CN102727890A - Application of anti-recombinant human keratinocyte growth factor-2 antibody - Google Patents
Application of anti-recombinant human keratinocyte growth factor-2 antibody Download PDFInfo
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- CN102727890A CN102727890A CN2012102304642A CN201210230464A CN102727890A CN 102727890 A CN102727890 A CN 102727890A CN 2012102304642 A CN2012102304642 A CN 2012102304642A CN 201210230464 A CN201210230464 A CN 201210230464A CN 102727890 A CN102727890 A CN 102727890A
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Abstract
The invention adopts a recombinant human keratinocyte growth factor-2 immunized mouse to prepare an anti-KGF-2 (keratinocyte growth factor-2) polyclonal antibody and a KGF-2 monoclonal antibody, which have remarkable treatment effect to a psoriasis-like model of guinea pig. Because influences in different degrees are generated to the psoriasis-like model due to different doses, intradermic inflammatory reactions can be inhibited by virtue of a certain mechanism, besides proliferation of keratinocyte can be inhibited.
Description
Technical field
The invention belongs to biological technical field, be specifically related to the application of anti-recombinant human keratinized cell growth factor-2 (KGF-2) antibody aspect the treatment psoriasis.
Technical background
Psoriasis is a kind of chronic inflammatory disease dermatoses that receives controlled by multiple genes of common pilosity; The pathological characteristic features of its vital tissue is keratinocyte (keratinocyte; KC) hyperplasia, acanthosis and corium vasodilation are the dermatosis of main performance simultaneously with cell infiltration.The cause of disease and pathogenesis still imperfectly understand, and consider relevant with heredity, infection, dysbolismus, endocrine regulation and immune factor etc.About psoriatic treatment, mainly contain following several method at present both at home and abroad: 1, systemic administration, oral retinoic acid, oral immunity inhibitor such as ciclosporin, Radix Tripterygii Wilfordii, vein is given with immunomodulator etc.2, photochemotherapy.3, external preparation is like Daivonex, corticosteroid hormone and retinoid medicine for external use etc.4, the oral and external of Chinese medicine.In recent years; Based on psoriasis is to be the theory of immunoinflammatory disease of link of starting with the lymphocyte abnormal activation; People have developed the medicine of the various cytokines that discharge behind multiple inhibition T lymphocyte abnormal activation and the abnormal activation; So far oneself occurred conceptual dependency therewith 20 surplus kind be used to treat psoriatic biological product; Its mechanism of action has been contained from the starting point of T cell-stimulating and each intermediate link, like the generation or the activity of the angtigen presentation function that suppresses APC, the activation that suppresses the T cell and propagation, inhibition T cell adhesion, inflammation-inhibiting cytokine, utilize the immunoregulation effect of cytokine etc.The immunosuppressant selectivity height that these biotherapeutics are more traditional can play a role through conjoint therapy, shows development prospect preferably.
Research shows; Activated T lymphocyte, inflammatory cell, fibroblast and cytokine and the inflammatory mediator that produces that interact are the material bases that causes psoriasis pathology physically different; For the abnormal change of these cytokines and inflammatory mediator, anyly relate to directly or indirectly the research of psoriatic Pathophysiology and any medicine certainty.All show with external research in the body; In the psoriasis forming process; KC shows as abnormality proliferation and differentiation under the effect of some somatomedin; Like epidermal growth factor, transforming growth factor a and keratinocyte growth factor etc., wherein keratinocyte growth factor KGF, KGFR and NGF that possibly rise the abnormality proliferation of KC and differentiation and the protein expression of P75NGFR.The result finds KGF and KGFR.Mainly be expressed in psoriatic's skin basal layer and substrate upper strata, and the expression intensity in psoriasis, skin lesion raises significantly all, be illustrated in the hypertrophy, differentiation of psoriasis epidermis keratinocyte and play an important role.In vitro study shows DNA growing ability that KGF stimulates KC than TGF and the strong 2-10 of EGF doubly, and the while, KGF also can promote the migration of KC.Xi Yanping etc. adopt the tissue slice immunohistochemistry technique to detect the distribution of KGF-2 in patients with psoriasis vulgaris skin lesion, non-skin lesion and normal skin.The result shows that the positive test symbol of KGF-2 shows that all apparently higher than matched group KGF-2 plays an important role in psoriasis vulgaris skin lesion, the non-skin lesion in psoriasis KC abnormality proliferation.Researchs such as Kovacs also show.Activated lymphocyte can stimulate fibroblast to produce KGF-2 in the psoriatic lesion, is the state that continues hyper-proliferative thereby keep KC.
The applicant has invented a kind of method for preparing of recombinant human keratinocyte growth factor-2 by secretion expression; A kind of expression vector of recombinant human keratinized cell growth factor-2 is provided; It contains the secretion signal peptide-coding sequence, can the KGF-2 PE be expressed in the cell pericentral siphon, and the host cell that contains this recombiant plasmid is through the low temperature multigelation; Recombiant protein is discharged in the buffer, does not destroy proteic activity.Its aminoacid sequence is identical with natural human body keratinized cell growth factor-2, has applied for Chinese patent, patent No. ZL200810030155.4, and obtained patent right, and Granted publication number is CN101538571B.
Summary of the invention
The purpose of this invention is to provide the psoriatic medicine of a kind of treatment, anti-recombinant human keratinized cell growth factor-2 (KGF-2) antibody.
The application of anti-recombinant human keratinized cell growth factor-2 antibody in preparation treatment psoriasis medicine;
Described recombinant human keratinized cell growth factor-2 is by Chinese patent ZL200810030155.4, the preparation of a kind of method for preparing of recombinant human keratinocyte growth factor-2 by secretion expression;
Described anti-recombinant human keratinized cell growth factor-2 antibody is monoclonal antibody.
Another object of the present invention is the psoriatic medicine of a kind of treatment, and it is the vaseline emulsifiable paste of anti-recombinant human keratinized cell growth factor-2 antibody;
The vaseline emulsifiable paste concentration of described anti-recombinant human keratinized cell growth factor-2 antibody is 0.047mg/ml-0.189mg/ml.
The present invention adopts the recombinant human keratinized cell growth factor-2 immune mouse; Prepare anti-KGF-2 polyclonal antibody and KGF-2 monoclonal antibody; All to remarkable therapeutical effect being arranged with the Cavia porcellus psoriasis model; Because of dosage is different psoriasis model is produced influence in various degree, decapacitation suppresses outside the increment of keratinocyte, still can suppress the intradermal inflammatory reaction through certain mechanism.
Description of drawings
Fig. 1 is hybridoma cell strain 2G6 ascites SDS-PAGE result, wherein 1. Marker; 2,3. unpurified ascites; 4,5. ascites behind the purification.
The specific detection result of the anti-KGF-2 monoclonal antibody of Fig. 2.
Fig. 3 Cavia porcellus animal model.
The hard of hearing skin of Fig. 4 normal guinea pig (* 40).
Fig. 5 psoriasis modeling hard of hearing skins of 3 all Cavia porcelluss (* 200).
Fig. 6 psoriasis model group (not treatment) hard of hearing skin of Cavia porcellus (* 200).
Fig. 7 psoriasis hydrocortisone butyrate hard of hearing skin of group Cavia porcellus (* 200).
Fig. 8 psoriasis KGF-2 antibody hard of hearing skin of 20 times of dilution groups Cavia porcellus (* 200).
Fig. 9 psoriasis KGF-2 antibody hard of hearing skin of 40 times of dilution groups Cavia porcellus (* 200).
Figure 10 psoriasis KGF-2 antibody hard of hearing skin of 80 times of dilution groups Cavia porcellus (* 200).
The specific embodiment:
Press the method for preparing (notification number CN101538571B) of a kind of recombinant human keratinocyte growth factor-2 by secretion expression of Chinese patent (9ZL200810030155.4); Preparation antigen KGF2,, choose 4 of the Balb/c mices in 6～8 ages in week; With 10 μ gKGF2; Use distilled water diluting, as immunogen immune Balb/c mice, antibody tires in the mensuration of taking a blood sample after the 4th immunity serum.The titration of serum is through 4 subcutaneous abdomen multi-point injection immunity, and 4 mices all produce anti-KGF-2 antibody.Sero-fast tiring reaches 1:3200, meets the requirement of cell fusion.
After impacting immune 3 d, mouse boosting cell and the Sp2/0 cell that is in exponential phase by the 5:1 mixed, with indirect elisa method screening hybridoma supernatant, are chosen the cloning of strong positive porocyte.Adopt limiting dilution assay, amplification culture is frozen step by step after cultivating through 2～3 sub-clones builds strain.
The preparation and the purifying antibody of ascites prepare ascites by conventional method, and mouse peritoneal injecting fluid paraffin sensitization 1～2 all pneumoretroperitoneum injection strong positive hybridomies behind 7～10 d, are collected ascites, and packing is frozen subsequent use.
The culture supernatant of utilizing indirect ELISA method to detect hybridoma cell strain 2G6 respectively tires, ascites is not tired behind purification ascites and the purification, and the result sees table 2.2;
The titration result of table 2.2 cells and supernatant and ascites
| The cell strain supernatant ascites of tiring is tired and is tired behind the purification |
| 2G6 ?＞1:6400 ＞1:2.56×10 5 ＞1:1.28×10 5 |
Serum, ascites McAb tire and 1. the Ig subclass detects serum, the ascites McAb employing indirect elisa method of tiring.RhbFGF is diluted to 10 μ g/ml with carbonate buffer solution, encapsulates in 96 orifice plates, one anti-be the serum of doubling dilution or ascites, and two resist and are the sheep anti-mouse igg of HPR labelling.With the OPD colour developing, wavelength 490 nm read the OD value.Judge as positive with P/N >=2.1.2. the evaluation of Ig subclass: the ELISA method according to the monoclonal antibody parting kit description introduction of Mus source is carried out.
According to the test kit explanation, utilize the subclass type of the ELISA method detection hybridoma cell strain 2G6 of antigen mediation, see table 3, the result shows that this antibody is the IgG1 type.
Table 3 monoclonal antibody subgroup identification
| Cell strain IgA IgM IgG1 IgG2a IgG2b IgG3 |
| 2G6 0.081 0.172 0.121 ? 0.101 ? 0.120 ? ?0.103 |
The stability test of hybridoma cell strain 2G6 secretory antibody
Frozen 2～3 months hybridoma recovery back continuous passage was cultivated more than 4 generations, detect cell conditioned medium liquid with indirect ELISA method and tire, confirm the stability of hybridoma secretion monoclonal antibody according to tiring.
Respectively at frozen back 30d, 60d, 90d recovery hybridoma, get cell culture supernatant, indirect ELISA method is measured antibody titer, and the result sees table 4; Can find out and tire more stable at minute inner cell strain secretory antibody.
The stability of table 4 hybridoma secretory antibody
| Natural law 30 60 90 |
| 1:3200 1:3200 1:3200 tires |
Protein concentration and purity obtain 2 protein peaks through the rProteinA column purification, and 1 peak is the nonspecific proteins peak, and Fractional Collections the 2nd peak is through detecting protein concentration at 400～1 900 μ g/ml.SDS-PAGE result (Fig. 1) shows heavy, two protein bands of light chain, and relative molecular mass is respectively 55 000 and 25 000, and its purity can reach more than 90%.
Be the encrusting substance coated elisa plate with BSA, KGF and KGF-2 respectively; Establish negative control simultaneously; After sealing, add the 2G6 monoclonal antibody; Press each hole OD490 value of indirect ELISA program determination, the ratio of the ratio of calculating K GF-2 hole and negative hole and BSA hole and KGF hole and negative control hole, thereby the specificity of definite anti-KGF2 monoclonal antibody.KGF-2 monoclonal antibody specific detection result sees Fig. 2, and the P/N value is the highest in the time of can finding out the excretory monoclonal antibody of 2G6 and detect former KGF-2 reaction, and with the P/N value of BSA and KGF all less than 2, explain that the monoclonal antibody that obtains is that specificity is directed against KGF-2.
Embodiment 2KGF-2
McAb is to the therapeutical effect of psoriasis Cavia porcellus psoriasis model
The foundation of Cavia porcellus psoriasis model
Get propranolol hydrochloride 5g; With 50 % ethanol is solvent; Make medicine dissolution, add Azone (azone)-propylene glycol 5ml as compound accelerant, adding PVPK30 (polyvinyl pyrrolidone homopolymer) 5g is filmogen; Add 50 % ethanol to 100ml, preparation propranolol hydrochloride breast liniment.Get 50 of body weight 350～450g Cavia porcelluss, male and female half and half, it is hard of hearing that the 5 % propranolol hydrochlorides that prepare breast liniment evenly is applied to the Cavia porcellus ears, and 4 times/d, 3 weeks of logotype.It is wide to get 5 Cavia porcellus ears after 3 weeks immediately, FFPE, and HE dyeing is observed its histology and is changed (it is thus clear that typical psoriasiform changes; Parakeratosis, granular layer reduces, acanthosis; Trochanterellus prolongs, high dermis cell infiltration, and high dermis telangiectasis).
The visible a large amount of desquamations of Cavia porcellus auricle of experimental group BIAO and BEN naked eyes, telangiectasis, pachyderma the psoriasiform skin lesion occurs, (Fig. 3).The HE coloration result shows: the visible poor horny layer of normal guinea pig skin, and granular layer is about the 1--3 layer, prickle cell layer about 3--and 5 layers, basal layer is the monolayer cylindrical cell.True epidermis has a common boundary more flat, and intradermal is dispersed in minority monocyte infiltration (Fig. 4).The whole BIAO and BEN of model group all can be seen in various degree acanthosis, trochanterellus and extend to be and stretch the toothed oak shape on bar-shaped, the dermal papilla and become and telangiectasis extensive or focal parakeratosis (Fig. 5).
Monoclonal antibody is to the effect of psoriasis Cavia porcellus psoriasis model
45 Cavia porcelluss are divided into 5 groups at random, 9 every group.1 group is model group; 2 groups is that the excretory anti-KGF-2 monoclonal anti body and function vaseline dilution of hybridoma cell strain 2G6 is original 20 multiple dose groups (0.189mg/ml); 3 groups is that the excretory anti-KGF-2 monoclonal antibody dilution of hybridoma cell strain 2G6 is original 40 multiple dose groups (0.095mg/ml); 4 groups is that the excretory anti-KGF-2 monoclonal antibody dilution of hybridoma cell strain 2G6 is original 80 multiple dose groups (0.047mg/ml), hydrocortisone butyrate (hydrocortisone butyrate) group.Model group need not any medicine, recovers matched group naturally as the skin lesion model; After 2 weeks of medication, use 3% pentobarbital sudden death Cavia porcellus, get its ears auricle, 10% formalin fixed 24h.Draw materials (every auricle is all got its middle body) dehydration, embedding (noting making auricle during embedding), section (4um is thinly-sliced), HE dyeing perpendicular to tangent plane.Microscopically is observed variations such as ear skin horny layer, granular layer, prickle cell layer, basal cell layer, intradermal inflammatory cell; And epidermal thickness is surveyed with micrometer in (* 200) under optical microscope; Counting inflammatory cell number is carried out each group difference property relatively.Adopt SPSS13.0 software, the SABC result is analyzed with equal t inspection statistics analytic process between group.
Under the light microscopic, except that all not seeing Munro microabscess and parakeratosis, pathological change and inconsistent is respectively organized in experiment; Under the model group light microscopic; It is thus clear that the minimizing of hyperkeratosis and granular layer (≤1 layer), significant acanthosis, 15-24 layer; Trochanterellus prolongs obviously, and intradermal inflammatory cell infiltration quantity reaches telangiectasis more and increases (Fig. 6).Hydrocortisone butyrate treatment group, epidermal thickness lower than other groups obviously, and compare with model group, and the inflammatory cell counting also significantly reduces (Fig. 7).KGF2 mab treatment group, then the difference because of concentration embodies different biological activity (Fig. 8,9,10).
With reference to the Baker methods of marking, every part of BIAO and BEN is carried out histological score analysis (typical psoriatic lesion scoring 4.0-10.0) one by one. see table 5, use histological score that this methods of marking obtains each group and see table 6.
The t assay shows that the treatment group is compared with model group has significant difference (P＜0. 05), and the illustrative experiment medicine has therapeutical effect to the psoriasis animal model.But 60 times of dilution groups of hydrocortisone butyrate group and KGF-2 relatively, and P＜0.05 explains that KGF-2 is a dosage dependency line medicine, the KGF2 action effect higher dosage of low dosage poor.
Each experimental group inflammatory cell count difference differnce table 7
Equal 10 * 20 visuals field are observed down, get 3 visuals field respectively, take the photograph figure.The application ID A2000 digital image analysis system counting single nucleus of intradermal (except appendages and the blood vessel).
With model group relatively, P＜0. 05,20 times of dilution groups of KGF2 and 40 times of dilution groups of KGF-2,60 times of dilution groups of KGF2, hydrocortisone butyrate group be P＜0. 05 relatively, 60 times of dilution groups comparison P＜0. 05 of hydrocortisone butyrate group and KGF-2.
Table 7 is the result show; The treatment group can significantly reduce the cell infiltration of psoriasis animal model than model group, and KGF-2 antibody 20 dilution groups alleviate effect to inflammatory cell and are superior to the hydrocortisone butyrate group, but along with the decline of diluted concentration; To the inhibition ability drop of inflammatory cell, effect is weaker than the hydrocortisone butyrate group.
Each experimental group epidermal thickness difference is seen table 8
Equal 10 * 20 visuals field are observed down, get 3 visuals field respectively, take the photograph figure.Application ID A2000 digital image analysis system meter skin thickness, the mm of unit.
Compare with model group, P＜0. 05, hydrocortisone butyrate group and KGF-2 Antybody therapy group are relatively; P＜0. 05 are influenced epidermal thickness by the visible medicine of table 8, and all there were significant differences between treatment group and model group; P＜0. 05, yet, KGF-2 antibody group to the influence of epidermal thickness less than hydrocortisone butyrate; There is significant difference P＜0. 05.
Choosing the Balb/c mice in 6～8 ages in week, is immunogen immune Balb/c mice with KGF-2, through 4 subcutaneous abdomen multi-point injection immunity; 4 mices all produce anti-KGF-2 antibody; The antibody titer of serum reaches 1:3200, and serum with 20 times of dilute serums of vaseline, is adopted embodiment 2 methods; Psoriasis Cavia porcellus psoriasis model is treated, and its effect is a little less than the therapeutic effect of the excretory anti-KGF-2 monoclonal antibody of hybridoma cell strain 2G6.
This experimental result shows; Anti-KGF-2 polyclonal antibody and monoclonal antibody; All to remarkable therapeutical effect being arranged with the Cavia porcellus psoriasis model; Because of dosage is different psoriasis model is produced influence in various degree, decapacitation suppresses outside the increment of keratinocyte, still can suppress the intradermal inflammatory reaction through certain mechanism.Clear and definite with the probability of KGF-2 monoclonal antibody as the psoriatic a kind of new drug targets of treatment, and laboratory reference is provided for developing efficient, special monoclonal antibody drug.
Claims (5)
1. the application of anti-recombinant human keratinized cell growth factor-2 antibody in preparation treatment psoriasis medicine.
2. according to the application of the anti-recombinant human keratinized cell growth factor-2 antibody of claim 1 in preparation treatment psoriasis medicine; It is characterized in that: described recombinant human keratinized cell growth factor-2 is by Chinese patent ZL200810030155.4, the preparation of a kind of method for preparing of recombinant human keratinocyte growth factor-2 by secretion expression.
3. the application of anti-recombinant human keratinized cell growth factor-2 antibody according to claim 1 and 2 in preparation treatment psoriasis medicine, it is characterized in that: described anti-recombinant human keratinized cell growth factor-2 antibody is monoclonal antibody.
4. treat psoriatic medicine for one kind, it is characterized in that: it is the vaseline emulsifiable paste of anti-recombinant human keratinized cell growth factor-2 antibody.
5. the psoriatic medicine of a kind of treatment according to claim 4, it is characterized in that: the vaseline emulsifiable paste of described anti-recombinant human keratinized cell growth factor-2 antibody, its concentration are 0.047mg/ml-0.189mg/ml.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1234071A (en) * | 1996-08-13 | 1999-11-03 | 人类基因组科学公司 | Keratinocyte grouth factor -2(KGF-2 or fibroblast growth factor-12, FGF-12) |
| CN1359299A (en) * | 1999-06-02 | 2002-07-17 | 人类基因组科学公司 | Keratinocyte growth factor-2-formulations |
| US6903072B2 (en) * | 1995-02-14 | 2005-06-07 | Human Genome Sciences, Inc. | Keratinocyte growth factor-2 |
| CN101538571A (en) * | 2009-02-17 | 2009-09-23 | 温州医学院 | Method for preparing recombinant human keratinocyte growth factor-2 by secretion expression |
-
2012
- 2012-07-05 CN CN2012102304642A patent/CN102727890A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6903072B2 (en) * | 1995-02-14 | 2005-06-07 | Human Genome Sciences, Inc. | Keratinocyte growth factor-2 |
| CN1234071A (en) * | 1996-08-13 | 1999-11-03 | 人类基因组科学公司 | Keratinocyte grouth factor -2(KGF-2 or fibroblast growth factor-12, FGF-12) |
| CN1359299A (en) * | 1999-06-02 | 2002-07-17 | 人类基因组科学公司 | Keratinocyte growth factor-2-formulations |
| CN101538571A (en) * | 2009-02-17 | 2009-09-23 | 温州医学院 | Method for preparing recombinant human keratinocyte growth factor-2 by secretion expression |
Non-Patent Citations (2)
| Title |
|---|
| KOVACS D等: "Immunohistochemical analysis of keratinocyte growth factor and fibroblast growth factor 10 expression in psoriasis", 《EXPERIMENTAL DERMATOLOGY》 * |
| 梅向林等: "FGF10单克隆抗体对豚鼠银屑病样模型的作用研究", 《中华医学会第十八次全国皮肤病学术年会论文汇编》 * |
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Application publication date: 20121017 |