WO2022078185A1 - Mutant d'interleukine-2 - Google Patents

Mutant d'interleukine-2 Download PDF

Info

Publication number
WO2022078185A1
WO2022078185A1 PCT/CN2021/120510 CN2021120510W WO2022078185A1 WO 2022078185 A1 WO2022078185 A1 WO 2022078185A1 CN 2021120510 W CN2021120510 W CN 2021120510W WO 2022078185 A1 WO2022078185 A1 WO 2022078185A1
Authority
WO
WIPO (PCT)
Prior art keywords
mutant
amino acid
il2rα
binding
substitution
Prior art date
Application number
PCT/CN2021/120510
Other languages
English (en)
Chinese (zh)
Inventor
赵耀
张维
彭璐佳
张建军
朱笑婷
郭建云
董明晖
Original Assignee
北京志道生物科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 北京志道生物科技有限公司 filed Critical 北京志道生物科技有限公司
Publication of WO2022078185A1 publication Critical patent/WO2022078185A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/55—IL-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/10—Cells modified by introduction of foreign genetic material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention belongs to the field of molecular biology, and particularly relates to an interleukin-2 mutant.
  • Interleukin-2 (IL-2), discovered in 1976 and then known as T cell growth factor (TCGF), is a globular glycoprotein that plays an important role in maintaining the normal function of T lymphocytes and NK cells .
  • Natural IL-2 is a polypeptide consisting of 133 amino acid residues, with a molecular weight of about 15kD, and three cysteine residues located at positions 58, 105 and 125, respectively.
  • Post-translational modifications include Thr glycosylation at position 3, and cysteine residues at positions 58 and 105 form disulfide bonds, which are mainly composed of four ⁇ -helices and some linking sequences (loops) that are essential for their function. ) composed of higher-order structures (Bazan et al., Science 257, 410-413 (1992)).
  • IL-2 is mainly produced by activated T cells, it can promote the proliferation and differentiation of T cells, maintain T cell activity; stimulate the generation, proliferation and activation of natural killer (NK) cells, and induce cytotoxic T lymphocytes (CTL) and induces and activates lymphokine-activated killer (LAK) and tumor-infiltrating lymphocytes; promotes the expression of cytokines and cytolytic molecules by T cells, and promotes the proliferation of B cells (Waldmann et al., Nat Rev Immunol 6, 595-601 (2009) )); these cells have or indirectly have the effect of killing foreign microbial infected cells and cancerous cells, so IL-2 has good antiviral, anticancer effects and wide clinical application potential.
  • NK natural killer
  • LAK lymphokine-activated killer
  • IL-2 mediates its effects by binding to the IL-2 receptor (IL2R), which consists of three subunits, ⁇ (CD25), ⁇ (CD122), and ⁇ (CD132) receptor subunits.
  • IL2R IL-2 receptor
  • ⁇ receptors are mainly expressed on the surface of T suppressor cells (Treg) and some endothelial cells (endothelial cells), while ⁇ and ⁇ receptor subunits are highly expressed on effector T cells (Teff) and NK cells.
  • T suppressor cells Te suppressor cells
  • Teff effector T cells
  • NK cells effector T cells
  • the affinity of IL-2 for the complex form of different receptor subunits is different.
  • IL-2 has the highest affinity for the complex composed of ⁇ , ⁇ and ⁇ receptor subunits.
  • the affinity of the complex composed of IL-2 is moderate (about 100-fold lower), and IL-2 can transmit signals after binding to the combination of both forms of receptor subunits (Minami et al., Annu Rev Immunol 11, 245-268 ( 1993)).
  • IL-2 can transmit signals after binding to the combination of both forms of receptor subunits (Minami et al., Annu Rev Immunol 11, 245-268 ( 1993)).
  • High doses of IL-2 can neutralize the immunosuppression caused by Treg activation by activating a large number of effector T cells, and at the same time, there will be more toxic side effects, as well as activation induced cell apoptosis.
  • IL-2 aldesleukin
  • VLS is caused by the expression of high-affinity receptors ( ⁇ , ⁇ and ⁇ subunits) of IL-2 on endothelial cells (Krieg et al., Proc Nat Acad Sci USA 107, 11906-11 (2010)), so attenuation or elimination of Alpha receptor binding will reduce the function of IL-2 to promote T-suppressive cell proliferation activity, and also reduce the binding to endothelial cell alpha receptors, thereby reducing or eliminating the toxic and side effects caused by IL-2 therapy.
  • high-affinity receptors ⁇ , ⁇ and ⁇ subunits
  • Alpha receptor binding will reduce the function of IL-2 to promote T-suppressive cell proliferation activity, and also reduce the binding to endothelial cell alpha receptors, thereby reducing or eliminating the toxic and side effects caused by IL-2 therapy.
  • the binding sites of IL-2 and ⁇ receptor subunits are mainly at amino acid positions 37, 38, 41, 42, 43, 44, 45, 61, 62, 65, 68 and 72 (Rickert.M et al. (2005). )Science 308:1477-1480), Merck and Roche or other scientific institutions made some mutations around these IL-2 surface amino acids that bind to ⁇ receptor subunits, such as Merck's mutants (R38W, F42K, WO2008003473A2) , reducing the interaction with the alpha receptor subunit to achieve effector T cell activation to enhance efficacy; while Roche's IL-2 mutants (F42A, Y45A and L72G, US 2016/0208017A1), which do not interact with alpha receptors Binding and, but can normally bind to ⁇ and ⁇ receptor subunits, and can exert effects, is currently in clinical practice.
  • reducing or eliminating the interaction of IL-2 with the alpha receptor subunit may be an important aspect of treatment efficacy and reducing the side effects of treatment in cancer patients.
  • the technical problem to be solved by the present invention is to provide an IL-2 mutant with reduced binding to high-affinity receptors.
  • a first aspect of the present invention provides an IL-2 mutant.
  • IL-2 On the basis of IL-2, one or more mutations of substitution, deletion and addition of amino acid sites related to IL2R ⁇ binding are performed to obtain An IL-2 mutant with reduced binding ability to IL2R ⁇ ; wherein, the amino acid sites related to IL2R ⁇ binding are positions 30-75 of wild-type IL-2.
  • the amino acid site related to the binding of IL2R ⁇ is positions 35-75 of wild-type IL-2; alternatively, the amino acid site related to the binding of IL2R ⁇ is positions 37-75 of wild-type IL-2.
  • substitution and addition of amino acid residues that select mutations that can make the IL-2 mutant structure tend to be stable and/or less energetic.
  • one or more mutations of substitutions, deletions and additions are made to one or more amino acids in positions 35-45.
  • amino acids at positions 35-37 and 41-43 were substituted, and amino acids at positions 38-40 were deleted.
  • amino acid at position 45 was also substituted.
  • amino acid position 35 is replaced by K35G or K35M; amino acid position 36 is replaced by L36G or L36H; amino acid position 37 is replaced by T37G; amino acid position 41 is replaced by T41G or T41L; amino acid position 42 is replaced by T41G or T41L
  • substitution of amino acid is F42G or G42D; the substitution of amino acid 43 is K43G; the substitution of amino acid 45 is Y45G.
  • substitutions, deletions and additions are made to one or two amino acids in positions 31-32.
  • amino acids at positions 31-32 were substituted.
  • the 31st amino acid is replaced by Y31G; the 32nd amino acid is replaced by K32G.
  • cysteine at position 125 is also mutated to an amino acid with a smaller side chain.
  • amino acids with smaller side chains include alanine and glycine.
  • amino acid sequence of the wild-type IL-2 is shown in SEQ ID NO.1.
  • amino acid sequence of the IL-2 mutant is shown in SEQ ID NO.3-7.
  • a second aspect of the present invention provides an isolated polynucleotide encoding an IL-2 mutant as described above.
  • a third aspect of the present invention provides an expression vector comprising an isolated polynucleotide as described above.
  • a fourth aspect of the present invention provides a host cell comprising an isolated polynucleotide as described above.
  • a fifth aspect of the present invention provides a composition comprising the IL-2 mutant as described above and a pharmaceutically acceptable carrier.
  • the sixth aspect of the present invention provides the use of the IL-2 mutant as described above in the manufacture of a medicament or a preparation for treating a disease.
  • a seventh aspect of the present invention provides the use of an IL-2 mutant as described above in the manufacture of a composition for stimulating the immune system of an individual.
  • An eighth aspect of the present invention provides a method of producing an IL-2 mutant, the method comprising culturing a host cell as described above under conditions suitable for expressing the IL-2 mutant.
  • IL-2 mutant of the present invention one or more mutations of substitution, deletion and addition of amino acid sites related to IL2R ⁇ binding in IL-2 are performed, thereby reducing the binding with IL2R ⁇ , and can also increase IL-2R ⁇ binding. 2
  • the IL-2 mutant in the present invention is a new direction for reducing VLS or reducing or eliminating the toxic and side effects caused by IL-2 treatment.
  • Figure 1 is a schematic diagram of the three-dimensional structure of IL-2 and IL2R ⁇ (PDB ID 2b5i).
  • Fig. 2 is the sequence comparison diagram (part) of IL-2 mutant and IL-2wt C125A in the embodiment of the present invention.
  • Fig. 3 is an SDS-PAGE electropherogram of IL-2 mutants in the examples of the present invention.
  • “reduction” means adding the reducing agent 2-mercaptoethanol to the loading buffer;
  • “non-reducing” means not adding the reducing agent 2-mercaptoethanol to the loading buffer.
  • FIG. 4 is a CTLL2 cell proliferation experiment of IL-2 mutants in the examples of the present invention.
  • the relative amino acid positions of IL-2 mutants and wild-type IL-2 are calculated based on the amino acid sequence of wild-type IL-2 (such as SEQ ID NO. 1).
  • the nucleotide sequence of wild-type IL-2 is shown in SEQ ID NO.2.
  • IL2R ⁇ refers to interleukin-2 receptor ⁇ , also known as “ ⁇ receptor subunit”
  • IL2R ⁇ refers to interleukin-2 receptor ⁇ , also known as “ ⁇ receptor subunit”
  • IL2R ⁇ refers to interleukin-2 receptor ⁇ , also known as “ ⁇ receptor subunit”
  • IL2R ⁇ refers to interleukin-2 receptor ⁇ , also known as “ ⁇ receptor subunit”
  • IL2R ⁇ refers to the complex formed by interleukin-2 receptor ⁇ and receptor ⁇ , also known as " ⁇ and ⁇ receptor”. body subunit complex”.
  • mutation includes substitutions, deletions and additions to amino acids.
  • the amino acid sites in IL-2 that are related to the binding of IL2R ⁇ , that is, positions 30-75 are mutated.
  • the base sequence for mutation can be IL-2 wild type, or it can be 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, Sequences of 95%, 96%, 97%, 98%, 99% and more than 99% homology.
  • one or more of substitutions, deletions and additions are made to one or more of amino acids at positions 35-45 to reduce binding of the IL-2 mutant to IL2R ⁇ .
  • one or more of substitutions, deletions and additions are made to one or more of amino acids 31-32 and 35-45 to reduce the interaction of the IL-2 mutant with IL2R ⁇ . combine.
  • IL-2 is located at the 37th, 38th, 41st, 42nd, 43rd, 44th, 45th, 61st, 62th, 65th, 68th and 72nd amino acid positions and IL2R ⁇ . Therefore, through bioinformatics and protein engineering design, mutations, deletions, and additions were performed at the 30th to 75th amino acids to change the binding of IL-2 to IL2R ⁇ .
  • amino acid sequences of the obtained IL-2 mutants are shown in Table 1:
  • Expression hosts can be E. coli or mammalian cells.
  • IL-2wt(C125A) and the mutant were expressed respectively, and purified and prepared relying on the HPC4 tag carried at the C-terminal of the molecule.
  • IL-2wt C125A, SEQ ID NO.1
  • DH10B was transformed, sequenced and maintained to obtain the desired IL-2 wild-type and mutant plasmids.
  • IL-2wt (C125A) and IL-2 mutant were prepared.
  • G418 solution Weigh 250mg Geneticin TM , add 4.5ml ultrapure water to dissolve, dilute to 5ml ultrapure water, filter with 0.22um membrane, store at -20°C
  • PEI solution Weigh 50mg PEI, add 45ml ultrapure water to dissolve, adjust pH to 7.0 with 1M NaOH, dilute to 50ml ultrapure water, filter with 0.22um membrane, and store at -20°C
  • Plasmids were prepared in advance in 2 ml endotoxin-depleted centrifuge tubes.
  • Solution A Plasmid 1 ⁇ g/mL + Opti-MEM TM 33.3ul/mL
  • Liquid B PEI 2 ⁇ g/mL+Opti-MEM TM 33.3ul/mL
  • the cell supernatant was collected by centrifugation at 8500 rpm for 15 min.
  • IL-2wt(C125A) and IL-2 mutants are C-terminally tagged with HPC4 and can therefore be affinity purified using HPC4 antibody-conjugated media followed by gel filtration chromatography (superdex200) for further purification The protein with higher purity was obtained. After purification, it was estimated that the expression level of IL-2wt C125A was ⁇ 9.9 mg/L, and the expression levels of 384 and 386 were 18.6 mg/L and 19.6 mg/L, respectively. SDS-PAGE analysis was performed according to the method described in "Molecular Cloning", and the results are shown in Figure 3.
  • the proteins used in the experiments were all produced by our company, and IL2R ⁇ -his, IL2R ⁇ -Fc/Fc and IL2 mutants were obtained by transient expression and affinity purification of HEK293.
  • Buffer formulation (10 mM HEPES, 150 mM NaCl, 3 mM EDTA, 0.1% BSA and 0.05% Tween 20); ProA sensor (Pall Fortebio, Catalog #18-5010); HISIK sensor (Pall Fortebio, Catalog #18) -5120); BLI equipment is Octet RED96 produced by Pall Fortebio Company; Data acquisition and analysis work were carried out with Data acquisition 11.0 and Data analysis 11.0 software respectively.
  • IL2R ⁇ -Fc/Fc was diluted with buffer to a concentration of 10ug/ml, added to the second column of the 96-well assay plate, and the control program was set to Loading, 600s.
  • the IL2 mutant was diluted to 100nM with buffer, then 1:1 serially diluted down 6 gradients (7 gradients in total) to a concentration of 1.625nM and a concentration of 0, added to the 96-well assay plate 5-9 columns, respectively, control program Medium is set to Association, 200s. Buffer was added to columns 1, 4, 10, and 11 of the 96-well assay plate, and glycine with pH 1.7 was added to column 12. The sample volumes of the above samples and solutions were both 200ul.
  • CTLL-2 T cell
  • the proliferation assay of CTLL-2 is a commonly used assay to measure the activity of interleukin-stimulated immune cells at the cellular level. Therefore, the biological activity of IL-2 mutants was examined here by proliferation experiments of CTLL-2 cells.
  • CTLL-2 cells Resuspend the cells in culture medium containing FBS and Rat-T-Stim.
  • MTS addition add 20 ⁇ l to each well AQueous One Solution Reagent, 37 degrees, 5% CO 2 incubate for 2 to 4 hours.

Abstract

La présente invention divulgue un mutant d'IL-2. Sur la base de l'IL-2 humaine, les sites d'acides aminés associés à une liaison à l'IL2Rα sont soumis à une ou plusieurs mutations par substitution, délétion et addition pour obtenir un mutant d'IL-2 présentant une capacité de liaison réduite à l'IL2Rα, les sites d'acides aminés associés à la liaison à l'IL2Rα étant les positions 30 à 75 de l'IL-2 de type sauvage. L'interaction entre le mutant d'IL-2 de la présente invention et l'IL2Rα est réduite et la quantité d'expression est augmentée.
PCT/CN2021/120510 2020-10-18 2021-09-25 Mutant d'interleukine-2 WO2022078185A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202011114023.7 2020-10-18
CN202011114023 2020-10-18
CN202110597623.1 2021-05-31
CN202110597623.1A CN114369153A (zh) 2020-10-18 2021-05-31 一种白介素-2突变体

Publications (1)

Publication Number Publication Date
WO2022078185A1 true WO2022078185A1 (fr) 2022-04-21

Family

ID=81138691

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/120510 WO2022078185A1 (fr) 2020-10-18 2021-09-25 Mutant d'interleukine-2

Country Status (2)

Country Link
CN (1) CN114369153A (fr)
WO (1) WO2022078185A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2022320553A1 (en) * 2021-07-30 2024-02-01 Yunquan Biotechnology (Beijing) Co., Ltd. Human interleukin-2 variant and use thereof
CN117903283A (zh) * 2022-10-19 2024-04-19 北京志道生物科技有限公司 一种il-2突变体

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009061853A2 (fr) * 2007-11-05 2009-05-14 Massachusetts Institute Of Technology Polypeptides d'interleukine-2 (il-2) mutants
CN103492411A (zh) * 2011-02-10 2014-01-01 罗切格利卡特公司 突变体白介素-2多肽
TN2013000151A1 (en) * 2011-11-10 2014-11-10 Centro Inmunologia Molecular Polypeptides derived from il-2 having agonist activity for the therapy of cancer and chronic infections
CN104231068A (zh) * 2014-01-27 2014-12-24 苏州发士达生物科技有限公司 人白细胞介素ii突变体及其应用
CN111018961A (zh) * 2019-12-17 2020-04-17 北京志道生物科技有限公司 白介素-2衍生物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009061853A2 (fr) * 2007-11-05 2009-05-14 Massachusetts Institute Of Technology Polypeptides d'interleukine-2 (il-2) mutants
CN103492411A (zh) * 2011-02-10 2014-01-01 罗切格利卡特公司 突变体白介素-2多肽
TN2013000151A1 (en) * 2011-11-10 2014-11-10 Centro Inmunologia Molecular Polypeptides derived from il-2 having agonist activity for the therapy of cancer and chronic infections
CN104231068A (zh) * 2014-01-27 2014-12-24 苏州发士达生物科技有限公司 人白细胞介素ii突变体及其应用
CN111018961A (zh) * 2019-12-17 2020-04-17 北京志道生物科技有限公司 白介素-2衍生物

Also Published As

Publication number Publication date
CN114369153A (zh) 2022-04-19

Similar Documents

Publication Publication Date Title
WO2021120350A1 (fr) Dérivé d'interleukine-2
CN110437339B (zh) 一种以白介素15为活性成分的融合蛋白型药物前体
Nagem et al. Crystal structure of recombinant human interleukin-22
CA2814814C (fr) Polypeptides derives de l'il-2 presentant une activite agoniste pour le traitement du cancer et des infections chroniques
WO2022078185A1 (fr) Mutant d'interleukine-2
EP3047024B1 (fr) Compositions et méthodes destinées à traiter les maladies et les troubles auto-immuns et inflammatoires
EP0955365A2 (fr) Cristallisation du M-CSF
PT1076704E (pt) Agonistas e antagonistas selectivos da il-2
CN112724259B (zh) 人血清白蛋白与白介素2的融合蛋白及其用途
BRPI0517932B1 (pt) Muteína humana de beta-interferon, polinucleotídeo, vetor de expressão, célula animal, método para preparação de referida muteína e composição farmacêutica compreedendo a mesma
ES2255067T3 (es) Receptores para la interleucina-12 humana.
PT767796E (pt) Proteina quimiotactica
EP3901167A1 (fr) Nouvelle interleukine 2 immunosuppressive
ES2320743T3 (es) Mutantes de quimiocina que actuan como antagonistas de quimiocinas.
KR20180038553A (ko) 질환 및 장애를 치료하기 위한 인터류킨-10을 사용하는 방법
JP2003047483A (ja) インターロイキン−６スプライス変異体
ES2627816T3 (es) Variantes del pro-dominio de tace como inhibidor de TNF-a y su uso médico
JP2008154583A (ja) インターロイキン−１関連遺伝子およびタンパク質
KR20240004453A (ko) 변형된 과립구 집락-자극 인자(g-csf) 및 이에 결합하는 키메라 사이토카인 수용체
WO2011147320A1 (fr) Antagoniste du facteur d'activation des lymphocytes b et son procédé de préparation et son utilisation
WO2024046280A1 (fr) Dérivé d'il-21 modifié par du polyéthylène glycol et son utilisation
CN117384273A (zh) 一种聚乙二醇修饰的il-2衍生物及其应用
CN114380919A (zh) 经修饰的il-2分子及其用途
KR20230095612A (ko) 신규 면역 억제 인터루킨 2 (Interleukin 2) 아날로그
CN115947820A (zh) 一种水溶性提高的il-2衍生物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21879231

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21879231

Country of ref document: EP

Kind code of ref document: A1