized peptides.
  • the specific ligand is a synthesized peptide mimicking a sequence of a receptor structure.
  • the receptor is the endothelin-l receptor, protease activated receptors 1 and 2 and/or ⁇ 1 -adrenergic receptor.
  • the autoantibodies are directed against a molecule selected from the group consisting of endothelin-l receptor, protease activated receptors 1 and 2 and/or ⁇ 1 -adrenergic receptor.
  • the invention is characterized by a parallel or subsequent combination with ⁇ -blockers or intravenous immunoglobulin.
  • a treatment of a patient suffering from coronary arterial occlusion, angina pectoris, pulmonary hypertension, occlusion of peripheral arterial vessels, Raynaud syndrome and scleroderma a preferred embodiment of the use of the specific ligand for human immunoglobulin in the manufacture of a column for the treatment of a patient.
  • the peptides shown in the table are able to bind to antibodies or to neutralize antibodies, preferably autoantibodies.
  • the reverse sequences may also comprise D- amino acids.
  • Epitopes of the muscarinergic M2 receptor (2 nd loop) may also be used for this purpose; as well as the epitopes of Alphal B and Alphai D receptors (1 st and 2 nd loop), since the antibody interacts specifically with the three receptor subtypes.
  • sequences shown in line 1 of the table may be used in the treatment of essential, refractory and/or pulmonary hypertension.
  • the peptides shown in line 2 and 3 of the table may be used in the treatment of preeclampsia, humoral kidney rejection and/or malign hypertension.
  • the peptides shown in line 4, 5, 6 and 7 may be used in the treatment of Chagas Disease, dilated cardiomyopathy (DCM), myocarditis and/or cardiomyopathy.
  • the peptides of line 4 are preferred in the treatment of Chagas Disease, cardiomyopathy and/or DCM.
  • the peptides of line 5 and/or 7 are preferred in the treatment of DCM.
  • the peptides of line 6 are preferred in the treatment of DCM and/or myocarditis.
  • the peptides shown in line 8 and 9 may be used in the treatment of the following diseases: Raynaud's phenomenon, pulmonary hypertension, scleroderma, angina pectoris, occlusion of arteries and veins, especially of leg veins and of brain arteries.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Zoology (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Wood Science & Technology (AREA)
  • Public Health (AREA)
  • General Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Immunology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Plant Pathology (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Rehabilitation Therapy (AREA)
  • Rheumatology (AREA)
  • Toxicology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Cette invention concerne des peptides et des molécules d'acide nucléique codant ces peptides, qui interagissent avec des autoanticorps associés à l'occlusion de l'artère coronaire, à l'angine de poitrine, à l'hypertension pulmonaire, à l'occlusion des vaisseaux artériels périphériques, au syndrome de Raynaud et à la sclérodermie. Elle concerne ces peptides en tant que tels, une composition pharmaceutique comprenant ces molécules d'acide nucléique et ces peptides, et l'utilisation de ces peptides - notamment en aphérèse - pour le traitement de l'occlusion de l'artère coronaire, de l'angine de poitrine, de l'hypertension pulmonaire, de l'occlusion des vaisseaux artériels périphériques, du syndrome de Raynaud et de la sclérodermie. Les peptides de l'invention se lient de façon minimale au récepteur de l'endothéline-1 et pour certaines maladies, en sus du récepteur 1, 2 ou 3 activé par la protéase ou du récepteur alpha-1 adrénergique.
PCT/EP2008/005044 2007-06-13 2008-06-13 Peptides de liaison aux autoanticorps et leur utilisation pour le traitement de maladies vasculaires WO2008151847A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US94369707P 2007-06-13 2007-06-13
EP07090115 2007-06-13
EP07090115.2 2007-06-13
US60/943,697 2007-06-13
EP07076097 2007-12-18
EP07076097.0 2007-12-18

Publications (1)

Publication Number Publication Date
WO2008151847A1 true WO2008151847A1 (fr) 2008-12-18

Family

ID=39884314

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2008/005044 WO2008151847A1 (fr) 2007-06-13 2008-06-13 Peptides de liaison aux autoanticorps et leur utilisation pour le traitement de maladies vasculaires

Country Status (1)

Country Link
WO (1) WO2008151847A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009090227A2 (fr) * 2008-01-15 2009-07-23 Mdc Max-Delbrück-Centrum Für Molekulare Medizin Berlin-Buch Peptides ayant une affinité de liaison à un anticorps qui reconnaît un épitope sur une boucle α1 2 ou une boucle β2 1 d'un adrénorécepteur
WO2009143944A2 (fr) * 2008-04-18 2009-12-03 Gert Baumann Traitement de la thromboangéite oblitérante par élimination d'auto-anticorps
WO2011015381A1 (fr) * 2009-08-05 2011-02-10 Celltrend Gmbh Méthode de pronostic de l’hypertension artérielle pulmonaire par détection des anticorps anti-par1
WO2011015380A1 (fr) * 2009-08-05 2011-02-10 Celltrend Gmbh Méthode de pronostic de l’hypertension artérielle pulmonaire par détection des anticorps anti-par2
WO2011046462A1 (fr) * 2009-10-12 2011-04-21 Angport Limited Composition pour le traitement de la sclérose en plaques
US20160222084A1 (en) * 2013-03-15 2016-08-04 The Board Of Regents Of The University Of Oklahoma Compositions Comprising D-Amino Acid Peptides and Methods of Production and Use Thereof for Inhibiting Autoantibodies
US10662212B2 (en) 2014-03-13 2020-05-26 Universitat Basel Carbohydrate ligands that bind to IGM antibodies against myelin-associated glycoprotein
US11091591B2 (en) 2015-09-16 2021-08-17 Universität Basel Carbohydrate ligands that bind to antibodies against glycoepitopes of glycosphingolipids

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001021660A1 (fr) * 1999-09-21 2001-03-29 Affina Immuntechnik Gmbh Peptides contre les autoanticorps responsables de la cmd
US20030113798A1 (en) * 2000-12-19 2003-06-19 Burmer Glenna C. Antigenic peptides, such as for G protein-coupled receptors (GPCRS), antibodies thereto, and systems for identifying such antigenic peptides
WO2004051280A2 (fr) * 2002-11-29 2004-06-17 Max-Delbrück-Centrum für Molekulare Medizin Identification d'autoanticorps agonistes
US20070026396A1 (en) * 2003-01-31 2007-02-01 Gerd Wallukat Peptides directed against antibodies, which cause cold-intolerance, and the use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001021660A1 (fr) * 1999-09-21 2001-03-29 Affina Immuntechnik Gmbh Peptides contre les autoanticorps responsables de la cmd
US20030113798A1 (en) * 2000-12-19 2003-06-19 Burmer Glenna C. Antigenic peptides, such as for G protein-coupled receptors (GPCRS), antibodies thereto, and systems for identifying such antigenic peptides
WO2004051280A2 (fr) * 2002-11-29 2004-06-17 Max-Delbrück-Centrum für Molekulare Medizin Identification d'autoanticorps agonistes
US20070026396A1 (en) * 2003-01-31 2007-02-01 Gerd Wallukat Peptides directed against antibodies, which cause cold-intolerance, and the use thereof

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
DORFFEL W V ET AL: "Immunoadsorption in idiopathic dilated cardiomyopathy, a 3-year follow-up", INTERNATIONAL JOURNAL OF CARDIOLOGY, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 97, no. 3, 1 December 2004 (2004-12-01), pages 529 - 534, XP004724572, ISSN: 0167-5273 *
DRAGUN D ET AL: "Activating AT1R and ETAR autoantibodies serve as biomarkers and link autoimmunity and vasculopathy in systemic sclerosis", JOURNAL OF HYPERTENSION, vol. 26, no. Suppl. 1, June 2008 (2008-06-01), & 18TH SCIENTIFIC MEETING OF THE EUROPEAN-SOCIETY-OF-HYPERTENSION/22ND SCIENTIFIC MEETING OF THE INTER; BERLIN, GERMANY; JUNE 14 -19, 2008, pages S330 - S331, XP008098293, ISSN: 0263-6352 *
ELIES R ET AL: "STRUCTURAL AND FUNCTIONAL ANALYSIS OF THE B CELL EPITOPES RECOGNIZED BY ANTI-RECEPTOR AUTOANTIBODIES IN PATIENTS WITH CHAGAS'DISEASE", JOURNAL OF IMMUNOLOGY, AMERICAN ASSOCIATION OF IMMUNOLOGISTS, US, vol. 157, no. 9, 1 January 1996 (1996-01-01), pages 4203 - 4211, XP000929117, ISSN: 0022-1767 *
KOWALA M C ET AL: "SELECTIVE BLOCKADE OF THE ENDOTHELIN SUBTYPE A RECEPTOR DECREASES EARLY ATHEROSCLEROSIS IN HAMSTER FED CHOLESTEROL", AMERICAN JOURNAL OF PATHOLOGY, AMERICAN SOCIETY FOR INVESTIGATIVE PATHOLOGY, US, vol. 146, no. 4, 1 April 1995 (1995-04-01), pages 819 - 826, XP000603034, ISSN: 0002-9440 *
LIAO YU-HUA ET AL: "Autoantibodies against AT1-receptor and alpha1-adrenergic receptor in patients with hypertension", HYPERTENSION RESEARCH. CLINICAL AND EXPERIMENTAL, OSAKA, JP, vol. 25, no. 4, 1 July 2002 (2002-07-01), pages 641 - 646, XP002412981, ISSN: 0916-9636 *
LUTHER H P ET AL: "Alpha1-adrenergic receptor antibodies in patients with primary hypertension", HYPERTENSION, XX, vol. 29, no. 2, 1 January 1997 (1997-01-01), pages 678 - 682, XP002197208, ISSN: 0194-911X *
OKRUHLICOVA ET AL: "Localization of ET-1 receptors in cultured myocytes and nonmyocytes using patients' sera autoantibodies", JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, ACADEMIC PRESS, GB, vol. 42, no. 6, 25 May 2007 (2007-05-25), pages S31 - S32, XP022091018, ISSN: 0022-2828 *
WALLUKAT GERD ET AL: "Agonistic Autoantibodies against the endothelin 1 ETA- and alpha 1-adrenergic- receptor in the sera of patients with idiopathic pulmonary arterial hypertension", CIRCULATION, vol. 116, no. 16, Suppl. S, October 2007 (2007-10-01), & 80TH ANNUAL SCIENTIFIC SESSION OF THE AMERICAN-HEART-ASSOCIATION; ORLANDO, FL, USA; NOVEMBER 04 -07, 2007, pages 503, XP008098294, ISSN: 0009-7322 *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8455442B2 (en) 2008-01-15 2013-06-04 Mdc Max-Delbruck-Centrum Fur Molekulare Medizin Berlin-Buch Peptides having binding affinity to an antibody which recognizes an epitope on an α1 loop 2 or β2 loop 1 of an adrenoreceptor
EP2244718B1 (fr) * 2008-01-15 2017-06-07 Mdc Max-Delbrück-Centrum Für Molekulare Medizin Berlin - Buch Peptides dotés d'une affinité de liason à un anticorps qui reconnaît un épitope sure une boucle 2 alpha 2 ou une boucle 1 beta 2 d'un adrénorécepteur
WO2009090227A3 (fr) * 2008-01-15 2010-02-04 Mdc Max-Delbrück-Centrum Für Molekulare Medizin Berlin-Buch Peptides ayant une affinité de liaison à un anticorps qui reconnaît un épitope sur une boucle α1 2 ou une boucle β2 1 d'un adrénorécepteur
US9574017B2 (en) 2008-01-15 2017-02-21 Mdc Max-Delbruck-Centrum Fur Molekulare Medizin Berlin-Buch Peptides having binding affinity to an antibody which recognizes an epitope on an α1 loop 2 or β2 loop 1 of an adrenoreceptor
WO2009090227A2 (fr) * 2008-01-15 2009-07-23 Mdc Max-Delbrück-Centrum Für Molekulare Medizin Berlin-Buch Peptides ayant une affinité de liaison à un anticorps qui reconnaît un épitope sur une boucle α1 2 ou une boucle β2 1 d'un adrénorécepteur
US8663147B2 (en) 2008-04-18 2014-03-04 Gert Baumann Treatment of thromboangiitis obliterans by removal of autoantibodies
US20110105980A1 (en) * 2008-04-18 2011-05-05 Gert Baumann Treatment of thromboangiitis obliterans by removal of autoantibodies
WO2009143944A3 (fr) * 2008-04-18 2010-08-05 Gert Baumann Traitement de la thromboangéite oblitérante par élimination d'auto-anticorps
WO2009143944A2 (fr) * 2008-04-18 2009-12-03 Gert Baumann Traitement de la thromboangéite oblitérante par élimination d'auto-anticorps
WO2011015380A1 (fr) * 2009-08-05 2011-02-10 Celltrend Gmbh Méthode de pronostic de l’hypertension artérielle pulmonaire par détection des anticorps anti-par2
WO2011015381A1 (fr) * 2009-08-05 2011-02-10 Celltrend Gmbh Méthode de pronostic de l’hypertension artérielle pulmonaire par détection des anticorps anti-par1
WO2011046462A1 (fr) * 2009-10-12 2011-04-21 Angport Limited Composition pour le traitement de la sclérose en plaques
US9896491B2 (en) 2009-10-12 2018-02-20 Lifebio Laboratories Llc Composition for treatment of multiple sclerosis
EA024832B1 (ru) * 2009-10-12 2016-10-31 ЛАЙФБИО ЛАБОРАТОРИС ЭлЭлСи Олигопептид, связывающий гидролизующие аутоантитела к основному белку миелина mbp, композиции и способ лечения рассеянного склероза
US20160222084A1 (en) * 2013-03-15 2016-08-04 The Board Of Regents Of The University Of Oklahoma Compositions Comprising D-Amino Acid Peptides and Methods of Production and Use Thereof for Inhibiting Autoantibodies
US20180291085A1 (en) * 2013-03-15 2018-10-11 The Board Of Regents Of The University Of Oklahoma Compositions Comprising D-Amino Acid Peptides and Methods of Production and Use Thereof for Inhibiting Autoantibodies
US10899822B2 (en) 2013-03-15 2021-01-26 The Board Of Regents Of The University Of Oklahoma Compositions comprising D-amino acid peptides and methods of production and use thereof for inhibiting autoantibodies
US10662212B2 (en) 2014-03-13 2020-05-26 Universitat Basel Carbohydrate ligands that bind to IGM antibodies against myelin-associated glycoprotein
US11220523B2 (en) 2014-03-13 2022-01-11 Universität Basel Carbohydrate ligands that bind to IgM antibodies against myelin-associated glycoprotein
US11091591B2 (en) 2015-09-16 2021-08-17 Universität Basel Carbohydrate ligands that bind to antibodies against glycoepitopes of glycosphingolipids

Similar Documents

Publication Publication Date Title
WO2008151847A1 (fr) Peptides de liaison aux autoanticorps et leur utilisation pour le traitement de maladies vasculaires
EP2001899B1 (fr) Peptides dirigés contre des auto-anticorps associés au glaucome et utilisation de ces peptides
ES2737731T5 (es) Medios de cromatografía de afinidad para la eliminación de anticuerpos anti-A y/o anti-B
JP4890453B2 (ja) 分離マトリックス及び精製法
JP2014502272A (ja) アフィニティークロマトグラフィーマトリックス
US8440609B2 (en) Peptides against autoantibodies causing intolerance to cold and use thereof
JP2003088381A (ja) 新規ペプチド、生産方法、新規吸着体、吸着器および吸着方法
KR100445644B1 (ko) 면역글로블린과그의복합체를위한흡착제,흡착방법그리고흡착장치
JP2019517789A (ja) 変異免疫グロブリン結合ポリペプチド
US7741050B2 (en) Identification of agonistic autoantibodies
EP2199305A1 (fr) Peptides contre les anticorps associés au CRPS et utilisation de ces peptides
CA2568694A1 (fr) Adsorbant de mif
US11104705B2 (en) Methods for removing bacterial toxins from a biological fluid
JP2019521959A (ja) 分離マトリックスを洗浄および／または消毒する方法
JP6906547B2 (ja) ミックスモードアフィニティクロマトグラフィー用担体
JPH0622633B2 (ja) 吸着体およびそれを用いた除去装置
US20090023662A1 (en) Identification of Agonistic Autoantibodies Associated with Humoral Kidney Rejection
JP2015074626A (ja) 免疫グロブリンＧに対する親和性を有するペプチド及びそれを用いたＩｇＧ型抗体吸着材
US9708372B2 (en) Agonistic autoantibodies to the alpha1-adrenergic receptor and the beta2-adrenergic receptor in Alzheimer's and vascular dementia
JP6864882B2 (ja) 免疫グロブリンＧに対する親和性を有するペプチドを担持したＩｇＧ型抗体吸着材
JPH06105910A (ja) 抗ヌクレオリン抗体吸着材
JPH0625287A (ja) ポリペプチドおよびそれを用いた抗血小板抗体吸着材
JPH06121834A (ja) 抗血小板抗体吸着材
JPH06218050A (ja) 抗血小板抗体吸着材
JPH0460585B2 (fr)

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08759316

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08759316

Country of ref document: EP

Kind code of ref document: A1