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

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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Withdrawn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
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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
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Publication date
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Application filed by Sanofi SA filed Critical Sanofi SA
Publication of EP2558489A1 publication Critical patent/EP2558489A1/fr
Withdrawn legal-status Critical Current

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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.

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  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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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

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EP2558489A1 true EP2558489A1 (fr) 2013-02-20

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

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WO2013103811A2 (en) 2012-01-05 2013-07-11 Boston Medical Center Corporation Slit-robo signaling for diagnosis and treatment of kidney disease
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
US10513537B2 (en) 2016-05-11 2019-12-24 Ge Healthcare Bioprocess R&D Ab Separation matrix
US10889615B2 (en) 2016-05-11 2021-01-12 Cytiva Bioprocess R&D Ab Mutated immunoglobulin-binding polypeptides
WO2017194592A1 (en) 2016-05-11 2017-11-16 Ge Healthcare Bioprocess R&D Ab Method of storing a separation matrix
US10703774B2 (en) 2016-09-30 2020-07-07 Ge Healthcare Bioprocess R&D Ab Separation method
US11753438B2 (en) 2016-05-11 2023-09-12 Cytiva Bioprocess R&D Ab Method of cleaning and/or sanitizing a separation matrix
US10654887B2 (en) 2016-05-11 2020-05-19 Ge Healthcare Bio-Process R&D Ab Separation matrix
US10730908B2 (en) 2016-05-11 2020-08-04 Ge Healthcare Bioprocess R&D Ab Separation method
KR20200016292A (ko) * 2017-06-02 2020-02-14 화이자 인코포레이티드 재조합 robo2 단백질, 조성물, 방법 및 그의 용도
US11406682B2 (en) 2017-08-24 2022-08-09 Bar-Ilan University Roundabout (Robo) receptor inhibitors and uses thereof
EP3959231A4 (en) * 2019-04-23 2023-01-25 The Regents Of The University Of California COMPOSITIONS AND PROCESSES USEFUL IN THE PROMOTION OF DAIRY PRODUCTION

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

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