EP1848452A2 - Utilisation d'agents bloquant l'interaction entre le récepteur nkg2d et le ligand nkg2d, pour traiter des maladies auto-immunes - Google Patents

Utilisation d'agents bloquant l'interaction entre le récepteur nkg2d et le ligand nkg2d, pour traiter des maladies auto-immunes

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Publication number
EP1848452A2
EP1848452A2 EP05773900A EP05773900A EP1848452A2 EP 1848452 A2 EP1848452 A2 EP 1848452A2 EP 05773900 A EP05773900 A EP 05773900A EP 05773900 A EP05773900 A EP 05773900A EP 1848452 A2 EP1848452 A2 EP 1848452A2
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EP
European Patent Office
Prior art keywords
soluble
nkg2d
seq
blocker
disease
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EP05773900A
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German (de)
English (en)
Inventor
Alexander Steinle
Manuel Friese
Heinz Wiendl
Michael Weller
Bettina Schreiner
Robert Weissert
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Eberhard Karls Universitaet Tuebingen
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Eberhard Karls Universitaet Tuebingen
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1774—Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
    • 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

Definitions

  • the present invention relates to the use of NKG2D receptor / NKG2D ligand interaction blockers for the manufacture of a medicament for the treatment of autoimmune diseases.
  • Autoimmunity is based on a specific, adaptive immune response against the body's own antigens. Normally, the immune system leaves the body's own substances unmolested and fights only foreign bodies. Autoimmunity can be thought of as a result of a breakdown in tolerance to endogenous substances and / or a defective control and regulatory mechanism of the immune system. The exact causes of the emergence of autoimmune diseases are hitherto unknown. However, it is assumed that hereditary factors also play a role in addition to environmental factors. T-lymphocytes seem to be on the trigger
  • Autoimmune diseases can be subdivided into tissue-specific or organ-specific as well as systemic, ie non-organ-specific autoimmune diseases.
  • the disease multiple sclerosis is an example of an organ-specific, presumably T-cell-mediated autoimmune disease in humans.
  • cytokines involved in the induction of autoimmune diseases are blocked by antagonists, such as interleukin-1 and tumor necrosis factor- ⁇ antagonists.
  • the activating immune receptor NKG2D is expressed on natural cell (NK) cells and several T-cell subpopulations, including CD8 + T cells.
  • NK cells are an important component of the innate immune system and, as such, involved in the immune defense of viruses and tumors.
  • the interaction of signals of activating and inhibitory receptors determines the activation of NK cells.
  • cytotoxic lymphocytes that is, NK cells and CD8 + T cells, recognize virus-infected or malignant body cells, which can be eliminated as a result.
  • NK cells and CD8 + T cells recognize virus-infected or malignant body cells, which can be eliminated as a result.
  • CD8 + ⁇ ß T cells and NK cells were also shown to express NKD2D on ⁇ T cells.
  • the receptor NKG2D is constitutively expressed on the cell surface and is associated with the adapter protein DAP10. After interaction with its MHC class I-like ligands, the receptor NKG2D mediates via the adapter protein an activation signal into the cytotoxic lymphocytes.
  • MHC class I chain-like molecules A MICA
  • MICB MHC class I chain-like molecules A
  • ULBP ULl6-binding proteins 1, 2, 3 and 4
  • RAETlE ULl6-binding proteins 1, 2, 3 and 4
  • the various NKG2D ligands have different expression patterns. According to the current state of knowledge, the ligands are not or only to a small extent expressed by normal body cells while their expression is upregulated under pathological conditions, for example in transformations (eg epithelial tumors, gliomas, leukemias), infections (eg by the human cytomegalovirus (HCMV) or by Mycobacterium tuberculosis) or in cellular stress.
  • transformations eg epithelial tumors, gliomas, leukemias
  • infections eg by the human cytomegalovirus (HCMV) or by Mycobacterium tuberculosis
  • HCMV human cytomegalovirus
  • Mycobacterium tuberculosis Mycobacterium tuberculosis
  • the object of the present invention is therefore to provide substances for the preparation of a medicament which serve for the prophylaxis and / or therapy of autoimmune diseases.
  • this object is achieved by the provision of at least one blocker of the NKG2D receptor / NKG2D ligand interaction, which is selected from the group comprising soluble NKG2D receptor, soluble MICA, soluble MICB, soluble ULBPl, soluble ULBP2, soluble ULBP3, soluble ULBP4, soluble RAETlL, soluble RAETlG, and allelic variants or fragments or derivatives of said blockers, as well as synthetically engineered NKG2D receptor / NKG2D ligand interaction blockers.
  • NKG2D ligand expression in pancreas could be detected by diseased NOD (“nonobese diabeti ⁇ ”) mice.
  • NOD nonobese diabeti ⁇ mice
  • the same work group was also able to show that a blockade of the NGK2D Receptor by anti-NKG2D monoclonal antibody in NOD mice could prevent the onset of the disease.
  • soluble NKG2D ligands can cause them to bind to the NKG2D receptor expressed on surfaces of (inter alia) NK cells, but this can not be activated, since a cell-cell contact is presumably necessary for this purpose agile is.
  • fragment means each fragment of one of the mentioned soluble peptides, which, like the soluble protein, can bind to the NKG2D receptor.
  • derivatives means any protein modifications which have modifications that differ from the soluble protein, for example amino acid substitutions in particular at the sites of soluble proteins via which the binding of the proteins to the NKG2D receptor is not mediated. Also, such proteins or peptides derived from the blockers can be used for a use according to the invention.
  • allelic variants means all variants of nucleotide sequences of the genes coding for the proteins mentioned, which are at least heretofore known in the art: for example, 56 alleles have hitherto been identified for MICA (see for example, on the website of the EMBL-EBI (European Bioinformatics Institute) www.ebi.ac.uk/imgt/hla) and for MICB 16 alleles.
  • fragments, derivatives or allelic variants of the abovementioned blockers are understood as meaning all substances which have the same binding properties as the mentioned blockers of the NKG2D receptor / NKG2D ligand interaction.
  • any low molecular weight synthetically produced blocker of NKG2D receptor / NKG2D-ligand interaction can be identified, for example, by adding synthetic substances, e.g. For example, by combinatorial chemistry, in the "high throughput” method, blocking of the interaction between recombinantly produced soluble MICA immobilized, for example, on microtiter plates or so-called “beads" and with recombinantly produced soluble, biotinylated NKG2D is analyzed.
  • Binding of NKG2D to MICA can be detected via streptavidin conjugates (eg, streptavidin-phycoerythrin in flow cytometry or streptavidin-horseradish peroxidase in ELISA method).
  • streptavidin conjugates eg, streptavidin-phycoerythrin in flow cytometry or streptavidin-horseradish peroxidase in ELISA method.
  • Such identified synthetic blockers can then be used in functional experiments, eg. In cytotoxic experiments with NK cells.
  • antibodies which are directed against the NKG2D receptor or fragments thereof, for example, can also be used as blockers.
  • Polyclonal antibodies can be obtained in a conventional manner by immunization of animals, in particular of rabbits, by means of Injection of the antigen or fragments thereof, and anschlie ⁇ the purification of the immunoglobulin are obtained.
  • Monoclonal anti-NKG2D receptor antibodies can be obtained according to standard protocols in accordance with the principle described by Köhler and Milstein ("Continuous cultures of fused cells secreting antibodies of predefined specificity", Nature 256: 495-497, 1975) Mice are then immunized and subsequently immortalized antibody-producing cells of the immunized animals, for example by fusion with myeloma cells., Then the supernatant of the resulting hybridomas is screened for monoclonal anti-NKG2D receptor antibodies by standard immunological assays for therapeutic or diagnostic use in humans For example, these animal antibodies may be chimerized in a conventional manner (see, for example, Neuberger et al., Recombinant possessing novel effector functions Nature 312: 604-608, 1984) or humanized (see, for example, Riechmann et al. Reshaping human antibodies for therapy ", Nature 332: 323-327, 1988).
  • the blocker used is a protein or peptide which contains an amino acid sequence which is selected from the sequences listed in the attached sequence listing with the SEQ ID No. 1 to SEQ ID NO. 15, and in particular a protein which has an amino acid sequence which is selected from the sequences having the SEQ ID No. 1 to SEQ ID No. 15.
  • the peptide listed in the attached sequence listing with SEQ ID NO. 1 of the attached sequence listing represents the complete (full-length) amino acid sequence of the NKG2D receptor. This has a cytoplasmic domain (AS 1-51), a transmembrane domain (AS 52-72) and an ectodomain (AS 73-216).
  • the amino acid sequence of SEQ ID No. 2 of the attached Sequence Listing herein identifies the sequence encompassing this ectodomain.
  • SEQ ID no. 3 of the attached sequence listing is the sequence of MICA * 01
  • Figure 5 identifies the sequence of MICB * 02.
  • SEQ ID NOS: 4 and 6 are each sequence sections of MICA * 01 and MICB * 02. Under the SEQ ID-Nm.
  • Se ⁇ quenzprotokolls are each the full-length sequences and sequence sections of the proteins ULBPl, ULBP2, listed ULBP3, ULBP4, RAETlL and RAETlG.
  • An overview of the already known sequences and their database identification numbers (Accession Number) can be found in the attached Table 1.
  • blockers that is, soluble NKG2D receptor, soluble MICA / B, and soluble ULBP molecules, be prepared recombinantly for use.
  • Suitable for expression are, for example, Sf9 insect cell len or eukaryotic expression systems, such as 2931 or COS7 cells.
  • the autoimmune diseases are selected from the group comprising multiple sclerosis, diabetes type I, rheumatoid arthritis, psoriasis, spondylarthritis, celiac disease, Behcet's disease, Crohn's disease, ulcerative colitis and systemic lupus erythematosus (SLE) ,
  • the use takes place in the case of thrust-shaped multiple sclerosis, preferably in the initial phase of relapsing-remitting multiple sclerosis.
  • multiple sclerosis in the inflammatory foci (plaques) i.a. T lymphocytes, B lymphocytes and macrophages, which is considered an indication of an autoimmune reaction.
  • autoantibodies against various components of the myelin sheath could be detected, for example against basal myelin proteins, proteolipid proteins or against the myelin oligodendrocyte glycoprotein (MOG).
  • MOG myelin oligodendrocyte glycoprotein
  • recombinantly produced interferon .beta. Is currently used, in particular in the case of a scholastic disease course.
  • the autoimmune disease diabetes type I is based on a cell-mediated chronic and irreversible destruction of the insulin-producing ⁇ -cells of the pancreas, whereby a peptide presented on the ⁇ -cells is presumably recognized by autoimmune T-lymphocytes, which in turn encode the ⁇ -cells destroy.
  • Rheumatoid arthritis is an autoimmune disease in which an immune response of T lymphocytes, B lymphocytes and macrophages is presumably induced by an alteration of synovial cells, which leads to antibody formation against synovial cells.
  • hydrolases, collagenases and lysosomal enzymes are released, leading to the destruction of articular cartilage.
  • a therapy is currently taking place with anti-inflammatory drugs, corticosteroids, including antirheumatic drugs, as well as anti-TNF- ⁇ antagonists.
  • NKG2D mode of action in the pathogenesis of autoimmune diseases is induction of NKG2D ligands by cellular stress or viral or bacterial infections on the cells of organs or tissues affected by autoimmunity.
  • This induced expression of NKG2D ligands could then mediate lysis of the corresponding cells by NK cells.
  • This not only destroys the corresponding tissue, but also releases a large number of autoantigens, which in turn could be taken up by antigen-presenting cells and presented via MHC molecules, which could lead to the activation of potentially autoreactive T cells.
  • autoreactive T cells could also be activated directly by NKG2D ligand expression on the affected tissue.
  • the invention further relates to a pharmaceutical composition which contains at least one blocker of the NKG2D receptor / NKG2D ligand interaction.
  • the pharmaceutical composition contains at least one blocker selected from the group comprising soluble NKG2D receptor, soluble MICA, soluble MICB, soluble ULBPl, soluble ULBP2, soluble ULBP3, soluble ULBP4, soluble RAETLL, soluble RAETlG, and the like allelic variants or fragments or derivatives of said blockers, as well as synthetically produced blockers of NKG2D receptor / NKG2D ligand interaction.
  • soluble NKG2D receptor soluble MICA, soluble MICB, soluble ULBPl, soluble ULBP2, soluble ULBP3, soluble ULBP4, soluble RAETLL, soluble RAETlG, and the like allelic variants or fragments or derivatives of said blockers, as well as synthetically produced blockers of NKG2D receptor / NKG2D ligand interaction.
  • the invention further relates to a pharmaceutical composition which contains as a blocker a protein which contains an amino acid sequence which is selected from the sequences SEQ ID-N0 listed in the attached sequence listing. 1 to SEQ ID-Wr. 15, and in particular a protein having such an amino acid sequence.
  • composition also contains several of the mentioned Blo ⁇ ker.
  • the composition may also contain other additives and / or carriers which are commonly used in the preparation of a pharmaceutical composition to be administered.
  • Such ingredients are for Diluents, binders, suspending agents, lubricants, stabilizers, etc. These include, but are not limited to, for example, water, saline, alcohols, vegetable oils, polyetylene glycols, monoglycerides, etc. An overview of such ingredients can be found, for example, in A. Tippe, "Handbook of Pharmaceutical Excepients", 3rd Edition 2000, American Pharmaceutical Association and Pharmaceutical Press.
  • the composition will be formulated, that is to say for example in the form of capsules, tablets or else liquid preparations which, for example, can also be injected or administered intravenously.
  • the administration can also be carried out depending on the patient and the disease, systemically or locally and with a subtle direction.
  • composition may have other active ingredients or drugs, such as interferons and the like.
  • the pharmaceutical composition can then be used in autoimmune diseases,. such as multiple sclerosis, type I diabetes, rheumatoid arthritis, psoriasis, spondylarthritis, celiac disease, Behcet's disease, Crohn's disease, ulcerative colitis and systemic lupus erythematosus (SLE).
  • autoimmune diseases such as multiple sclerosis, type I diabetes, rheumatoid arthritis, psoriasis, spondylarthritis, celiac disease, Behcet's disease, Crohn's disease, ulcerative colitis and systemic lupus erythematosus (SLE).
  • Fig. 1 NKG2D ligand expression in the CNS in patients with multiple sclerosis as well as in human microglia:
  • FIG. 1A Immunohistochemical staining of demyelinated CNS lesions ("plaque” or "shadow plaque") of MS patients.
  • MHC-II MHC class II molecules
  • BAMOl MIC molecules
  • MBP Major Basic Protein
  • FIG. 1B Quantification of MICA transcripts by means of real-time PCR in the CNS of healthy (“normal”) versus MS patients (“MS”) with normalization to the T98G glioma cell line and of immature dendritic cells (DC “imm”) versus mature DC (“DC mature”) versus isolated microglia.
  • Fig. 2 NKG2D ligand expression in the CNS and in microglial cells in the experimental autoimmune encephalomyelitis of mice Fig. 2A: Detection of RAE-I and NKG2D in the CNS of C57BL / 6 mice on the day of EAE induction (day 0) as well as on day 10 and 20 after EAE induction by immunoblot. The numbers represent the units of relative densitometry (day 0 normalized to 1.0). To control the amount of protein applied, ⁇ -actin was detected.
  • FIG. 2B Quantification of RAE-l ⁇ transcripts by means of real-time PCR in the CNS of C57BL / 6 mice ("normal”) and C57BL / 6 mice after EAE induction ("EAE") with standardization on the mouse Glioma cell line GL261, as well as in isolated astrocytes and microglial cells of C57BL / 6 mice.
  • Fig. 3 Effect of NKG2D blockade in experimental autoimmune encephalomyelitis (EAE).
  • Fig. 3A Average "clinical score" of six H2-K b -MICA transgenic mice (open circles) and six non-transgenic siblings (closed circles) on days 0 to 30 after EAE induction.
  • Fig. 3B Average "clinical score" on days 0 to 25 after EAE induction of five C57BL / 6 mice on administration of soluble NKG2D (open circles, the sixth mouse showed no symptoms) and of six mice on administration of PBS (closed PBS or sNKG2D was administered on days 0, 2, 4, 6, 8, and 10 intraperitoneally.
  • Fig. 3C MOG peptide-specific T cell proliferation in mice in which EAE was induced and treated with either PBS or soluble NKG2D as described in Fig. 3B. Spleen cells were stimulated with 1 ⁇ g / ml or 10 ⁇ g / ml MOG peptide.
  • Fig. 3D Average "clinical score" on days 0 to 30 after EAE induction of six C57BL / 6 mice each with administration of soluble NKG2D (open circles) and when PBS was given (closed circles) PBS or SNKG2D was on Days 10, 12, 14, 16, 18, and 20 administered intraperitoneally.
  • Fig. 3E MOG-peptide-specific T cell proliferation in mice in which EAE was induced and treated with either PBS or soluble NKG2D as described in Fig. 3D. Spleen cells were stimulated with 1 ⁇ g / ml or 10 ⁇ g / ml MOG peptide.
  • BAMO1 mouse IgG 1
  • anti-MICA / B anti-mouse RAE-l ⁇
  • anti-mouse NKG2D R & D Systems
  • anti- ⁇ -actin Santa Cruz Biotechnologies
  • the human malignant glioma cell line T98G was developed by Dr. med. Tribolet (Lausanne, Switzerland) received.
  • the mouse glioma cell line GL261 was a gift from XO Brakefield (Harvard Medical School Boston, USA).
  • the cells were cultured in DMIM medium supplemented with 2 mM L-glutamine (Gibco Life Technologies, Paisley, UK), 10% FCS (Bio ⁇ hrom KG, Berlin, Germany) and penicillin (100 IU / ml) / streptomycin (100 ⁇ g / ml). ml; Gibco).
  • the brain tissue of the mice was isolated.
  • the tissue was suspended in lysis buffer (50 mM Tris-HCl (pH 8) with 120 mM NaCl, 5 mM EDTA, 0.5% NP-40, 2 ⁇ g / ml aprotinin, 10 ⁇ g / ml leupeptin and 100 ⁇ g / ml PMSF) disrupted by means of ultrasound.
  • lysis buffer 50 mM Tris-HCl (pH 8) with 120 mM NaCl, 5 mM EDTA, 0.5% NP-40, 2 ⁇ g / ml aprotinin, 10 ⁇ g / ml leupeptin and 100 ⁇ g / ml PMSF
  • Aliquots of the tissue lysates were electrophoresed on 12% SDS-PAGE gels under non-reducing conditions and transferred to nitrocellulose.
  • the total amount of protein of the lysates was 40 ⁇ g per lane.
  • glial cells were obtained from adult patients during a surgical resection performed to treat non-tumor-related incurable epilepsy. Tissue samples were taken in regions beyond the active site. The methodological isolation and cultivation of adult human microglia has already been described, for example, by Yong et al. ("Culture of Cells from Human Brain Biopsies", pp.
  • the less adherent oligodendroglia were removed by gentle shaking.
  • the remaining microglia 1.2 x 10 5 cells (cm 2 ) were 95% pure, which could be confirmed by immunocytochemistry.
  • Mouse microglial cells were isolated from primary mixed brain cell cultures by using a modified, already described method (see Magnus et al., J. Neuropol., Ex. Neurol., 2002, 61 (9): 760-766).
  • RNA extraction and cDNA synthesis were carried out by standard methods. Quantitative analysis of gene expression was performed by QRT-PCR using the ABI Prism 7000 Sequence Detection System (Applied Biosystems, Rothstadt, Germany) as previously described (see Wiendl et al., Brain, 2003, 126: 1026-1035 ). The cDNA amplification was detected using SYBRGreen chemistry. The Zyklus ⁇ parameters were for two minutes at 50 0 C, for ten minutes at 95 ° C, and forty cycles each fifteen seconds dena turing at 95 0 C and one minute annealing at 60 0 C. The data were performed with the ABI PRISM® Detection system analyzed and quantified using the ⁇ C ⁇ method for relative quantification.
  • the recombinant soluble mouse NKG2D receptor without the amino-terminal cytoplasmic region and the transmembrane domain was produced in Sf9 insect cells (Invitrogen, Düsseldorf, Germany) using the BAC-to-BAC system (Gibco Life Technologies, UK) ,
  • the expression construct (SEQ ID NO: 24) has an amino terminal FLAG / hexahistidine tag sequence (see Steinle et al., "Interactions of human NKG2D with its ligands MICA, MICB and homologs of the mouse RAE-I protein family", Immunogenetics 53: 279-287, 2001)
  • the sequence of the mouse NKG2D receptor (full-length) is reproduced in the enclosed sequence listing with SEQ ID No. 23.
  • mice Female C57BL / 6 mice were purchased from Charles River Labratories (Sulzfeld, Germany). MICA transgenic C57BL / 6 mice (kindly provided by Dr. Spies, Fred Hutchinson Cancer Research Center, Seattle) express MICA * 07 cDNA under the control of an MHC class I promoter, MHC class I gene K b . For the experiments, mice were used at the age of six to eight weeks.
  • EAE experimental autoimmune encephalomyelitis
  • mice express a MICA * 07 cDNA constitutively under the control of an MHC class I promoter (H-2K b ) and have high concentrations of soluble MICA in the serum (45-90 ng / ml). Because of this, NKG2D expression is markedly reduced in these transgenic mice, presumably by ligand-induced downregulation, and NKG2D-mediated NKG2D effector functions are severely impaired. Compared to non-transgenic mice, a significant delay in the onset of disease symptoms was observed in the MICA transgenic mice (Figure 3A).
  • mice were given soluble NKG2D (sNKG2D) (as described under 1.8 and 1.10) to study the interaction of the ligands with the To interrupt receptor in different phases of the EAE.
  • sNKG2D soluble NKG2D
  • SNKG2D was administered on days zero to ten (early phase). It could be observed that during sNKG2D treatment during the early phase EAE broke much later (FIG. 3B). Only five of the six mice in the sNKG2D-treated group also developed disease.
  • MOG-peptide-specific T-cell proliferation of spleen mice from mice treated with sNKG2D was significantly reduced compared to spleen cells from control-treated mice (Figure 3C).
  • Table 1 SEQ ID NO. Name, Length Definition / Special Features Acc. No.

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Abstract

L'invention concerne l'utilisation d'agents bloquant l'interaction entre le récepteur NKG2D et le ligand NKG2D, pour produire un médicament conçu pour traiter des maladies auto-immunes, en particulier la sclérose en plaques, ainsi que pour bloquer le récepteur NKG2D. Selon l'invention, les agents bloquants sont sélectionnés dans le groupe rassemblant : le récepteur NKG2D soluble, MICA soluble, MICB soluble, ULBP1 soluble, ULBP2 soluble, ULBP3 soluble, ULBP4 soluble, RAET1L soluble, RAET1G soluble, ainsi que les variantes alléliques ou fragments ou dérivés desdits agents bloquants, et les agents bloquant l'interaction entre le récepteur NKG2D et le ligand NKG2D, obtenus par synthèse.
EP05773900A 2004-08-30 2005-08-08 Utilisation d'agents bloquant l'interaction entre le récepteur nkg2d et le ligand nkg2d, pour traiter des maladies auto-immunes Withdrawn EP1848452A2 (fr)

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DE102004042894A DE102004042894A1 (de) 2004-08-30 2004-08-30 Verwendung von Blockern der NKG2D-Rezeptor-/NKG2D-Liganden-Interaktion bei Autoimmunerkrankungen
PCT/EP2005/008579 WO2006024367A2 (fr) 2004-08-30 2005-08-08 Utilisation d'agents bloquant l'interaction entre le récepteur nkg2d et le ligand nkg2d, pour traiter des maladies auto-immunes

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KR101615935B1 (ko) 2007-12-14 2016-04-28 노보 노르디스크 에이/에스 인간 ｎｋｇ2ｄ에 대한 항체 및 그것의 용도
US8796420B2 (en) 2009-12-31 2014-08-05 Avidbiotics Corp. Non-natural MIC proteins
WO2012091756A1 (fr) * 2010-12-30 2012-07-05 Avidbiotics Corp. Protéines mic non naturelles
US8658765B2 (en) 2009-12-31 2014-02-25 Avidbiotics Corp. Non-natural MIC proteins
JP6018079B2 (ja) * 2010-12-30 2016-11-02 アビッドバイオティクス コーポレイション 非天然ｍｉｃタンパク質
AU2014229476B2 (en) 2013-03-15 2019-07-11 Novelogics Biotechnology, Inc. Antibodies to MICA and MICB proteins
WO2017176762A1 (fr) 2016-04-06 2017-10-12 Nanotics, Llc Particules comprenant des sous-particules ou des échafaudages d'acide nucléique
AU2017344411A1 (en) 2016-10-19 2019-05-09 Novelogics Biotechnology, Inc. Antibodies to MICA and MICB proteins
CN112500497B (zh) * 2020-12-14 2021-06-08 南京凯地医疗技术有限公司 Cltx-nkg2d双特异性嵌合抗原受体细胞及其制备方法和应用

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HUP0300919A2 (hu) * 2000-03-24 2003-07-28 Micromet Ag Többfunkciós polipeptidek NKG2D receptor komplex epitóp kötőhellyel
MXPA04003057A (es) * 2001-10-04 2005-06-20 Immunex Corp Proteina 4 de enlace ul16.

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