WO2008135259A2 - Composition de molécules d'anticorps - Google Patents
Composition de molécules d'anticorps Download PDFInfo
- Publication number
- WO2008135259A2 WO2008135259A2 PCT/EP2008/003586 EP2008003586W WO2008135259A2 WO 2008135259 A2 WO2008135259 A2 WO 2008135259A2 EP 2008003586 W EP2008003586 W EP 2008003586W WO 2008135259 A2 WO2008135259 A2 WO 2008135259A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- antibody molecule
- antibody
- cells
- heavy chain
- variable
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title description 11
- ZJPGOXWRFNKIQL-JYJNAYRXSA-N Phe-Pro-Pro Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=CC=C1 ZJPGOXWRFNKIQL-JYJNAYRXSA-N 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 22
- 239000013598 vector Substances 0.000 description 9
- 229960005395 cetuximab Drugs 0.000 description 8
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 6
- 230000009450 sialylation Effects 0.000 description 6
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 5
- 239000002299 complementary DNA Substances 0.000 description 5
- 230000009089 cytolysis Effects 0.000 description 5
- 239000012636 effector Substances 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 108090001090 Lectins Proteins 0.000 description 4
- 102000004856 Lectins Human genes 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 239000002523 lectin Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 125000005629 sialic acid group Chemical group 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 229950010131 puromycin Drugs 0.000 description 3
- 230000002269 spontaneous effect Effects 0.000 description 3
- 238000001890 transfection Methods 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- 229910052693 Europium Inorganic materials 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 102000005348 Neuraminidase Human genes 0.000 description 2
- 108010006232 Neuraminidase Proteins 0.000 description 2
- 239000000020 Nitrocellulose Substances 0.000 description 2
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 239000012228 culture supernatant Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004520 electroporation Methods 0.000 description 2
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 229920001220 nitrocellulos Polymers 0.000 description 2
- 239000012679 serum free medium Substances 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 241000533316 Acanthis flammea Species 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- 101100022253 Aedes aegypti MAL1 gene Proteins 0.000 description 1
- 101150074155 DHFR gene Proteins 0.000 description 1
- 230000004544 DNA amplification Effects 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 108020005067 RNA Splice Sites Proteins 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000005889 cellular cytotoxicity Effects 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 229940082789 erbitux Drugs 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- LNYNHRRKSYMFHF-UHFFFAOYSA-K europium(3+);triacetate Chemical compound [Eu+3].CC([O-])=O.CC([O-])=O.CC([O-])=O LNYNHRRKSYMFHF-UHFFFAOYSA-K 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229960003330 pentetic acid Drugs 0.000 description 1
- 210000004976 peripheral blood cell Anatomy 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- 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
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
- C07K2317/41—Glycosylation, sialylation, or fucosylation
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
Definitions
- Antibody molecule composition
- the cDNA sequence was extended by Ncol/Nhel in the case for the VL and Ncol/Sall in the case of the VH and the cDNA was generated.
- the NcoI/Sall-cut variable heavy chain cDNA fragment VH was cloned into the Ncol/Sall- cut BS-Leader vector as described in WO2004/065423.
- the BS-Leader vector includes a cloning cassette to introduce the T cell receptor signal peptide sequence at the 5' end and a splice donor sequence at the 3' end of the variable domains.
- variable light chain VL of the corresponding antibody was designed with an additional splice donor site at the 3 'end of the coding cDNA and was cloned via Ncol/Nhel into the likewise digested BS-Leader vector. Thereafter, each Hindlll/BamHI fragment from the BS- Leader vector was cloned into the corresponding eukaryotic expression vector.
- vectors (pEFpuroC ⁇ lV H , pEFdhfrCicVu pEFdhfr mu tC ⁇ V L ) comprise EF-l ⁇ -promoter and HCMV enhancer, SV40 origin, polyadenylation signal, puromycin resistance gene in the vector for the heavy chain and the murine dihydrofolase gene (dhfr) for CHO cell expression or SEQ ID No 1
- EEKGIKYKFEVYEKKD SEQ ID No 1) for NM-F9, K562, NM-H9, NM-D4, or NM- H9D8 expression for selection and gene amplification in the vector for the light chain, as well as the genomic sequences of the human constant ⁇ l region for the heavy chain or the human constant K region for the light chain.
- Variable Heavy chain SEQ ID No 1) for NM-F9, K562, NM-H9, NM-D4, or NM- H9D8 expression for selection and gene amplification in the vector for the light chain, as well as the genomic sequences of the human constant ⁇ l region for the heavy chain or the human constant K region for the light chain.
- CHOdhfr- ATCC No. CRL-9096 cells were co-transfected with a mixture of above described vectors for the heavy and light chains (1 :1 to 1 :3) by lipofectamin or electroporation for the adherent cell line.
- growth medium was changed to selection medium (DMEM + 10% dialysed FCS + 2 mM L- glutamine + 5 ⁇ g/ml puromycin + 50 mM methotrexate) for 1 week.
- selection medium DMEM + 10% dialysed FCS + 2 mM L- glutamine + 5 ⁇ g/ml puromycin + 50 mM methotrexate
- NM-H9D8 (DSM ACC2806) and NM-F9 (DSM ACC2606), adapted to serum-free medium X-Vivo 20 was performed under serum-free conditions using electroporation. Two days post-transfection, growth medium was changed to selection medium (X- Vivo 20 + 0.75 ⁇ g/ml puromycin + 50 nM methotrexate) for 1 week.
- the stably transfected cells secreting the Cetuximab were cultivated in serum free medium until a cell density of about 1 to 2 x 10 6 cells/ml was reached.
- the chimeric antibody was purified using a protein A column (HiTrap r-protein A FF, Amersham Pharmacia Biotech).
- the purified antibody fraction eluted by sudden pH change was re-buffered in PBS and concentrated using Centriprep centrifuge tubes (cut off 50 kDa, Millipore).
- PBMC peripheral blood mononuclear cells
- ADCC antibody-dependent cellular cytotoxicity
- Target cells (LS174T, 3 x 10 6 ) were incubated for 6 minutes on ice in 100 ⁇ l of europium buffer (50 mM HEPES, pH 7.4, 93 mM NaCl, 5 mM KCl, 2 mM MgCl 2 , 10 mM diethylenetriaminepentaacetic acid, 2 mM europium(III)acetate), electroporated in a Nucleofector II (Amaxa) with program A-OI l , and subsequently incubated on ice for another 6 min.
- europium buffer 50 mM HEPES, pH 7.4, 93 mM NaCl, 5 mM KCl, 2 mM MgCl 2 , 10 mM diethylenetriaminepentaacetic acid, 2 mM europium(III)acetate
- the cells were washed 5 times in RPMI 1640/5% FCS and seeded in a 96- well round-bottom plate (Nunc; 5 x 10 3 cells in 100 ⁇ l per well).
- a 96- well round-bottom plate (Nunc; 5 x 10 3 cells in 100 ⁇ l per well).
- human peripheral blood cells 80 ⁇ l per well were added as effector cells, using an effector/target cell ratio of 80:1.
- 80 ⁇ l RPMI/FCS with no effector cells was added to determine spontaneous release. Maximum release was determined after complete lysis of the target cells with 1% Triton X-100.
- the ADCC activity of the Cetuximab isolated from NM-H9D8 is significantly higher than the ADCC activity of the Cetuximab isolated from the CHOdhfr- cells.
- Glycans of at least lOO ⁇ g purified antibody were cleaved by acid hydrolysis.
- Sialic acids were labelled specifically by conjugation with the fluorescence dye DMB.
- Analysis was performed by HPLC e.g. on an Asahipak-NH2 column to separate the saccharides. Identification and calculation of sialic acids was performed by standard substances of appropriate sialic acids.
- Lectins which bind preferentially to alpha2-6 or alpha2-3 linked sialic acids were used to characterize the antibody sialylation by ELISA or Western blot analysis.
- ELISA experiments were performed by coating the purified antibodies expressed in the different cell lines in wells of microtiter plates (2 ⁇ g/ml, 50 ⁇ l per well) and detecting by appropriate biotinylated lectins.
- Dependence of lectin binding by sialylation was checked by neuraminidase treatment (0.1U/ml and incubation at room temperature for lhour). Results are illustrated in figure 1 and/or 2.
- Cetuximab and Erbitux are used as synonyms and mean both the antibody variable sequences of light and heavy chain accessible in public data bases independent of the cell or cell line producing the antibody.
- Figure legends are used as synonyms and mean both the antibody variable sequences of light and heavy chain accessible in public data bases independent of the cell or cell line producing the antibody.
- FIG. 1 ELISA analysis was performed to identify the differently sialylated antibody molecule compositions expressed in CHOdhfr-, NM-F9, or NM-H9D8. Sialylation was analysed (A) by SNA which detects alpha2-6 sialylation with or without neuraminidase treatment and (B) by MAL I which detects alpha2-3 sialylation.
- FIG. 2 Western blot analysis was performed to identify the differently sialylated heavy chain of antibody molecule compositions expressed in CHOdhfr- or NM-H9D8. Proteins were transfered to nitrocellulose and visualized by SNA which detects 2-6 sialylation.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oncology (AREA)
- Biophysics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Peptides Or Proteins (AREA)
Abstract
L'invention concerne un anticorps comprenant au moins une chaîne lourde variable et une chaîne légère variable. La chaîne lourde variable est: QVQLKQSG PGLVQPSQSLS ITCTVSGFSLTNYGVHWVRQS PGKGLEWLGVIWS GGNTDYN TPFTSRLSiNKDNSKSQVFFKMNSLQSH Γ;TAI Y YCARALT YYDYEFAYWGQGTLVTVSTASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS 7YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQ QGNVFSCSVMHEGLHNHYTQKSLSLSPGK; et/ou la chaîne légère variable est: DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTKGSPRLLIKYASESISGIPS RFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFI FPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP07090094 | 2007-05-04 | ||
EP07090094.9 | 2007-05-04 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2008135259A2 true WO2008135259A2 (fr) | 2008-11-13 |
WO2008135259A3 WO2008135259A3 (fr) | 2009-04-09 |
Family
ID=39944059
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2008/003586 WO2008135259A2 (fr) | 2007-05-04 | 2008-05-05 | Composition de molécules d'anticorps |
Country Status (1)
Country | Link |
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WO (1) | WO2008135259A2 (fr) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106470697A (zh) * | 2014-09-16 | 2017-03-01 | 依姿魅力有限公司 | 抗egfr抗体以及其用途 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2450289A1 (fr) * | 2003-03-20 | 2005-05-19 | Imclone Systems Incorporated | Methode de production d'un anticorps ciblant le recepteur du facteur de croissance epidermique |
US20070148170A1 (en) * | 2005-10-03 | 2007-06-28 | Desjarlais John R | Fc Variants With Optimized Fc Receptor Binding Properties |
US20050142133A1 (en) * | 2003-12-03 | 2005-06-30 | Xencor, Inc. | Optimized proteins that target the epidermal growth factor receptor |
JP4913604B2 (ja) * | 2004-02-13 | 2012-04-11 | グリコトープ ゲーエムベーハー | 高活性糖タンパク質−製造条件、及びその効率的製造方法 |
JP5767779B2 (ja) * | 2006-09-10 | 2015-08-19 | グリコトープ ゲーエムベーハー | 抗体の発現のための骨髄白血病起源のヒト細胞の使用 |
-
2008
- 2008-05-05 WO PCT/EP2008/003586 patent/WO2008135259A2/fr active Application Filing
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106470697A (zh) * | 2014-09-16 | 2017-03-01 | 依姿魅力有限公司 | 抗egfr抗体以及其用途 |
EP3110447A4 (fr) * | 2014-09-16 | 2017-08-23 | Ease Charm Limited | Anticorps anti-egfr et leurs utilisations |
CN106470697B (zh) * | 2014-09-16 | 2019-10-25 | 兴盟生物医药(苏州)有限公司 | 抗egfr抗体以及其用途 |
US10759860B2 (en) | 2014-09-16 | 2020-09-01 | Synermore Biologics Co., Ltd. | Anti-EGFR antibody and uses of same |
Also Published As
Publication number | Publication date |
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WO2008135259A3 (fr) | 2009-04-09 |
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