EP2558489A1 - Protéine de fusion robo1-fc et son utilisation dans le traitement des tumeurs - Google Patents

Protéine de fusion robo1-fc et son utilisation dans le traitement des tumeurs

Info

Publication number
EP2558489A1
EP2558489A1 EP11719346A EP11719346A EP2558489A1 EP 2558489 A1 EP2558489 A1 EP 2558489A1 EP 11719346 A EP11719346 A EP 11719346A EP 11719346 A EP11719346 A EP 11719346A EP 2558489 A1 EP2558489 A1 EP 2558489A1
Authority
EP
European Patent Office
Prior art keywords
protein
robo1
slit
seq
robol
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP11719346A
Other languages
German (de)
English (en)
French (fr)
Inventor
Francis Blanche
Béatrice Cameron
Tarik Dabdoubi
Frédérique DOL-GLEIZES
Pierre Fons
Jean-Pascal Herault
Catherine Prades
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi SA
Original Assignee
Sanofi SA
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=42830780&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP2558489(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Sanofi SA filed Critical Sanofi SA
Publication of EP2558489A1 publication Critical patent/EP2558489A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • 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
    • C07K14/475—Growth factors; Growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/01—Hydrolysed proteins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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

Definitions

  • the extracellular domain of the Robol isoform b protein consists of the Ig1 and Ig2 domains. These domains correspond to the peptide of SEQ ID NO.2 encoded by the nucleotide sequence SEQ ID NO.1, or a sequence exhibiting at least 80%, 85%, 90%, 95% or 99% identity with the SEQ ID sequences. NO.2.
  • Another aspect of the invention is the use of a Robo1-Fc molecule as a diagnostic tool for detecting overexpression of a Slit family molecule in a patient. Indeed, it has been shown that the Slit pathway is involved in many cancers. The provision of a test to evaluate a deregulation of the Slit signaling pathway is very useful in order to select patients likely to respond to a treatment based on the administration of a Robo1-Fc molecule.
  • This diagnostic tool may be in the form of a ready-to-use kit, comprising a Robo1-Fc molecule in a form adapted to its contact with a biological sample of a patient (blood, urine, tumor biopsy) susceptible to overexpress a Slit molecule.
  • the cDNA corresponding to the D1-D2 domains was cloned into the eukaryotic expression vector pXL4912 in order to express these two domains containing a Histag in the C-terminal position.
  • the cDNA sequence used to express this recombinant protein corresponds to the sequence SEQ ID NO.13.
  • the recombinant protein obtained is named Slit-2-D1 D2 and corresponds to the protein sequence SEQ ID NO.14.
  • the cDNA coding for the human Slit1 protein corresponds to the reference protein described NP_003052.
  • a fragment of this cDNA was amplified by PCR from the human brain cDNA library (Ref 639300, Clontech).
  • the cDNA corresponding to the D2 domain was cloned into the eukaryotic expression vector pXL5020 in order to express this domain containing a Histag in the C-terminal position.
  • the cDNA sequence used to express this recombinant protein corresponds to the sequence SEQ ID NO.19.
  • the recombinant protein obtained is named Slit-1 -D2 and corresponds to the protein sequence SEQ ID NO.20.
  • Example 3 Study of the affinity of recombinant Robo1-Fc proteins for Slit proteins and for heparin using three methods: ELISA, SPR and FACS a. Affinity of Robo1-Fc proteins for heparin
  • the human protein Slit2-D2 was fixed on lmmulon-4 enzyme-linked plates (VWR Scientific Inc. Swedesboro, NJ). A concentration range (from 20 ⁇ g ml to 0.02 ⁇ g ml) of the Robo1-Fc L1 and Robo1-Fc L2 variants was added and then detected using peroxidase-conjugated goat anti-human IgG antibody (Sigma, ref. A0170-1: 50000 dilution). Revelation was performed with the TMB-H 2 0 2 substrate (Interchim ref # UP664780) and measurements with the 450 nm plate reader. The results obtained are reported in FIG. 2.
  • the Robo1-Fc Slit-2-less protein has no affinity to heparin and is therefore a negative heparin mutant. d. Evaluation of the interaction of the Robo1-Fc protein with murine Slit-2 protein
  • This example describes the interaction of the Robo1-Fc L1 fusion protein with the murine mSlit-2-D2 protein by ELISA assay.
  • the murine mSlit-2-D2 protein was fixed on a lmmulon-4 enzyme-linked box (VWR Scientific Inc. Swedesboro, NJ).
  • a concentration range (from 2 ⁇ g mL to 0.002 ⁇ g mL) of the Robo1-Fc L1 fusion protein was added and then detected by the peroxidase-conjugated goat anti-human IgG antibody (Sigma, ref A0170- dilution to 1: 50000).
  • Revelation was performed with the TMB-H 2 0 2 substrate (Interchim ref # UP664780) and measurements with the plate reader at 450 nm. The results obtained are reported in Table 4 below.
  • This example describes the determination of the affinity constant of the Robo1-Fc L1 fusion protein with human Slit-2 protein (in this Slit-2-D2 experiment) by SPR (Surface Plasmon Resonance, BIAcore 2000).
  • SPR Surface Plasmon Resonance, BIAcore 2000.
  • the interaction between the Robo1-Fc protein and the human Slit2 protein was analyzed after attaching the Robo1-Fc fusion protein to a CM5 chip.
  • the kinetic measurements are carried out according to the protocol of Canziani et al., 2004.
  • Table 5 Robo-Fc Ll affinity constant with human Slit2-D2 by SPR (steady-state analysis)
  • the cells were plated into a 96-well plate 48 hours post-transfection, and the Robo1-Fc protein was added in a range of 0.01 to 3 mg / L for 30 minutes at 4 ° C.
  • the Robo1-Fc protein is either the Robo-Fc L1 bio-therapeutic agent, or the Robo1-Fc Slit-2-less mutant, or the Robo1-Fc Heparin-less mutant.
  • the cells were washed and the Alexa 488-labeled human anti-Fc antibody (ref: A-1 1013, Invitrogen) was incubated for 30 min at 4 ° C. Then the labeled HEK293 cells are quantified by FACS (Geomean).
  • Figure 3 depicts binding of HEK293 cells to Robo1-Fc protein via fluorescence measured in FACS in the absence of Slit-2 expression.
  • the Robo1-Fc protein and the Robo1-Fc Slit-2-minus mutant bind to the HEK293 cells while the Robo1-Fc Heparin-min mutant does not bind.
  • Robo1-Fc therefore binds in part to HEK293 cells via heparin binding at low concentrations of Robo1-Fc of 0.3 to 0.03 mg / L.
  • Figure 4 depicts binding of HEK293 cells to Robo1-Fc protein via fluorescence measured in FACS when Slit-2-N is expressed by transient transfection. Only the Robo1-Fc protein binds to HEK293 cells expressing Slit-2N. The Robo1-Fc Slit-2-minus and Robo1-Fc Heparin-min mutants do not bind (or almost no) in the range of Robo1-Fc 3.0 to 0, 3 mg / L compared to the Robo1-Fc L1 biotherapeutic protein.
  • Table 7 describes the FACS measured affinity constants of the Robo1-Fc protein when the Slit-2-N, Slit-2-D1 D2 or Slit-2-D2 proteins are expressed in the HEK293 line.
  • the Robo1-Fc Slit-2-minus mutant was found to be Slit-2 negative and the Robo1-Fc Heparin-min mutant has a lower affinity for Slit2 than the bio-therapeutic protein.
  • Robo1-Fc binds to Slit-2-N and Slit-2-D1 D2 expressed by HEK293 cells with comparable affinities that are better than that with Slit-2-D2.
  • This example describes the pharmacokinetic profile and plasma concentration of the Robo1-Fc protein injected once in intravenous (iv) mice.
  • the mice were anesthetized, blood was collected and collected in a tube containing 10 ⁇ l of citrate (CPD-A, C). -4431 Sigma) and 2 ⁇ of protease inhibitors (Complete Protease Inhibitor Mix, Roche Molecular Biochemical).
  • the tubes were centrifuged and the plasma samples were collected and frozen at -20 ° C.
  • the Slit2 protein (Slit-2-D2) was coated in the wells of the 96-well dishes, the plasma samples diluted to 1/5000 and 1/20000 were contacted for one hour at 37 ° C.
  • the anti-human Fc antibodies conjugated to peroxidase (ref. 31413, Pierce) was then incubated and revealed with TMB-H 2 0 2 (ref UP664780, Interchim) and the absorbance was read at 450 nm.
  • a standard range was made with each purified Robo1-Fc protein.
  • the plasma concentrations of the Robo1-Fc L1 and Robo1-Fc L2 proteins are shown in FIG. 5.
  • the pharmacokinetic parameters are described in the following table 8 and show that the protein is stable after injection in the mouse.
  • Table 8 Pharmacokinetic Parameters of Robo1-Fc Proteins After IV Injection in Mice
  • Example 5 Description of the Robo1-Fc bio-therapeutic protein improved for its homogeneity in the N-terminal position.
  • This example describes the expression plasmid, the production and physico-chemical characterization of another Robo1-Fc protein named Robo1-Fc L3 which is different from the Robo1-Fc L1 protein by the absence of the first two residues Ser20 and Arg21.
  • the cDNA cloned into the plasmid pXL4904 was modified by PCR to remove the Ser20 and Arg21 codons and fused the next codon (Leu22) to the coding sequence of the peptide signal of nterleukin 2.
  • the expression plasmid pXL5004 was then generated. , see Figure 1.
  • the cDNA sequence used to express this recombinant protein corresponds to the sequence SEQ ID NO.23.
  • the Robo1-Fc L3 protein was produced, purified and characterized as described in Example 1. N-terminal analysis showed that this purified protein was perfectly homogeneous.
  • the recombinant protein obtained is named Robo1-Fc L3 and corresponds to the protein sequence SEQ ID NO.24.
  • the in vitro angiogenesis model corresponds to a rearrangement of human venous endothelial cells on a monolayer of human dermal fibroblasts. Briefly, fibroblasts (Lonza) are seeded in 24-well plates (Becton Dickinson) at 40,000 cells / well in 1 ml of medium. After 3 days of proliferation (J3), human venous endothelial cells (HUVEC-Lonza) are seeded on the 10-fold fibroblast cell monolayer.
  • EGM ® medium Endothelial Basal Medium, Lonza
  • FCS fetal calf serum - Lonza
  • hEGF Human Recombinant Epidermal Growth Factor - Lonza
  • the cells are fixed with ethanol and labeled with an antibody specific for anti-CD31 HUVECs, followed by an anti-alkaline phosphaphatase antibody and then revealed with an alkaline-phosphatase substrate (J 1 1).
  • Quantitation of the tubules labeled with the anti-CD31 antibody is carried out by means of microscope image acquisitions (objective X4) and the analysis of the length of the pseudo-tubules is carried out with the aid of a computer software. image (BIOCOM-Visiolab 2000 software) ( Figure 6).
  • Robo1-Fc L1 500 ⁇ g / ml shows inhibitory activity of the formation of tubules formed by HUVECs.
  • the Robo1-Fc L1 molecule was evaluated in a mouse aortic ring model. Briefly, mouse aorta are removed and cleaned and cut into a 1 mm (J0) section. These rings are included in rat collagen in the presence of VEGF at 10 ng / ml, the Robo1-Fc L1 molecule or a negative control Robo1-Fc Slit-2-less at a concentration of 500 ⁇ g / ml. Tubules will form from the ring thus mimicking in vitro the formation of neovessels. After 6 days, a quantification of the marked tubules is carried out thanks to microscope image acquisitions (objective X3) (FIG. 7A) and the analysis of the length of the pseudo-tubules is carried out using software image (BIOCOM- Visiolab 2000 software) ( Figure 7).
  • Robo1-Fc L1 (500 ⁇ g / ml) shows a strong Inhibitory activity of formation of tubules formed in comparison with the Robo1-Fc Slit-2-less molecule used as a negative control.
  • the Robo1-Fc L1 molecule was evaluated in a model of pulmonary cancer tumor in C57 / BI6 mice. at. Murine model of lung tumor
  • mice Female C57 / BI6 mice aged 8 weeks were anesthetized. The area at the left shoulder blade of the mouse has been shaved and disinfected. A 1 cm incision was made above the scapula.
  • the cells to be injected come from a Lewis lung carcinoma (ATCC, CRL-1642) tumor line.
  • the cells were mixed with Matrigel® in a ratio of 1 vol Matrigel to 4 vol of cells.
  • the cell concentration was 62500 cells / ml.
  • Cells were injected into the lung at a rate of 20 ⁇ per mouse and then the wound was sutured.
  • mice were euthanized.
  • the rib cage was opened, the left lung and the mediastinal chain were removed.
  • the tumor on the left lung was measured using an electronic caliper to determine the tumor volume according to the formula: I2XLX0.52.
  • the mediastinal chain is weighed. The results are expressed as mean value ⁇ standard deviation at the mean. Statistical analysis was done by a Student parametric test. b.
  • mice carrying a pulmonary tumor with the recombinant protein Robo1-Fc The treatment using the Robo1-Fc protein was carried out as follows: A preparation containing the Robo1-Fc protein was injected at the dose of 25 mg / kg / day intraperitoneally at D10, D14, D17, and J21 post injection of tumor cells. The control group was injected with PBS buffer (10 ml / kg). vs. Results
  • the average tumor volume obtained in the group treated with the Robo1-Fc recombinanate protein was 21.45 ⁇ 2.16 mm3; the mean tumor volume obtained in the control group was 39.93 ⁇ 8.41 mm3.
  • the reduction in tumor volume in the animals treated with the Robo1-Fc protein is 46%. This difference is statistically significant (p ⁇ 0.05).
  • the average weight of the mediastinal chain (metastatic lymph nodes) obtained in the group treated with the Robo1-Fc protein is 12.50 ⁇ 1 .26 mg.
  • the average weight of the mediastinal chain obtained in the control group is 30.67 ⁇ 7.69 mg.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Toxicology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biotechnology (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Wood Science & Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Oncology (AREA)
  • Plant Pathology (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Pulmonology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Steroid Compounds (AREA)
EP11719346A 2010-04-14 2011-04-08 Protéine de fusion robo1-fc et son utilisation dans le traitement des tumeurs Withdrawn EP2558489A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR1052829A FR2958936A1 (fr) 2010-04-14 2010-04-14 Proteine de fusion robo1-fc et son utilisation dans le traitement des tumeurs
PCT/FR2011/050811 WO2011128561A1 (fr) 2010-04-14 2011-04-08 Protéine de fusion robo1-fc et son utilisation dans le traitement des tumeurs

Publications (1)

Publication Number Publication Date
EP2558489A1 true EP2558489A1 (fr) 2013-02-20

Family

ID=42830780

Family Applications (1)

Application Number Title Priority Date Filing Date
EP11719346A Withdrawn EP2558489A1 (fr) 2010-04-14 2011-04-08 Protéine de fusion robo1-fc et son utilisation dans le traitement des tumeurs

Country Status (26)

Country Link
US (1) US9493529B2 (zh)
EP (1) EP2558489A1 (zh)
JP (1) JP5858442B2 (zh)
KR (1) KR20130059329A (zh)
CN (1) CN102884076A (zh)
AR (1) AR080891A1 (zh)
AU (1) AU2011239839B2 (zh)
BR (1) BR112012026020A2 (zh)
CA (1) CA2796303A1 (zh)
CL (1) CL2012002879A1 (zh)
CR (1) CR20120508A (zh)
DO (1) DOP2012000265A (zh)
EA (1) EA201291044A1 (zh)
EC (1) ECSP12012230A (zh)
FR (1) FR2958936A1 (zh)
GT (1) GT201200275A (zh)
IL (1) IL222382A (zh)
MA (1) MA34221B1 (zh)
MX (1) MX338981B (zh)
NI (1) NI201200155A (zh)
PE (1) PE20130199A1 (zh)
SG (1) SG184529A1 (zh)
TN (1) TN2012000473A1 (zh)
TW (1) TW201142024A (zh)
UY (1) UY33334A (zh)
WO (1) WO2011128561A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130273049A1 (en) * 2010-12-23 2013-10-17 Sanofi Robo1-fc fusion protein for use in the treatment of hepatocarcinoma

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR112014016493A2 (pt) 2012-01-05 2021-08-10 Boston Medical Center Corporation sinalização slit-robo para diagnóstico e tratamendo de doença renal
US11566082B2 (en) 2014-11-17 2023-01-31 Cytiva Bioprocess R&D Ab Mutated immunoglobulin-binding polypeptides
CN107298715B (zh) * 2016-04-15 2021-05-04 阿思科力(苏州)生物科技有限公司 Slit2D2-嵌合抗原受体及其应用
US10730908B2 (en) 2016-05-11 2020-08-04 Ge Healthcare Bioprocess R&D Ab Separation method
CN109311948B (zh) 2016-05-11 2022-09-16 思拓凡生物工艺研发有限公司 清洁和/或消毒分离基质的方法
US10654887B2 (en) 2016-05-11 2020-05-19 Ge Healthcare Bio-Process R&D Ab Separation matrix
EP3455243B1 (en) 2016-05-11 2021-03-24 Cytiva BioProcess R&D AB Separation matrix
JP7106187B2 (ja) 2016-05-11 2022-07-26 サイティバ・バイオプロセス・アールアンドディ・アクチボラグ 分離マトリックスを保存する方法
US10703774B2 (en) 2016-09-30 2020-07-07 Ge Healthcare Bioprocess R&D Ab Separation method
US10889615B2 (en) 2016-05-11 2021-01-12 Cytiva Bioprocess R&D Ab Mutated immunoglobulin-binding polypeptides
AU2018278809B2 (en) 2017-06-02 2022-03-31 Boston Medical Center Corporation Recombinant ROBO2 proteins, compositions, methods and uses thereof
US11406682B2 (en) 2017-08-24 2022-08-09 Bar-Ilan University Roundabout (Robo) receptor inhibitors and uses thereof
EP3932430A4 (en) * 2019-02-27 2023-02-01 Daewoong Pharmaceutical Co., Ltd. ALBUMIN-RELATED COMPOSITION COMPRISING LRRD2 OF THE SLIT3 PROTEIN FOR THE PREVENTION OR TREATMENT OF BONE DISEASES
CA3136663A1 (en) * 2019-04-23 2020-10-29 The Regents Of The University Of California Compositions and methods useful in promoting milk production

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6136310A (en) 1991-07-25 2000-10-24 Idec Pharmaceuticals Corporation Recombinant anti-CD4 antibodies for human therapy
US20060122373A1 (en) 1997-04-04 2006-06-08 Millennium Pharmaceuticals, Inc. Delta3, FTHMA-070, Tango85, Tango77, SPOIL,NEOKINE, Tango129 and integrin alpha subunit protein and nucleic acid molecules and uses thereof
EP1025231B1 (en) * 1997-10-20 2003-07-16 The Regents of the University of California Robo: a family of polypeptides and nucleic acids involved in nerve cell guidance
CA2324284A1 (en) * 1998-04-02 1999-10-14 Rigel Pharmaceuticals, Inc. Peptides causing formation of compact structures
AU2001283062A1 (en) * 2000-08-02 2002-02-13 The Johns Hopkins University Endothelial cell expression patterns
AU2003220173A1 (en) 2002-03-08 2003-09-22 Abgent, Inc. Detection and modulation of slit and roundabount (robo) mediated angiogenesis and uses thereof
JP4643450B2 (ja) * 2003-08-08 2011-03-02 株式会社ペルセウスプロテオミクス 癌高発現遺伝子
BRPI0507174A (pt) * 2004-01-28 2008-04-01 Syntonix Pharmaceuticals Inc proteìnas de fusão hormÈnio-fc (fsh-fc) heterodiméricas estimuladoras de folìculo para o tratamento da infertilidade
KR20150006085A (ko) * 2006-04-05 2015-01-15 애브비 바이오테크놀로지 리미티드 항체 정제
CL2007003411A1 (es) 2006-11-28 2008-07-04 Centelion Proteina fusion que consiste en una region fc de una inmunoglobulina con un fragmento o dominio soluble de un receptor para fgf; polinucleotido que la codifica y vector y celula que lo comprenden; composicion farmaceutica que comprende la proteina fu
TWI570135B (zh) * 2007-04-27 2017-02-11 建南德克公司 高效、穩定且非免疫抑制之抗－ｃｄ４抗體
MX346172B (es) 2007-08-29 2017-03-10 Sanofi - Aventis Anticuerpos anti - cxcr5 humanizados, derivados de los mismos y su uso.
EP2050764A1 (en) 2007-10-15 2009-04-22 sanofi-aventis Novel polyvalent bispecific antibody format and uses thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2011128561A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130273049A1 (en) * 2010-12-23 2013-10-17 Sanofi Robo1-fc fusion protein for use in the treatment of hepatocarcinoma

Also Published As

Publication number Publication date
GT201200275A (es) 2014-01-24
TW201142024A (en) 2011-12-01
MX2012011822A (es) 2012-11-12
CN102884076A (zh) 2013-01-16
NI201200155A (es) 2013-02-05
US9493529B2 (en) 2016-11-15
UY33334A (es) 2011-12-01
TN2012000473A1 (fr) 2014-01-30
CR20120508A (es) 2012-11-01
SG184529A1 (en) 2012-11-29
DOP2012000265A (es) 2013-02-28
CL2012002879A1 (es) 2013-03-22
MA34221B1 (fr) 2013-05-02
BR112012026020A2 (pt) 2016-06-28
CA2796303A1 (fr) 2011-10-20
WO2011128561A1 (fr) 2011-10-20
IL222382A (en) 2016-06-30
IL222382A0 (en) 2012-12-31
AU2011239839A1 (en) 2012-11-08
AU2011239839B2 (en) 2015-08-20
MX338981B (es) 2016-05-06
US20130039912A1 (en) 2013-02-14
JP2013523172A (ja) 2013-06-17
AR080891A1 (es) 2012-05-16
JP5858442B2 (ja) 2016-02-10
PE20130199A1 (es) 2013-03-09
EA201291044A1 (ru) 2013-04-30
KR20130059329A (ko) 2013-06-05
ECSP12012230A (es) 2012-11-30
FR2958936A1 (fr) 2011-10-21

Similar Documents

Publication Publication Date Title
EP2558489A1 (fr) Protéine de fusion robo1-fc et son utilisation dans le traitement des tumeurs
EP2318529B1 (en) Fgfr extracellular domain acidic region muteins
EP2315781B1 (fr) Antagonistes specifiques du recepteur fgf-r4
JPWO2018079702A1 (ja) ラクトフェリン／アルブミン融合タンパク質及びその製造方法
JP2010529859A (ja) ＴＧＦ−βＩＩ型受容体の２つのＴＧＦ−β結合ドメインを含有する融合タンパク質
US20170137503A1 (en) Antagonists of bmp9, bmp10, alk1 and other alk1 ligands, and uses thereof
JP7005019B2 (ja) 組織修復のための二重特異性治療用タンパク質
TW201107471A (en) Polypeptides selective for αvβ3 integrin conjugated with a variant of human serum albumin (HSA) and pharmaceutical uses thereof
EP2655408B1 (en) Robo1-fc fusion protein for use in the treatment of hepatocarcinoma
KR20170126504A (ko) 아밀린 유사체
WO2010126169A1 (ja) Alk1阻害剤を有効成分とする血管障害を抑制するための医薬組成物
KR20240074000A (ko) 항 her3 항체-약물 콘주게이트 투여에 의한 egfr-tki 저항성의 비소세포 폐암의 치료 방법
EP2013232B1 (fr) Utilisation de ligands synthetiques multivalents de la nucleoline de surface pour le traitement du cancer ou de l'inflammation
CN110092837B (zh) Uti融合蛋白
WO2012122941A1 (zh) 抗乙型肝炎病毒x蛋白多肽药物
JP2021529763A (ja) Ｆｇｆ−２１製剤
FR2969617A1 (fr) Proteine de fusion robo1-fc et son utilisation dans le traitement des tumeurs.
CN116134138A (zh) 靶向细胞内诱瘤蛋白的抗体、或其单链可变片段与癌细胞穿透肽的融合蛋白、及其用途
RU2825102C2 (ru) Рекомбинантные белки с доменами ccn и слитые белки
CN110709415A (zh) 重组robo2蛋白、组合物、方法及其用途
WO2002064165A1 (fr) Inhibiteurs de la proliferation cellulaire comprenant un facteur de transcription ets ou un gene codant ce dernier
TW201307393A (zh) 用於治療肝癌之Ｒｏｂｏ１－Ｆｃ融合蛋白

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20121114

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1176945

Country of ref document: HK

17Q First examination report despatched

Effective date: 20160404

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20160817

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1176945

Country of ref document: HK