DE10161739A1 - New fusion protein, useful for selective treatment of monocytic leukemia, comprises a lipopolysaccharide-binding protein and a cell-damaging domain, cytotoxic or immune-response promoting domain - Google Patents
New fusion protein, useful for selective treatment of monocytic leukemia, comprises a lipopolysaccharide-binding protein and a cell-damaging domain, cytotoxic or immune-response promoting domainInfo
- Publication number
- DE10161739A1 DE10161739A1 DE2001161739 DE10161739A DE10161739A1 DE 10161739 A1 DE10161739 A1 DE 10161739A1 DE 2001161739 DE2001161739 DE 2001161739 DE 10161739 A DE10161739 A DE 10161739A DE 10161739 A1 DE10161739 A1 DE 10161739A1
- Authority
- DE
- Germany
- Prior art keywords
- domain
- lipopolysaccharide
- lbp
- cell
- damaging
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 102000052508 Lipopolysaccharide-binding protein Human genes 0.000 title claims abstract description 21
- 108010053632 Lipopolysaccharide-binding protein Proteins 0.000 title claims abstract description 21
- 102000037865 fusion proteins Human genes 0.000 title claims abstract description 21
- 108020001507 fusion proteins Proteins 0.000 title claims abstract description 21
- 231100000433 cytotoxic Toxicity 0.000 title abstract description 4
- 230000007402 cytotoxic response Effects 0.000 title abstract 3
- 230000028993 immune response Effects 0.000 title abstract 3
- 230000001737 promoting effect Effects 0.000 title abstract 3
- 206010024305 Leukaemia monocytic Diseases 0.000 title description 2
- 201000006894 monocytic leukemia Diseases 0.000 title description 2
- 239000002158 endotoxin Substances 0.000 claims abstract description 9
- 102000029749 Microtubule Human genes 0.000 claims abstract description 6
- 108091022875 Microtubule Proteins 0.000 claims abstract description 6
- 210000004688 microtubule Anatomy 0.000 claims abstract description 6
- 108091005804 Peptidases Proteins 0.000 claims abstract description 5
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims abstract description 4
- 102000004190 Enzymes Human genes 0.000 claims abstract description 3
- 108090000790 Enzymes Proteins 0.000 claims abstract description 3
- 101710163270 Nuclease Proteins 0.000 claims abstract description 3
- 239000004365 Protease Substances 0.000 claims abstract description 3
- 108090000787 Subtilisin Proteins 0.000 claims abstract description 3
- 150000007523 nucleic acids Chemical group 0.000 claims abstract 3
- 238000010367 cloning Methods 0.000 claims abstract 2
- 239000013598 vector Substances 0.000 claims abstract 2
- 102000013446 GTP Phosphohydrolases Human genes 0.000 claims description 5
- 108091006109 GTPases Proteins 0.000 claims description 5
- 102000004157 Hydrolases Human genes 0.000 claims description 4
- 108090000604 Hydrolases Proteins 0.000 claims description 4
- 108010058607 HLA-B Antigens Proteins 0.000 claims description 3
- 102000006390 HLA-B Antigens Human genes 0.000 claims description 3
- 241000219995 Wisteria Species 0.000 claims description 2
- 230000026731 phosphorylation Effects 0.000 claims description 2
- 238000006366 phosphorylation reaction Methods 0.000 claims description 2
- 102100030497 Cytochrome c Human genes 0.000 claims 1
- 108010075031 Cytochromes c Proteins 0.000 claims 1
- 125000002842 L-seryl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])O[H] 0.000 claims 1
- 238000004140 cleaning Methods 0.000 claims 1
- XKMLYUALXHKNFT-UUOKFMHZSA-N Guanosine-5'-triphosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XKMLYUALXHKNFT-UUOKFMHZSA-N 0.000 abstract description 13
- 229920006008 lipopolysaccharide Polymers 0.000 abstract description 6
- 102000018832 Cytochromes Human genes 0.000 abstract description 4
- 108010052832 Cytochromes Proteins 0.000 abstract description 4
- 102000036292 Death effector domains Human genes 0.000 abstract description 4
- 108091010866 Death effector domains Proteins 0.000 abstract description 4
- 102000010170 Death domains Human genes 0.000 abstract description 3
- 108050001718 Death domains Proteins 0.000 abstract description 3
- 108010091938 HLA-B7 Antigen Proteins 0.000 abstract description 2
- 102100027221 CD81 antigen Human genes 0.000 abstract 1
- 102000016911 Deoxyribonucleases Human genes 0.000 abstract 1
- 108010053770 Deoxyribonucleases Proteins 0.000 abstract 1
- 102000004533 Endonucleases Human genes 0.000 abstract 1
- 108010042407 Endonucleases Proteins 0.000 abstract 1
- 101000914479 Homo sapiens CD81 antigen Proteins 0.000 abstract 1
- 108091028043 Nucleic acid sequence Proteins 0.000 abstract 1
- 102000006382 Ribonucleases Human genes 0.000 abstract 1
- 108010083644 Ribonucleases Proteins 0.000 abstract 1
- 108020004707 nucleic acids Proteins 0.000 abstract 1
- 102000039446 nucleic acids Human genes 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 10
- 230000003211 malignant effect Effects 0.000 description 9
- 230000006907 apoptotic process Effects 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 102000004243 Tubulin Human genes 0.000 description 4
- 108090000704 Tubulin Proteins 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 210000004292 cytoskeleton Anatomy 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 2
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 210000003714 granulocyte Anatomy 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 210000001616 monocyte Anatomy 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- MQLACMBJVPINKE-UHFFFAOYSA-N 10-[(3-hydroxy-4-methoxyphenyl)methylidene]anthracen-9-one Chemical compound C1=C(O)C(OC)=CC=C1C=C1C2=CC=CC=C2C(=O)C2=CC=CC=C21 MQLACMBJVPINKE-UHFFFAOYSA-N 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 102000004091 Caspase-8 Human genes 0.000 description 1
- 108090000538 Caspase-8 Proteins 0.000 description 1
- 101000946889 Homo sapiens Monocyte differentiation antigen CD14 Proteins 0.000 description 1
- 102100035971 Molybdopterin molybdenumtransferase Human genes 0.000 description 1
- 102100035877 Monocyte differentiation antigen CD14 Human genes 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 241000607626 Vibrio cholerae Species 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 108010024999 gephyrin Proteins 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/70532—B7 molecules, e.g. CD80, CD86
-
- 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
-
- 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
- C07K14/70596—Molecules with a "CD"-designation not provided for elsewhere
-
- 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
- C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/795—Porphyrin- or corrin-ring-containing peptides
- C07K14/80—Cytochromes
-
- 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
-
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
-
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/52—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea
- C12N9/54—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea bacteria being Bacillus
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
Abstract
Description
Die Erfindung betrifft die Bereiche der Immunologie, Molekularbiologie und Onkologie. The invention relates to the fields of immunology, molecular biology and Oncology.
Als Leukämie bezeichnet man die ungehemmte, bösartige Vermehrung weisser Blutkörperchen. Charakteristisch ist eine sehr hohe Zahl der malignanten Zellen in Blut. Leukämien können lymphocytisch, myelocytisch oder monocytisch sein. Leukemia is the uninhibited, malignant increase in white Blood cells. A very high number of malignant cells is characteristic in blood. Leukaemias can be lymphocytic, myelocytic or monocytic his.
(C. A. Janeway und P. Travers, 1995 Immunologie, Spektrum akademischer Verlag, S. 610). (C.A. Janeway and P. Travers, 1995 Immunology, Spectrum Academic Verlag, p. 610).
Leukämien sind schwer zu heilen. Leukaemias are difficult to cure.
Die Chemotherapie und Bestrahlung sind erstens nicht effektiv und zweitens nicht selektiv. Zahl und Härte der Nebenwirkungen und Gegenanzeigen sind gross. Firstly, chemotherapy and radiation are not effective and secondly not selective. The number and severity of side effects and contraindications are large.
Die Aufgabe der Erfindung ist monocytische Leukämien effektiv und selektiv zu heilen. The object of the invention is to effectively and selectively monocytic leukaemias heal.
Myelomonocytische Zellen bzw. Monozyten, Makrophagen, Granulozyten exprimieren unter anderem ein Molekül namens CD 14. Das ist das Rezeptor für den Komplex aus Lipopolysaccharid und Lipopolysaccharid - bindendem Protein (LBP). (C. A. Janeway und P. Travers, 1995 Immunologie, Spektrum akademischer Verlag, S. 590, J. Roitt, J. Brostoff, D. Male 1998 immunology S. 398). Dieses Molekül CD 14 dient als Therapieansatz bei dieser Erfindung. Myelomonocytic cells or monocytes, macrophages, granulocytes express, among other things, a molecule called CD 14. This is the receptor for the complex of lipopolysaccharide and lipopolysaccharide - binding Protein (LBP). (C.A. Janeway and P. Travers, 1995 Immunology, Spectrum academic publisher, p. 590, J. Roitt, J. Brostoff, D. Male 1998 immunology S. 398). This CD 14 molecule serves as a therapeutic approach in this invention.
Die Aufgabe der Erfindung wird dadurch gelöst, dass mindestens ein Lipopolysaccharid - Bindeprotein (LBD) mit mindestens einer zytotoxischen oder Immunreaktionsfördernder Domäne bzw. einer zellschädigenden Domäne (D) fusioniert wird. Dieses Fusionsprotein wird in eine Lipopolysaccharid-Lösung getan und die LBP-Domäne bindet ein Komplex mit Lipopolysaccharid (L). Das Fusionsprotein kann man als D-LBP abkürzen bzw. bezeichnen und D- LBP-Lipopolysacchaid wird als D-LBP + L bezeichnet. The object of the invention is achieved in that at least one Lipopolysaccharide binding protein (LBD) with at least one or Immune response-promoting domain or a cell-damaging domain (D) is merged. This fusion protein is in a lipopolysaccharide solution done and the LBP domain binds a complex with lipopolysaccharide (L). The fusion protein can be abbreviated or called D-LBP and D- LBP-Lipopolysacchaid is called D-LBP + L.
Sobald malignante myelomonocytische Zellen D-LBP + L aufnehmen, werden sie entweder von cytotoxischen T-Zellen vernichtet oder sie können sich werden auf eine andere Weise spezifisch bzw. zielgerichtet und selektiv geschädigt. Einige Beispiele für diese zellschädigende Domänen werden im Folgenden aufgelistet. As soon as malignant myelomonocytic cells take up D-LBP + L they either get destroyed by cytotoxic T cells or they can are specifically or specifically and selectively damaged in another way. Some examples of these cell-damaging domains are shown below listed.
Eine Mikrotubuli-Bindedomäne (MBP), wie z. B. Gephyrin, Tau, MID-1 etc. bindet Mikrotubuli bzw. Zytoskelett, hemmt somit die Zellteilung und kann Apoptose induzieren. A microtubule binding domain (MBP), e.g. B. Gephyrin, Tau, MID-1 etc. binds microtubules or cytoskeleton, inhibits cell division and can Induce apoptosis.
Ein Enzym, GTPase bzw. GTP Hydrolase verwandelt GTP in GDP und Phosphat, also degradiert GTP. GTP bildet Komplexe mit Tubulinen und ist notwendig für die Tubulinen-Polymerisation. An enzyme, GTPase or GTP Hydrolase converts GTP into GDP and Phosphate, i.e. degrades GTP. GTP forms complexes with tubulins and is necessary for tubulin polymerization.
Tubuline, sowie Aktine, sind in Zellen sowohl in monomerischer als auch in polymerischer Form vorhanden. Tubulins, as well as actins, are in cells both in monomeric and in polymeric form available.
Man betrachtet zwei Typen der Tubulin-Untereinheiten, und es gibt dementsprechend vier Reaktionen bzw. Assoziation und Dissiziation von GTP- und GDP Tubulinen, die an Polymer-Enden ablaufen. One looks at two types of tubulin subunits, and there are accordingly four reactions or association and dissection of GTP and GDP tubulins that run off polymer ends.
Monomerisches Tubulin ist meistens in der GTP-Form vorhanden. Nachdem es in Polymer eingestellt wird, hydrolysiert Tubulin das gebundene GTP-Molekül zu GDP. Monomeric tubulin is mostly present in the GTP form. After it set in polymer, tubulin hydrolyzes the bound GTP molecule to GDP.
Nukleotidhydrolyse macht Mikrotubuli dynamisch instabil. Diese dynamische Instabilität der Mikrotubuli wurde in vitro und in lebenden Zellen beobachtet (Zach W. Hall with 11 Contributors, 1992 An Introduction to Molecular Neurobiology, Sinauer Associates, mc. S. 250-253). Nucleotide hydrolysis makes microtubules dynamically unstable. This dynamic Microtubule instability has been observed in vitro and in living cells (Zach W. Hall with 11 Contributors, 1992 An Introduction to Molecular Neurobiology, Sinauer Associates, mc. Pp. 250-253).
Also hydrolysiert bzw. degradiert die in eine Tumorzelle eingeführte Domäne mit der GTPase bzw. GTP-Hydrolase-Aktivität GTP-Moleküle und vermindert somit ihre Konzentration. Also können die Tubuline bzw. GTP-bindende Monomer-Tubuline nicht mehr oder geringer GTP-Moleküle binden. Sobald diese Tubulin-Einheiten GTP-Moleküle nicht mehr oder geringer binden, können sie also entsprechend nicht mehr oder geringer in Polymere integriert werden. D. h. Polymere können nicht mehr verlängert bzw. gebildet werden. So the domain inserted into a tumor cell hydrolyzes or degrades with the GTPase or GTP hydrolase activity, GTP molecules and thus reduces their concentration. So the tubulins or No more or less GTP-binding monomer tubulins bind GTP molecules. Once these tubulin units GTP molecules no longer or less bind, so they can no longer or less accordingly in polymers to get integrated. I.e. Polymers can no longer be extended or formed become.
Die dynamische Instabilität der Polymere nimmt auch zu. The dynamic instability of the polymers is also increasing.
Also kann diese Tumorzelle kein Zytoskelett mehr bilden und folglich sich nicht mehr weiter teilen. Es ist auch möglich dass, das in dieser Tumorzelle vorhandenes Zytoskelett wegen der zunehmender dynamischer Instabilität zerfällt. So this tumor cell can no longer form a cytoskeleton and consequently cannot share more. It is also possible that in this tumor cell existing cytoskeleton disintegrates due to increasing dynamic instability.
Ein anderes Enzym Protease wie z. B. Subtilisin spaltet Proteinen und kann ebenfalls zytotoxisch wirken und Apoptose induzieren. Another enzyme protease such as B. Subtilisin cleaves proteins and can also have a cytotoxic effect and induce apoptosis.
Eine Membranpenetrationsdomäne (MPD) kann Lipidmembranen penetrieren und somit zur leichteren Internalisierung des Fusionsproteines sowie zum Kalzium-Ioneneinfluss ins Zytoplasma und folglich zur Apoptose führen. A membrane penetration domain (MPD) can penetrate lipid membranes and thus for easier internalization of the fusion protein and for Calcium ion influence in the cytoplasm and consequently lead to apoptosis.
DD (death domäne) und DED (death-effector domäne) der FLICE-Moleküle können ebenfalls Apoptose induzieren. DD (death domain) and DED (death-effector domain) the FLICE molecules can also induce apoptosis.
Zytochrom C ist auch fähig Apoptose zu induzieren. Cytochrome C is also able to induce apoptosis.
HLA-B 7 bzw. CD 81 und CD 86 sind fähig zytotoxische T-Zell-Reaktionen hervorzurufen. HLA-B 7 or CD 81 and CD 86 are capable of cytotoxic T cell reactions cause.
Fc Regionen der Antikörper können ebenfalls Immunreaktionen auslösen. Endotoxine wie z. B. Vibrio-Cholera-Toxin können Proteinsynthese hemmen. Also können die aufgelisteten Domänen mit LBP fusioniert werden und diese Fusionsproteinen sind fähig malignante myelomonocytische Zellen entweder spezifisch zu blockieren oder zu vernichten. Fc regions of the antibodies can also trigger immune reactions. Endotoxins such as B. Vibrio-cholera toxin can inhibit protein synthesis. So the domains listed can be merged with LBP and this Fusion proteins are capable of malignant myelomonocytic cells either specifically block or destroy.
Z. B. nimmt eine malignante myelomonocytische Zelle eine MBD-LBP-Fusion bzw. MBD-LBP + L auf. Nach der Aufnahme bzw. Internalisierung mehrerer dieser Fusionsproteinen oder Fusionsprotein-Lipopolysaccharid-Komplexen wird sich eine malignante myelomonocytische Zelle nicht mehr teilen können. Sobald eine Tumorzelle sich nicht mehr teilen kann, stirbt sie. For example, a malignant myelomonocytic cell takes one MBD-LBP-Fusion or MBD-LBP + L. After admission or internalization several of these fusion proteins or A malignant myelomonocytic cell will no longer share fusion protein-lipopolysaccharide complexes can. As soon as a tumor cell can no longer divide, it dies.
Man soll diese Therapie in der Klinik mit Bluttransfusionen und Filtrationen bzw. Aufreinigungen kombinieren um getötete malignante Zellen aus dem Blut- Kreislauf zu entfernen und somit eine Blutverschmutzung und Vergiftung von Patienten zu verhindern. One should this therapy in the clinic with blood transfusions and filtrations or purifications combine to kill malignant cells from the blood To remove circulation and thus blood pollution and poisoning To prevent patients.
In der Tabelle sind einige Kombinationen bzw. Fusionsproteinen und Fusionprotein-Lipopolysaccharid-Komplexe gegen malignante myelomonocytische Zellen bzw. gegen malignanten Makrophagen, Monozyten und Granulozyten dargestellt. In the table are some combinations or fusion proteins and Fusion protein-lipopolysaccharide complexes against malignant myelomonocytic Cells or against malignant macrophages, monocytes and granulocytes shown.
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 Increase in the energetic level. Can between domains Joint domains, such as B. five wisteria (5G).
Die Fusionsproteinen werden rekombinant hergestellt.
Tabelle
MBP-LBP + L
HLA-B7 bzw.
CD 81-LBP + L
CD 86-LBP + L
DD-LBP + L
DED-LBP + L
Zytochrom c-LBP + L
GTPase/GTP-Hydrolase-LBP + L
Protease-LBP + L
Fc-LBP + L
Nuklease-LBP + L
MBP-LBP
HLA-B 7 bzw.
CD 81-LBP
CD 86-LBP
DD-LBP
DED-LBP
Zytochrom c-LBP
GTPase/GTP-Hydrolase-LBP
Protease-LBP
Fc-LBP
Nuklease-LBP
The fusion proteins are produced recombinantly. Table MBP-LBP + L
HLA-B7 or
CD 81-LBP + L
CD 86-LBP + L
DD-LBP + L
DED-LBP + L
Cytochrome c-LBP + L
GTPase / GTP hydrolase LBP + L
Protease LBP + L
Fc-LBP + L
Nuclease LBP + L
MBP-LBP
HLA-B 7 or
CD 81 LBP
CD 86 LBP
DD-LBP
DED LBP
Cytochrome c-LBP
GTPase / GTP hydrolase LBP
Protease LBP
Fc LBP
Nuclease LBP
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2001161739 DE10161739A1 (en) | 2001-12-15 | 2001-12-15 | New fusion protein, useful for selective treatment of monocytic leukemia, comprises a lipopolysaccharide-binding protein and a cell-damaging domain, cytotoxic or immune-response promoting domain |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2001161739 DE10161739A1 (en) | 2001-12-15 | 2001-12-15 | New fusion protein, useful for selective treatment of monocytic leukemia, comprises a lipopolysaccharide-binding protein and a cell-damaging domain, cytotoxic or immune-response promoting domain |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE10161739A1 true DE10161739A1 (en) | 2003-06-26 |
Family
ID=7709392
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE2001161739 Ceased DE10161739A1 (en) | 2001-12-15 | 2001-12-15 | New fusion protein, useful for selective treatment of monocytic leukemia, comprises a lipopolysaccharide-binding protein and a cell-damaging domain, cytotoxic or immune-response promoting domain |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE10161739A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10350122A1 (en) * | 2003-10-28 | 2005-06-16 | Alexander Cherkasky | New fusion protein, useful for treating leukemia and solid tumors, comprises specific antigen-binding, microtubulin-binding and immune response-inducing regions, also related nucleic acid |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995000641A1 (en) * | 1993-06-17 | 1995-01-05 | Xoma Corporation | Lipopolysaccharide binding protein derivatives |
| WO2001077148A2 (en) * | 2000-04-05 | 2001-10-18 | Merck Patent Gmbh | Human lipid binding protein 1 |
-
2001
- 2001-12-15 DE DE2001161739 patent/DE10161739A1/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995000641A1 (en) * | 1993-06-17 | 1995-01-05 | Xoma Corporation | Lipopolysaccharide binding protein derivatives |
| WO2001077148A2 (en) * | 2000-04-05 | 2001-10-18 | Merck Patent Gmbh | Human lipid binding protein 1 |
Non-Patent Citations (1)
| Title |
|---|
| DE-AN 2001-00494 Biotechabs,Biochim.Biophys.Acta Mol.Cell Biol.Lipids, 2000,1488,3,S.245-254 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10350122A1 (en) * | 2003-10-28 | 2005-06-16 | Alexander Cherkasky | New fusion protein, useful for treating leukemia and solid tumors, comprises specific antigen-binding, microtubulin-binding and immune response-inducing regions, also related nucleic acid |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Hoggatt et al. | Rapid mobilization reveals a highly engraftable hematopoietic stem cell | |
| Kreger | Detection of a cytolytic toxin in the venom of the stonefish (Synanceia trachynis) | |
| CN1946290A (en) | Modified serum albumin with reduced affinity for nickel and copper | |
| Bigotte et al. | Degeneration of trigeminal ganglion neurons caused by retrograde axonal transport of doxorubicin | |
| DE10161739A1 (en) | New fusion protein, useful for selective treatment of monocytic leukemia, comprises a lipopolysaccharide-binding protein and a cell-damaging domain, cytotoxic or immune-response promoting domain | |
| Yamauchi et al. | Microtubule-associated protein interactions with actin filaments: evidence for differential behavior of neuronal MAP-2 and tau in the presence of phosphatidylinositol | |
| Joist et al. | Retention of platelet fibrin stabilizing factor during the platelet release reaction and clot retraction | |
| Dorahy et al. | Capture by chemical crosslinkers provides evidence that integrin α IIb β 3 forms a complex with protein tyrosine kinases in intact platelets | |
| Busch et al. | Nuclear proteins of tumors and other tissues: a review | |
| DE10162870A1 (en) | New fusion protein, useful for treatment of B cell tumors, comprises B cell-specific ligand attached to a cytotoxic or immunostimulating component | |
| Rüegg | The proteins associated with contraction in lamellibranch ‘catch’muscle | |
| Perry | The biochemistry of muscle | |
| DE10161738A1 (en) | New fusion protein, useful for selective treatment of T cell tumors, comprises T cell ligand linked to cytostatic or immunostimulating component | |
| Brown et al. | Protease activation of Gl nuclei isolated from Chinese hamster fibroblasts | |
| DE3714351C2 (en) | ||
| DE10161899A1 (en) | New fusion protein, useful for treating Hodgkin's disease, comprises a ligand specific for an antigen-presenting cell and a cell-damaging domain | |
| Joag et al. | Mechanisms of lymphocyte‐mediated lysis | |
| Błogowski et al. | Perioperative release of pro-regenerative biochemical signals from human renal allografts subjected to ischemia–reperfusion injury | |
| Abrams et al. | Effect of ascorbic acid on rheumatoid synovial fluid | |
| Lemon et al. | Concentrations of free serum digoxin after treatment with antibody fragments. | |
| Dirscherl et al. | A nonclassical MHC class IU lineage locus in zebrafish with a null haplotypic variant | |
| BERTMAR | On the development of the jugular and cerebral veins in fishes | |
| Marchesi | The relevance of research on red cell membranes to the understanding of complex human disease: a personal perspective | |
| Huehns et al. | Further studies on the isolation and properties of α-chain sub-units of haemoglobin | |
| Eley | Purification of chicken pancreas nuclease by substrate elution from phosphorylated cellulose |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| OM8 | Search report available as to paragraph 43 lit. 1 sentence 1 patent law | ||
| OP8 | Request for examination as to paragraph 44 patent law | ||
| 8131 | Rejection |