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WO2006005361A1 - Peptides susceptibles de se lier au recepteur tie2, acides nucleiques codant pour lesdits peptides et utilisations desdits peptides - Google Patents

Peptides susceptibles de se lier au recepteur tie2, acides nucleiques codant pour lesdits peptides et utilisations desdits peptides Download PDF

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Publication number
WO2006005361A1
WO2006005361A1 PCT/EP2004/007722 EP2004007722W WO2006005361A1 WO 2006005361 A1 WO2006005361 A1 WO 2006005361A1 EP 2004007722 W EP2004007722 W EP 2004007722W WO 2006005361 A1 WO2006005361 A1 WO 2006005361A1
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Prior art keywords
peptide
tie2 receptor
peptides
tie2
binding
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PCT/EP2004/007722
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English (en)
Inventor
Roselyne-Lucile Tournaire-Binetruy
Jaques Pouyssegur
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Centre National De La Recherche Scientifique
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Priority to PCT/EP2004/007722 priority Critical patent/WO2006005361A1/fr
Publication of WO2006005361A1 publication Critical patent/WO2006005361A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • G01N33/6845—Methods of identifying protein-protein interactions in protein mixtures
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/475—Assays involving growth factors
    • G01N2333/515—Angiogenesic factors; Angiogenin

Definitions

  • the present invention relates to peptides liable to bind to the Tie2 receptor, to nucleic acids encoding them, and to the uses of said peptides.
  • Angiogenesis the formation of new blood vessels sprouting from pre-existing vasculature, is required for embryonic development, for several female reproductive functions, and for wound healing and other repair processes. Angiogenesis also occurs in several diseases, and its importance in solid tumor growth and metastasis has been demonstrated in multiple studies (reviewed in Carmeliet, 2003).
  • the generation of new capillaries and their remodeling involve a multistep process, which includes the destabilization of established vessels, endothelial cell migration and proliferation, and the formation of new vascular tubes, which are stabilized by mesenchymal components. Blocking any one of these steps would inhibit the formation of new vessels, and therefore affect tumor growth and generation of metastases.
  • FGF-2 fibroblast growth factor 2
  • VEGF vascular endothelial growth factor
  • the angiopoietins/Tie2 receptor pathway has been recently identified as another endothelial cell-specific proangiogenic system, which plays a critical part in promoting vascular homeostasis and vessel maturation, as well as vascular destabilization and remodeling (Sato et al, 1995).
  • the Tie2 tyrosine kinase receptor is expressed specifically on endothelial cells (Dumont et al, 1992 ; Suri et al, 1996).
  • the interruption of Tie2 signaling with soluble, dominant-negative receptors can significantly inhibit tumor growth in mice (Lin et al, 1997 ; Siesmeister et al., 1999).
  • an Angl-antisense RNA approach reduces tumor growth and tumor angiogenesis (Schim et al, 2001).
  • a nuclease- resistant RNA aptamer that binds Ang2 has been reported to inhibit both Ang2 signaling and FGF-2 angiogenesis (White et al, 2003).
  • Angl acts as an agonist of Tie2 (Davis et al, 1996), whereas Ang2 appears to be a context-dependent antagonist/agonist (Maisonpierre et al, 1997 ; Mochizuki et al, 2002).
  • Targeted disruption of Angl and Tie2-coding genes and overexpression of Ang2 results in embryonic death with similar vascular defects (Dumont et al, 1994 ; Sato et al, 1995 ; Suri et al, 1996 ; Maisonpierre et al, 1997 ).
  • Angl is involved in normal interactions between endothelial cells and their underlying supporting pericytes, as well as in the maintenance of vascular stability.
  • an object of the invention is to provide new peptides which bind to Tie2, the antagonist or agonist properties of which with respect to the Tie2 receptor are well characterized, the sequences of said peptides presenting essentially no homology with the sequences of the natural ligands of Tie2.
  • Another object of the invention is to provide the nucleic acid sequences encoding said peptides.
  • Still another object of the invention is to provide pharmaceutical compositions comprising said peptides.
  • 7-mer peptide library is meant a collection of 7 residues long peptides, and in particular a collection wherein all the 7 residues long peptides are present ⁇ i.e. the 7 20 possible peptides).
  • the binding of a peptide belonging to a phage Ml 3 peptide library to the Tie2 receptor can be detected for instance by ELISA as follows:
  • 96-well microtiter plates are coated with the extracellular domain of the Tie2 receptor linked to the immunoglobulin domain Fc or with Fc alone at 4 ⁇ g/ml and. incubated overnight at 4°C. * Wells are blocked with 0.5% bovine serum albumin. Phage particles (10 12 particles/ml) are added to each well and incubated 1 h at room temperature. Wells are washed 15 times with 0.1% Tween 20 in PBS and the amount of bound phage is detected with peroxidase- conjugated anti-M13 phage antibody. To quantify only the binding to Tie2, the signal measured on an Fc-coated surface is subtracted. Non-displaying Ml 3 phage particles can be used as negative controls.
  • Agonist or antagonist properties of peptides with respect to the Tie2 receptor can be detected by evaluating the MAP kinase (MAPK), or the Tie receptor, phosphorylation status of cells contacted with said peptides.
  • MAPK MAP kinase
  • a peptide is said to have agonist properties with respect to the Tie2 receptor if it is liable to promote the phosphorylation of p42/p44 MAPK, or of the Tie2 receptor, in cells expressing Tie2.
  • HUVECs Human Umbilical Vein Endothelial Cells
  • HUVECs Human Umbilical Vein Endothelial Cells
  • a peptide to be evaluated After 6 h, cells are incubated for 1 h with a peptide to be evaluated, and optionally stimulated for 10 mn with Angl (300 ng/ml). Cells are then lysed in Laemmli buffer. Proteins are separated on a SDS-PAGE (7.5%), and electr ⁇ phoretically transferred onto polyvinylidone difluoride membrane. Membranes are probed with an anti-phospho ⁇ 42/p44 MAPK monoclonal antibody or an anti-p42 MAP Kinase antibody.
  • the immunoreactive bands are visualised with ECL system, and the relative quantities of phosphorylated p42/p44 MAPK (determination of an agonist) and unphosphorylated p42/p44 MAPK (determination of an antagonist) are evaluated.
  • Peptides having agonist properties with respect to the Tie2 receptor are useful in particular to promote neovascularisation or vessel growth, in vitro or in vivo.
  • Therapeutic applications include healing promotion, tissue reconstruction, ovarian induction, or reperfusion of ischemic areas.
  • Peptides having antagonist properties with respect to the Tie2 receptor are useful in particular for the inhibition of angiogenesis, more particularly for the inhibition of endothelial growth and/or proliferation.
  • Therapeutic applications include tumor treatment, age related macular degeneration, diabetic retinopathy, rheumatoid arthritis, allograft or xenograft rejection, acrocyanosis, or sclerodermia.
  • Angiopoietins are proteins which share similar structural features and bind to the Tie2 receptor, such as Angl and Ang2 for example.
  • the capacity of peptides to inhibit or to favour the binding of angiopoietins to the Tie2 receptor can be evaluated through competitive binding experiments. Such experiments can be carried out by using surface plasmon resonance, a method well known to the man skilled in the art, as described in Example 2.
  • the capacity of peptides to mimic the binding of angiopoietins to the Tie2 receptor can be evaluated by comparing the MAPK phosphorylation status of Tie2 expressing cells contacted with the peptides, with that of Tie2 expressing cells contacted with angiopoietins.
  • the MAPK phosphorylation status of Tie2 expressing cells can be determined as described above.
  • the capacity of peptides to mimic the binding of angiopoietins to the Tie2 receptor can be evaluated by comparing the Tie2 receptor phosphorylation status of Tie2 expressing cells contacted with the peptides, with that of Tie2 expressing cells contacted with angiopoietins.
  • the present invention relates to the above defined use of a 7-mer peptide library, for screening peptides liable:
  • the present invention relates to the above defined use of a 7-mer peptide library, for screening peptides liable:
  • the invention relates to the above defined use of a 7-mer peptide library, for screening peptides liable to inhibit both the binding of Angl and Ang2 to the Tie2 receptor.
  • the present invention also relates to a process for screening a 7-mer peptide liable to
  • T4 is a potent inhibitor of angiogenesis in vivo.
  • T4 is a 7-residue long peptide, which makes it a desirable peptidic drug, since small peptides are usually more stable in biological media than larger peptides.
  • the invention also relates to prokaryotic or eukaryotic cells transformed with a nucleic acid as defined above and/or a recombinant vector as defined above.
  • the invention relates to the use of T4, for the manufacture of a medicament useful for
  • peptides as defined above are coupled to markers, such as fluorescent or radioactive markers, to be used for the detection of vasculature tissues or cells in imaging methods.
  • Figures 4A-4C represent Western blots of HUVECs hydrolysates revealed by anti-p42 MAPK antibodies or anti-phosphorylated p42/p44 MAPK (pp42, pp44).
  • HUVECs were stimulated with Angl or FGF-2 in the absence (control) or presence of peptide T4 (ImM). Similar results were obtained in two different experiments.
  • Figures 6a-6D represents a picture of the network of blood vessels formed in chick embryos treated by PBS (Figure 6A), the T7 peptide ( Figure 6B), or the T4 peptide ( Figures 6C-6D). Bars : lmm in upper and lower panels.
  • Example 1 peptide selection hi order to select peptides binding Tie2, a random 7-mer M 13 phage-display library was screened for binding to Tie2-Fc. Biopanning was adapted from the Ph.D.-7 kit standard procedure (New England Biolabs) and described previously (Binetray-Tournaire et al, 2000). Tie2-Fc was used to coat microtiter plates at 10 ⁇ g/ml.
  • DNA sequences were determined by DNA and amino acid sequence analysis with a A310 sequencer using the ABI PRISM dye terminators (P.E. Biosystems). Alignment between the peptide sequence and the Angl or Ang2 primary sequence was determined using the MULTALIGN software. Each selected clone was assayed by ELISA for binding to Tie2-Fc. Briefly, the ELISA assays were carried out as follows: 96-well plates (Maxisorp, Nunc International) were coated with Tie2-Fc or Fc at 4 ⁇ g/ml and incubated overnight at 4°C. Wells were blocked with 0.5% bovine serum albumin. Phage particles (10 12 particles/ml) were added to each well and incubated 1 h at room temperature.
  • Table I shows that only T7 and T8 share a sequence homology, with two identical residues: RH. Table I. Multiple alignment of selected clones.
  • Tl, T4, T6, T7, T8 and TlO were then produced and their ability to compete with Ang2 for binding to Tie2 was tested by ELISA, using a fixed peptide concentration (500 ⁇ M).
  • each phage carries several copies of the minor coat protein pill-fused heptapeptide, and this may result in a multivalent binding of the phage to Tie2 coated receptors.
  • the observations might also be due to the fact that, unlike synthetic peptides, phage-linked peptides can be conformationally constrained by the phage coat proteins.
  • Example 2 in vitro activity of the selected peptide
  • peptide T4 was chosen for further studies.
  • the inhibition by peptide T4 of the Angl/Ang2 binding to Tie2 was further characterized by surface plasmon resonance ( Figure 3).
  • Mixtures of Angl (0.33 ⁇ g/ml) or Ang2 (1 ⁇ g/ml) with peptides T4 or T7 (0 to 1 mM) were then injected at a flow rate of 10 ⁇ l/min over the Tie2-Fc/protein A surface for 3 minutes.
  • Negative controls obtained by injecting the Ang/peptide mixtures directly onto the protein A surface, were substracted to determine the specific binding profiles of Angl orAng2 to Tie2 in the presence or absence of peptide.
  • the angiopoietin concentration was chosen to obtain a linear association phase over a time lapse of more than 100s: the slopes of the different association profiles were measured, and plotted against the concentration of peptide to calculate the inhibition constants (Ki).
  • Tie2 is an endothelial cell-restricted receptor
  • T4 could inhibit Angl signal transduction in human umbilical vein endothelial cells (HUVECs).
  • Angl had been previously shown to activate the MAPK signaling cascade in HUVECs.
  • the pharmacological inhibition of ERK activation with PD98059 suppressed Angl-induced migration (Kim et al., 2002), as well as the antiapoptotic properties of Angl (Harfouche et al,
  • HUVECs were isolated from umbilical cord veins by collagenase perfusion and were cultivated on gelatinized-dishes in SFM medium (Invitrogen) supplemented with 20% fetal calf serum, 100 ⁇ g/ml of heparin, 20 ng/ml of FGF-2, 10 ng/ml of EGF (Sigma), 50 units/ml penicillin and 50 ⁇ g/ml streptomycin. Only cells from passages 2 to 5 were used for experiments.
  • Figure 4 A shows that Angl induced a strong p42/p44 phosphorylation. Angl binding to Tie2 expressed by endothelial cells was specifically responsible for this MAPK activation, as it was completely abolished by recombinant soluble Tie2 receptor.
  • Figure 4BV Results show that T4 completely inhibited the activation of MAPK induced by Angl, whereas peptide T7 at the same concentration had no inhibitory effect.
  • T4 suppressed Angl-induced MAPK activity in a dose dependent manner with an IC50 between 150 or 200 ⁇ M.
  • T4 did not activate MAPK phosphorylation.
  • FGF-R receptor tyrosine kinase
  • Endothelial cell migration assays were performed using a 24-well chemotaxis chamber
  • Example 4 in vivo anti- angiogenic activity of the selected peptide
  • the chick chorioallantoic membrane (CAM) assay which is usually employed as an in vivo model to both study physiological angiogenesis and test pro- and anti-angiogenic compounds (Kim et ah, 2003 ; Yan et ah, 2003), was chosen.
  • CAM assays were performed as previously described (Le Noble et al, 1993). Briefly, fertile normal brown leghorn eggs were incubated for 2 days in a humidified atmosphere at 37°C. At day 2, a rectangular window was made in the egg shell, the window was covered with scotch tape to prevent dehydration and the eggs were reincubated until day 7.
  • peptide T4 (NLLMAAS) inhibited, in a concentration-dependent manner, the binding of Angl and Ang2 to immobilized Tie2. It also specifically inhibited Angl -induced signal transduction and the migration of human endothelial cells. Moreover, the Inventors have demonstrated that this peptide can inhibit angiogenesis in vivo, in a well-characterized model of angiogenesis, the CAM assay. Although T4 may block both Angl and Ang2 binding to Tie2, the resulting effect is an inhibition of angiogenesis.
  • NLLMAAS short peptide
  • This specific inhibitor of the Tie2 pathway is a good lead compound for the development of therapeutic agents against tumor angiogenesis.
  • the small size of this peptide offers the possibility of designing structurally mimetic non- peptidic molecules via standard organic synthesis. This could result in the production of inexpensive drugs to be administered orally.
  • this bioactive peptide is useful to dissect the signal transduction mechanisms involving the Tie2 receptor in endothelial cells which express multiple receptors and provides a potent tool to inhibit angiogenesis in vivo.
  • VEGF vascular endothelial growth factor
  • Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. Dev. Cell 3, 411-423.
  • Angiopoietin-1 activates both anti- and proapoptotic mitogen-activated protein kinases. FASEB J. 17, 1523-1525.
  • EphB ligand, ephrinB2 suppresses the VEGF- and angiopoietin 1 -induced Ras/mitogen- activated protein kinase pathway in venous endothelial cells. FASEB J. 16, 1126-1128.
  • angiopoietin-1 a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell. 87, 1171-1180.

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Abstract

La présente invention concerne l'utilisation d'une bibliothèque de peptides 7-mer pour le criblage de peptides susceptibles de se lier au récepteur Tie2, lesdits peptides présentant des propriétés agonistes ou antagonistes par rapport au récepteur Tie2.
PCT/EP2004/007722 2004-07-13 2004-07-13 Peptides susceptibles de se lier au recepteur tie2, acides nucleiques codant pour lesdits peptides et utilisations desdits peptides WO2006005361A1 (fr)

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008049227A1 (fr) * 2006-10-27 2008-05-02 Sunnybrook Health Sciences Center Agonistes tie 2 multimères et leurs utilisations dans la stimulation de l'angiogenèse
US20110143993A1 (en) * 2009-12-15 2011-06-16 The Brigham And Women's Hospital, Inc. Endothelial basement membrane targeting peptide ligands
WO2011134056A1 (fr) * 2010-04-28 2011-11-03 Sunnybrook Health Sciences Centre Procédés et utilisations d'agents de liaison à tie2 et/ou d'agents d'activation de tie2
WO2012162561A2 (fr) 2011-05-24 2012-11-29 Zyngenia, Inc. Complexes plurispécifiques multivalents et monovalents, et leurs utilisations
EP2433968A4 (fr) * 2009-05-20 2012-12-05 Pharmabcine Inc Anticorps à double ciblage de forme nouvelle, et utilisation de celui-ci
EP2671891A2 (fr) 2008-06-27 2013-12-11 Amgen Inc. Inhibition d'ang-2 pour traiter la sclérose en plaques
US9017670B2 (en) 2011-08-19 2015-04-28 Regeneron Pharmaceuticals, Inc. Anti-Tie2 antibodies and uses thereof
US9822175B2 (en) 2008-12-10 2017-11-21 Ablynx N.V. Amino acid sequences directed against the angiopoietin/tie system and polypeptides comprising the same for the treatment of diseases and disorders related to angiogenesis
EP3424530A1 (fr) 2013-03-15 2019-01-09 Zyngenia, Inc. Complexes multispécifiques monovalents et multivalents et leurs utilisations
US10314882B2 (en) 2013-04-11 2019-06-11 Sunnybrook Research Institute Methods, uses and compositions of Tie2 agonists
US10316105B2 (en) 2011-08-19 2019-06-11 Regeneron Pharmaceuticals, Inc. Anti-TIE2 antibodies and uses thereof
WO2021207099A3 (fr) * 2020-04-06 2021-11-18 Vasomune Therapeutics, Inc. Thérapeutiques pour lutter contre le coronavirus et méthodes de traitement

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WO2003072542A2 (fr) * 2001-11-20 2003-09-04 Duke University Biomateriaux interfaciaux
WO2004006862A2 (fr) * 2002-07-16 2004-01-22 Children's Medical Center Corporation Methode de modulation de l'angiogenese

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WO2003072542A2 (fr) * 2001-11-20 2003-09-04 Duke University Biomateriaux interfaciaux
WO2004006862A2 (fr) * 2002-07-16 2004-01-22 Children's Medical Center Corporation Methode de modulation de l'angiogenese

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Title
DENG S-J ET AL: "IDENTIFYING SUBSTRATES FOR ENDOTHELIUM-SPECIFIC TIE-2 RECEPTOR TYROSINE KINASE FROM PHAGE-DISPLAYED PEPTIDE LIBRARIES FOR HIGH THROUGHPUT SCREENING", COMBINATORIAL CHEMISTRY AND HIGH THROUGHPUT SCREENING, HILVERSUM, NL, vol. 4, no. 6, September 2001 (2001-09-01), pages 525 - 533, XP001036555, ISSN: 1386-2073 *
TOURNAIRE R ET AL: "A short synthetic peptide inhibits signal transduction, migration and angiogenesis mediated by Tie2 receptor", EMBO REPORTS 2004 UNITED KINGDOM, vol. 5, no. 3, 2004, pages 262 - 267, XP002321017, ISSN: 1469-221X *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008049227A1 (fr) * 2006-10-27 2008-05-02 Sunnybrook Health Sciences Center Agonistes tie 2 multimères et leurs utilisations dans la stimulation de l'angiogenèse
US8957022B2 (en) 2006-10-27 2015-02-17 Sunnybrook Health Sciences Centre Multimeric tie 2 agonists and uses thereof in stimulating angiogenesis
EP2671891A2 (fr) 2008-06-27 2013-12-11 Amgen Inc. Inhibition d'ang-2 pour traiter la sclérose en plaques
US9822175B2 (en) 2008-12-10 2017-11-21 Ablynx N.V. Amino acid sequences directed against the angiopoietin/tie system and polypeptides comprising the same for the treatment of diseases and disorders related to angiogenesis
EP2433968A4 (fr) * 2009-05-20 2012-12-05 Pharmabcine Inc Anticorps à double ciblage de forme nouvelle, et utilisation de celui-ci
US10125194B2 (en) 2009-05-20 2018-11-13 Pharmabcine Inc. Dual targeting antibody of novel form, and use thereof
US20110143993A1 (en) * 2009-12-15 2011-06-16 The Brigham And Women's Hospital, Inc. Endothelial basement membrane targeting peptide ligands
WO2011134056A1 (fr) * 2010-04-28 2011-11-03 Sunnybrook Health Sciences Centre Procédés et utilisations d'agents de liaison à tie2 et/ou d'agents d'activation de tie2
US9186390B2 (en) 2010-04-28 2015-11-17 Sunnybrook Health Sciences Center Methods and uses of TIE2 binding and/or activating agents
WO2012162561A2 (fr) 2011-05-24 2012-11-29 Zyngenia, Inc. Complexes plurispécifiques multivalents et monovalents, et leurs utilisations
CN106963946A (zh) * 2011-08-19 2017-07-21 瑞泽恩制药公司 抗tie2抗体及其用途
US9546218B2 (en) 2011-08-19 2017-01-17 Regeneron Pharmaceuticals, Inc. Anti-Tie2 antibodies and uses thereof
US9017670B2 (en) 2011-08-19 2015-04-28 Regeneron Pharmaceuticals, Inc. Anti-Tie2 antibodies and uses thereof
US10316105B2 (en) 2011-08-19 2019-06-11 Regeneron Pharmaceuticals, Inc. Anti-TIE2 antibodies and uses thereof
US10442864B2 (en) 2011-08-19 2019-10-15 Regeneron Pharmaceuticals, Inc. Anti-Tie2 antibodies and uses thereof
US10752702B2 (en) 2011-08-19 2020-08-25 Regeneron Pharmaceuticals, Inc. Anti-TIE2 antibodies and uses thereof
EP3424530A1 (fr) 2013-03-15 2019-01-09 Zyngenia, Inc. Complexes multispécifiques monovalents et multivalents et leurs utilisations
US10314882B2 (en) 2013-04-11 2019-06-11 Sunnybrook Research Institute Methods, uses and compositions of Tie2 agonists
WO2021207099A3 (fr) * 2020-04-06 2021-11-18 Vasomune Therapeutics, Inc. Thérapeutiques pour lutter contre le coronavirus et méthodes de traitement
CN115666543A (zh) * 2020-04-06 2023-01-31 血管免疫治疗公司 冠状病毒治疗剂和治疗方法

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