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WO2018103038A1 - Conjugué et son utilisation - Google Patents

Conjugué et son utilisation Download PDF

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Publication number
WO2018103038A1
WO2018103038A1 PCT/CN2016/109008 CN2016109008W WO2018103038A1 WO 2018103038 A1 WO2018103038 A1 WO 2018103038A1 CN 2016109008 W CN2016109008 W CN 2016109008W WO 2018103038 A1 WO2018103038 A1 WO 2018103038A1
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Prior art keywords
conjugate
peptide
brain
individual
amino acid
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PCT/CN2016/109008
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English (en)
Chinese (zh)
Inventor
芦颖
韩化敏
田雨佳
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拜西欧斯（北京）生物技术有限公司
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Priority to CN201680091448.6A priority Critical patent/CN110049994B/zh
Priority to PCT/CN2016/109008 priority patent/WO2018103038A1/fr
Publication of WO2018103038A1 publication Critical patent/WO2018103038A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof

Definitions

  • the present application relates generally to the field of biomedical technology, and more particularly, to a diagnostic method and tool for brain nerve damage diseases.
  • Brain nerve injury disease is a disease caused by damage to the nerves of the brain, which is generally a damage cascade, which ultimately leads to multiple pathways of nerve cell damage.
  • the downstream post-synaptic density 95 protein (PSD-95) plays an important role in interacting with various proteins during brain damage.
  • Ischemic stroke is one of the common brain nerve damage diseases.
  • the lesions of acute ischemic stroke are classified into ischemic penumbra and ischemic central area according to whether the damage of nerve cells is reversible.
  • the two are a dynamic pathophysiological process, and the blood flow in the ischemic penumbra determines the area.
  • Brain tissue returns to normal or develops into a key factor in cerebral infarction. Therefore, early understanding of the blood flow and nerve cell status in the lesion, at the appropriate time to restore the blood supply of the ischemic penumbra, is conducive to the survival of nerve cells in this area and the recovery of brain tissue function.
  • Accurately judging the extent of the ischemic penumbra, grasping the information about the blood supply artery, the degree of hypoperfusion and the metabolic state of the brain can provide a basis for clinical diagnosis and treatment.
  • the diagnosis of brain nerve injury disease is mainly based on early imaging examination, but the imaging diagnosis (X-ray, CT, MRI, ultrasound, etc.) mainly shows the final effect of some molecular changes, that is, the organ has undergone organic changes. After observation, it can only be used for disease detection with anatomical changes, and the brain damage that occurs can not be judged and diagnosed early.
  • CT computer tomography
  • Conventional CT examinations have a low positive predictive value in the short-term onset of brain neurological injury, thus causing delays in the diagnosis of the disease.
  • the current development of molecular imaging technology can detect abnormalities at the cellular and molecular levels in the disease process, detect abnormalities before the disease with no anatomical changes, and explore the effects of drugs to explore the occurrence, development and outcome of the disease.
  • the reagents for sub-imaging diagnosis are of great significance for the early diagnosis of neurological injury of the brain.
  • the application provides a conjugate comprising a peptide and a detectable label comprising the amino acid sequence YEKLLDTEI (SEQ ID NO: 1) or a functional variant thereof.
  • the present application provides a method of diagnosing a brain nerve injury disease in an individual or evaluating a state of a nerve injury in an individual brain, the method comprising:
  • the individual is administered a conjugate comprising a peptide and a detectable label comprising the amino acid sequence YEKLLDTEI (SEQ ID NO: 1) or a functional variant thereof;
  • the detectable marker is detected in an area of the individual suspected of developing a nerve injury in the brain.
  • the present application provides a kit for diagnosing a brain nerve injury disease or evaluating a brain damage state of an individual brain, comprising a conjugate comprising a peptide and a detectable label,
  • the peptide contains the amino acid sequence YEKLLDTEI (SEQ ID NO: 1) or a functional variant thereof.
  • the present application provides a method of treating a brain nerve injury disease or condition, the method comprising:
  • the conjugate is administered to the individual, the conjugate comprising a peptide comprising the amino acid sequence YEKLLDTEI (SEQ ID NO: 1) or a functional variant thereof;
  • the individual is treated for treatment of a brain neurologically damaging disease.
  • the functional variant is a variant produced by one or more conservative substitutions of the LDTEI moiety in YEKLLDTEI, preferably the conservative substitution is selected from D and Substitution between E, substitution between L, V and I, and substitution between T and S.
  • the functional variant is a variant produced by replacing the LDTEI portion of YEKLLDTEI with any of the following sequences: LDTEL, LDTEV, LDTDI, LDTDL, LDTDV, LDSEI, LDSEL, LDSEV, LDSDI, LDSDL, LDSDV, LETEI, LETEL, LETEV, LETDI, LETDL, LETDV, VDTEI, VDTEL, VDTEV, VDTDI, VDTDL, VDTDV, IDTEI, IDTEL, IDTEV, IDTDI, IDTDL, IDTDV, IETEI, IETEL, IETEV, IETDI, IETDL, IETDVD.
  • the peptide is a chimeric peptide comprising the amino acid sequence YEKLLDTEI or a functional variant thereof and an internalization peptide, preferably the internalization peptide comprises the amino acid sequence YGRKKRRQRRR (SEQ ID NO: 2).
  • the chimeric peptide comprises the amino acid sequence YGRKKRRQRRRYEKLLDTEI (SEQ ID NO: 3).
  • the detectable label is selected from the group consisting of a radionuclide, an isotope, an optical label, a magnetic substance, and any combination of the above.
  • the radionuclide is selected from the group consisting of 124 I, 18 F, 11 C, 99m Tc, 123 I, and any combination thereof.
  • the optical label is selected from the group consisting of a fluorescent dye, a fluorescent protein, a chemiluminescent dye, a quantum dot, and any combination of the above.
  • the magnetic material is selected from the group consisting of nanoparticles comprising a ruthenium complex, superparamagnetic iron oxide nanoparticles, and any combination of the above.
  • the brain nerve injury disorder is ischemic stroke.
  • Figure 1 is a graph showing the interaction of P5 with the PDZ1-2 domain by the Pull-down assay.
  • M represents the DNA molecular weight marker; Lane 1 is His+PDZ1-2+P5; Lane 2 is P5 alone; Lane 3 is His+P5; Lane 4 is His+PDZ1-2.
  • the elution band shown in lane 1 contains both P5 and PDZ1-2, confirming that P5 is capable of binding to the PDZ1-2 domain.
  • Figure 2 is a graph showing the distribution of conjugate FP5 in rat brain after normal control rats and MCAO model modeling.
  • Fig. 3 is a graph showing the results of TTC staining of rat brain tissue after normal control rats and MCAO model.
  • Figure 4A is a graph showing the distribution of conjugate FP5 in the brain of rat rats at different ischemic times
  • Figure 4B is a graph showing the results of TTC staining of rat brain tissue at different ischemic times.
  • the application provides a conjugate comprising a peptide and a detectable label comprising the amino acid sequence YEKLLDTEI (SEQ ID NO: 1) or a functional variant thereof.
  • conjugates refers to a substance formed by the combination of two or more independently functional moieties.
  • the conjugates of the present application comprise a peptide and a detectable label, wherein the peptide functions as a biological function and the detectable label functions as an indicator.
  • the detectable label may be a peptide independent entity or part of the peptide itself.
  • amino acid with a detectable isotope can be involved in the synthesis of the peptide, or one or more amino acids on the peptide chain can be labeled with an isotope displacement to achieve a "detectable" purpose.
  • the conjugate is useful for molecular imaging.
  • the detectable label is selected from the group consisting of a radionuclide, an isotope, an optical label, a magnetic substance, and any combination of the above.
  • a radionuclide is an unstable nucleus that spontaneously emits radiation and forms a stable nuclides by decay.
  • the radionuclide detectable labels include, but are not limited to, 124 I, 18 F, 11 C, 99m Tc, and 123 I.
  • the optical label is selected from the group consisting of a fluorescent dye, a fluorescent protein, a chemiluminescent dye, a quantum dot, and any combination of the above.
  • optically labeled conjugates include, but are not limited to, fluorescent dye-labeled conjugates, fluorescent protein-labeled conjugates, chemiluminescent dye-labeled conjugates, quantum dot-labeled conjugation And Raman probes.
  • a fluorescent dye generally refers to a substance that absorbs a light wave of a certain wavelength and emits another light wave having a wavelength greater than that of the absorbed light. Most of them are compounds containing a benzene ring or a heterocyclic ring and having a conjugated double bond.
  • fluorescent dyes include, but are not limited to, allophycocyanin, indole dicarbocyanine, indole tricarbocyanine, thiadicarbocyanine, fluorescein, thiorhodamine, ROX, sulfur Derodamin, Nile Red, R-phycocyanin, C-phycocyanin, thiadicarbocyanine, fluorescein isothiocyanate (FITC), albino allergen, AlexaFluor488 and indocyanine green (ICG) ).
  • the fluorescent dye is FITC.
  • the fluorescent protein includes, but is not limited to, green fluorescent protein, yellow fluorescent protein, red fluorescent protein, blue fluorescent protein.
  • Chemiluminescence is the radiation of light produced by the absorption of chemical energy by molecules of a substance.
  • Chemiluminescent dyes include, but are not limited to, horseradish peroxidase.
  • a quantum dot is a nanoparticle composed of a group II-VI or a group III-V. Since electrons and holes are quantum confined, the continuous band structure becomes a discrete energy level structure with molecular characteristics. Fluorescence can be emitted.
  • quantum dots include, but are not limited to, noble metal nanomaterials such as gold, silver, etc.; semiconductor nanomaterials such as cadmium selenide quantum dots; inorganic non-metallic nanomaterials such as carbon quantum dots, graphene quantum dots Wait.
  • the Raman probe is a conjugate established by Raman spectroscopy, which can be used for molecular imaging.
  • a peptide of the present application comprising the amino acid sequence YEKLLDTEI (SEQ ID NO: 1) or a functional variant thereof can be prepared as a Raman probe.
  • a Raman probe can be prepared by coupling a peptide of the present application containing the amino acid sequence YEKLLDTEI (SEQ ID NO: 1) or a functional variant thereof to a gold nanoparticle.
  • the detectable label can be a magnetic substance.
  • the magnetic material can be a nanoparticle containing a ruthenium complex and/or a superparamagnetic iron oxide nanoparticle.
  • the functional variant is a variant produced after one or more conservative substitutions of the LDTEI moiety in YEKLLDTEI.
  • the conservative substitution is selected from the group consisting of a substitution between D and E, a substitution between L, V and I, and a substitution between T and S.
  • the functional variant is a variant produced by replacing the LDTEI portion of SEQ ID NO: 1 with any of the following sequences: LDTEL, LDTEV, LDTDI, LDTDL, LDTDV, LDSEI, LDSEL , LDSEV, LDSDI, LDSDL, LDSDV, LETEI, LETEL, LETEV, LETDI, LETDL, LETDV, VDTEI, VDTEL, VDTEV, VDTDI, VDTDL, VDTDV, IDTEI, IDTEL, IDTEV, IDTDI, IDTDL, IDTDV, IETEI, IETEL, IETEV , IETDI, IETDL, IETDVD.
  • the functional variants disclosed herein further comprise the same as at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, or even higher than the peptides mentioned above.
  • Sexual amino acid sequence It is known in the art that "identity" between two proteins is determined by aligning the sequence of a second protein substituted with the amino acid sequence of one protein and its conserved amino acid. Determination of two proteins using computer algorithms and methods well known to those skilled in the art The degree of identity between the two. The identity between two amino acid sequences is preferably determined by using the BLASTP algorithm.
  • the functional variants disclosed herein include substitutions, deletions, additions and/or amino acid residues at 1, 2, 3, 4, 5 or more compared to the peptides mentioned above. Or the insertion differs from the specific peptide disclosed above.
  • a functional variant can be distinguished from a particular peptide disclosed above by one or more substitutions, deletions, additions, and/or insertions. These variants may be naturally occurring or may be synthetically produced, for example, by modifying one or more of the above-described peptide sequences disclosed herein and evaluating them according to any of a variety of techniques well known in the art as described herein. Biological activity.
  • the peptide comprising the amino acid sequence YEKLLDTEI (SEQ ID NO: 1) or a functional variant thereof is a chimeric peptide comprising the amino acid sequence YEKLLDTEI or a functional variant thereof and an internalization peptide.
  • Internalized peptides also known as transmembrane peptides, are widely used in the field of protein drugs, and their function is to promote the uptake and absorption of active peptides bound thereto by cells.
  • the internalization peptide can be a Tat peptide, wherein one non-limiting example of a Tat peptide is YGRKKRRQRRR (SEQ ID NO: 2).
  • the internalization peptide comprises the amino acid sequence YGRKKRRQRRR (SEQ ID NO: 2).
  • the chimeric peptide comprises the amino acid sequence YGRKKRRQRRRYEKLLDTEI (SEQ ID NO: 3).
  • peptides described above can optionally be derivatized (e.g., acetylated, phosphorylated, and/or glycosylated) to promote affinity for the target, to facilitate its ability to be transported across the cell membrane, or Promote stability.
  • derivatized e.g., acetylated, phosphorylated, and/or glycosylated
  • the present application provides a method of diagnosing an individual's brain nerve injury disease or evaluating an individual's brain nerve damage state (eg, a cerebral ischemic state), the method comprising:
  • the individual is administered a conjugate comprising a peptide and a detectable label comprising the amino acid sequence YEKLLDTEI (SEQ ID NO: 1) or a functional variant thereof;
  • the detectable marker is detected in an area of the individual suspected of developing a nerve injury in the brain.
  • the expression level of the peptide of the present application can be correlated with brain nerve damage (e.g., cerebral ischemic state), and the level of expression of the peptide can be reflected by detecting the level of the detectable marker, thereby indicating the degree of brain damage.
  • brain nerve damage e.g., cerebral ischemic state
  • the method can further comprise comparing the level of the detected detectable marker to a threshold level of the normal individual to determine an abnormal expression level.
  • the threshold level of a normal individual can be a predetermined value, map, etc., and can additionally be obtained from a normal individual.
  • brain neurological disorders include stroke or spinal cord injury, ischemic or traumatic injury to the brain or spinal cord, and damage to central nervous system (CNS) neurons, including acute CNS injury, ischemic Stroke or spinal cord injury, as well as hypoxia, ischemia, mechanical injury and neurodegenerative diseases, anxiety, epilepsy, stroke-induced damage.
  • CNS central nervous system
  • the brain nerve injury disorder is an ischemic stroke.
  • the administration can be oral administration. In some embodiments, the administration can be an injection administration.
  • the conjugate can be used for molecular imaging.
  • Molecular imaging requires the use of appropriate imaging equipment.
  • Imaging devices include, but are not limited to, imaging devices for CT, optical imaging, PET, conventional nuclear medicine SPECT, MRI, and MRS imaging.
  • the characteristics of the conjugate administered in the method of the second aspect may be the same as in the first aspect unless otherwise stated.
  • the present application provides a kit for diagnosing a brain nerve injury disease or evaluating a brain damage state of an individual brain, comprising a conjugate comprising a peptide and a detectable label,
  • the peptide contains the amino acid sequence YEKLLDTEI (SEQ ID NO: 1) or a functional variant thereof.
  • the characteristics of the conjugate included in the kit of the third aspect may be the same as the first aspect unless otherwise stated.
  • the present application provides a method of treating a brain nerve injury disease or condition, the method comprising:
  • the conjugate is administered to the individual, the conjugate comprising a peptide comprising the amino acid sequence YEKLLDTEI (SEQ ID NO: 1) or a functional variant thereof;
  • the individual is treated for treatment of a brain neurologically damaging disease.
  • the present application also provides a method of treatment based on the detection of a brain nerve injury disease or condition.
  • the treatment for a brain nerve injury disorder can be a systemic administration of a drug against a neurological brain injury disease.
  • the drug can also be delivered directly to the site of injury (eg, a portion of the detectable level of expression of the marker) by topical administration (eg, vascular or local injection).
  • the drug targeted to the site can be selected based on the site of the injury and delivered by systemic or oral administration.
  • the Tat transmembrane peptide YGRKKRRQRRR was selected and ligated to a different number of amino acids to form a peptide library.
  • the peptide molecules in the peptide library were respectively interacted with the PDZ1-2 domain expressed and purified in vitro, and the polypeptide was initially screened according to the strength of the interaction force.
  • the PDZ domain refers to a modular protein domain of approximately 90 amino acids and is characterized by a synaptic protein PSD-95, a Drosophila-separating connexin, a Discs-Large (DLG), and an epithelial tight junction protein Z01 (Z01). There is significant (eg, at least 60%) sequence identity.
  • the PDZ domain typically displays a retained core consensus sequence (Doyle, D.A., 1996, Cell 85: 1067-76).
  • Exemplary PDZ domain-containing proteins and PDZ domain sequences are disclosed in U.S. Patent Application Serial No. 10/714,537.
  • the immobilized molecule is PDZ1-2 protein, molecular weight: ⁇ 20kD, concentration: 2mg/ml; mobile phase molecule (analyte): polypeptide to be screened, molecular weight: ⁇ 2kD, concentration: 10mg/ml.
  • the CM5 chip was used for fixation using a Biacore 3000 instrument.
  • the running buffer is PBS+0.005% Tween 20. Fixation was carried out using an amino coupling method.
  • the concentration of the ligand was 10 ⁇ g/ml.
  • the fixing buffer was 10 mM sodium acetate, pH 4.0. Fixed amount: 1400 RU, fixed to flow cells 2.
  • the flow rate used was 10 ⁇ l/ml and the ligand was injected for 1 minute.
  • 10 mM Gly at pH 2.0 + 2.5 was used as a regenerant, and regeneration was carried out at a flow rate of 30 ⁇ l/min.
  • the injection time is 30s.
  • Kinetic analysis was performed using the following conditions: control channel: flow cell 1; running buffer was PBS; concentration gradient was 6.25 nM, 12.5 nM, 25 nM, 50 nM, 100 nM, 200 nM, 400 nM using Kinetic Analysis Wizard mode; injection time It was 1 minute; the dissociation time was 2 min; the flow rate was 30 ⁇ l/min.
  • the data was fitted using the Biaevaluation 4.1 software.
  • the quasi-sum model is a 1:1 binding model.
  • the dissociation constant KD value is inversely proportional to the force.
  • the chimeric peptide P5 was further tested in the following experiments.
  • Example 2 Pull-down assay to detect the interaction between P5 and PDZ1-2 domain
  • the column was equilibrated with 100 ⁇ l of His beads and 1 ml of MCAC-0 buffer for 5 min. Concussion at 4 °C. The mixture was centrifuged at 5000 g for 1 minute at 4 ° C, and the supernatant was discarded. 1 mg of PDZ1-2 protein was added to the mixture and made up to 1 ml with buffer. The mixture was spun for 1 hour at 4 °C. The mixture was then centrifuged at 5000 g for 1 minute at 4 ° C and the supernatant was discarded. Wash 3 times with 1 ml of MCAC-0 buffer for 5 minutes each time (at 4 ° C, shake wash).
  • both the P5 and PDZ1-2 domains were included in the elution band of polypeptide P5, thereby confirming that polypeptide P5 is capable of binding to the PDZ1-2 domain.
  • the focal cerebral ischemia-reperfusion model was improved.
  • CCA common carotid artery
  • ECA external carotid artery
  • pterygopalatine artery The 0.26 mm monofilament nylon fishing line head end 0.5 cm was coated with paraffin and marked at a length of 20 mm. All rats were inserted through the right CCA incision, in which the pterygopalatine artery was temporarily clamped to prevent mis-insertion.
  • the length of the suture is about 18-20 mm from the CCA bifurcation, depending on the animal's weight. Embed the right middle cerebral artery, then suture the skin and fix the end of the wire to the skin. After the ischemia reached 2 hours, the suture was carefully taken out to form a reperfusion. The body temperature was maintained at (37 ⁇ 0.5) °C during ischemia and 2 h after reperfusion. The success of the model is that the left limb is paralyzed after the patient is anesthetized, and the standing is unstable. When the tail is lifted, it turns to one side.
  • Neurological deficit signs were scored according to Longa and Bederson's 5-point method and scored 24 hours after waking of the animals. 0 points: no symptoms of nerve damage; 1 point: can not fully extend the contralateral forepaw; 2 points: turn to the opposite side; 3 points: dump to the opposite side; 4 points: can not be self-issued, loss of consciousness. The higher the score, the more serious the animal's behavioral disorder.
  • Animals Adult SD rats (Vitronius), SPF grade, body weight 220-250 g, male.
  • Instruments and medicines 1 line scissors, 2 eye surgery scissors, 4 bends, 4#, 5# surgical sutures, 6 ⁇ 17 triangular needles, 0.26 mm diameter bolts, and needle holders.
  • a conjugate (hereinafter referred to as FP5) was prepared using FITC-labeled P5 polypeptide, and preparation and labeling were performed by Kingsray Biotech, Inc., and the conjugate structure was FITC-YGRKKRRQRRRYEKLLDTEI (P5, SEQ ID NO: 3).
  • Rat body temperature maintenance instrument ZS-T small animal living body imager SI-Image AMIX.
  • the experiment was divided into a normal control group and a model group at different time points of ischemia.
  • FP5 (10mg/kg)
  • Each group of rats was administered by tail vein injection.
  • FP5 fluorescently labeled FP5 dissolved in physiological saline, 10 mg/kg, was injected through the tail vein, respectively.
  • the rats were sacrificed at different ischemic time points, and the brain tissues were quickly taken out and placed in a small animal living imaging system device for fluorescence detection.
  • the brain tissue was placed in a TTC dye solution (purchased from Solite Biotech Co., Ltd.) for staining to determine the correlation between the ischemic region and the FP5 distribution.
  • the removed brain tissue was placed in a 5 ml solution containing 2% TTC, and incubated at 37 ° C for 30 minutes in the dark, and the brain was flipped once every 5 minutes. After TTC staining, the normal tissue was rose red, and the infarcted tissue was unstained and white.
  • the normal mouse brain can be completely stained by TTC, and there is no distribution of the fluorescently labeled polypeptide, and the ischemic part of the ischemic rat brain cannot be stained by TTC, and the fluorescently labeled polypeptide is distributed in
  • the middle artery region is the ischemic site of the core ischemic region, suggesting that FP5 can be targeted to the ischemic site and play an indicative role.
  • the fluorescence intensity scale the amount of distribution in the ischemic core region is more, in the penumbra The area is relatively small, and the amount of distribution is related to the degree of ischemia.
  • the rat MCAO model was modeled for 5 min, 10 min, 20 min, and 30 min, respectively, and FP5 dissolved in physiological saline was injected through the tail vein, 10 mg/kg. Rats were sacrificed 30 min after peptide injection. The brain tissue was quickly taken out and placed in a small animal living imaging system device for fluorescence detection. The results are shown in Fig. 4B. As the ischemic time prolongs, the ischemic area of the rat brain gradually increases, and the ischemia of the brain tissue can cause all ischemia of the hemisphere.
  • FP5 It can timely indicate the brain tissue damage caused by ischemia in a short period of time, and can distinguish the core and semi-dark areas of ischemia, and its distribution is related to the degree of ischemia. This has a timely and effective indication of the diagnosis of the ischemic area.

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Abstract

L'invention concerne un conjugué comprenant un peptide et un marqueur détectable, le peptide comprenant une séquence d'acides aminés YEKLLDTEI (SEQ ID NO : 1) ou un variant fonctionnel de celui-ci. L'invention concerne également un procédé de diagnostic de maladies liées à une lésion du nerf cérébral à l'aide du conjugué comprenant le peptide et l'étiquette détectable, et un kit utilisé pour diagnostiquer des maladies associées à une lésion du nerf cérébral.
PCT/CN2016/109008 2016-12-08 2016-12-08 Conjugué et son utilisation WO2018103038A1 (fr)

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CN201680091448.6A CN110049994B (zh) 2016-12-08 2016-12-08 一种缀合物及其应用
PCT/CN2016/109008 WO2018103038A1 (fr) 2016-12-08 2016-12-08 Conjugué et son utilisation

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EP3524257A4 (fr) * 2016-10-10 2020-07-01 Biocells (Beijing) Biotech Co., Ltd. Utilisation d'un polypeptide associé à une lésion nerveuse excitatrice dans la prévention, l'atténuation ou le traitement de la douleur
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WO2019006691A1 (fr) * 2017-07-05 2019-01-10 拜西欧斯（北京）生物技术有限公司 Peptide destiné au traitement, à l'atténuation ou à la prévention d'une hémorragie cérébrale et son utilisation
WO2019006692A1 (fr) * 2017-07-05 2019-01-10 拜西欧斯（北京）生物技术有限公司 Composé pour traiter, atténuer ou prévenir une maladie liée au système nerveux et son utilisation

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CN104582724A (zh) * 2012-06-13 2015-04-29 梅里亚有限公司 重配btv和ahsv疫苗
CN104797603A (zh) * 2012-09-27 2015-07-22 不列颠哥伦比亚大学 肽导向的蛋白敲低
CN105873942A (zh) * 2013-11-04 2016-08-17 组织基因公司 使用pten抑制剂治疗损伤的神经

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EP3450448A4 (fr) * 2016-04-27 2019-04-17 Biocells (Beijing) Biotech Co., Ltd. Peptide thérapeutique destiné aux lésions liées à la neurotoxicité excitatrice
US11229675B2 (en) 2016-04-27 2022-01-25 Biocells (Beijing) Biotech Co., Ltd. Therapeutic peptides for excitatory neurotoxicity-related injuries
EP3524257A4 (fr) * 2016-10-10 2020-07-01 Biocells (Beijing) Biotech Co., Ltd. Utilisation d'un polypeptide associé à une lésion nerveuse excitatrice dans la prévention, l'atténuation ou le traitement de la douleur
US12398176B2 (en) 2018-08-27 2025-08-26 Regeneron Pharmaceuticals, Inc. Use of Raman spectroscopy in downstream purification

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