DE10160248A1 - New fusion protein, useful for treating e.g. tumors, viral infections and autoimmune disease, comprises an Fc antibody region and at least one other domain and improves the response of antigen-presenting cells - Google Patents
New fusion protein, useful for treating e.g. tumors, viral infections and autoimmune disease, comprises an Fc antibody region and at least one other domain and improves the response of antigen-presenting cellsInfo
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- DE10160248A1 DE10160248A1 DE2001160248 DE10160248A DE10160248A1 DE 10160248 A1 DE10160248 A1 DE 10160248A1 DE 2001160248 DE2001160248 DE 2001160248 DE 10160248 A DE10160248 A DE 10160248A DE 10160248 A1 DE10160248 A1 DE 10160248A1
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Classifications
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- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/7051—T-cell receptor (TcR)-CD3 complex
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- 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
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- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/70521—CD28, CD152
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- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/70528—CD58
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- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/70539—MHC-molecules, e.g. HLA-molecules
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- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70596—Molecules with a "CD"-designation not provided for elsewhere
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
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Abstract
Description
Die Erfindung betrifft die Bereiche der Immunologie, Molekularbiologie und Onkologie. Die Aufgabe der Erfindung ist Immunreaktionen auf Viren Tumoren, autoreaktive Proteinen und Zellen wie z. B. Autoantikörper, Autoantigen-spezifische T-Zell-Rezeptoren (TZR) der autoreaktiven T- Zellen, Autoantigen-spezifische B-Zell-Rezeptoren (BZR) der autoreaktiven B-Zellen und autoantigen-spezifische MHC der "unprofessionellen" Antigen-präsentierenden Zellen (APZ), zu verbessern. Die Aufgabe der Erfindung wird dadurch gelöst, dass Fc Regionen mit spezifischen Domänen fisioniert werden. The invention relates to the fields of immunology, molecular biology and Oncology. The object of the invention is immune reactions to viruses Tumors, autoreactive proteins and cells such as B. autoantibodies, Autoantigen-specific T cell receptors (TCR) of the autoreactive T- Cells, autoantigen-specific B-cell receptors (BZR) of autoreactive B cells and autoantigen-specific MHC's "unprofessional" antigen-presenting cells (APZ) to improve. The object of the invention is achieved in that Fc regions with specific domains.
Die Kombinationen zur Herstellung rekombinanter Fusionsproteinen, sowie deren konkrete Beispiele und Anwendungen sind in den Tabellen 1, 2, 3 und 4 dargestellt. The combinations for the production of recombinant fusion proteins, as well their specific examples and applications are in Tables 1, 2, 3 and 4 shown.
Das Fc Fragment bzw. die Fc. Region eines Antikörpers bindet sein Rezeptor, welches meistens von Makrophagen exprimiert wird, und dadurch wird der Antigen-Antikörper-Komplex vom Makrophagen aufgenommen. The Fc fragment or the Fc. Region of an antibody binds its receptor, which is mostly expressed by macrophages and thereby the Antigen-antibody complex taken up by the macrophage.
Durch Fusionen von Fc-Fragmenten mit spezifischen Bindedomänen kann man zielgerichteter pathogene Proteinen oder andere Substanzen, die von diesen spezifischen Bindedomänen erkannt und gebunden werden, entfernen, bzw. zur Phagozytose durch Makrophagen führen. By fusing Fc fragments with specific binding domains one can targeted pathogenic proteins or other substances derived from these specific binding domains are recognized and bound, or removed Phagocytosis caused by macrophages.
In der Tabelle 1 sind Fc Fusionen verallgemeinert dargestellt. Das sind also Fusionsproteinen enthaltend Liganden, Rezeptoren, Antigene, Autoantigene oder andere Domänen die mit Fc Regionen fusioniert sind. Table 1 shows generalized Fc fusions. So those are Fusion proteins containing ligands, receptors, antigens, autoantigens or other domains merged with Fc regions.
Die Fusionsproteinen können His-tag oder andere Tags für die Reinigung, sowie Tyr oder Ser-tag für die Phosphorylierung durch Kinasen bzw. zur Erhöhung des energetischen Niveaus, enthalten zwischen Domänen können sich Gelenkdomänen, wie z. B. fünf Glyzine (5G) befinden. The fusion proteins can be His-tag or other tags for purification, and Tyr or Ser-tag for phosphorylation by kinases or Increasing the energetic level that can be contained between domains Joint domains, such as B. five wisteria (5G).
In der Tabelle 2 sind Fc-Ligand-Fusionen bzw. Fusionsproteinen gegen Tumoren dargestellt. Fc Regionen werden entweder mit kompletten Liganden oder ihren spezifischen Binderegionen fusioniert. In Table 2, Fc-ligand fusions or fusion proteins are against Tumors shown. Fc regions are either complete with ligands or their specific binding regions.
Die Fc-CD 153-Fusion soll gegen die Hodgkin-Krankheit wirken. Die Hodgkin-Krankheit ist eine Erkrankung, bei der anscheinend antigenpräsentierende Zellen verändert sind, die den dendritischen Zellen ähneln. Beim Hodgkin-Lymphom herrschen Lymphocyten vor. Diese Form der Hodgkin-Krankheit hat weitaus bessere Heilungsaussichten als die noduläre Sklerose genannte form, bei der nichtlymphatische Zellen dominieren. (C. A. Janeway und P. Travers, 1995 Immunologie, Spektrum akademischer Verlag, S. 606) The Fc-CD 153 fusion is said to work against Hodgkin's disease. Hodgkin's disease is a condition that appears to be antigen-presenting cells are altered by the dendritic cells resemble. Hodgkin's lymphoma is dominated by lymphocytes. This form of Hodgkin's disease has far better healing prospects than nodular sclerosis form in which non-lymphatic cells dominate. (C.A. Janeway and P. Travers, 1995 Immunology, spectrum academic publisher, p. 606)
Der Standort der Krankheit ist die Peripherie. Der charakteristische Oberflächenmarker ist CD 30. (C. A. Janeway und P. Travers, 1995 Immunalogie, Spektrum akademischer Verlag, S. 273). The location of the disease is the periphery. The characteristic surface marker is CD 30. (C.A. Janeway and P. Travers, 1995 Immunalogy, spectrum academic publisher, P. 273).
CD 30 wird also von Monozyten bzw. Makrophagen exprimiert. CD 30 is therefore expressed by monocytes or macrophages.
CD 153 (38-40 kDa) oder CD 30L (Ligand für CD 30) bindet CD 30 und ist ein Mitglied der TNF (tumor necrosis factor)-Familie. (I. Roitt, J. Brostoff, D. Male, 1998 Immunology, S. 398, 401). CD 153 (38-40 kDa) or CD 30L (ligand for CD 30) binds CD 30 and is a member the TNF (tumor necrosis factor) family. (I. Roitt, J. Brostoff, D. Male, 1998 Immunology, Pp. 398, 401).
Die Fusionsproteinen Fc-FK 506, Fc-CD 58 und Fc-CD 72 sollen gegen T-Zellen- Tumoren wirken. The fusion proteins Fc-FK 506, Fc-CD 58 and Fc-CD 72 are said to be Tumors work.
T-Zell-Tumoren repräsentieren monoklonale Auswünchse normaler Zell-populationen. Jeder einzelne T-Zell-Tumor hat ein normales Äquivalent und behält viele der Eigenschaffen der Zelle bei, von der er abstammt. Einige von diesen Tumoren repräsentieren massive Answünchse eines seltenen Zelltyps wie z. B. die allgemeine akute lymphatische Leukämie, die von einer lymphalischen Vorläuferzelle abstammt. T cell tumors represent monoclonal outgrowths of normal cell populations. Every single T cell tumor has a normal equivalent and retains many of them Properties of the cell from which it is derived. Represent some of these tumors massive growths of a rare cell type such as B. the general acute lymphatic Leukemia derived from a lymphoid progenitor cell.
Es gibt unterschiedliche T-Zell-Tumoren, die durch entsprechende charakteristische Oberflächenmarker gekennzeichnet sind. Bei allgemeinen akuten lymphatischen Leukämie sind die Moleküle CD 10, CD 19 und CD 20 charakteristische Oberflachenmarker. There are different T cell tumors characterized by corresponding ones Surface markers are marked. For general acute lymphoblastic leukemia the molecules CD 10, CD 19 and CD 20 are characteristic surface markers.
Thymome leiten sich von Thymusstroma- oder Thymusepithelzellen ab und ihre charakterische Oberflächenmarker sind Cytokeratine. Bei der akuten lymphatischen Leukämie (T-ALL) ist CD 1 charakterisches oberflächenmarker. Thymomas are derived from thymic stroma or thymic epithelial cells and theirs typical surface markers are cytokeratins. In acute lymphoblastic leukemia (T-ALL) is CD 1's characteristic surface marker.
Bei Sezary-Syndrom, adulten T-Zell-Leukämie und chronischer lymphocytischen Leukämie (C LL) sind CD 3/TZR, CD 4 oder CD 8 charakterische Oberflächenmarker. (C. A. Janeway und P. Travers, 1995 Immunologie, Spertrum akademischer Verlag, S. 273). T-Zell-spezifische Liganden sind z. B. CD 58, FK 506 und CD 72 bzw. ihre extrazellulären Regionen CD 58 oder LFA-3 wiegt 55-70 kd, bindet CD 2 und ist ein Adhäsionsmolekül. Seine Exodomäne bindet CD 2. CD 2 wird von T-Zellen, aber auch von Thymocyten und natürlichen Killerzellen bzw. ihren Subpopulationen exprimiert. With Sezary syndrome, adult T cell leukemia and chronic lymphocytic Leukemia (C LL) are CD 3 / TZR, CD 4 or CD 8 characteristic surface markers. (C.A. Janeway and P. Travers, 1995 Immunology, Spertrum academic publisher, p. 273). T cell specific ligands are e.g. B. CD 58, FK 506 and CD 72 or their extracellular Regions CD 58 or LFA-3 weighs 55-70 kd, binds CD 2 and is an adhesion molecule. Its exodomain binds CD 2. CD 2 is used by T cells, but also by thymocytes and natural killer cells or their subpopulations expressed.
FK 506 ist ein immunsuppressives Polypeptid, das T-Zellen inaktiviert, in dem es die Signalübermittlung über den T-Zel-Rezeptoren (TZR) hemmt. FK 506 und Cyclosporin A sind die bei der Organtransplantation meistverwerdeten Immunsuppressiva. FK 506 is an immunosuppressive polypeptide that inactivates T cells by making it Inhibits signal transmission via the T-cell receptors (TZR). FK 506 and Cyclosporin A are the most commonly used immunosuppressants in organ transplantation.
CD 72 ist ein C-Typ-Lektin wiegt 42 kd, und ist Ligand bzw. seine Exodomäne ist Ligand für CD 5. CD 72 is a C-type lectin weighing 42 kd and is a ligand or its exodomain is a ligand for CD 5.
CD 5 wird von T-Zellen, Thymocyten und einer Untergruppe von B-Zellen exprimiert. (C. A. Janeway und P. Travers, 1995 Immunologie, Spektrum akademischer Verlag, S. 589-604 und I. Roitt, J. Brostoff, D. Male 1998 Immunology, S. 398-401). Die Fusionsproteinen Fc-CD5 Fc-CD 28 sollen gegen B-Zell-Tumoren wirken. CD 5 is made up of T cells, thymocytes and a subset of B cells expressed. (C.A. Janeway and P. Travers, 1995 Immunology, Spectrum Academic Verlag, pp. 589-604 and I. Roitt, J. Brostoff, D. Male 1998 Immunology, pp. 398-401). The fusion proteins Fc-CD5 Fc-CD 28 are said to act against B cell tumors.
B-Zell-Tumoren stellen klonale Auswüchse, von B-Zellen verschiedener Entwicklungsstadien dar. Es gibt unterschiedliche B-Zell-Tumoren, wie z. B. multiples Myelom bzw. Leukämie der Plasmazellen verschiedener Isotypen, Waldström- Makroglobulinämie bzw. Leukämie der IgM-sezernirernden B-Zellen, Follikel Zentrum- Lymphom, Burkitt-Lymphom bzw. Leukämie reifer B-Zellen, Prä-B-Leukämie etc. (C. A. Janeway und P. Travers, 1995 Immunologie, Spektrum akademischer Verlag, S. 233). B-Zell-spezifische Liganden sind z. B. CD 5 und CD 8 bzw. ihre extrazelluläre Regionen. CD 5 wiegt 67 kd und bindet an CD 72. CD 72 wird von B-Zellen exprimiert und ist ein C- Typ-Lektin. B cell tumors represent clonal outgrowths, different from B cells Development stages. There are different B-cell tumors, such as. B. multiples Myeloma or leukemia of the plasma cells of different isotypes, Waldström Macroglobulinemia or leukemia of the IgM-secreting B cells, follicle center Lymphoma, Burkitt's lymphoma or leukemia of mature B cells, pre-B leukemia etc. (C.A. Janeway and P. Travers, 1995 Immunologie, Spektrum academic publisher, p. 233). B-cell specific ligands are e.g. B. CD 5 and CD 8 or their extracellular regions. CD 5 weighs 67 kd and binds to CD 72. CD 72 is expressed by B cells and is a C- Type lectin.
CD 28 wiegt 44 kd und bindet CD 80 (B7.1) und B7.2. CD 80 wird von einer Untergruppe von B-Zellen exprimiert. CD 80 bindet CD 28 und CD 152 (CTLA-4). (C. A. Janeway und P. Travers, 1995 Immunologie, Spektrum akademischer Verlag S. 589-593 und I. Roitt, J. Brostoff, D. Male 1998, Immunology, S. 398-401). CD 28 weighs 44 kd and binds CD 80 (B7.1) and B7.2. CD 80 is owned by a subgroup expressed by B cells. CD 80 binds CD 28 and CD 152 (CTLA-4). (C.A. Janeway and P. Travers, 1995 Immunology, spectrum academic publisher pp. 589-593 and I. Roitt, J. Brostoff, D. Male 1998, Immunology, pp. 398-401).
In der Tabelle 3 sind Fc-Fusionen gegen Autoimmunerkrankungen und zwar Fc- Autoantigen, Fc-autoantigenes Peptid, Fc-Rezeptor, Fc-Rezeptor-Exo bzw. Ligand- Binde-Domäne dargestellt. Table 3 shows Fc fusions against autoimmune diseases, namely Fc- Autoantigen, Fc autoantigenic peptide, Fc receptor, Fc receptor exo or ligand Binding domain shown.
Die Fc-MBP (82-104)-Fusion soll gegen Multiple Sklerose (MS) wirken. The Fc-MBP (82-104) fusion is said to work against multiple sclerosis (MS).
MBP(Myelin-basisches Protein) bzw. seine immundominante Region 82-104 ist das Autoantigen bei der MS. MBP (myelin-based protein) or its immunodominant region 82-104 is that Autoantigen in MS.
Ein MBP-spezifisches Antikörper bindet die MBP (82-104)-Domäne der Fc-MBP (82-104)-Fusion und wird vom Makrophagen aufgenommen. An MBP-specific antibody binds the MBP (82-104) domain of the Fc-MBP (82-104) fusion and is absorbed by the macrophage.
Eine MBP-spezifische T-Zelle bzw. ihr MBP-spezifischer Z-Zell-Rezeptor(TZR) bindet die MBP(82-104)-Domäne der Fc-MBP(82-104)-Fusion und diese autoreakteve T-Zelle wird vom Makrophagen vernichtet. Also führt die Fc-MBP-Fusion dazu, dass Makropfagen MBP-spezifische T-Zellen vernichten. An MBP-specific T cell or its MBP-specific Z cell receptor (TZR) binds the MBP (82-104) domain of the Fc-MBP (82-104) fusion and this autoreactive T cell is destroyed by the macrophage. So the Fc-MBP merger leads to macro maintenance Destroy MBP-specific T cells.
Die Fc-GAD bzw. Fc-GSD (Glutaminsäuredecarboxylase) und Fc-GAD autoantigenes Peptid-Fusionen, soure Fc-Insulinrezeptor-Fusion sollen gegen Diabetes mellitus wirken. GAD ist das initiierende Autoantigen bei dieser Krankheit (H. von Boehmer and A. Sarukhan, 1999 Science Vol. 284, 14 May. S. 1135-1137 und J. W. Yoon et al. 1999. Science Vol. 284, 14 May, S. 1183-1187). The Fc-GAD and Fc-GSD (glutamic acid decarboxylase) and Fc-GAD autoantigenes Peptide fusions, sour Fc-insulin receptor fusion are said to work against diabetes mellitus. GAD is the initiating autoantigen for this disease (H. von Boehmer and A. Sarukhan, 1999 Science Vol. 284, May 14, pp. 1135-1137 and J.W. Yoon et al. 1999. Science Vol. 284, 14 May, pp. 1183-1187).
Ein GAD-spezifisches Antikörper bindet GAD. Domäne der Fc-GAD-Fusion und wird vom Makrophagen aufgenommen. Eine GAD-spezifische T-Zelle bzw. ihr GAD- spezifischer TZR bindet GAD-Domäne der Fc-GAD-Fusion und wird ebenfalls von Makrophagen vernichtet. A GAD-specific antibody binds GAD. Domain of the Fc-GAD fusion and will taken up by the macrophage. A GAD-specific T cell or its GAD specific TZR binds GAD domain of the Fc-GAD fusion and is also used by Macrophages destroyed.
Die Fc-DNA-Bindedomäne (DBD) die mit einer bestimmter DNA-Sequenz ein Komplex bildet sowie Fc-RNA-Binde Domäne mit RNA, Fc-Histon-Fusionen, und Fc- Ribonucleoprotein-Fusionen sollen gegen die systemische Lupus erythematosus (SLE) wirken. The Fc-DNA binding domain (DBD) is a complex with a specific DNA sequence forms as well as Fc-RNA binding domain with RNA, Fc-histone fusions, and Fc- Ribonucleoprotein fusions are said to be against systemic lupus erythematosus (SLE) Act.
ds DNA ist das Autoantigen bei dieser Krankheit. Es gibt auch andere Autoantigene, wie z. B. RNA, Histone und Ribonukleoproteinen. DNA is the autoantigen for this disease. There are also other autoantigens, such as B. RNA, histones and ribonucleoproteins.
Das Wirkungsmechanismus ist das selbe, wie bei den oben beschriebenen Fusionen. The mechanism of action is the same as that of the fusions described above.
Die Fusionen Fc-TSHR oder Fc-TSHR-Exo- bzw. Ligandbindedomäne sollen gegen die Basedow-Krankheit wirken. TSHR ist das entsprechende Autoantigen. The mergers Fc-TSHR or Fc-TSHR exo or ligand binding domain are said to be against the Graves' disease work. TSHR is the corresponding autoantigen.
Die Fusionen Fc-AchR (Acetylcholin-Rezeptor) bzw. Fc-AchR-Alpha-Untereinheit, Region 125-147 oder 131-147 sollen gegen die Krankheit Myastenia gravis wirken. AchR bzw. AchR-Alpha-Untereinheit, Region 125-147 oder 131-147 ist das Autoantigen bei dieser Krankheit. The fusions Fc-AchR (acetylcholine receptor) and Fc-AchR-alpha subunit, Region 125-147 or 131-147 are said to work against the disease Myastenia gravis. AChR or AchR alpha subunit, region 125-147 or 131-147 is the autoantigen at this disease.
Die Fusionen Fc-Desmoglein 1, Fc-Desmoglein 3, Fc-BP 180 und Fc-Kollagen-Typ 7 sollen gegen die Autoimmunerkrankungen der Haut, und zwar Pemphigus foliaceus, Pemphigus vulgaris, bullöses Pemphigoid und Epidermolyse bullosa aquesita wirken. The fusions Fc-Desmoglein 1, Fc-Desmoglein 3, Fc-BP 180 and Fc-collagen type 7 are supposed to fight the autoimmune diseases of the skin, namely Pemphigus foliaceus, Pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa aquesita work.
Desmoglein 1 ist das Autoantigen bei Pemphigus foliacens. Desmoglein 3 ist das Autoantigen bei Pemphigus vulgaris. Desmoglein 1 is the autoantigen in Pemphigus foliacens. Desmoglein 3 is the autoantigen in Pemphigus vulgaris.
BP-180 ist das Autoantigen beibullösem Pemphigoid, und Kollagen-Typ 7 ist das Autoantigen bei der Epidermolyse bullosa aquesita. BP-180 is the autoantigen of bulbar pemphigoid, and collagen type 7 is Autoantigen in epidermolysis bullosa aquesita.
Die Fusion bestehend aus Fc Region und der nicht-kollagenösen Domäne des Basalmembran -Kollagens-Typ-4, soll gegen die Krankheit Good-Pasture-Syndrom wirken. The fusion consisting of the Fc region and the non-collagenous domain of the basement membrane -Collagen type-4, is said to work against Good Pasture syndrome.
Nicht-kollagenöse Domäne des Basal-membran-Kollagens-Typ-4 ist das Autoantigen bei dieser Krankheit. The non-collagenous domain of basal membrane collagen type 4 is the autoantigen in this disease.
Die Fusion bestehend aus Fc Region und dem Oberflächenantigen des Hepatitis-B-Virus oder seiner Region soll gegen die Krankheit Polyarteriitis nodosa wirken. Das Oberflächen antigen des Hepatitis-B-Virus induziert diese Autoimmunerkrankung. The fusion consisting of the Fc region and the surface antigen of the hepatitis B virus or its region is said to work against the disease polyarteritis nodosa. The surface Antigen of the hepatitis B virus induces this autoimmune disease.
Die Fusion bestehend aus Fc Region und dem Hitzeschockprotein (HSP) soll gegen die rheumatische Arthritis wirken. HSP ist vermutlich das Autoantigen bei dieser Krankheit. Die Fusion bestehend aus Fc Region und dem Integrin gp IIb-IIIa aus Blutplättchen soll gegen die autoimmunen Thrombopenie wirken. The fusion consisting of Fc region and the heat shock protein (HSP) is said to be against the rheumatic arthritis work. HSP is believed to be the autoantigen for this disease. The fusion consisting of Fc region and the integrin gp IIb-IIIa from platelets is said to against autoimmune thrombopenia.
Dieses Protein aus Bluttplättchen ist das Autoantigen bei dieser Krankheit. This platelet protein is the autoantigen for this disease.
Die Fusion bestehend aus Fc Region und Rhesus-Antigene und Fc-I-Antigen-Fusion sollen gegen die hämolytische Anämie wirken. The fusion consisting of Fc region and Rhesus antigens and Fc-I antigen fusion are supposed to work against hemolytic anemia.
Rhesus-Antigene und das I-Antigen sind Autoantigene bei dieser Krankheit. Rhesus antigens and the I antigen are autoantigens in this disease.
Der Wirkungsmechanismus der Fc Fusionen ist identisch. Fc-Autoantigen, bzw. Fc- autoantigenes Peptid-Fusionen wirken nicht mehr gegen Autoantikörper und autoreaktive T- Zellen, sondern auch gegen autoreaktive B-Zellen und unprofessionelle autoreaktive Antigen -Präsentierende Zellen (APZ), wie z. B. Makrophagen. The mechanism of action of the Fc mergers is identical. Fc autoantigen or Fc autoantigenic peptide fusions are no longer effective against autoantibodies and autoreactive T- Cells, but also against autoreactive B cells and unprofessional autoreactive antigen -Presenting cells (APZ), such as B. Macrophages.
Ein Autoantikörper bindet die autoantigene Domäne einer Fc-Autoantigen-Fusion. Fc- Region wird von einem Fc-Rezeptor eines Makrophagen erkannt und danach nimmt Makrophage den Komplex bestehend aus dieser Fc-Autoantigen-Fusion und dem für dieses Autoantigen spezifischen Auto-Antikörper auf. So wird die Zahl der Autoantikörper vermindert und dies führt zur Linderung. An autoantibody binds the autoantigenic domain of an Fc-autoantigen fusion. Fc Region is recognized by a macrophage Fc receptor and then taken Macrophage the complex consisting of this Fc-autoantigen fusion and the one for this Autoantigen specific auto-antibodies. So the number of autoantibodies diminishes and this leads to relief.
Eine autoreaktive T-Zelle besitzt ein Autoantigen-spezifisches T-Zell-rezeptor (TZR). Dieses autoreaktives TZR bindet die autoantigene Domäne einer Fc-Autoantigen-Fusion. Die Fc-Region wird von einem Makrophagen erkannt und somit wird ein Kampf eines Makrophagen und einer autoreaktiven T-Zelle hervorgerufen. Der Makrophage kann diese T -Zelle vernichten und aufnehmen. An autoreactive T cell has an autoantigen-specific T cell receptor (TZR). This autoreactive TZR binds the autoantigenic domain of an Fc-autoantigen fusion. The Fc region is recognized by a macrophage and thus a fight becomes one Macrophages and an autoreactive T cell. The macrophage can this T - Destroy and take in the cell.
Dieses Mechanismus kann zur Ausrottung autoreaktiven T-Zellen führen. Im Falle der Multiplen Sklerose, bedeutet die Ausrottung der MBP-spezifischen T-Zellen eine Heilung dieser Krankheit. This mechanism can lead to the extinction of autoreactive T cells. In case of Multiple sclerosis, the eradication of MBP-specific T cells means a cure this disease.
Eine autoreaktive B-Zelle besitzt ein Autoantigen-spezifisches B-Zell-Rezeptor (BZR). Dieses autoreaktives BZR bindet die autoantigene Domäne einer Fc-Autoantigen-Fusion. Die Fc Region wird von einem Makrophagen erkannt und somit wird ein Kampf eines Makrophagen und einer autoreaktiven B-Zelle hevor gerufen. Der Makrophage kann diese B -Zelle vernichten und aufnehmen. Dies kann zur Ausrottung autoreaktiver B-Zellen führen. Eine unprofessionelle autoreaktive APZ besitzt ein Autoantigen-spezifisches MHC. Dieses autoreaktives MHC bindet die autoantigene Domäne einer Fc-Autoantigen-Fusion. Die Fc- Region wird von einem Makrophagen erkannt und somit wird ein Kampf eines Makrophagen und einer unprofessionellen autoreaktiven APZ hervorgerufen. An autoreactive B cell has an autoantigen-specific B cell receptor (BZR). This autoreactive BZR binds the autoantigenic domain of an Fc-autoantigen fusion. The Fc region is recognized by a macrophage and thus a fight becomes one Macrophages and an autoreactive B cell called before. The macrophage can this B - Destroy and take in the cell. This can lead to the eradication of autoreactive B cells. An unprofessional autoreactive APZ has an autoantigen-specific MHC. This autoreactive MHC binds the autoantigenic domain of an Fc-autoantigen fusion. The Fc Region is recognized by a macrophage and thus becomes a battle of a macrophage and an unprofessional autoreactive APZ.
Also können Fc-Autoantigen Fusionen zur völligen Bekämpfung und Ausrottung der Autoimmunerkrankungen führen. So Fc-autoantigen mergers can be used to completely combat and eradicate the mergers Cause autoimmune diseases.
In der Tabelle 4 sind antivirale Fc Fusionen dargestellt. Viren haben Rezeptoren bzw. Oberflächen Wirtszell-Schlüssel moleküle, über die ein Virus in diese Zelle gelangen kann. Für Epstein-Barr-Virus (EBV) ist CR 2(CD 21) das Rezeptor. Für Poliovirus ist CD/55 das Rezeptor. Für HIV ist CD 4 das Rezeptor. Influenza-Viren werden von bestimmten T- und B-Zell rezeptoren sowie bestimmten MHC erkannt. Table 4 shows antiviral Fc fusions. Viruses have receptors or Surface host cell key molecules through which a virus can get into this cell. CR 2 (CD 21) is the receptor for Epstein-Barr virus (EBV). For poliovirus, CD / 55 is that Receptor. CD 4 is the receptor for HIV. Influenza viruses are identified by certain T and B cell receptors and certain MHC recognized.
Also können die Fusionsproteinen Fc-CR 2 bzw. Fc-CD 21, Fc-CD 155, Fc-CD 4, Fc- TZR. FC-BZR und Fc-MHC entsprechend gegen EBV, Polioviren, HIV und Influenza wirken. Betrachtet man als Beispiel die Wirkung des Fusionsproteins Fc-CR 2 bzw. Fc- CD21. Die CR 2 bzw. CD 21-Domäne der Fc-CR 2 bzw. Fc-CD 21-Fusion erkannt die Oberfläche des EBV. Fc Region wird vom Fc Rezeptor eines Makrophagen erkannt und dieser Makrophage nimmt den Komplex bestehend aus der Fc-CR 2 bzw. Fc-CD 21- Fusion und dem EBV auf, wonach die Vernichtung des EBV bzw. die Virolyse (ein Fachausdruck des Erfinders) stattfindet. The fusion proteins Fc-CR 2 or Fc-CD 21, Fc-CD 155, Fc-CD 4, Fc- TCR. FC-BZR and Fc-MHC accordingly against EBV, polioviruses, HIV and influenza Act. If we consider the effect of the fusion protein Fc-CR 2 or Fc- as an example CD21. The CR 2 or CD 21 domain of the Fc-CR 2 or Fc-CD 21 fusion recognized the Surface of the EBV. Fc region is recognized by the Fc receptor of a macrophage and this macrophage takes the complex consisting of the Fc-CR 2 or Fc-CD 21- Fusion and the EBV on, after which the destruction of the EBV or the virolysis (a Expression of the inventor) takes place.
- 1. Fc-L (ein Ligand) 1. Fc-L (a ligand)
- 2. Fc-R (ein Rezeptor) 2. Fc-R (a receptor)
- 3. Fc-A (ein Antigen) 3. Fc-A (an antigen)
- 4. Fc-Auto A (ein Autoantigen oder eine autoantigene Region) 4. Fc-Auto A (an autoantigen or an autoantigenic region)
- 5. Fc D (eine beliebige Domäne) 5. Fc D (any domain)
1. a Fc-L(Ligand)
b 1 Fc-L-His tag
b 2 His tag-Fc-L
c 1 Fc-5G-L-His tag
c 2 His tag-Fc-5G-L
d 1 Fc-5G-L5G His tag
d 2 His-tag-5G-Fc-5G-L
2. a Fc-R (Rezeptor oder Rezeptor-Exodomäne)
b 1 Fc-R-His tag
b 2 His tag-Fc-R
c 1 Fc-5G-R-His tag
c 2 His tag-Fc-5G-R
d 1 Fc-5G-R-5G-His tag
d 2 His tag-5G-Fc-5G-R
3. a Fc-A
b 1 Fc-A-His tag
b 2 His tag-Fc-A
c 1 Fc-5G-A-His tag
c 2 His tag-Fc-5G-A
d 1 Fc-5G-A-5G-His tag
d 2 His tag-5G-Fc-5G-A
4. a Fc-Auto A
b 1 Fc-Auto A-His tag
b 2 His tag-Fc-Auto A
c 1 Fc-5G-Auto A-His tag
c 2 His tag-Fc-5G-AutoA
d 1 Fc-5G-Auto A-5G-His tag
d 2 His tag-5G-Fc-5G-Auto A
5. a Fc-D
b 1 Fc-D-His tag
b 2 His tag-Fc-D
c 1 Fc-5G-D-His tag
c 2 His tag-fc-5G-D
d 1 Fc-5G-D-5G-His tag
d 2 His tag-5G-Fc-5G-D
Tabelle 2
Anti-tumor: Fc-L (Ligand)
Anti Hodgkin-Krankheit: Fc-CD 153
Anti-T-Zell-Tumoren: Fc-FK 506
Fc-CD 58
Fc-CD 72
Anti-B-Zell-Tumoren:
Fc-CD 5
Fc-CD 28
Fc-CTLA-4
Tabelle 3
Antiautoimmun: Fc-Autoantigen
Fc-autoantigenes Peptid bzw. immunodominante Region des Autoantigens
Fc-Rezeptor
Fc-Rezeptor-Region z. B. Exo- bzw. Ligand-Bindedomäne
Anti-Multiple-Sklerose:
Fc-MBP (82-104)(Myelin-Basisches Protein, Region 82-104)
Fc-MBP
Anti-Diabetes mellitus: Fc-GAD oder
Fe-GSD (Glutaminsäure-Decaorboxylase)
Fc-GAD-autoantigenes Peptid
Fc-Insulinrezeptor
Anti-Lupus: (Anti-SLE (Systemisches Lupus erythematosus))
Fc-DBD + DNA Komplex
Fc-RBD + RNA Komplex
Fc-ein Histon
Fc-RNP, ein Ribonukleoproteinen
Anti-Basedow-Krankheit:
Fc-TSHR
Fc-TSHR-Exodomäne
Anti-myastenia gravis:
Fc-AchR
Fc-AchR-Alpha - unter einheit - Region 125-147 oder 131-147
Anti-Pemphigus foliaceus:
Fc-Desmoglein 1
Anti-Pemphigus vulgaris:
Fc-Desmoglein 3
Anti-bullöses Pemphigoid:
Fc-BP 180
Anti-Epidermolyse bullosa aquesita:
Fc-Kollagen-Typ-7
Anti-Goodpasture-Syndrom:
Fc-nichtkollagenöse Domäne des Basalmembran-kollagens-Typ-4
Anti-Polyarteriitis nodosa:
Fc-Oberflächenantigen des Hepatitis-B-Virus oder seine Region
Anti-rheumatische Arthitis:
Fc-Hsp (Hitze-schockproteinen)
Anti-autoimmune Thrombopenie:
Fc-Integrin gp II b : II a aus Blutplättchen
Anti-hämolytische Anämie:
Fc-Rhesus-Antigene
Fc-I-Antigen
Tabelle 4
Antiviral
Anti-Epstein-Barr-Virus (EBV):
Fc-CR 2(Fc-CD21)
Anti Polio virus: Fc-CD 155
Anti-HIV: Fc-CD 4
Anti Influenza: Fc-TZR
Fc-BZR
Fc-MHC
1. a Fc-L (ligand)
b 1 Fc-L-His day
b 2 His tag-Fc-L
c 1 Fc-5G-L-His tag
c 2 His tag-Fc-5G-L
d 1 Fc-5G-L5G His tag
d 2 His-tag 5G-Fc-5G-L
2. a Fc-R (receptor or receptor exodomain)
b 1 Fc-R-His day
b 2 His tag-Fc-R
c 1 Fc-5G-R-His tag
c 2 His tag-Fc-5G-R
d 1 Fc-5G-R-5G-His tag
d 2 His tag-5G-Fc-5G-R
3. a Fc-A
b 1 Fc-A-His day
b 2 His tag-Fc-A
c 1 Fc-5G-A-His tag
c 2 His tag-Fc-5G-A
d 1 Fc-5G-A-5G-His tag
d 2 His tag-5G-Fc-5G-A
4. a Fc car A
b 1 Fc-Auto A-His tag
b 2 His tag Fc car A
c 1 Fc-5G-Auto A-His tag
c 2 His tag-Fc-5G-AutoA
d 1 Fc-5G-Auto A-5G-His tag
d 2 His tag-5G-Fc-5G-Auto A
5. a Fc-D
b 1 Fc-D-His day
b 2 His tag-Fc-D
c 1 Fc-5G-D-His tag
c 2 His tag-fc-5G-D
d 1 Fc-5G-D-5G-His tag
d 2 His tag-5G-Fc-5G-D Table 2 Anti-tumor: Fc-L (ligand)
Anti Hodgkin's Disease: Fc-CD 153
Anti-T cell tumors: Fc-FK 506
Fc-CD 58
Fc-CD 72
Anti-B-cell tumors:
Fc-CD 5
Fc-CD 28
Fc-CTLA-4 Table 3 Anti-autoimmune: Fc autoantigen
Fc autoantigenic peptide or immunodominant region of the autoantigen
Fc receptor
Fc receptor region e.g. B. exo or ligand binding domain
Anti-multiple sclerosis:
Fc-MBP (82-104) (Myelin Basic Protein, Region 82-104)
Fc MBP
Anti-Diabetes Mellitus: Fc-GAD or
Fe-GSD (glutamic acid decaorboxylase)
Fc-GAD autoantigenic peptide
Fc insulin receptor
Anti-Lupus: (Anti-SLE (Systemic Lupus Erythematosus))
Fc-DBD + DNA complex
Fc-RBD + RNA complex
Fc-a histone
Fc-RNP, a ribonucleoprotein
Anti-Graves' disease:
Fc TSHR
Fc TSHR exodomain
Anti-myastenia gravis:
Fc AChR
Fc-AchR-Alpha - under unit - region 125-147 or 131-147
Anti-Pemphigus foliaceus:
Fc-Desmoglein 1
Anti-Pemphigus vulgaris:
Fc-Desmoglein 3
Anti-bullous pemphigoid:
Fc-BP 180
Anti-epidermolysis bullosa aquesita:
Fc-collagen type 7
Anti-Goodpasture's syndrome:
Fc non-collagenous domain of basement membrane collagen type 4
Anti-polyarteritis nodosa:
Fc surface antigen of the hepatitis B virus or its region
Anti-rheumatic arthitis:
Fc-Hsp (heat shock proteins)
Anti-autoimmune thrombopenia:
Fc integrin gp II b: II a from platelets
Anti-hemolytic anemia:
Fc rhesus antigens
Fc-I antigen Table 4 Antiviral
Anti-Epstein-Barr virus (EBV):
Fc-CR 2 (Fc-CD21)
Anti Polio virus: Fc-CD 155
Anti-HIV: Fc-CD 4
Anti Influenza: Fc-TZR
Fc BZR
Fc MHC
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2001160248 DE10160248A1 (en) | 2001-12-07 | 2001-12-07 | New fusion protein, useful for treating e.g. tumors, viral infections and autoimmune disease, comprises an Fc antibody region and at least one other domain and improves the response of antigen-presenting cells |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2001160248 DE10160248A1 (en) | 2001-12-07 | 2001-12-07 | New fusion protein, useful for treating e.g. tumors, viral infections and autoimmune disease, comprises an Fc antibody region and at least one other domain and improves the response of antigen-presenting cells |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE10160248A1 true DE10160248A1 (en) | 2003-06-26 |
Family
ID=7708441
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE2001160248 Ceased DE10160248A1 (en) | 2001-12-07 | 2001-12-07 | New fusion protein, useful for treating e.g. tumors, viral infections and autoimmune disease, comprises an Fc antibody region and at least one other domain and improves the response of antigen-presenting cells |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE10160248A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1606318A2 (en) | 2003-03-26 | 2005-12-21 | Apogenix GmbH | Improved fc fusion proteins |
| DE10161899B4 (en) * | 2001-12-17 | 2006-12-07 | Alexander Cherkasky | Fusion proteins against Hodgkin's disease |
| DE10161738B4 (en) * | 2001-12-15 | 2006-12-07 | Alexander Cherkasky | Fusion proteins against T-cell tumors |
| CN102470169A (en) * | 2009-07-30 | 2012-05-23 | 日本制药株式会社 | Autoantibody production inhibitor |
| DE102012015806A1 (en) | 2012-08-10 | 2014-02-13 | Alexander Cherkasky | New fusion protein comprising patient-specific region, which is encoded by a nucleic acid sequence or nucleic acid sequences of at least one individual, preferably human, useful for treating e.g. cancer and autoimmune diseases |
| EP2698386A1 (en) * | 2011-04-13 | 2014-02-19 | Nihon Pharmaceutical Co., Ltd. | Fusion protein |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997020048A2 (en) * | 1995-11-30 | 1997-06-05 | Bristol-Myers Squibb Company | Modified sfv molecules which mediate adhesion between cells and uses thereof |
| WO1997047321A1 (en) * | 1996-06-14 | 1997-12-18 | The Johns Hopkins University School Of Medicine | Use of chimeric vaccinia virus complement control proteins to inhibit complement |
| WO2001007081A1 (en) * | 1999-07-21 | 2001-02-01 | Lexigen Pharmaceuticals Corp. | Fc fusion proteins for enhancing the immunogenicity of protein and peptide antigens |
| WO2001036489A2 (en) * | 1999-11-12 | 2001-05-25 | Merck Patent Gmbh | Erythropoietin forms with improved properties |
-
2001
- 2001-12-07 DE DE2001160248 patent/DE10160248A1/en not_active Ceased
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997020048A2 (en) * | 1995-11-30 | 1997-06-05 | Bristol-Myers Squibb Company | Modified sfv molecules which mediate adhesion between cells and uses thereof |
| WO1997047321A1 (en) * | 1996-06-14 | 1997-12-18 | The Johns Hopkins University School Of Medicine | Use of chimeric vaccinia virus complement control proteins to inhibit complement |
| WO2001007081A1 (en) * | 1999-07-21 | 2001-02-01 | Lexigen Pharmaceuticals Corp. | Fc fusion proteins for enhancing the immunogenicity of protein and peptide antigens |
| WO2001036489A2 (en) * | 1999-11-12 | 2001-05-25 | Merck Patent Gmbh | Erythropoietin forms with improved properties |
Non-Patent Citations (3)
| Title |
|---|
| AN 2001-00494 BIOTECHABS in Biochim. Biophys. ActaMol. Cell Biol. Lipids 2000, 1488, 3, S. 245-54 * |
| AN 2001-04218 BIOTECHABS * |
| AN 2002:152716 BIOSIS * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10161738B4 (en) * | 2001-12-15 | 2006-12-07 | Alexander Cherkasky | Fusion proteins against T-cell tumors |
| DE10161899B4 (en) * | 2001-12-17 | 2006-12-07 | Alexander Cherkasky | Fusion proteins against Hodgkin's disease |
| EP1606318A2 (en) | 2003-03-26 | 2005-12-21 | Apogenix GmbH | Improved fc fusion proteins |
| CN102470169A (en) * | 2009-07-30 | 2012-05-23 | 日本制药株式会社 | Autoantibody production inhibitor |
| EP2465524A1 (en) * | 2009-07-30 | 2012-06-20 | Nihon Pharmaceutical Co., Ltd. | Autoantibody production inhibitor |
| EP2465524A4 (en) * | 2009-07-30 | 2013-01-09 | Nihon Pharmaceuticals Co Ltd | Autoantibody production inhibitor |
| EP2698386A1 (en) * | 2011-04-13 | 2014-02-19 | Nihon Pharmaceutical Co., Ltd. | Fusion protein |
| EP2698386A4 (en) * | 2011-04-13 | 2014-12-03 | Nihon Pharmaceutical Co Ltd | Fusion protein |
| US9243071B2 (en) | 2011-04-13 | 2016-01-26 | Nihon Pharmaceutical Co., Ltd | Fusion protein for suppression of autoantibodies |
| DE102012015806A1 (en) | 2012-08-10 | 2014-02-13 | Alexander Cherkasky | New fusion protein comprising patient-specific region, which is encoded by a nucleic acid sequence or nucleic acid sequences of at least one individual, preferably human, useful for treating e.g. cancer and autoimmune diseases |
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