CN103845730B - Anti-ST2/IL-1 R4 antibody is preparing the purposes in analgesic - Google Patents
Anti-ST2/IL-1 R4 antibody is preparing the purposes in analgesic Download PDFInfo
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- CN103845730B CN103845730B CN201210517242.9A CN201210517242A CN103845730B CN 103845730 B CN103845730 B CN 103845730B CN 201210517242 A CN201210517242 A CN 201210517242A CN 103845730 B CN103845730 B CN 103845730B
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Abstract
The present invention relates to analgesic field, do you be specifically related to anti-ST2/IL-1? R4 antibody is preparing the application in analgesic, confirm through experiment, anti-ST2/IL-1 of the present invention? R4 antibody thermal hyperalgesia that is irritated to the crymodynia of neuropathic pain mouse model and cancer pain mice has significant inhibitory action.Can be used as effective ingredient, prepare analgesic further, for clinical treatment chronic pain, especially treat neuropathic pain or cancer pain.
Description
Technical field
The present invention relates to analgesic field, be specifically related to anti-ST2/IL-1R4 antibody and preparing the application in analgesic, especially anti-ST2/IL-1R4 antibody is in the purposes in preparation treatment neuropathic pain, Cancer pain medicament.
Background technology
It is not only a kind of symptom that research discloses chronic pain, but a kind of disease.Clinical common trigeminal neuralgia, sciatica, lumbago and skelalgia, osteoarthrosis pain, cancer pain etc. all belong to the category of chronic pain.Described pain is that a kind of cure-pain stimulates, and causes psychology and spirit to change, causes depression, anxiety, affect patients ' life quality, cause heavy social economical burden.According to the relevent statistics, the adult of about 30% suffers from chronic pain, and the whole world reaches hundreds billion of dollar for the expense of chronic pain treatment every year.
" eliminate pain is the fundamental right of patient ".In reality patient this in fundamental right do not realized very well.The analgesic of prior art and treatment means very limited to the analgesic effect of chronic pain, and due to its higher adverse reaction rate, limit its further use clinically.Even if at present to the highly effective Endorphins medicine of acute pain as morphine, patient's life-time service also can produce drug resistance.Therefore further investigate the mechanism that chronic pain occurs, develops, find new AD-targeted drugs, explore more effective Therapeutic Method, become medical domain main points urgently to be resolved hurrily and difficult point.
ST2 is one of Toll-like/IL-1 receptor (IL-1R) superfamily member, encode a kind of solubility ST2 (soluableST2, sST2) and a kind of cross-film form ST2 part (ST2Ligand, ST2L).Both are produced by premessenger RNA alternative splicing, have common extracellular domain, but sST2 lack cross-film and intracellular Toll/IL-1 receptor domain.Research shows, transmembrane ST2L and auxilin (AcP) form the film surface receptor of IL-33 (newfound a kind of inflammatory cytokine in 2005) jointly.Research shows, IL-33/ST2 signal pathway participates in the cell-mediated immunne response of Th2, regulates growth and the function of mastocyte, plays a role in the lysis such as struvite, autoimmunity, cardiovascular, tumor.
The research relevant report of ST2 in pain only has one section.2008, VerriWA etc. studied discovery, and after the subcutaneous or ankle joint intracavitary administration of murine antigen, inflammation local ST2 expresses and increases; The mechanical hyperalgesia that sST2 can suppress antigen injection to cause, and this effect is realized by TNF-α-IL-1 β-IFN γ-ET-1-PGE2 path.The above results prompting periphery ST2 participates in arthritis pain.So far, there is not yet the report of ST2 and neuropathic pain and cancer pain, also nonreactive ST2 antibody direct analgesic report, and have no anti-ST2 antibody carries out Clinical Pain treatment report by Analgesic Mechanism.
Summary of the invention
The object of this invention is to provide the novelty teabag of anti-ST2/IL-1R4 antibody, be specifically related to anti-ST2/IL-1R4 antibody at preparation treatment chronic neuralgia, the application in the medicine of cancer pain.
Object of the present invention is achieved through the following technical solutions:
1, anti-ST2 antibody is purchased from R & D company (MouseST2/IL-1R4Antibody, AF1004).
2, anti-ST2 antibody is used for the treatment of neuralgia experiment:
Select male BALB/c mouse, set up the ligation of mice sciatic nerve branch according to a conventional method and cut off Neuropathic pain model (SNI model), within after modeling the 7th day, there is remarkable and stable neuralgia, intrathecal injection gives anti-ST2 antibody, observe medicine to the impact of pain behavior, comprise the impact of the super quick and mechanicalness allodynia of crymodynia
Result confirms: anti-ST2 antibody has remarkable analgesic activity to Neuropathic pain model mice.
3, anti-ST2 antibody is used for the treatment of cancer pain experiment:
Select female BAl BIc/c mice, set up mouse femur cancer pain model according to a conventional method, within after modeling the 11st day, occur remarkable and stable cancer pain, intrathecal injection gives anti-ST2 antibody, observes the impact of medicine on pain behavior (the super quick and mechanicalness allodynia of crymodynia),
Result confirms: anti-ST2 antibody has remarkable analgesic activity to cancer pain model mice, gives the pain behavior that anti-ST2 antibody capable significantly alleviates neuralgia and cancer pain mice in sheath.Anti-ST2/IL-1R4 antibody of the present invention can be used as effective ingredient, prepares further
analgesic, for clinical treatmentchronic pain, especially treats neuropathic pain or cancer pain.
accompanying drawing illustrates:
Fig. 1 neuralgia Establishment of mouse model, * * P<0.01, compares with Normal group.
The effect of the anti-ST2 antibody of Fig. 2 various dose and mechanical hyperalgesia irritated to neuralgia mice crymodynia, * * P<0.01, compares with model+IgG group.
Fig. 3 cancer pain Establishment of mouse model, * * P<0.01, compares with Normal group.
The effect of the anti-ST2 antibody of Fig. 4 various dose and mechanical hyperalgesia irritated to cancer pain mice crymodynia, * * P<0.01, compares with model+IgG group.
detailed description of the invention:
Embodiment 1
1, laboratory animal:
This experiment adopt SPF level BALB/C mice (male for Neuropathic pain model make, female for cancer pain modelling), 8 week age, body weight 16-20g(Chinese Academy of Sciences Experimental Animal Center).Rearing conditions is cleaning grade, 5-6/cage, supplies water arbitrarily.The complete randomized of laboratory animal is divided into groups.
2, analogue formation
1. Neuropathic pain model (SNI model) is cut off in the ligation of mice sciatic nerve branch: after the anesthesia of mouse peritoneal injection pentobarbital sodium, skin is cut in mouse hind leg upper limb, longitudinal dissociation muscle, expose sciatic nerve trunk and under branch---tibial nerve, common peroneal nerve and sural nerve, ligation also cuts off tibial nerve and common peroneal nerve, retain tiny sural nerve, avoid any damage simultaneously.By muscle, skin layer-by-layer suture, then antibacterial prevention done by lumbar injection antibiotic.Sham operated rats animal is not except carrying out neural ligation and cutting off, and all the other operations are all identical with operation group.
2. mouse femur cancer pain model: the method reported by Schwei etc., sets up mouse femur cancer pain model.After Animal Anesthesia, the skin incision of a long 0.5-1.0cm is cut along rectus femoris tendon direction by knee joint place, careful exposure patella, first punch along the puncture of femur long axis direction at patella with disposable sterilized 1mL syringe needle, then change 10uL microsyringe and enter marrow cavity of femur, slowly inject 4uL containing 1 × 10
4the cell suspending liquid (2.5 × 10 of individual 4T1 mouse mastopathy cell
6individual/ml) (Shanghai Inst. of Life Science, CAS cellular resources center) to femur.Seal pin hole with gelfoam after injection, aseptic cotton carrier dips in normal saline cleaning wound, applies a small amount of penicillin powder, skin closure.Matched group injection equivalent PBS or etc. calorimetric deactivation dead cell, all the other operations are all identical with operation group.
3, pain behavior evaluation
1. mechanicalness allodynia (mechanicalallodynia): the up-and-down method introduced according to Dixon, adopt vonFrey filament (Stoelting, WoodDale, Illinois, USA) stimulate the contracting foot reaction caused as mechanicalness allodynia index.
2. crymodynia super quick (coldallodynia): adopt the acetone (analytical pure that the syringe per injection 50ul of passivity syringe needle is housed, Chemical Reagent Co., Ltd., Sinopharm Group) to the skin place of sural nerve domination outside mice sole, after observed and recorded injection acetone, lift foot/lick the sufficient time as the super quick index of crymodynia.
3. thermal hyperalgesia (thermalhyperalgesia): in quiet environment, room temperature 22 scholar 1 DEG C, mice is placed in cylindrical space that the end is Metal constant temperature flat board, Metal constant temperature plate 50 scholar 0.5 DEG C by electronic feedback system holding temperature, is recorded it and terminates to lick the pawl response latency as thermal hyperalgesia index incubation period in this period of time to occurring licking rear solid end or jumping out the timing of Metal constant temperature plate from foot embedding device.
4, medication
1. intrathecal drug delivery: after mice isoflurane anesthesia, vertically inserts micro-sampling pin along L5, L6 spinous process middle, and entering subarachnoid space has clear and definite breakthrough sense, and visible tail whipping.
2. pharmaceutical intervention: give anti-ST2 antibody in sheath in the 7th day after the modeling of neuralgia mice, the change of 0.5,1.5,3,5,7,9,12h mice pain behavior after observation administration.Within the 11st day after the modeling of cancer pain mice, in sheath, give anti-ST2 antibody, the change of 1,2,3,4,6,8,24h mice pain behavior after observation administration.
Experimental data represents with mean ± standard error (mean ± SE), and application SPSS16.0 software is added up, and adopts one factor analysis of variance (onewayANOVA).Think that difference has significance with P<0.05.
Result shows:
1) neuralgia Establishment of mouse model: namely super quick the and mechanicalness allodynia of significant crymodynia appears on the 1st day in the ligation of mice sciatic nerve branch after cutting off, pain status started to stablize in the 7th day, and can last till that observation in the 14th day terminates, and the behavior of sham operated rats pain does not have significant change (as shown in Figure 1);
2) anti-ST2 antibody is to the analgesic activity of neuralgia mice: after modeling, the 7th day intrathecal injection gives anti-ST2 antibody 30ng, 100ng, 300ng, result shows, after 300ng administration 0.5 hour, namely the cold type of pain threshold of mice significantly rose, and this acts on 5 hours and reaches peak, 9 littlely still have analgesic effect, the 12nd hour event resolves constantly; And after 10ng anti-ST2 antibody administration, within 3-7 hour, also present certain analgesic activity; Dose dependent analgesic activity (as shown in Figure 2) is presented after anti-ST2 antibody administration;
3) cancer pain Establishment of mouse model: occur the super quick and mechanicalness allodynia of significant thermalgesia on the 2nd day after mouse femur injection 4T1 breast cancer cell, pain status started to stablize in the 10th day, last till to observe for the 14th day and terminate, and PBS and the behavior of dead cell (Heatkilledgroup) matched group pain do not have significant change (as shown in Figure 3)
4) anti-ST2 antibody is to the analgesic activity of cancer pain mice: after modeling, the 11st day intrathecal injection gives anti-ST2 antibody 100ng, 200ng, 400ng, result shows, after the anti-ST2 antibody administration of 400ng 2 hours, and the burning pain threshold of mice significantly rises, this acts on 3 hours and reaches peak, 9 littlely still have analgesic effect, the 12nd hour event resolves constantly, and within 3-7 hour, also present certain analgesic activity after 10ng anti-ST2 antibody administration; Dose dependent analgesic activity (as shown in Figure 4) is presented after anti-ST2 antibody administration.
Experimental result shows, gives the pain behavior that anti-ST2 antibody capable significantly alleviates neuralgia and cancer pain mice in sheath.Anti-ST2/IL-1R4 antibody of the present invention can be used as effective ingredient, prepares analgesic further, for clinical treatment chronic pain, especially treats neuropathic pain or cancer pain.
Claims (2)
1. the purposes of anti-ST2/IL-1R4 antibody in preparation treatment chronic pain medicine, described chronic pain is neuropathic pain or cancer pain.
2. purposes according to claim 1, wherein said anti-ST2/IL-1R4 antibody is MouseST2/IL-1R4Antibody, AF1004.
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| CN117487905A (en) * | 2023-12-29 | 2024-02-02 | 中日友好医院(中日友好临床医学研究所) | Use of IL-33 in the preparation of therapeutic/detection SANFH products |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101821412A (en) * | 2007-08-15 | 2010-09-01 | 艾德拉药物股份有限公司 | TOLL sample receptor modulators |
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| CN101821412A (en) * | 2007-08-15 | 2010-09-01 | 艾德拉药物股份有限公司 | TOLL sample receptor modulators |
Non-Patent Citations (4)
| Title |
|---|
| Emerging role of Toll-like receptors in the control of pain and itch;Liu T et al.;《Neurosci Bull》;20120508;第28卷(第2期);摘要，第1页倒数第1段-第5页第2段，图1-4，表1 * |
| IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice;Verri WA Jr et al.;《Pro Natl Acad Sci USA》;20080219;第105卷(第7期);2723-2728 * |
| Research progress on interleukin-33 and its roles in the central nervous system;Han P et al.;《Neuroscience bulletin》;20111001;第27卷(第5期);351-357 * |
| Toll样受体4：神经病理性疼痛潜在的治疗靶标;贾泽军等;《中国医学科学院学报》;20120629;第34卷(第2期);摘要，TLR4介导神经病理性疼痛的可能机制，靶向TLR4药物研发现状 * |
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