WO2023198155A1 - Anticorps pour traiter l'inflammation de la peau et des muqueuses et sa formulation - Google Patents

Anticorps pour traiter l'inflammation de la peau et des muqueuses et sa formulation Download PDF

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Publication number
WO2023198155A1
WO2023198155A1 PCT/CN2023/088120 CN2023088120W WO2023198155A1 WO 2023198155 A1 WO2023198155 A1 WO 2023198155A1 CN 2023088120 W CN2023088120 W CN 2023088120W WO 2023198155 A1 WO2023198155 A1 WO 2023198155A1
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antibody
seq
sequence
cdr
chain variable
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PCT/CN2023/088120
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English (en)
Chinese (zh)
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石韦
武建朝
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上海韦青医药科技咨询有限公司
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Priority to CN202380015298.0A priority Critical patent/CN118401551A/zh
Publication of WO2023198155A1 publication Critical patent/WO2023198155A1/fr

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    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • 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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons

Definitions

  • the invention belongs to the field of medical biotechnology, and specifically relates to an antibody and its preparation for treating skin and mucosal inflammation.
  • Skin and mucous membranes are the first barrier between the human body and the external environment. Factors that attack the skin or mucous membranes include chemical factors, microorganisms, hot and cold stimulation, ionizing radiation, and mechanical stimulation. These exogenous and endogenous damaging factors can cause various damaging lesions of the skin or mucous membranes. Therefore, a series of complex reactions occur locally and systemically in the skin or mucous membranes to localize and eliminate the damaging factors, and remove and absorb necrosis. Tissues and cells, and repairing damage, this is the body's defensive response - inflammation. The inflammatory response is regulated by a variety of inflammatory factors such as TNFa, IL-6, IL-5, IL-1, IL-8, etc. Abnormal inflammation brings a series of allergic reactions to the skin and mucous membranes of the body, such as erythema, edema, burning, Pain, itching, etc.
  • TNFa is the earliest and most important inflammatory mediator in the inflammatory response process. Its biological activity is mainly achieved by transmitting signals through specific receptors on the cell membrane.
  • TNFa receptors There are two types of TNFa receptors, namely TNF-RI and TNF-RII. Both TNF receptors are glycoproteins. Amino acid sequence analysis shows that the amino acid sequences of the extracellular regions of the two receptors are highly similar, but the intracellular regions are completely different. Differences play different roles.
  • TNF-RI has a wide range of effects, including killer cell activity, antiviral activity, induction of the expression of inflammatory factors such as Mn-SOD, ICAM-1, IL-6, and IL-5, promotion of fibroblast proliferation, and cell programming.
  • TNF-RII mainly transmits the proliferation signals of lymphocytes such as thymocytes and NK. It increases the TNF-RI-induced effect by promoting TNF ⁇ to bind to TNF-RI, and also increases the expression of ICAM-1.
  • TNF-RI is mainly distributed in epidermal keratinocytes, mucosal epithelial cells and dendritic cells in the upper dermis, while in In skin lesions, in addition to the above distribution, TNF-RI is also distributed around the blood vessels in the parakeratotic stratum corneum and upper dermis.
  • TNF-RII is distributed in eccrine ducts and dermal dendritic cells in normal skin, while in skin lesions, it is distributed in upper dermal blood vessels and perivascular infiltrating cells.
  • TNFa is involved in pain sensitization: inflammatory tissue sites and DRG neurons release a large amount of MMP-9, which can act on the TNFa precursor on the DRG primary sensory neurons to activate it and bind to the TNFR1 receptor, thereby causing TRPV1 channels The expression and sensitivity are increased and are involved in the occurrence and development of inflammatory pain.
  • IL-5 is an inflammatory factor secreted by cells such as eosinophils, NK cells, TC2CD8+T cells, mast cells, CD45+CD4+T cells, ⁇ -delta T cells, and IL-1 ⁇ -activated endothelial cells.
  • IL-5 performs many functions on eosinophils. These include downregulation of Mac-1, upregulation of IgA and IgG receptors, stimulation of secretion of lipid mediators (leukotriene C4 and PAF) and induction of granule release.
  • IL-5 also promotes eosinophil growth and differentiation; however, the exact role of IL-5 is unclear; it may act in an auxiliary manner.
  • IL-5 acts on eosinophils and mast cells and is involved in airway mucosal inflammation.
  • IL-6 can be synthesized by a variety of cells, including activated T cells and B cells, monocytes-macrophages, endothelial cells, epithelial cells, and fibroblasts.
  • IL-6 is a heterodimer composed of two glycoprotein chains ⁇ . The ⁇ chain lacks an intracellular region and can only bind to IL-6 with low affinity. The formed complex quickly binds to the high affinity ⁇ chain and transmits information into the cell through the ⁇ chain.
  • IL-6 acts on many target cells, including macrophages, hepatocytes, resting T cells, activated B cells and plasma cells; its functions: 1 Promote the expression of IL-2R on the surface of T cells, enhance IL-1 and Mitogenic effects of TNF on TH cells.
  • 2A as a stem cell stimulating factor, it induces the synthesis of acute phase response proteins in acute inflammatory reactions caused by infection or trauma, among which the increase of amyloid A and C-reactive protein is particularly obvious.
  • 3 Promote B cell proliferation, differentiation and production of antibodies; malignant B cells of multiple myeloma can both produce IL-6 and respond to IL-6, suggesting that IL-6 may serve as an autocrine growth factor for these cells.
  • 4IL-6 can also effectively promote cachexia induced by TNF and IL-1; promote glucocorticoid synthesis; stimulate osteoclast activity and keratinocyte growth; and can also promote bone marrow hematopoietic function.
  • IL-6 cannot stimulate corresponding cells to secrete other cytokines, and its autocrine effect on immune cells is relatively weak at physiological concentrations. It is suggested that its main immunological function is to enhance the effects of other cytokines. Yang Yan et al. reported itch-related inflammatory factor receptors. IL-2 and IL-6 in the leukocyte lysates of patients with allergic dermatitis are both itching substances. For example, when IL-2 is used to treat cancer, it will induce itching in the body. Both nerve cells and Schwann cells express IL-6 receptors, and the immunoreactivity of IL-6 on nerve fibers in patients with positive skin patch tests and prurigo nodularis is higher than that in normal people. In addition, studies have shown that IL-8 also has an itching effect, but the specific mechanism is still unclear.
  • the antibacterial polyclonal antibody contains antibodies to a variety of inflammatory factors such as TNFa, IL-6, IL-5, etc.
  • inflammatory factor antibody gel alone or in combination can quickly relieve mucosal and skin inflammation, such as oral ulcers, vaginitis, etc.
  • the permeability of the inflammatory mucosa and skin increases, and the inflammatory factor antibodies work locally without causing systemic immune suppression, which is safer and better.
  • the present invention first relates to a group of monoclonal antibodies directed against inflammatory factors.
  • the inflammatory factors are human interleukin 5 (IL-5) or human tumor necrosis factor (TNFa).
  • the monoclonal antibodies are:
  • the monoclonal antibody against human interleukin 5 has the VH amino acid sequence of the heavy chain variable region as shown in SEQ ID NO: 6; the (VL) amino acid sequence of the light chain variable region as shown in SEQ ID NO: As shown in 8;
  • VH amino acid sequence of the heavy chain variable region is shown in SEQ ID NO: 2; the (VL) amino acid sequence of the light chain variable region is shown in SEQ ID NO: 4 .
  • the anti-human interleukin 5 (IL-5) monoclonal antibody is 59C4, and the VH amino acid sequence of the heavy chain variable region of the 59C4 antibody is shown in SEQ ID NO: 6; the ( VL) amino acid sequence is shown in SEQ ID NO:8.
  • the CDR classification of the heavy chain variable region VH of the 59C4 antibody is as follows:
  • the CDR-H1 sequence is shown in SEQ ID NO.20, SEQ ID NO.20: DYYIN
  • the CDR-H2 sequence is shown in SEQ ID NO.21, SEQ ID NO.21: EIYPGSGNTYYNEKFKG
  • the CDR-H3 sequence is shown in SEQ ID NO.22, SEQ ID NO.22: LTYYGSSYDYFDY
  • the CDR division of the light chain variable region VL of the 59C4 antibody is as follows:
  • the CDR-L1 sequence is shown in SEQ ID NO.23, SEQ ID NO.23: ENIYSN
  • the CDR-L2 sequence is shown in SEQ ID NO.24, SEQ ID NO.24: AAT
  • the CDR-L3 sequence is shown in SEQ ID NO.25, SEQ ID NO.25: QHFWNTPYT
  • the anti-human tumor necrosis factor (TNFa) monoclonal antibody is T10E8, and the VH amino acid sequence of the heavy chain variable region of the T10E8 antibody is shown in SEQ ID NO: 2; the (VL) amino acid of the light chain variable region The sequence is shown as SEQ ID NO:4;
  • the CDR classification of the heavy chain variable region VH of the T10E8 antibody is as follows:
  • the CDR-H1 sequence is shown in SEQ ID NO.14, SEQ ID NO.14: SYTLS
  • the CDR-H2 sequence is shown in SEQ ID NO.15, SEQ ID NO.15: YISSGGSNTYYPDTVKG
  • the CDR-H3 sequence is shown in SEQ ID NO.16, SEQ ID NO.16: QGYYRYVLYAMDY
  • the CDR division of the light chain variable region VL of the T10E8 antibody is as follows:
  • the CDR-L1 sequence is shown in SEQ ID NO.17, SEQ ID NO.17: SASSSVSHMH
  • the CDR-L2 sequence is shown in SEQ ID NO.18, SEQ ID NO.18: DTSKLAS
  • the CDR-L3 sequence is shown in SEQ ID NO.19, SEQ ID NO.19: QQWSSNPIT.
  • the monoclonal antibody is a humanized modified monoclonal antibody, which includes the heavy chain and light chain variable regions of the 59C4 antibody, or the heavy chain and light chain variable regions of the T10E8 antibody;
  • the 59C4 humanized antibody is: a humanized antibody containing the heavy chain and light chain variable regions of the 59C4 antibody and the human antibody IgG1 constant region (Fc);
  • the T10E8 humanized antibody is a humanized antibody that includes the heavy chain and light chain variable regions of the T10E8 antibody and the human antibody IgG1 constant region (Fc).
  • the invention also relates to nucleotide fragments encoding said monoclonal antibodies.
  • the present invention also relates to nucleotide fragments encoding the monoclonal antibody light chain variable region and heavy chain variable region, preferably,
  • sequence of the nucleotide fragment encoding the heavy chain variable region VH of the 59C4 antibody is shown in SEQ ID NO: 5, and the sequence of the nucleotide fragment encoding the light chain variable region VL of the 59C4 antibody is shown in SEQ ID NO. NO:7 shown;
  • sequence of the nucleotide fragment encoding the heavy chain variable region VH of the T10E8 antibody is shown in SEQ ID NO: 1
  • sequence of the nucleotide fragment encoding the light chain variable region VL of the T10E8 antibody is shown in SEQ ID NO. Shown in NO:3.
  • the present invention also relates to an antibody pharmaceutical preparation composition containing the monoclonal antibody.
  • the antibody pharmaceutical preparation composition contains a therapeutically effective amount of the monoclonal antibody and necessary pharmaceutical excipients.
  • the antibody pharmaceutical preparation composition is an antibody gel preparation, which contains: carbomer, distilled water, PBS, glycerol, ethyl paraben, 2 mg of antibody, and necessary pH regulator.
  • the antibody gel preparation contains: 12 grams of carbomer 940#, 300 ml of distilled water, 40-50 ml of 10mM PBS, 40 grams of glycerol, 4 ml of 1% ethyl hydroxyphenyl ester, 2 mg of antibody, and the pH adjustment
  • the agent is 1N sodium hydroxide.
  • the present invention also relates to a method for preparing the antibody gel preparation, which method includes the following steps:
  • the sufficient swelling at low temperature is swelling at 4°C.
  • the method is:
  • the present invention also relates to the application of the monoclonal antibody, the antibody pharmaceutical preparation composition, and the antibody gel preparation in the preparation of drugs for treating skin and/or mucosal inflammation;
  • the skin and/or mucosal inflammation is oral mucosal inflammation or vaginal inflammation.
  • the treatment of inflammation is to relieve inflammatory reactions caused by the release of inflammatory factors, such as erythema, edema, burning, pain, itching, etc.; the inflammatory factors are TNFa and/or IL-5.
  • inflammatory factors such as erythema, edema, burning, pain, itching, etc.
  • the inflammatory factors are TNFa and/or IL-5.
  • TNFa has a significant pro-apoptotic effect on L929, and the IC50 value of T10E8 antibody that inhibits the effect of TNFa is 180ng/ml.
  • IMDM incomplete medium serum-free medium IMDM (Hyclone, SH30228.01)
  • HAT complete medium IMDM containing 20% fetal calf serum plus 2% HAT (sigma, H0262),
  • Mouse fibroblast L929 Jiangsu KGI Biotechnology Co., Ltd., KG087
  • TF-1 cells a cell line for laboratory use, gifted by Teacher Yin from the School of Pharmacy of Xuzhou Medical University.
  • Actinomycin D hy-17559, MedChemExpress.
  • Carbomer 940# presented by Jiangsu Xidian Pharmaceutical Excipients Co., Ltd.
  • Inflammatory factors for immunity were purchased from Acrobiosystems, and their antigen information is as follows:
  • Recombinant human tumor necrosis factor, rhTNFa is a human tumor necrosis factor expressed in HEK293 cells. It contains the amino acid sequence Val77-Leu233 fragment (Accession#P01375-1), which induces WEH1-13VAR cytotoxicity. The half effective dose is 0.007-0.012ng/ ml (activity data see Human TNF-alpha Protein,Tag Free,low endotoxin(active trimer)(MALS verified) -ACROBiosystems ).
  • Recombinant human interleukin 5, rhIL-5a, human interleukin 5 expressed using HEK293 cells contains the amino acid sequence Ile20-Ser134 fragment (Accession#P05113-1). Immunosolid-phase IL-5 receptor ELISA analysis results show that this cell The factor can bind to the IL-5 receptor (activity data see Human IL-5 Protein, His Tag-ACROBiosystems ).
  • Each inflammatory factor was mixed in equal proportions according to the following formula, and 6-week-old BABL/c mice were immunized.
  • step (3) The third immunization is performed two weeks after the second immunization.
  • the immunization method is the same as step (2).
  • mice Ten days after the third immunization, collect the tail vein blood of the mice, centrifuge and collect the serum to measure the titer (detected by ELISA method). Mice with a titer of more than 100,000 are ready for fusion. Three days before fusion, take 25ug of antigen ( Without adjuvant), the injection volume is 200ul/animal.
  • mice were killed by neck dissection, soaked in 75% alcohol and then aseptically separated from the spleens of the mice on a clean bench, and the adhering tissues outside the spleen were separated and removed.
  • TNFa tumor necrosis factor
  • TNFa mediates L929 cell apoptosis by binding to the TNF receptor on the cell membrane. Especially in the presence of actinomycin D, this pro-apoptotic effect is more obvious, so we used the MTT method to measure L929 cell apoptosis. The rate indirectly reflects the activity of TNFa.
  • the cell apoptosis rate is positively correlated with the amount of TNF ⁇ added.
  • TNFa and anti-TNFa antibodies are added simultaneously during the culture of L929 cells.
  • the anti-TNFa antibodies specifically bind to the receptor binding site on TNFa. Since the receptor binding site on TNFa is occupied by the anti-TNFa antibody, TNFa can no longer bind to its receptor, and TNFa interrupts the pro-apoptotic pathway mediated by its receptor, thereby achieving the anti-TNFa antibody's ability to inhibit TNFa from promoting apoptosis of L929 cells. effect.
  • the neutralizing effect of anti-TNFa antibodies on TNFa activity was measured by detecting the inhibitory rate of antibodies against TNF ⁇ -promoted cell apoptosis.
  • MTT cell proliferation and toxicity detection kit (Beyotime Biotechnology, Cat. No. C0009) to determine the number of apoptotic cells. Add 10 ⁇ l MTT reagent to each well and incubate in a cell culture incubator for 8 hours. There will be varying degrees of dark purple pine needles at the bottom of the 96-well plate. So Formazan appears. Add 100 ⁇ l/well of Formazan dissolution solution and wait for 6 hours in a cell culture incubator until Formazan is completely dissolved. Use a microplate reader to measure the absorbance at 595 nm.
  • TNFa had a significant pro-apoptotic effect on L929, and adding the antibody TNFa antibody T10E8 to the culture system inhibited the apoptosis of L929 cells.
  • the IC50 value of T10E8 antibody for inhibiting TNFa is 180ng/ml ( Figure 1)
  • interleukin 5 can promote the proliferation of human erythroid leukemia tumor cells TF-1 (premyeloid cells). After adding anti-IL-5 antibodies to the culture system, the antibodies that could significantly inhibit the proliferation of TF-1 showed better neutralizing activity than the control antibodies.
  • TF-1 cells in complete culture medium RPMI-1640 (PM150110) + 2ng/ml rhGM-CSF + 10% FBS (164210-500) + 1% P/S (PB180120)
  • RPMI-1640 PM150110
  • FBS 164210-500
  • P/S 1% P/S
  • the anti-IL5 antibody 59C4 prepared in Example 1 was diluted with basal medium (RPMI1640) in freshly passaged TF-1 cells (initial concentration is 50ug/ml, 3 times gradient dilution, 10 dilutions degree) and 0.5ng/ml interleukin-5, premix and react for 2 hours at room temperature, add it to a 96-well plate where TF-1 has been passaged for 6-8 hours, set duplicate wells, and set control antibody wells.
  • basal medium RPMI1640
  • IL-5 promotes TF-1 cell proliferation
  • half effective concentration IC50 of 59C4 antibody to inhibit IL-5 activity is 800ng/ml ( Figure 2).
  • the nucleotide sequence of the antibody heavy chain variable region VH encoding gene is shown in SEQ ID NO:1, and the encoded heavy chain variable region VH amino acid sequence is shown in SEQ ID NO:2;
  • the nucleotide sequence of the gene encoding the antibody light chain variable region VL is shown in SEQ ID NO:3, and the amino acid sequence of the encoded light chain variable region VL is shown in SEQ ID NO:4;
  • the coding gene sequence of the anti-IL-5 antibody 59C4 monoclonal antibody was determined. The results are:
  • the nucleotide sequence of the antibody heavy chain variable region VH encoding gene is shown in SEQ ID NO:5, and the encoded heavy chain variable region VH amino acid sequence is shown in SEQ ID NO:6;
  • the nucleotide sequence of the gene encoding the antibody light chain variable region VL is shown in SEQ ID NO:7, and the amino acid sequence of the encoded light chain variable region VL is shown in SEQ ID NO:8.
  • amino acid sequence of the kappa chain constant region of the human antibody IgG1 constant region is:
  • amino acid sequence of the heavy chain constant region is:
  • Antibody gel composition 12 grams of carbomer 940#, 300 ml of distilled water, 40-50 ml of 10mM PBS, 10-15 ml of 1N sodium hydroxide, 40 grams of medicinal glycerin, 4 ml of 1% ethyl hydroxyphenyl ester, and 2 mg of antibody.
  • the prepared antibody gel can be packaged aseptically.
  • vaginitis There were 10 patients with vaginitis, excluding senile vaginitis and juvenile vaginitis. Patients use antibody gel two to three times a day for 5 days. The patient's itching symptoms were significantly reduced 15 minutes after applying the antibody gel, and the effect lasted for more than 4 hours.

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Abstract

L'invention concerne un anticorps pour traiter l'inflammation de la peau et des muqueuses et sa formulation. L'anticorps est un anticorps dirigé contre un facteur inflammatoire, le facteur inflammatoire étant l'interleukine 5 humaine (IL-5) ou un facteur de nécrose tumorale humain (TNFa). L'anticorps est un anticorps monoclonal dirigé contre l'interleukine 5 humaine (IL-5), comprenant une région variable de chaîne lourde (VH) ayant une séquence d'acides aminés représentée dans SEQ ID NO : 6 et une région variable de chaîne légère (VL) ayant une séquence d'acides aminés représentée dans SEQ ID NO : 8. Un anticorps monoclonal dirigé contre le facteur de nécrose tumorale humain (TNFa), comprenant une région variable de chaîne lourde (VH) ayant une séquence d'acides aminés représentée dans SEQ ID NO : 2 et une région variable de chaîne légère (VL) ayant une séquence d'acides aminés représentée dans SEQ ID NO : 4.
PCT/CN2023/088120 2022-04-15 2023-04-13 Anticorps pour traiter l'inflammation de la peau et des muqueuses et sa formulation WO2023198155A1 (fr)

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CN202380015298.0A CN118401551A (zh) 2022-04-15 2023-04-13 用于治疗皮肤及粘膜炎症的抗体及其制剂

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101177453A (zh) * 2006-11-07 2008-05-14 旭华（上海）生物研发中心有限公司 抗人肿瘤坏死因子α的重组嵌合抗体
WO2010136483A2 (fr) * 2009-05-28 2010-12-02 Glaxo Group Limited Protéines de liaison à l'antigène
CN102464718A (zh) * 2010-11-05 2012-05-23 财团法人工业技术研究院 人源化之单克隆抗体、其氨基酸序列与核苷酸序列与其用途
CN102958537A (zh) * 2010-04-07 2013-03-06 Abbvie公司 TNF-α结合蛋白
CN111303284A (zh) * 2018-12-12 2020-06-19 尚华科创投资管理（江苏）有限公司 抗人白细胞介素5(il-5)单克隆抗体及其应用
CN112745389A (zh) * 2019-10-29 2021-05-04 瑞阳(苏州)生物科技有限公司 结合人il-5的单克隆抗体及其应用
US20220098297A1 (en) * 2019-04-26 2022-03-31 Y-Biologics Inc. BISPECIFIC ANTIBODY SPECIFICALLY BINDING TO IL-17A AND TNF-Alpha

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101177453A (zh) * 2006-11-07 2008-05-14 旭华（上海）生物研发中心有限公司 抗人肿瘤坏死因子α的重组嵌合抗体
WO2010136483A2 (fr) * 2009-05-28 2010-12-02 Glaxo Group Limited Protéines de liaison à l'antigène
CN102958537A (zh) * 2010-04-07 2013-03-06 Abbvie公司 TNF-α结合蛋白
CN102464718A (zh) * 2010-11-05 2012-05-23 财团法人工业技术研究院 人源化之单克隆抗体、其氨基酸序列与核苷酸序列与其用途
CN111303284A (zh) * 2018-12-12 2020-06-19 尚华科创投资管理（江苏）有限公司 抗人白细胞介素5(il-5)单克隆抗体及其应用
US20220098297A1 (en) * 2019-04-26 2022-03-31 Y-Biologics Inc. BISPECIFIC ANTIBODY SPECIFICALLY BINDING TO IL-17A AND TNF-Alpha
CN112745389A (zh) * 2019-10-29 2021-05-04 瑞阳(苏州)生物科技有限公司 结合人il-5的单克隆抗体及其应用

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