CN1634979A - Ligand of NKG2D acceptor and use - Google Patents

Ligand of NKG2D acceptor and use Download PDF

Info

Publication number
CN1634979A
CN1634979A CN 200410096051 CN200410096051A CN1634979A CN 1634979 A CN1634979 A CN 1634979A CN 200410096051 CN200410096051 CN 200410096051 CN 200410096051 A CN200410096051 A CN 200410096051A CN 1634979 A CN1634979 A CN 1634979A
Authority
CN
China
Prior art keywords
mica
cell
nkg2d
polypeptide
peptide
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.)
Granted
Application number
CN 200410096051
Other languages
Chinese (zh)
Other versions
CN1291998C (en
Inventor
田志刚
刘文涛
张斌
魏海明
郑晓东
张建
孙汭
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hefei Ruida Immune Drug Research Institute Co Ltd
Original Assignee
University of Science and Technology of China USTC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Science and Technology of China USTC filed Critical University of Science and Technology of China USTC
Priority to CN 200410096051 priority Critical patent/CN1291998C/en
Publication of CN1634979A publication Critical patent/CN1634979A/en
Application granted granted Critical
Publication of CN1291998C publication Critical patent/CN1291998C/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Landscapes

  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention disclosed a ligand of a NKG2D acceptor and application thereof. The ligand of the NKG2D acceptor provided in the invention is a polypeptide with one of the following amino acid sequences: 1) MICA-P1:DGSVQ; 2) MICA-P2:KDLRMTLAHIK; 3) MICA-P3:THYHAMHADCLQ; 4) MICA-P2L:KTWDRETRDLTGKDLRMTLAHIKDQ; 5) MICA-P3L:EDAMKTKTHYHAMHADCLQELRRYLKS. The polypeptide has a small molecular weight and a good solubility, and can be widely used in treatment of rejection of autoimmune disease and allotransplantation.

Description

The part of NKG2D acceptor and application thereof
Technical field
The present invention relates to the part and the application thereof of NKG2D acceptor, particularly relate to can with NKG2D receptor-specific bonded micromolecule polypeptide part, and the medicinal use of these micromolecule polypeptides.
Background technology
Natural killer cell (Natural Killer, the NK cell) is an important member of natural immune system, realize its immunoregulation effect by cytotoxicity, release cytokine and chemokine, its activity is mediated by the signal that interaction produced of the respective ligand on a series of activation on the cytolemma and inhibition acceptor and the target cell.NK cell in the normal body is owing to the negative conditioning signal that the inhibition acceptor is mediated is occupied an leading position; be in and kill and wound holddown; the inhibition acceptor is exercised its immune surveillance function by the variation of the MHC-I quasi-molecule of differentiation normal cell and morbid state cell: the target cell of disappearance MHC-I quasi-molecule can be removed by the NK cell, and the target cell of normal expression MHC-I quasi-molecule is not by the NK cell killing.
Yet, evidence suggests that the reactivity acceptor of NK cell is also played an important role in the activation of NK cell with in regulating.The NKG2D acceptor is a reactivity acceptor on the NK cell, the part MICA of the NKG2D that expresses on it and the target cell in conjunction with the time, the NK cell just can be activated, that is to say that the activation signal that is mediated by NKG2D causes the NK cell insensitive to the negative conditioning signal that the inhibition acceptor is mediated, this is the reason that target cell that some can normal expression MHC-I quasi-molecule also can be removed by the NK cell.CD8 +T, gamma delta T and scavenger cell etc. all are the important members who exercises the normal immune surveillance function of human body, and NKG2D has expression on these cells, also be the reactivity acceptor of these cells.But, these cells (NK cell, CD8 +T, gamma delta T and scavenger cell etc.) excessive activation they produce to be attacked normal cell, thereby cause pathological state, produce rejection as autoimmune diseases such as habitual abortion, SLE and inflammatory bowel, heteroplastic transplantation organ.Using immunosuppressor is a kind of more common treatment means, but use more immunosuppressor at present and mainly have following shortcoming: the specific aim of these immunosuppressor is poor, its retarding effect is omnibearing, can cause the low comprehensively of body immunity after long-term the extensive application; Be easy to take place secondary infection etc.Also there are following two kinds of methods of employing to treat: to make free MICA molecule and NKG2D combination,, can reduce NK cell, CD8 owing to can block the binding site of NKG2D and its part MICA +The killing activity of T cell (Groh V, Wu J, Yee C, Spies T.Tumour-derived soluble MICligands impair expression of NKG2D and T-cell activation.Nature 2002; 419:734-738); Perhaps use the combination of its part of NKG2D monoclonal antibody blocking-up NKG2D MICA, can reduce the activation (LiP of NK cell equally, Willie ST, Bauer S, Morris DL, Spies T, Strong RK.Crystal structure of the MHCclass I homolog MIC-A, a gammadelta T cell ligand.Immunity 1999; 10:577-584; Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T.Activation of NK cells and Tcells by NKG2D, a receptor for stress-inducible MICA.Science 1999; 285:727-729).Though these two kinds of method specificitys are good, all have the characteristics and the remarkable advantages of highly significant, because the molecular weight of MICA molecule and NKG2D monoclonal antibody is big, amino-acid residue quantity is more, and permeability is low, and the medicine effective concentration in the unit volume is not very high; And be easy to produce antibody after the prolonged application in vivo, lessen the curative effect.
Summary of the invention
The purpose of this invention is to provide can with NKG2D receptor-specific bonded part.
The part of NKG2D acceptor provided by the present invention, for having the polypeptide of one of following aminoacid sequence:
1)MICA-P1：DGSVQ；
2)MICA-P2：KDLRMTLAHIK；
3)MICA-P3：THYHAMHADCLQ；
4)MICA-P2L：KTWDRETRDLTGKDLRMTLAHIKDQ；
5)MICA-P3L：EDAMKTKTHYHAMHADCLQELRRYLKS。
MICA-P1, MICA-P2 and MICA-P3 are shorter in the aforementioned polypeptides, are small peptide; Other two kinds of MICA-P2L, MICA-P3L are longer, are long peptide.Polypeptide of the present invention can be directly synthetic with artificial synthesis, also the encoding gene of these polypeptide can be merged or be inserted into expression vector respectively, and transfection host cell is produced with gene engineering method then.
Another object of the present invention provides the medicinal use of polypeptide of the present invention.
NK cell and CD8 +T cell etc. is the main effects cell based on the autoimmune disorder and the heteroplastic transplantation rejection of cellular immunization, NK cell and CD8 +Cause abnormal activation after the ligand molecular MICA combination of expressing on NKG2D that expresses on the T cell and the target cell, cause pathology damage, the inventor confirms by experiment, small peptide of the present invention can combine with NKG2D, sealing NKG2D and MICA binding site molecule point can be played, NK cell and CD8 can be suppressed +The abnormal activation of T cell can be used as NK cell and CD8 +The specific immunosuppressive agent of T cell is used for the treatment of the rejection of autoimmune disease and heteroplastic transplantation.
Can one or more polypeptide of the present invention be activeconstituents, be prepared as the medicine that treatment autoimmune disease and/or heteroplastic transplantation are repelled.
Wherein, the activeconstituents of described medicine is preferably the composition of described MICA-P1, described MICA-P2 and described MICA-P3; To be preferably be 1 to the ratio of weight and number of MICA-P1, MICA-P2 and MICA-P3 in the composition: 2-3: 2-3.
The another kind of preferred version of the activeconstituents of described medicine is the composition of described MICA-P1, described MICA-P2L and described MICA-P3L; The ratio of weight and number of MICA-P1 described in the composition, described MICA-P2L and described MICA-P3L is preferably 1: 6-7: 6-7.
When using, said medicine can also add one or more pharmaceutically acceptable carriers when needing.Described carrier comprises thinner, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant of pharmaceutical field routine etc., can also add flavouring agent, sweeting agent etc. in case of necessity.Common formulations has tablet, capsule, soft capsule, dripping pill, injection liquid, freeze-dried powder, oral liquid, dispersible tablet etc., all can be according to the ordinary method preparation of pharmaceutical field.Effectively using dosage is 0.05-0.5mg/Kg/ day.
The present invention is reference template according to the interaction zone of MICA molecule and NKG2D with the MICA molecule, design, synthetic one group can with the micromolecule polypeptide of NKG2D specific combination, can optionally reduce by NK, CD8 +The cell immune response that abnormal activation such as T and scavenger cell is caused, but not comprehensively reduce the immune response of body helps avoiding the tendency that is easy to secondary infection that is caused behind the life-time service; Institute's synthetic polypeptide molecular weight is little, seldom cause the immune response of body, and solvability is good, permeability is strong, is easy to arrive site of action and plays a role, can realize and the identical effect of full molecule MICA of NKG2D monoclonal antibody and solubility, also avoid its side effect simultaneously; Polypeptide of the present invention can adopt existing ordinary method to prepare, and technology maturation can be widely used in the rejection for the treatment of autoimmune disease and heteroplastic transplantation.
Description of drawings
Figure 1A is the secondary structure synoptic diagram of MICA-NKG2D compound molecule;
Figure 1B is the position view of the reference template of polypeptide of the present invention at the MICA-NKG2D compound molecule;
Fig. 2 A is the retarding effect of polypeptide of the present invention to NK92 cell killing Hela cytosis;
Fig. 2 B is the retarding effect of different concns polypeptide of the present invention to NK92 cell killing Hela cytosis;
Fig. 2 C is the retarding effect of polypeptide of the present invention to NK92 cell killing K526 cytosis;
Fig. 3 A is the retarding effects of different small peptide combinations to NK92 cell killing Hela cytosis;
Fig. 3 B is the retarding effect of peptide composition of the present invention to NK92 cell killing Hela cytosis;
Fig. 3 C compares the retarding effect of NK92 cell killing Hela cytosis with sMICA for two kinds of combinations of polypeptide of the present invention (P1+P2+P3, P1+P2L+P3L);
Fig. 4 kills and wounds YAC-1 cell inhibiting effect for polypeptide of the present invention to the mouse liver lymphocyte;
Fig. 5 is the therapeutic action of polypeptide of the present invention to the mouse liver injury model.
Embodiment
The polypeptide ligand of embodiment 1, NKG2D acceptor
1, the design of peptide sequence is with synthetic
Shown in Figure 1A and Figure 1B, the albumen database PDB file that provides according to NCBI, the interaction of NKG2D-MICA complex body is relevant with the ring-type joining region between β 1 and β 2 chains, so the ring-type joining region (13-21) between the β 1 of MICA and β 2 chains can be used as first reference template of peptide section design; α 1 structural domain of MICA comprises and the interactional helical region of NKG2D-A (70-80), can be used as second reference template of peptide section design; α 2 structural domains of MICA have a helical region that is made of 10 amino-acid residues (152-161), comprise the interactional residue with NKG2D-B, can be used as the 3rd reference template of peptide section design.
For ease of synthetic, slightly different between amino acid sequence of polypeptide of the present invention and its reference template, and two long slightly peptide sections can simulated templates α 1 and the entire structure territory of α 2, obtain 5 small peptides altogether, difference called after MICA-P1, MICA-P2, MICA-P3, MICA-P2L and MICA-P3L:MICA-P1, with the β 1 of MICA and the ring-type joining region (16-20) between β 2 chains is reference template, is made up of 5 amino-acid residues, and sequence is DGSVQ; MICA-P2 is a reference template with α 1 structural domain and the interactional helical region of NKG2D-A (72-82) of MICA, is made up of 11 amino-acid residues, and sequence is KDLRMTLAHIK; MICA-P3 is a reference template with α 2 structural domains and the interactional helical region of NKG2D-B (156-167) of MICA, and bent 12 amino-acid residues are formed, and sequence is THYHAMHADCLQ; MICA-P2L is a reference template with α 1 structural domain and the interactional helical region of NKG2D-A (58-84) of MICA, is made up of 25 amino-acid residues, and sequence is KTWDRETRDLTGKDLRMTLAHIKDQ; MICA-P3L is a reference template with α 2 structural domains and the interactional helical region of NKG2D-B (147-173) of MICA, is made up of 27 amino-acid residues, and sequence is EDAMKTKTHYHAMHADCLQELRRYLKS.The hydrophobic amino acid of three small peptides (MICA-P1, MICA-P2 and MICA-P3) is no more than 50% of amino acid sum separately, and is positioned at the peptide intersegmental part; MICA-P2 is identical with the position of reference template in MICA albumen of MICA-P2L, MICA-P3 and MICA-P3L, but the length difference.
In addition, the irrelevant peptide (sequence of Px: of design HLA-E functional zone RDTAQIFRVNLRT) as negative control.
These peptide sections can adopt conventional solid phase synthesis process synthetic, through the HPLC purifying, purity greater than 95% or more (Wang beneficial friend, Chen Zhengying, Pan's peace. synthesizing of calcitonin-gene-related peptide. Chinese pharmaceutical chemistry magazine, 1997,7 (4): 287-290).
The sequence and the character of the synthetic small peptide of table 1.
The polypeptide title The position Aminoacid sequence pI
?MICA-P1 16-20 ?DGSVQ 3.0
?MICA-P2 72-82 ?KDLRMTLAHIK 10.6
?MICA-P3 156-167 ?THYHAMHADCLQ 6.3
?MICA-P2L 58-84 ?KTWDRETRDLTGKDLRMTLAHIKDQ 9.8
?MICA-P3L 147-173 ?EDAMKTKTHYHAMHADCLQELRRYLKS 8.8
2, the polypeptide two-dirnentional structure is analyzed
Adopt two kinds of methods (ANTHEPROT 4.3-Garnier and ANTHEPROT 4.3-Gibrat) that 5 peptide sections of the present invention are carried out the two-dirnentional structure analysis, the result is as shown in table 2, analysis revealed: the two-dirnentional structure of institute's synthetic small peptide exists with stable α spiral form, is similar to the two-dirnentional structure of its design reference template.
The two-dirnentional structure of the synthetic small peptide of table 2
Sequence number The position Analytical procedure Two-dirnentional structure
?MICA-P1 16-20 ? A B D?G?S?V?Q T?T?C?E?E C?C?C?E?E
?MICA-P2 72-82 ? A B K?D?L?R?M?T?L?A?H?I?K H?H?H?H?H?H?H?H?H?H?H H?H?H?H?H?H?H?H?H?H?H
?MICA-P3 156-167 ? A B T?H?Y?H?A?M?H?A?D?C?L?Q H?H?H?H?H?H?H?H?H?H?H?H H?H?H?H?H?H?H?H?H?H?H?H
?MICA-P2L 58-84 ? A B K?T?W?D?R?E?T?R?D?L?T?G?K?D?L?R?M?T?L?A?H?I?K?D?Q C?C?C?C?T?E?T?T?H?T?C?T?T?C?C?C?H?H?H?H?H?H?H?H?H C?C?H?H?H?C?H?H?H?C?C?C?C?H?H?H?H?H?H?H?H?H?H?H?H
?MICA-P3L 147-173 ? A B E?D?A?M?K?T?K?T?H?Y?H?A?M?H?A?D?C?L?Q?E?L?R?R?Y?L?K?S H?H?H?H?H?H?H?H?H?H?H?H?H?H?H?H?H?H?H?H?H?H?H?H?H?H?H H?H?H?H?H?H?H?H?H?H?H?H?H?H?H?H?H?H?H?H?H?H?H?T?T?T?H
A. pass through the two-dirnentional structure of the small peptide of ANTHEPROT 4.3-Garnier methods analyst; B. pass through the two-dirnentional structure of the small peptide of ANTHEPROT4.3-Gibrat methods analyst; H: represent spiral; E: representative is folding; T: represent corner; C: represent random coil.
The inhibition experiment of embodiment 2, polypeptide of the present invention
1, small peptide P1, P2, P3 kill and wound the cell inhibiting effect (P1 is MICA-P1 in an embodiment, and other embodiment represent identical therewith) of expressing the MICA surface molecular to NK clone
Adopt 51The test of Cr isotropic substance cell killing is observed small peptide and NK clone is killed and wounded the cell inhibiting effect of expressing the MICA surface molecular.
NK clone-NK92 cell expressing NKG2D, Hela cell expressing MICA surface molecular, NK92 cell and Hela cell action effect cell and target cell are adopted in this experiment respectively, add the various combination of each bar peptide, the solution of different concns experimentizes, and experiment is used 51Cr isotropic substance method for releasing is measured the killing-efficiency (every in an embodiment experimental group parallel control is no less than 3, and other embodiment are identical therewith) of NK92 cell.
Imitating the target ratio is 10: 1, adds 10 in the every hole of Tissue Culture Plate 5Individual (100 μ l) NK92 cell and concentration are small peptide solution (with PBS solution as solvent) the 5 μ l of 20nM, and making its final concentration is 1nM.Negative control add concentration be 200nM irrelevant peptide Px solution (with PBS solution as solvent) 5 μ l, making its final concentration is 10nM.And with the PBS solution of volume as blank, 37 ℃, 5%CO 2Incubation 0.5 hour, and then add 51The Hela cell 10 of Cr (available from Chinese isotropic substance main office) mark 4Individual (100 μ l) sets maximum release group (10 in the experiment 4Individual target cell adds 1%TritonX-100 solution, and cumulative volume is 200 μ l) and natural release group (only add 10 4Individual target cell, cumulative volume are 200 μ l), after finishing culture plate is done slightly centrifugal, 37 ℃, 5%CO 2Incubation 4 hours is got 100 μ l supernatant liquors, and the r-counting calculates kill rate=(test group cpm value-natural release group cpm value)/(maximum release group cpm value-natural release group cpm value) * 100% as follows.
Shown in Fig. 2 A, peptide section P1, P2 and P3 all have the inhibition effect to the effect of NK92 cell killing target cell Hela; And irrelevant peptide concentration does not show the inhibition effect when being 10nM yet.
Small peptide is in 1-1 * 10 -6In the concentration range of nM to the interaction retarding effect of NKG2D/MICA shown in Fig. 2 B, be dose-dependence.
2, small peptide P1, P2, P3 are to the effect of NK92 cell killing target cell K526
With K526 cell (this cell is not expressed the MICA molecule) as target cell, adopt method same as described above test small peptide P1, P2, P3 effect to NK92 cell killing target cell K526, the result is shown in Fig. 2 C, and the result shows that small peptide P1, P2, P3 do not have influence to the effect of NK92 cell killing target cell K526.
Above-mentioned two experimental results confirm that small peptide P1, P2, P3 can the special interactions that suppresses NKG2D/MICA.
3, the inhibition effect of the different compositions of polypeptide of the present invention
With PBS preparation P1, P2, P3, P2L, P3L and P1+P2 (ratio of weight and number of P1: P2 is 1: 2.6), P1+P3 (ratio of weight and number of P1: P3 is 1: 2.8), P2+P3 (ratio of weight and number of P2: P3 is 1: 1.1), P1+P2L (ratio of weight and number of P1: P2L is 1: 6), P1+P3L (ratio of weight and number of P1: P3L is 1: 6.5), P2L+P3 (ratio of weight and number of P2L: P3 is 2.1: 1) and P1+P2+P3 (ratio of weight and number of P1: P2: P3 is 1: 2.6: 2.8), the solution of P1+P2L+P3L (ratio of weight and number of P1: P2L: P3L is 1: 6: 6.5) composition, its concentration is 20nM.
Carry out NK92 cell killing HeLa cell inhibiting effect experiment with above-mentioned solution, and compare with soluble M ICA molecule (final concentration of reaction system is 1nM), the result is respectively shown in Fig. 3 A, Fig. 3 B and Fig. 3 C.The result shows, and the combination of per two small peptides (P1+P2, P1+P3, P2+P3, the final concentration of reaction system is 1nM) and have stronger restraining effect (Fig. 3 A) than single small peptide, suppress efficient and rise to 32% (P2+P3) from 18% (P3); When three small peptide combined action, suppress efficient and reach 38%, approached the MICA molecule (Fig. 3 C) of solubility.Simultaneously, when replacing P2 and P3 with P2L and P3L, all show stronger retarding effect (Fig. 3 B) during regardless of independent or combined action, the long Toplink of this explanation is sealed more site, has stronger retarding effect; The retarding effect of P1+P2L+P3L has reached the peer-level (Fig. 3 C) of soluble M ICA molecule.
Embodiment 3, polypeptide of the present invention kill and wound the restraining effect of target cell to mouse lymphocyte
(concentration is 2mM with the PBS solution of P1+P2+P3 composition, the ratio of weight and number of P1: P2: P3 is 1: 2.6: 2.8) inject C56BL/6 mouse (available from Chinese Academy of Sciences's Shanghai Experimental Animal Center) with the dosage of 50 μ g peptide composition/g body weight, after 4 hours, results mouse liver lymphocyte, do the effector cell with these cells, with the YAC-1 cell is target cell, carries out the cell killing experiment; And with the negative contrast of mouse liver lymphocyte with the Px solution-treated of dosage, mouse liver lymphocyte with the PBS solution-treated of volume is a blank, its result as shown in Figure 4, the mouse liver lymphocyte that small peptide was handled descends 36.67% to the lethal effect of YAC-1 cell than PBS group (Px group and PBS group are analyzed indifference by statistics), shows that the lymphocytic lethal effect of mouse liver can part be suppressed by small peptide.
The liver lymphocyte of mouse comprises NK cell and T cell, and these cells are all expressed the NKG2D molecule, and the NKG2D molecule of mouse has similar aminoacid sequence and structure to people's NKG2D molecule; YAC-1 cell surface expression RAE-1 molecule, the RAE-1 of mouse, H-60 equimolecular exercise and the similar function of MICA molecule, promptly as the part of NKG2D.The result of present embodiment shows that polypeptide of the present invention also can seal the NKG2D molecule of mouse.
The blocking effect that the autoimmunity that embodiment 4, small peptide of the present invention mediate NKG2D damages
In order further to prove the blocking effect of small peptide of the present invention to the autoimmunity damage of NKG2D mediation, small peptide of the present invention is applied to sword bean A (Con-A) inductive mouse hepatitis model, this is the cell-mediated liver injury model of a kind of typical T.
With Con-A with 15 μ g/g body weight intravenous injection C56BL/6 mouse after, liver injury will take place in mouse, after 6 hours in the blood plasma gpt (ALT) rise to 5433 ± 692IU/ml; (concentration is 2mM with the PBS solution of P1+P2+P3 composition in injection Con-A, the ratio of weight and number of P1: P2: P3 is 1: 2.6: 2.8) inject (inhibition group) with the dosage of 50 μ g peptide composition/g body weight, the PBS solution of injection and inhibition group peptide composition solution equal volume is as the blank group in injection Con-A, after 6 hours in the blood plasma of inhibition group mouse ALT be 3195 ± 461IU/L, inhibiting rate is 41.19%; The irrelevant peptide Px 50 μ g/g body weight of injection in injection Con-A, irrelevant peptide Px is not effect (negative control group) then; Result such as Fig. 5, show small peptide of the present invention can alleviate the Con-A inductive specifically, by the liver injury of NKG2D mediation.

Claims (6)

1, the part of NKG2D acceptor, for having the polypeptide of one of following aminoacid sequence:
1)MICA-P1：DGSVQ；
2)MICA-P2：KDLRMTLAHIK；
3)MICA-P3：THYHAMHADCLQ；
4)MICA-P2L：KTWDRETRDLTGKDLRMTLAHIKDQ；
5)MICA-P3L：EDAMKTKTHYHAMHADCLQELRRYLKS。
2, a kind of medicine for the treatment of autoimmune disease and/or heteroplastic transplantation repulsion, its activeconstituents is at least one in the following peptide family:
1)MICA-P1：DGSVQ；
2)MICA-P2：KDLRMTLAHIK；
3)MICA-P3：THYHAMHADCLQ；
4)MICA-P2L：KTWDRETRDLTGKDLRMTLAHIKDQ；
5)MICA-P3L：EDAMKTKTHYHAMHADCLQELRRYLKS。
3, medicine according to claim 2 is characterized in that: the activeconstituents of described medicine is the composition of described MICA-P1, described MICA-P2 and described MICA-P3.
4, medicine according to claim 3 is characterized in that: the ratio of weight and number of MICA-P1 described in the described composition, described MICA-P2 and described MICA-P3 is 1: 2-3: 2-3.
5, medicine according to claim 2 is characterized in that: the activeconstituents of described medicine is the composition of described MICA-P1, described MICA-P2L and described MICA-P3L.
6, medicine according to claim 5 is characterized in that: the ratio of weight and number of MICA-P1 described in the described composition, described MICA-P2L and described MICA-P3L is 1: 6-7: 6-7.
CN 200410096051 2004-11-26 2004-11-26 Ligand of NKG2D acceptor and use Expired - Fee Related CN1291998C (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN 200410096051 CN1291998C (en) 2004-11-26 2004-11-26 Ligand of NKG2D acceptor and use

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN 200410096051 CN1291998C (en) 2004-11-26 2004-11-26 Ligand of NKG2D acceptor and use

Publications (2)

Publication Number Publication Date
CN1634979A true CN1634979A (en) 2005-07-06
CN1291998C CN1291998C (en) 2006-12-27

Family

ID=34847834

Family Applications (1)

Application Number Title Priority Date Filing Date
CN 200410096051 Expired - Fee Related CN1291998C (en) 2004-11-26 2004-11-26 Ligand of NKG2D acceptor and use

Country Status (1)

Country Link
CN (1) CN1291998C (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101945893A (en) * 2007-12-14 2011-01-12 诺沃-诺迪斯克有限公司 Anti-human nkg2d monoclonal antibodies and use thereof
CN102020717A (en) * 2010-11-05 2011-04-20 扬州大学 Active factor for enhancing lymphocyte targeting killing tumors and preparation method thereof

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9127064B2 (en) 2006-12-21 2015-09-08 Novo Nordisk A/S Antibodies against human NKG2D and uses thereof
US10526409B2 (en) 2006-12-21 2020-01-07 Novo Nordisk A/S Antibodies against human NKG2D and uses thereof
CN101945893A (en) * 2007-12-14 2011-01-12 诺沃-诺迪斯克有限公司 Anti-human nkg2d monoclonal antibodies and use thereof
CN101945893B (en) * 2007-12-14 2015-02-25 诺沃-诺迪斯克有限公司 Anti-human NKG2D monoclonal antibodies and use thereof
CN102020717A (en) * 2010-11-05 2011-04-20 扬州大学 Active factor for enhancing lymphocyte targeting killing tumors and preparation method thereof
CN102020717B (en) * 2010-11-05 2012-09-26 扬州大学 Active factor for enhancing lymphocyte targeting killing tumors and preparation method thereof

Also Published As

Publication number Publication date
CN1291998C (en) 2006-12-27

Similar Documents

Publication Publication Date Title
CN102727861B (en) Treatment of t-cell mediated diseases
RU2423383C2 (en) Ox40l antibodies
FI101937B (en) Method for producing monoclonal antibody reactive with human n cachectin
TWI224108B (en) Interleukin-18-receptor proteins
CN108992661B (en) Application of polypeptide in preparation of intravenous, intraperitoneal or nasal administration medicine
WO1994020122A1 (en) A method for treating autoimmune diseases using alpha-interferon and/or beta-interferon
CN102307896A (en) Fibronectin type III domain based scaffold compositions, methods and uses
RU2010141826A (en) Means for the treatment of diseases
JP2009185057A (en) Copolymer for suppression of autoimmune disease, and method for using the same
DE69411342T2 (en) POLYPEPTIDE BOMBESIN ANTAGONISTS
US20130078238A1 (en) Methods and Compositions for Treating Hepatitis with Anti-CD3 Immune Molecule Therapy
RU2014101207A (en) NEW INDICATIONS FOR USE IN TREATMENT BY ANTIBODIES AGAINST IL-1-BETA
CN109106942A (en) Application of polypeptide capable of passing blood brain barrier in preparation of medicine
WO2023214576A1 (en) Cyclic compound having selective kras inhibitory effect on hras and nras
CN109265557A (en) Application of ziconotide and TAT peptide fusion polypeptide in preparation of medicine
CN109265558A (en) Application of improved ziconotide in preparation of medicines
CN1872873A (en) Function of cytoinhibition peptide for treating rheumatoid arthritis
CN1291998C (en) Ligand of NKG2D acceptor and use
US8475800B2 (en) Phosphorylated derivatives of a U1-70K peptide and their use in the treatment of autoimmune pathologies
DE69630682T2 (en) SYNTHETIC PEPTIDES AND MEDICINAL PRODUCTS FOR THE TREATMENT OF SYSTEMIC LUPUS ERYTHEMATODES
CN109232744A (en) Improved ziconotide
AU648777B2 (en) Method of treating septic shock
CN109265556A (en) Polypeptide suitable for intravenous, intraperitoneal or nasal administration
CN109232745A (en) Polypeptide capable of passing blood brain barrier
CN109232746A (en) Fusion polypeptide of ziconotide and TAT peptide

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20190306

Address after: 230001 Room 01, 21 Floor, F5 Building, Phase II, Innovation Industrial Park, 2800 Innovation Avenue, Hefei High-tech Zone, Anhui Province

Patentee after: Hefei Ruida immune Drug Research Institute Co Ltd

Address before: 230026 No. 96, Jinzhai Road, Hefei, Anhui

Patentee before: University of Science and Technology of China

CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20061227

Termination date: 20191126