CN106831989A - The IgG antibody of the anti-sialic acid binding domain-immunoglobulin sample agglutinin 7 in people source and its application - Google Patents
The IgG antibody of the anti-sialic acid binding domain-immunoglobulin sample agglutinin 7 in people source and its application Download PDFInfo
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- CN106831989A CN106831989A CN201710003849.8A CN201710003849A CN106831989A CN 106831989 A CN106831989 A CN 106831989A CN 201710003849 A CN201710003849 A CN 201710003849A CN 106831989 A CN106831989 A CN 106831989A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2851—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
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- Health & Medical Sciences (AREA)
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- Immunology (AREA)
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- General Health & Medical Sciences (AREA)
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- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Peptides Or Proteins (AREA)
Abstract
The anti-sialic acid binding domain-immunoglobulin sample agglutinin 7 in people source（Sialic acid binding immunoglobulin like lectin 7, Siglec 7）IgG antibody and its application, the amino acid sequence of weight chain variable district is as shown in SEQ ID NO.2；The amino acid sequence of light chain variable district is as shown in SEQ ID NO.9.Experimental result confirms that the human antibody can specifically bind with Siglec 7, and the anti-antibody of Siglec 7 in people source can effectively facilitate lethal effect of the immunocytes such as NK to tumour cell.Therefore, monoclonal antibody of the invention can be applied to the clinical treatment of the related neoplasms immunization therapy, the related immunological diseases of Siglec 7 and organ transplant of the binding partners of overexpression Siglec 7.
Description
Technical field
The invention belongs to monoclonal antibody drug technical field, it is related to a kind of anti-sialic acid binding domain-immunoglobulin sample aggegation
People's resource monoclonal of -7 (sialic acid-binding immunoglobulin-like lectin-7, Siglec-7) of element resists
The protein molecular of body gene and its coding and its derivative, and the human monoclonal antibody is in tumour, organ transplant and is immunized
Application in the clinical treatments such as property disease.
Background technology
Sialic acid binding domain-immunoglobulin sample agglutinin (sialic acid-binding immunoglobulin-like
Lectin, Siglec) be immunoglobulin superfamily important member, can be by recognizing that sugar chain structure containing sialic acid is mediated
Interaction between cell and cell or pathogen.Recent years research display, Siglec families cell activation, propagation and
Played a significant role in Apoptosis, while important regulating and controlling effect is also played in inherent immunity and adaptive immunity, in addition
The regulation and control of tumour immunity tolerance can also be participated in.
Siglecs is immunoglobulin superfamily member, and its molecular structure common feature is that have the ability for combining sialic acid.
Sialic acid binding domain-immunoglobulin sample agglutinin, is expressed in immunocyte surface, mediate both inhibitory signal.Exempt from other inhibitions
Epidemic disease receptor family is similar, such as NK (NK cells) immunoglobulin-like receptor and leukocytic immunity albumen sample acceptor,
Siglecs is transmembrane molecule, and immunity receptor Tyrosine Inhibitory Motifs (immunoreceptor is included in cytoplasmic tail
Tyrosine based inhibitory motifs, ITIMs), there is immunoglobulin superfamily region extracellular.With other
Immunoglobulin superfamily is compared, and the characteristic of Siglecs is the sialylated carbohydrate of part of its high specific, different
In most of other immunity receptor associated proteins.The mankind have found 14 kinds of Siglec：Sialoadhesin (Siglec-1,
CD169), CD22 (Siglec-2), CD33 (Siglec-3) related to myelin glycoprotein (MAG, Siglec-4) and new
Near CD33 related Siglec (Siglec-5-11).Except Siglec-4 is expressed in nerve cell, most of Siglecs family
Race is expressed in hematopoietic cell.
Sialic acid binding domain-immunoglobulin sample agglutinin 7 (Siglec-7) is made up of 467 amino acid, is I type cross-film eggs
In vain, the important member of the super race of immunoglobulin, mainly the V areas by an extracellular N-terminal and Liang Ge C areas immunoglobulin-like
Domain, transmembrane region and kytoplasm inner region are constituted, the identification in N- terminal immunoglobulin spline structures domain V areas mediation sialic acid (SIA),
Kytoplasm inner region contains two Immuno-Tyrosines and suppresses motif (ITIM).Nearly film motif ITIM tyrosine phosphorylations, raise inhibition
Phosphatases, so that mediate downstream EGFR-TK phosphorylation, and transmit inhibition signal to intracellular.
Siglec-7 is main to express on NK cells, T cell and monocyte.The differentiation of Siglec-7 participation NK cells,
Multiple physiology courses such as development and death, are the critical function acceptors for adjusting NK cell inherent immunities.Human NK cell's inhibition
The sialic acid poly carbohydrate ligands of acceptor siglec-7 wide expression on the tumour cell of different tissue sources, the table of siglec7
Up to the cytotoxicity for determining the anti-NK cellular sensitivities of the original NK cells of the mankind and tolerance tumour cell, anti-siglec-7/ resists
Physical efficiency effectively improves the cytotoxicity of NK cells.Using the Siglec-7 on NK cells or the part on malignant cell as
Target spot, may prove a good ideas of cancer therapy, expanded by this strategy or made up it is existing, based on NK
Cellular immunotherapy method is active to strengthen the antineoplastic immune of NK cells.The immunization therapy of anti-Siglec-7 antibody, Ke Neng
There is potential application value in the clinical treatment of the diseases such as organ transplant, autoimmune disease, tumour.
The content of the invention
The technical problem of solution：The present invention provides a kind of the anti-of anti-sialic acid binding domain-immunoglobulin sample agglutinin -7 in people source
Body IgG and its application.
Technical scheme：The IgG antibody of the anti-sialic acid binding domain-immunoglobulin sample agglutinin -7 in people source, the V of the antibodyHChain
Complementary determining region there is following CDRs amino acid sequences：
V shown in SEQ ID NO.3H-CDR1；
V shown in SEQ ID NO.4H-CDR2；
V shown in SEQ ID NO.5H-CDR3；
And the V of the antibodyLThe complementary determining region of chain has following CDRs amino acid sequences：
V shown in SEQ ID NO.10L-CDR1；
V shown in SEQ ID NO.11L-CDR2；
V shown in SEQ ID NO.12L-CDR3。
The IgG antibody of the anti-sialic acid binding domain-immunoglobulin sample agglutinin -7 in people source, the amino acid sequence of weight chain variable district
As shown in SEQ ID NO.2；The amino acid sequence of light chain variable district is as shown in SEQ ID NO.9.And above-mentioned sequence is through one
Or multiple amino acid additions, delete, replace, the conservative mutation of modification and the conservative variant that obtains.
The IgG antibody of the anti-sialic acid binding domain-immunoglobulin sample agglutinin -7 in people source, the amino acid sequence of heavy chain constant region
As shown in SEQ ID NO.7；The amino acid sequence of constant region of light chain is as shown in SEQ ID NO.14.And above-mentioned sequence is through one
Or multiple amino acid additions, delete, replace, the conservative mutation of modification and the conservative variant that obtains.
The nucleotide sequence of the IgG antibody of the anti-sialic acid binding domain-immunoglobulin sample agglutinin -7 in encoding human source, coding weight
The nucleotide sequence of chain variable region is that the nucleotide sequence of coding light chain variable region is SEQ ID NO.8 institutes shown in SEQ ID NO.1
Show.
The nucleotide sequence of the IgG antibody of the anti-sialic acid binding domain-immunoglobulin sample agglutinin -7 in encoding human source, coding weight
The nucleotide sequence of chain constant region is that shown in SEQ ID NO.6, the nucleotide sequence of coding constant region of light chain is SEQ ID NO.13 institutes
Show.
The IgG antibody of the above-mentioned anti-sialic acid binding domain-immunoglobulin sample agglutinin -7 in people source prepare immunotherapy of tumors,
Applied in Siglec-7 related immunological diseases and the clinical treatment medicine of organ transplant.
A kind of medicine for immunotherapy of tumors, active ingredient is the anti-sialic acid binding domain-immunoglobulin in above-mentioned people source
The IgG antibody and its derivative of sample agglutinin -7.
A kind of medicine for preventing or treating autoimmune disease, active ingredient is that the anti-sialic acid combination in above-mentioned people source is exempted from
The IgG antibody and its derivative of epidemic disease globulin sample agglutinin -7.
A kind of prevention or the medicine for the treatment of organs naltrindole, active ingredient are that the anti-sialic acid in above-mentioned people source is combined
The IgG antibody and its derivative of immunoglobulin-like agglutinant -7.
Beneficial effect：The invention provides a kind of people source Dan Ke with high specific, the anti-Siglec-7 of high-affinity
Grand antibody.Antibody function analysis result shows that the human antibody can specifically bind with Siglec-7；In vitro cell experiment knot
Fruit confirms, when what of NK cells against tumor cells the anti-Siglec-7 antibody in people source can effectively improve or so.Therefore, it is of the invention
Monoclonal antibody can be applied to immunotherapy of tumors and Siglec-7 related immunological diseases and the clinical treatment of organ transplant.
Brief description of the drawings
The SDS-PAGE detection figures of Fig. 1 antibody purifications；
The ELISA detection figures of the anti-Siglec-7 antibody of Fig. 2；
The Western blot detection figures of the anti-Siglec-7 antibody of Fig. 3；
The anti-Siglec-7 antibody of Fig. 4 is schemed with the affinity detection of antigen binding.
Specific embodiment
It should be noted that the weight chain variable district and light chain variable district of the antibody are human antibody, and by itself and people source
The constant region connection of antibody, therefore referred to as full molecule human antibody.
The present invention prepares the people anti-Siglec-7 in source with Siglec-7 as target molecule on the basis of phage antibody library technique
IgG antibody.Further describe the present invention with reference to specific embodiment, advantages of the present invention and feature will be with description and
It is apparent.However, it should be understood that the embodiment is only exemplary, any limitation is not constituted to protection scope of the present invention.
It will be understood by those skilled in the art that without departing from the spirit of the invention, can be to the details of technical scheme and form
Modify or replace, but these modifications or replacement each fall within protection scope of the present invention.
Embodiment 1
The screening of the anti-Siglec-7 monoclonal antibodies in people source
1) solid-phase screening elisa plate is coated with the recombined human Siglec-7 albumen of R＆D companies, per the μ g of hole 2, washing is sealed up
Liquid is closed, is washed, add phage antibody library antibody, the uncombined phage antibody of washing removal.
2) trypsase is added, the phage antibody of specific binding is eluted, helper phage VCSM13 superinfection is added.
3) screening step more than repeating, carries out five wheels " absorption-wash-out-amplification " enrichment isolation altogether.
4) it is laid on the ampicillin for adding 100 μ g/mL after the bacteriophage dilution for obtaining last wheel screening and increment
Overnight incubation on culture plate, 60 single bacteriums of picking are fallen within Tissue Culture Plate, shake overnight incubation.
5) after overnight, transferase 45 μ L bacterium solutions to second block of plate, shaking culture are distinguished from first piece of each hole of plate.
6) helper phage VCSM13 superinfection, shaking culture are added；Centrifugation, the resuspended precipitation of culture medium shakes overnight incubation.
7) centrifuging and taking supernatant carries out ELISA detections, determines per hole 450nm and 650nm light absorption value, by A450nm~A650nm
Calculate per hole light absorption value.When P/N values (Positive/Negative) are more than 4, the bacterial strain is positive monoclonal bacteriophage bacterium
Strain.
8) positive colony is carried out into nucleic acid sequence analysis, the nucleotide sequence of encoding heavy chain variable region is the SEQ in sequence table
Shown in IDNO.1, the nucleotide sequence of coding light chain variable region is shown in the SEQ ID NO.8 in sequence table, so as to obtain a kind of base
Because of the correct Fab of sequence.
The preparation of the IgG antibody of the anti-Siglec-7 in people source
1) according to the variable region sequences for having obtained antibody, the primer of design Infusion PCR
According to the heavy chain pcr amplification primer thing HF and HR and light chain pcr amplification primer thing of Infusion PCR principle design antibody
LF and LR, this primer needs to include the base of the 15bp on expression vector and at least 15bp bases of insertion purpose fragment, inserts
Enter base at purpose fragment to be designed according to the principle that general primer is designed.
HF:5’-GGTGTCCACTCGCTACAGGTGCAGCTGGTG-3’
HR:5’-GCCCTTGGTGGATGCTGAGGAGACGGTGAC-3’
LF:5’-ACAGACGCTCGCTGCTCCTATGAGCTGACA-3’
LR:5’-GTTGGCCTTGGGCTGTAGGACGGTCAGCTT-3’
2) the amplification anti-Siglec-7 IgG antibodies heavy chain in people source, light chain
People source Fab with above-mentioned preparation is expanded with the upstream and downstream primer of the above-mentioned heavy chain being related to and light chain respectively as template
Heavy chain of antibody, light chain gene.
①PCR
Reaction system：
Reaction condition：
2. 2% agarose gel electrophoresis, ultraviolet lower observation purpose band, gel extraction.
3. glue reclaim kits target DNA fragment, deionized water wash-out.
3) double digestion IgG expression plasmids
IgG expression plasmid pFUSE-CHIg-hG1, pFUSE-CLIg-h λ (being purchased from Invivogen companies) include IgG1 types
The heavy chain and constant region of light chain alkali yl coding sequence in people source, the specific nucleotide sequence such as SEQ ID of encoding heavy chain constant
Shown in NO.7, the specific nucleotide sequence of coding constant region of light chain is as shown in SEQ ID NO.14.
1. the double digestion of pFUSE-CHIg-hG1, pFUSE-CLIg-h λ template vectors
Reaction system：
Reaction condition：37 DEG C of digestions are overnight.
2. 1% agarose gel electrophoresis, ultraviolet lower gel extraction.
3. glue reclaim kits target DNA fragment, deionized water wash-out.
4) Infusion PCR recombinant expression plasmids
Reaction system：
Reaction condition：50 DEG C of incubation 15min.
5 μ L reaction solution transformed competence colibacillus bacteriums are taken, is laid on the flat board of corresponding resistant, next day chooses clone and send sequencing.To survey
Sequence result correctly clones preservation strain and Amplification Culture, extracts plasmid.
5) expression of the anti-Siglec-7 IgG antibodies in people source
1. 250 μ L pFUSE-CHIg-hG1-H (i.e. 50 μ g) are taken in the Opti-MEM culture mediums of 1mL, 250 μ L are taken
PFUSE-CLIg-h λ-L (i.e. 50 μ g) take the 293Fectin of 200 μ L in 2.8mL's in the Opti-MEM culture mediums of 1mL
In Opti-MEM culture mediums, above-mentioned three kinds of mixed liquors are stored at room temperature 5min.
2. then by two plasmid mixed liquors it is well mixed after, add 500 μ L Opti-MEM culture mediums it is well mixed after
The mixed liquor of transfection reagent 293Fectin is directly added into, 20min is stood after being well mixed.Period processes 293F cells, by 293F
It is resuspended with 293F Expression Medium after cell centrifugation, then count and calculate cell viability ratio with trypan blue, inhale
Take 100 × 106Individual cell is 94mL with 293F Expression Medium constant volumes in blake bottle.
3. after 20min terminates, by the compound ready 293F cells of addition of DNA, 293Fectin of 6mL.
4. cell is placed in shaking table culture case and is cultivated, condition of culture 8%CO2, 120rmp 37 DEG C, cell collects after 6 days
Supernatant.
6) purifying of the anti-Siglec-7 IgG antibodies in people source
The cell conditioned medium that will be collected with 0.22 μm of membrane filtration, while by equilibrium liquid and eluent filter membrane.Use AKATA
Purifying instrument is purified according to the standard step that Protein A are purified, and with the speed loading of 1mL/min, is washed with the speed of 1.5mL/min
It is de-.As a result successful expression and IgG purification antibody.SDS-PAGE testing results are shown in Fig. 1.
The functional activity identification of the anti-Siglec-7 IgG antibodies in people source
1) ELISA
Restructuring human sialic binding domain-immunoglobulin sample aggegation is diluted with coating buffer (0.1M carbonate buffer solutions, pH 9.6)
- 9 to 2 μ g/mL of element are coated with the orifice plates of ELISA 96, and 100 μ L are added per hole, and 4 DEG C overnight；PBST (PBS contains 0.5%Tween20) 5%
Skim milk-lavation buffer solution closing, 37 DEG C of incubation 2h；After PBST washs 5 times, 100 μ L PA21 antibody (2 are added in each hole
μ g/mL initial concentrations, the dilution of 14 concentration gradients) 37 DEG C of 2h；With 1：The μ L/ holes of goat-anti people secondary antibody 100 of 2000 dilutions are added to
In hole, 37 DEG C of incubation 1h；The μ L/ holes of peroxidase substrate nitrite ion 100, use 2M sulfuric acid stopped reactions at room temperature after 10 minutes,
Upper machine testing colorimetric uses dual wavelength 450nm/690nm.Result such as Fig. 2 shows, the anti-Siglec-7 IgG antibodies in people source can be with
Siglec9 protein bindings.
2)Western blot
Neutrophil leucocyte cracking supernatant is carried out into 10%SDS-PAGE electrophoresis and electricity is gone on nitrocellulose membrane, by this film with
2 μ g/mL antibody at room temperature are incubated 1h, 1:2000 dilutions HRP- goat anti-human iggs (Beijing Zhong Shan companies) and ECL luminescence reagents box are (beautiful
Pierce companies of state) it is exposed to gel imaging system (Bio-Rad companies).
Result is as shown in Figure 3：The anti-Siglec-7 IgG antibodies in people source have specific binding with Siglec-7 albumen.
3) affinity detection
Optimize coupling condition according to antigen isoelectric point and according to the protocol of Biacore-X100control soft,
Slope optimum choice sodium acetate is used as coupling dilution buffer.Antigen samples are diluted to being coupled to after 25 μ g/mL with this buffer solution
On CM5 chips.The default horizontal 1500RU of coupling.Then antigen samples, dilution one are diluted with the Running buffer of pH 7.4
Series concentration is to 0uM, 5nM, 10nM, 2 0nM, 40nM, 80nM.Setting sample injection time is 180s, Dissociation time 10min, regeneration
Buffer solution 50mM pH 2.2Gly-HCl.Protocol according to BiacoreX-100control soft carries out upper machine survey
Examination.Affinity testing result is shown in Fig. 4, and KD values are 7.150 × 10-10M。
4) detection of antibody induction NK killing functions of immunocytes
Take healthy volunteer venous blood 20mL, anticoagulant heparin, add 1mL RosetteSep antibody complexes (1mL whole bloods/
50mLRosetteSep antibody complexes), 20min is incubated at room temperature, the isometric, PBS containing 2%FBS is added, it is placed in after mixing
On the ficoll lymphocyte separation mediums of volume, 2000rpm/min is centrifuged 20min at room temperature.Draw be located at PBS and plasma layer it
Between cell.Repetition is washed twice with PBS, standby.
As target cell, adjustment target cell concentration is 5x10 to K562 with exponential phase4/ mL, is inoculated in 96 orifice plates, 100 μ
L/ holes, 5 are compared by effect target:1,10:1、20:1 adds effector cell, and 100 μ L/ holes are set up antibody intervention group, add 10 μ g/mL's
Anti- Siglec-7 antibody, in 5%CO2Incubator in cultivate 24h, per hole add 15 μ L CCK-8 reagents, be placed in incubator
2h is incubated, 450nm wavelength OD values are detected with ELIASA；Simultaneously set up simple effector cell and simple Target cell wells, take 3 it is parallel
The average value of multiple holes, calculates killing rate.With not plus compared with the experimental group of antibody, antibody increases the killing ability of NK cells respectively
12.75%th, 19.83% and 35.26%.
Above cell experiment result is pointed out, and anti-human source Siglec-7 IgG antibodies have good immunologic competence, Neng Gouxian
The lethal effect of enhancing NK cells against tumor cells is write, shows that the antibody can be used for immunotherapy of tumors, Siglec-7 related
Immunity disease and the clinical treatment of organ transplant.
SEQUENCE LISTING
<110>Chinese People's Liberation Army Medical Research Institute Of Nanjing Military Region
<120>The IgG antibody of the anti-sialic acid binding domain-immunoglobulin sample agglutinin -7 in people source and its application
<130>
<160> 18
<170> PatentIn version 3.3
<210> 1
<211> 360
<212> DNA
<213>Artificial sequence
<400> 1
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggata caccttcacc ggctactata tgcactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtggtaa cacaaactat 180
gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240
atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagagatggg 300
gagactacgg tgactacgtt tgactactgg ggccagggaa ccctggtcac cgtctcctca 360
<210> 2
<211> 120
<212> PRT
<213>Artificial sequence
<400> 2
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Glu Thr Thr Val Thr Thr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 3
<211> 8
<212> PRT
<213>Artificial sequence
<400> 3
Gly Tyr Ile Phe Thr Gly Tyr Tyr
1 5
<210> 4
<211> 8
<212> PRT
<213>Artificial sequence
<400> 4
Ile Asn Pro Asn Ser Gly Asn Thr
1 5
<210> 5
<211> 13
<212> PRT
<213>Artificial sequence
<400> 5
Ala Arg Asp Gly Glu Thr Thr Val Thr Thr Phe Asp Tyr
1 5 10
<210> 6
<211> 990
<212> DNA
<213>Artificial sequence
<400> 6
gcatccacca agggcccatc tgtcttcccc ctggccccat cctccaagag cacctctggc 60
ggcacagctg ccctgggctg cctggtgaag gactacttcc ctgagcctgt gacagtgtcc 120
tggaactctg gcgccctgac cagcggcgtg cacaccttcc ctgctgtgct ccagtcctct 180
ggcctgtact ccctgagcag cgtggtgaca gtgccatcca gcagcctggg cacccagacc 240
tacatctgca atgtgaacca caagcccagc aacaccaagg tggacaagcg ggtggagccc 300
aagtcctgtg acaagaccca cacctgcccc ccatgccccg cccctgagct gctgggcggc 360
ccatctgtct tcctgttccc ccccaagccc aaggacaccc tgatgatctc ccggaccccc 420
gaggtgacct gtgtggtggt ggatgtgagc catgaggacc ccgaggtgaa gttcaactgg 480
tatgtggatg gcgtggaggt gcacaacgcc aagaccaagc cccgggagga gcagtacaac 540
agcacctacc gggtggtgag cgtgctgaca gtgctgcatc aggactggct gaatggcaag 600
gagtacaagt gcaaggtgtc caacaaggcc ctgcctgccc ccattgagaa gaccatctcc 660
aaggccaagg gccagccccg ggagccccag gtctacaccc tgcccccctc ccgggaggag 720
atgaccaaga accaggtgag cctgacctgc ctggtgaagg gcttctaccc cagcgacatt 780
gctgtggagt gggagagcaa cggccagcct gagaacaact acaagaccac cccccctgtg 840
ctggactctg atggctcctt cttcctgtac agcaagctga cagtggacaa gagccggtgg 900
cagcagggca atgtcttctc ctgctctgtg atgcatgagg ccctgcacaa ccactacacc 960
cagaagagcc tgtccctgtc ccccggcaag 990
<210> 7
<211> 330
<212> PRT
<213>Artificial sequence
<400> 7
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 8
<211> 321
<212> DNA
<213>Artificial sequence
<400> 8
tcctatgagc tgacacagcc accctcggtg tcagtgtccc caggacaaac ggccaggatc 60
acctgctctg gagatgcatt gccaaaaaaa tatgcttatt ggtaccagca gaagtcaggc 120
caggcccctg tgctggtcat ctatggggac agcaaacgac ccaccggaat ccctgagaga 180
ttctctggct ccagctcagg gataatggcc accttgacta tcagtggggc ccaggtggag 240
gatgaagctg actactattg ttactcaata gatatcagtg gtaatcgggt attcggcgga 300
gggaccaagc tgaccgtcct a 321
<210> 9
<211> 107
<212> PRT
<213>Artificial sequence
<400> 9
Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
1 5 10 15
Thr Ala Arg Ile Thr Cys Ser Gly Asp Ala Leu Pro Lys Lys Tyr Ala
20 25 30
Tyr Trp Tyr Gln Gln Lys Ser Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Gly Asp Ser Lys Arg Pro Thr Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Ile Met Ala Thr Leu Thr Ile Ser Gly Ala Gln Val Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Tyr Ser Ile Asp Ile Ser Gly Asn Arg
85 90 95
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 10
<211> 6
<212> PRT
<213>Artificial sequence
<400> 10
Ala Leu Pro Lys Lys Tyr
1 5
<210> 11
<211> 3
<212> PRT
<213>Artificial sequence
<400> 11
Gly Asp Ser
1
<210> 12
<211> 10
<212> PRT
<213>Artificial sequence
<400> 12
Tyr Ser Ile Asp Ile Ser Gly Asn Arg Val
1 5 10
<210> 13
<211> 315
<212> DNA
<213>Artificial sequence
<400> 13
cagcccaagg ccaaccccac cgtgaccctg ttccccccat cttctgagga gctgcaagcc 60
aacaaggcca ccctggtgtg cctgatctct gacttctacc ctggcgctgt gacagtggcc 120
tggaaggctg atggctctcc tgtgaaggct ggcgtggaga ccaccaagcc atctaagcag 180
tctaacaaca agtatgctgc ctcttcttac ctgtctctga cccctgagca gtggaagagc 240
caccggtctt actcttgcca ggtgacccat gagggctcta cagtggagaa gacagtggcc 300
cccacagagt gctct 315
<210> 14
<211> 105
<212> PRT
<213>Artificial sequence
<400> 14
Gln Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu
1 5 10 15
Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe
20 25 30
Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val
35 40 45
Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys
50 55 60
Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser
65 70 75 80
His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu
85 90 95
Lys Thr Val Ala Pro Thr Glu Cys Ser
100 105
<210> 15
<211> 30
<212> DNA
<213>Artificial sequence
<400> 15
ggtgtccact cgctacaggt gcagctggtg 30
<210> 16
<211> 30
<212> DNA
<213>Artificial sequence
<400> 16
gcccttggtg gatgctgagg agacggtgac 30
<210> 17
<211> 30
<212> DNA
<213>Artificial sequence
<400> 17
acagacgctc gctgctccta tgagctgaca 30
<210> 18
<211> 30
<212> DNA
<213>Artificial sequence
<400> 18
gttggccttg ggctgtagga cggtcagctt 30
Claims (9)
1. the IgG antibody of the anti-sialic acid binding domain-immunoglobulin sample agglutinin -7 in people source, it is characterised in that：The V of the antibodyHChain
Complementary determining region there is following CDRs amino acid sequences：
V shown in SEQ ID NO.3H-CDR1；
V shown in SEQ ID NO.4H-CDR2；
V shown in SEQ ID NO.5H-CDR3；
And the V of the antibodyLThe complementary determining region of chain has following CDRs amino acid sequences：
V shown in SEQ ID NO.10L-CDR1；
V shown in SEQ ID NO.11L-CDR2；
V shown in SEQ ID NO.12L-CDR3。
2. the IgG antibody of the anti-sialic acid binding domain-immunoglobulin sample agglutinin -7 in people source, it is characterised in that：The ammonia of weight chain variable district
Base acid sequence is as shown in SEQ ID NO.2；The amino acid sequence of light chain variable district is as shown in SEQ ID NO.9.
3. the IgG antibody of the anti-sialic acid binding domain-immunoglobulin sample agglutinin -7 in people source according to claim 1 or claim 2, it is special
Levy and be：The amino acid sequence of heavy chain constant region is as shown in SEQ ID NO.7；The amino acid sequence of constant region of light chain such as SEQ ID
Shown in NO.14.
4. the nucleotides of the IgG antibody of the anti-sialic acid binding domain-immunoglobulin sample agglutinin -7 in people source described in claim 2 is encoded
Sequence, it is characterised in that the nucleotide sequence of encoding heavy chain variable region is the nucleic acid of coding light chain variable region shown in SEQ ID NO.1
Sequence is shown in SEQ ID NO.8.
5. the nucleotides of the IgG antibody of the anti-sialic acid binding domain-immunoglobulin sample agglutinin -7 in people source described in claim 3 is encoded
Sequence, it is characterised in that the nucleotide sequence of encoding heavy chain constant is the nucleic acid that constant region of light chain is encoded shown in SEQ ID NO.6
Sequence is shown in SEQ ID NO.13.
6. the IgG antibody of the anti-sialic acid binding domain-immunoglobulin sample agglutinin -7 in people source described in claim 1 prepare prevention or
Application in treatment severe asthma, COPD, pulmonary embolism, autoimmune disease and/or tumour medicine.
7. a kind of medicine for immunotherapy of tumors, it is characterised in that active ingredient is the anti-saliva in people source described in claim 1
The IgG antibody and its derivative of liquid acid binding domain-immunoglobulin sample agglutinin -7.
8. it is a kind of prevent or treatment autoimmune disease medicine, it is characterised in that active ingredient be claim 1 described in
The IgG antibody and its derivative of the anti-sialic acid binding domain-immunoglobulin sample agglutinin -7 in people source.
9. it is a kind of prevent or treating organs naltrindole medicine, it is characterised in that active ingredient be claim 1 described in
The anti-sialic acid binding domain-immunoglobulin sample agglutinin -7 in people source IgG antibody and its derivative.
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Cited By (5)
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|---|---|---|---|---|
| CN109021105A (en) * | 2018-06-27 | 2018-12-18 | 中国人民解放军南京军区军事医学研究所 | The IgG antibody and its application of the anti-sialic acid binding domain-immunoglobulin sample agglutinin -7/9 of source of people |
| WO2019236965A1 (en) * | 2018-06-08 | 2019-12-12 | Alector Llc | Anti-siglec-7 antibodies and methods of use thereof |
| CN112672757A (en) * | 2018-09-25 | 2021-04-16 | 中央研究院 | Antibodies to sialic acid binding immunoglobulin-like lectins, pharmaceutical compositions comprising the same, and uses thereof |
| CN114031688A (en) * | 2022-01-06 | 2022-02-11 | 北京大学 | Humanized antibody and application thereof |
| US11390680B2 (en) | 2015-08-28 | 2022-07-19 | Alector Llc | Anti-Siglec-7 antibodies and methods of use thereof |
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| WO2001044808A2 (en) * | 1999-12-16 | 2001-06-21 | Universita Degli Studi Di Genova, Dipartimento Di Medicina Sperimentale | Methods of diagnosis and treatment by binding p75/airm1 |
| CN105367658A (en) * | 2015-12-02 | 2016-03-02 | 朱进 | Human-derived anti-sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) antibody IgG and application thereof |
| WO2016038064A1 (en) * | 2014-09-10 | 2016-03-17 | Innate Pharma | Cross reactive siglec antibodies |
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- 2017-01-04 CN CN201710003849.8A patent/CN106831989A/en active Pending
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| WO2001044808A2 (en) * | 1999-12-16 | 2001-06-21 | Universita Degli Studi Di Genova, Dipartimento Di Medicina Sperimentale | Methods of diagnosis and treatment by binding p75/airm1 |
| WO2016038064A1 (en) * | 2014-09-10 | 2016-03-17 | Innate Pharma | Cross reactive siglec antibodies |
| CN105367658A (en) * | 2015-12-02 | 2016-03-02 | 朱进 | Human-derived anti-sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) antibody IgG and application thereof |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11390680B2 (en) | 2015-08-28 | 2022-07-19 | Alector Llc | Anti-Siglec-7 antibodies and methods of use thereof |
| WO2019236965A1 (en) * | 2018-06-08 | 2019-12-12 | Alector Llc | Anti-siglec-7 antibodies and methods of use thereof |
| CN112512638A (en) * | 2018-06-08 | 2021-03-16 | 艾利妥 | anti-SIGLEC-7 antibodies and methods of use thereof |
| JP2021526794A (en) * | 2018-06-08 | 2021-10-11 | アレクトル エルエルシー | Anti-Siglec-7 antibody and how to use it |
| JP7382970B2 (en) | 2018-06-08 | 2023-11-17 | アレクトル エルエルシー | Anti-Siglec-7 antibody and method of use thereof |
| CN112512638B (en) * | 2018-06-08 | 2025-01-28 | 艾利妥 | Anti-SIGLEC-7 antibodies and methods of use thereof |
| US12227568B2 (en) | 2018-06-08 | 2025-02-18 | Alector Llc | Anti-Siglec-7 antibodies and methods of use thereof |
| CN109021105A (en) * | 2018-06-27 | 2018-12-18 | 中国人民解放军南京军区军事医学研究所 | The IgG antibody and its application of the anti-sialic acid binding domain-immunoglobulin sample agglutinin -7/9 of source of people |
| CN112672757A (en) * | 2018-09-25 | 2021-04-16 | 中央研究院 | Antibodies to sialic acid binding immunoglobulin-like lectins, pharmaceutical compositions comprising the same, and uses thereof |
| CN114031688A (en) * | 2022-01-06 | 2022-02-11 | 北京大学 | Humanized antibody and application thereof |
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