WO2015181393A1 - Nouveaux peptides à base de sfti et cyclotide - Google Patents

Nouveaux peptides à base de sfti et cyclotide Download PDF

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WO2015181393A1
WO2015181393A1 PCT/EP2015/062156 EP2015062156W WO2015181393A1 WO 2015181393 A1 WO2015181393 A1 WO 2015181393A1 EP 2015062156 W EP2015062156 W EP 2015062156W WO 2015181393 A1 WO2015181393 A1 WO 2015181393A1
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seq
peptides
acpa
peptide according
pdp
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Per-Johan Jakobsson
Ulf GÖRANSSON
Camilla Svensson
Lars Klareskog
Sunithi GUNASEKERA
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Per-Johan Jakobsson
Göransson Ulf
Camilla Svensson
Lars Klareskog
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention is related to bioengineered cyclic peptides containing citrul- line, based on SFTI (sunflower trypsin inhibitor) and cyclotides. These novel sequences have an effect in autoimmune diseases, e.g. citrullinated fibrinogen sequences that are grafted into the SFTI scaffold have been shown to block autoantibodies in rheumatoid arthritis and inhibit inflammation and pain. Further anti-citrullinated protein/peptide antibodies (ACPA) blocking agents including any ACPS active sequence listed in Table 2 and Table 4 can be used as diagnostic tools, i.e. for detection of subspecific antibodies as biomarkers, and for the isolation of subspecific antibodies.
  • ACPA anti-citrullinated protein/peptide antibodies
  • RA and ACPA Rheumatoid arthritis
  • RA Rheumatoid arthritis
  • ACPA anti-citrullinated protein/peptide antibodies
  • 60-70% of RA patients 2 '3 is one of the specific serological diagnostic markers of the disease. It is believed that ACPAs emerge as an immune response towards proteins containing citrul- line.
  • proteins/peptides arginines may be converted into citrulline by means of specific peptidylarginine deiminases, a process known as citrullination.
  • ACPA levels in patients are determined using enzyme-linked immunosorbent assay (ELISA), which employs citrullinated peptides that are cyclized via a disulfide bond.
  • ELISA enzyme-linked immunosorbent assay
  • ACPAs appear in early stages of disease ⁇ and are strongly associated with the genetic risk factor human leukocyte antigen-DRBi (HLADRBi) and polymorphisms in the protein tyrosine phosphatase N22 (PTPN22) gene 6 -?.
  • HLADRBi human leukocyte antigen-DRBi
  • PTPN22 protein tyrosine phosphatase N22
  • peptide scaffolds and chemistry developed at the University of Uppsala include the circular plant proteins known as cyclotides 18 and sunflower trypsin inhibitors (e.g. SFTI-i).
  • cyclotides 18 and sunflower trypsin inhibitors e.g. SFTI-i
  • Their use as drug scaffolds have been demonstrated in a series of recent studies. Proof-of- concept studies have been conducted for both cyclotides and SFTI-i for their ability to accommodate bioactive sequences within their three-dimensional framework while maintaining the overall peptide stability.
  • the SFTI scaffold comprises peptides with a head-to-tail circular backbone of 13 to 18 amino acids, including two cysteines connected by a disulfide bond. The sequences between the two cysteines form two loops.
  • the cyclotide scaffold comprises head to tail circular peptides of between 27 and 38 amino acids, including six cysteines connected by three disulfide bonds. The disulfide bonds are arranged in a so called cystine knot, i.e. Cys I is connected to Cys IV, Cys II to Cys V and Cys III to Cys VI. Cyclo- tides contain six loops, i.e. sequences between Cys residues.
  • Both scaffolds are characterized by their extraordinary biological and chemical stability, conferred by their cyclic amide peptide backbone combined with the presence of disulfide(s).
  • SFTI and cyclotide scaffolds being used originate from Asteraceae, Fabaceae, Violaceae, Rubia- ceae or Curcurbitaceae plant families.
  • the strategy of blocking autoantibodies using antigens grafted into these frameworks may also be used in other types of autoimmune diseases. They are also suitable for the normalization of altered bone metabolism treatment and treatment of fatigue.
  • the inventors have now developed potent ACPA blocking molecules and provided proof of concept that affinity purified ACPA can be neutralized in vitro and in vivo by stable molecules based on the amino acid primary structure of citrullinated fibrinogen peptides that have been previously identified in human arthritic tissue.
  • ACPA blocking agents include any peptidic compound or derivative that combine any ACPA active sequence epitope(s) and scaffold (s) below, in which the ACPA active sequence, or parts thereof, have been grafted into any loop of or loops of scaffold sequences.
  • ACPA binding agents for diagnostic purposes include ACPA blocking agents described above, which have been modified in a secondary loop with the purpose to facilitate binding to a column, ELISA-plate, or any other device.
  • ACPA active peptides include, but are not limited to, sequences in Table 2 and Table 4. ACPA active sequences also include
  • Scaffold sequences include sunflower trypsin inhibitory (SI I/SI ) peptides, which comprise a circular peptide backbone of 13 to 18 amino acids, a single disulfide bond between cysteines, and two loops defined as the sequences between cysteines. Examples include,
  • Scaffold sequences comprise cyclotides, e.g. from the Mobius (e.g. kalata Bi, kalata S, kalata B2) and bracelet subfamilies (e.g. cycloviolacin Oi - O20) and hybrids thereof, and the cyclotide like cyclic cystine knotted peptides from squash (Cucurbitacee; Momordica cochinchinensis Trypsin Inhibitor ⁇ ' peptides MCoTI-I to MCoTI-VHI).
  • Mobius e.g. kalata Bi, kalata S, kalata B2
  • bracelet subfamilies e.g. cycloviolacin Oi - O20
  • the cyclotide like cyclic cystine knotted peptides from squash Cucurbitacee; Momordica cochinchinensis Trypsin Inhibitor ⁇ ' peptides MCoTI-I to MCoTI
  • Cyclotide scaffolds sequences above include a cyclic backbone and disulfide bonds of CysI-CysIV, CysII-CysV and CysIII-CysVI, arranged in a cystine knot, and their sequences are of the following pattern:
  • Mobius cyclotides include, but are not limited to, cyclotides containing the following sequence pattern between Cysl and Cys III:
  • Bracelet sequences include, but are not limited to, cyclotides containing the following sequence pattern between Cys I and Cys III:
  • Selected bioactive (antigenic) epitopes are grafted into the scaffolds of sunflower trypsin inhibitor l (SFTI-i) and cyclotide Momordica conchinensis trypsin inhibitor II (MCoTI-II) in the design of stable ACPA neutralizer peptides.
  • SFTI-i sunflower trypsin inhibitor l
  • MCoTI-II cyclotide Momordica conchinensis trypsin inhibitor II
  • SFTI-i at the top is a 14 residue cyclic peptide isolated from the seeds of sunflower plants 2 3. It is stabilized by a single disulfide bond and a network of intramolecular hydrogen bonds.
  • MCoTI-II contains a cyclic cystine knot (CCK), in which three conserved disulfide bonds are arranged such that one disulfide penetrates an embedded ring formed by the two other disulfides and their interconnecting backbone 2 ⁇
  • CCK cyclic cystine knot
  • SFTI-I sunflower trypsin inhibitor I contains, as described above 14 amino acids in a cyclic peptide backbone, and one disulfide bond. The disulfide bond divides the peptide into two halves, which we call loops.
  • the natural function of SFTI is as a trypsin inhibitor - one of the loops contain a potent inhibitory sequence and loop 2 maintains the structure.
  • SFTI molecule known today.
  • the lower three structures in Figure 1 are all examples of cyclotides.
  • Peptides of this family of plant proteins are between 27 and 38 amino acids long and contain three disulfide bonds within their cyclic backbone. As such they contain six loops, i.e. sequences between cysteines. That gives the opportunity to insert more than one functional sequence: e.g. inserting one immunoblocking sequence and one albumin binding sequence to prolong half life in circulation.
  • the peptides have been explored to identify lead compounds, to isolate antigen specific ACPAs and to develop a tool for research and diagnostics.
  • cyclic backbones (also illustrated in Figure 1) in the peptide scaffolds in combination with disulfides give an extraordinary thermal, chemical and enzymatic stability.
  • the bioactive sequence in the example in Figure 2, namely the citrullinated fibrinogen peptide is inserted by replacing one of the loops in the peptides.
  • the trypsin inhibitory loop is exchanged and the structural loop is kept.
  • SFTI unsunflower trypsin inhibitor
  • cyclotide based peptides wherein SFTI and cyclotide peptides incorporate citrullinated sequence epitopes from fibrinogen peptides will be described with reference to the compounds listed below.
  • the first truncated peptide, with the suffix (lini), is as effective as the original one.
  • FIB 573 CIT (lini) as the starting peptide to insert into our scaffolds. All other peptides above, except the first three are macrocyclic, i.e. the N and C termini of the peptides are joined by an amide (peptide) bond.
  • New compounds according to the present invention include cyclic versions if FIB 573 CIT and FIB 573 CIT (lini), with Cit and Arg (as a control); and FIB 573 CIT (lini) inserted into that scaffold (with Cit and Arg).
  • the scaffold SFTI itself is also shown. We have also tested two different cyclotide scaffolds, kalata Bi and MCoTI-II, into the latter we have also inserted the shortest FIB 573 CIT peptide; (lin2).
  • CCP-i (cyclic citrullinated peptide I) is a published binder sequence of ACPA that is used as a positive control (note that this peptide is not cyclic N-C termini as SFTI, and cyclotides, it is called "cyclic” because it has one disulfide bond joining the two ends of the peptide).
  • Citrullinated peptides that have been identified as ACPA antigens, and truncated peptides containing both citmlline and arginine are synthetized in order to identify a minimal motif that can be grafted into the scaffolds.
  • the 573 a-fibrinogen peptide was targeted, and used in the proof of concept study described in detail below.
  • fib-a 573 is 21 residues long, but was truncated down to 15 and 11 residues, which may be regarded as more suitable lengths of sequence epitopes for grafting.
  • These peptides were tested in the ACPA neutralization assay and their IC50 determined. Peptides with the highest IC50 and lowest corresponding arginine control response were selected for optimization regarding stability and IC50. Then, these most potent linear analogues are i) head-to tail cyclized and ii) grafted onto cyclic peptide scaffolds to improve stability and IC50. Cyclic compounds are then tested in complex matrices like serum and blood for stability and sustained ACPA neutralization activity.
  • Cyclic peptides are synthesized using FMOC chemistry, combined with native chemical ligation for cyclization of peptide backbones.
  • the starting point of synthesis is chosen so that the final peptide contains a N-terminal Cys, and the linker chosen so that a C-terminal thioester is generated upon cleavage (ref 26).
  • the thus obtained thioesters can then be cyclized via native chemical ligation, forming an amide bond between the N and C termini. Cyclisation and folding (oxidation of disulfide bonds) are done in an established cyclization buffer (ref 26), Linear peptides are made using standard FMOC chemistry.
  • Synthesized peptides are analyzed by NMR to ensure that folded products are obtained (as judged from the dispersion of amide protons in ⁇ NMR).
  • Three-dimensional structure (3D) of active peptides will be determined using two dimensional NMR, including NOESY and TOCSY experiments.
  • Figure 3 shows that stability is gained by inserting FIB 573 CIT (lini) into the scaffold when incubated in human serum.
  • the four lines at the top represent peptide controls incubated in physiological salt solution.
  • grafted peptides i.e. peptides with the ACPA binding epitope inserted into the scaffold, has superior stability compared to both linear and head-to tail cyclic versions of FIB 573 CIT (lini).
  • Figure 4 shows that the same trend is seen in blood (human): the FIB 573 CIT (lini) shows superior stability compared to the other variants.
  • ACPA antibodies isolated are not fibrinogen specific, but are active against all citrullinated peptides including for example vimentin and alpha eno- lase as outlined above.
  • grafted and specific ACPA blockers we will use them to i) purify specific subspecificities of ACPA and ii) develop specific Elisa assays.
  • secondary loop(s) of the scaffold we will exploit the secondary loop(s) of the scaffold to introduce a handle for immobilization on columns and on microtiterplates.
  • a lysine will be introduced into the secondary loop of SFTI-FIB 573 CIT (lini), which will be used to immobilize the peptide to a NHS activated Sepharose-based column to isolate ACPA specific towards fib-a 573.
  • Specific antibody/peptide pairs will then be used to set up Elisa assays.
  • These assays will represent better models to monitor specific interactions, but will also be developed into a multiscreen Elisa platform that can identify which variant of ACPA that is present in individual patient samples (Fig 5).
  • Fig 5 multiscreen Elisa platform that can identify which variant of ACPA that is present in individual patient samples
  • Figure 5 shows the development of specific Elisa assays. Plates with our best candidate cyclic peptides will be used to develop a multiscreen Elisa. Streptavidin coated plates and a biotinylated linker will be used. (Note that we will replace any Lysine that is already present in the binding loop to prevent any interaction with the antibody binding loop).
  • ACPA neutralization assays We have purified ACPA from synovial fluid (SF) and plasma of RA patientss 0 .. The method allows purification of mg amounts of human ACPA and pools of ACPA are prepared by combin- ing material from 6-38 individuals. ACPA binding is measured using commercial ELISA assays. Our characterized fibrinogen peptides were individually or in combinations incubated with different ACPA pools and their blocking efficiency was expressed as percentage of inhibition and IC50. At physiological relevant concentration (deduced from concentrations in patient sera), the purified ACPA pool was treated with peptides containing the specific citrulline residues.
  • fibrinogen a chain peptide fragments "Cit573", “Cit59i” as well as fibrinogen ⁇ chain peptide fragments "Cit72”, “Cit74”, respectively.
  • the unmodified corresponding arginine peptides were used as controls.
  • Figure 6 shows dose-response curves for ACPA neutralizing peptides.
  • Cit573 resulted in the highest degree of ACPA neutralization, 84% (Figure 6.a) with an average calculated IC50 of 59 ⁇ .
  • Cit59i resulted in a similar dose response curve as peptide Cit573, although not as efficient.
  • a maximum of 63% ACPA neutralization was recorded for Cit59i ( Figure 6.b) and the IC50 calculated was 190 ⁇ .
  • the non-citrullinated version only showed marginal inhibition ( Figure 6.a).
  • the citrullinated peptides from the alpha chain displayed a synergistic effect reaching 91% inhibition ( Figure 7).
  • the dose-response curves for ACPA neutralization with fibrinogen peptides (Arg/Cit 573 and 591) in Figure 6 shows the following: Citrullinated 573 peptide ( Figure 6a) resulted in the highest degree of inhibition in the Elisa assay, 84%. Citrullinated 591 resulted in a similar dose response curve as peptide 573 ( Figure 6b).
  • X-axis show peptide concentrations ( ⁇ ) and Y-axis show the percentage of ACPA neutralization (%). Circles represent means of 2 to 7 experiments per ACPA pool and error bars represent SEM. * P ⁇ o.05 and ** P ⁇ o.ooi, significantly different from values found with arginine peptides.
  • Dose-response curves for ACPA neutralization with a combination of the two fibrino- gen-a chain peptides (Arg/Cit 573 and 591) in Figure 7 shows that two citrullinated peptides mixed together in equal amounts inhibit 91% of ACPA.
  • X-axis shows peptide concentration ( ⁇ ) and Y-axis shows the percentage of ACPA neutralization (%).
  • Figure 9 shows the effect of SFTI FIB 573 CIT (lini) on ACPA induced fibroblasts migration.
  • SFTI FIB 573 CIT (lini) reduced the fibroblasts migration rate in comparison to the treatment of the cells with ACPA alone.
  • X-axis shows the different conditions tested with the dermal fibroblasts and Y-axis shows migration rate fold.
  • mice treated with ACPA in the presence or absence of the described novel ACPA blocking compounds will be assessed by measuring changes in different pain modalities (sensitivity to mechanical and cold stimulation) and changes in normal behavior (locomotion, burrowing and gait).
  • CD14+ monocytes are isolated from peripheral blood of healthy individuals and/or ACPA positive RA patients and cul- tured in the presence of GM-CSF and IL-4 to generate dendritic cells (DC) or with GM-CSF to generate macrophages ( ⁇ ). Following 6 day incubation, DCs and ⁇ are incubated in the presence of RANKL and M-CSF, with or without ACPA IgG or flow through IgG (at a final concentration of 100 ng/ml). Osteoclasts differentiation is evaluated by total number of multinucleated TRAP+ cells.
  • the peptides are preferably administered intraarticularly, intraveneously or subcuta- neously dissolved in physiological saline solution.
  • SFTI FIB 573 CIT (lini) is given at a molar ratio of administered ACPA antibody/peptide of between 1/1000-10000; e.g. for an administered dose of 50 ug i.a. in the mouse in vivo model of pain-like behavior, 700 ug of SFTI FIB 573 CIT (lini) is given.
  • ACPA binding agents include ACPA blocking agents and may be used as diagnostic tools for purification and detection of ACPA. This includes different subpopulations of ACPA, ie antibodies directed to protein fragments, such as
  • the second loop of SFTI will then be used to anchor the peptide to a solid support, e.g a column for separation or a plate for development of Elisas.
  • the experimental animal model consists of an animal that is injected with antibodies that recognize citrullinated proteins (ACPA).
  • ACPA citrullinated proteins
  • the animal starts to develop pain that can be measured and quantified by conventional methods by anyone skilled to the art, like Von Frey filaments, hot plate, Hargreaves thermal test etc.
  • the effect of the inhibitor can be measured by comparing animals treated with ACPA with animals treated with the compound and ACPA.
  • ACPA anti-citrullinated protein antibodies
  • bradykinin Bi receptor antagonists engineered from a cyclotide scaffold for inflammatory pain treatment.
  • FIB 573 CIT (lin 2) 3 A EFP SXG KSS S Human cyclic FIB 573 CIT 4 CHHP GIA EFP SXG KSS SYS KQF Human derivative cyclic FIB 573 CIT (lin 1) 5 CGIA EFP SXG KSS SYS Human derivative cyclic FIB 573 ARG (lin 1 ) 6 CGIA EFP S R G KSS SYS Human derivative cyclic FIB 573 ALA (lin 1) 7 CGIA EFP S A G KSS SYS Human derivative
  • MCoTI-II (lin 2) 14 CPKILKKCRRDSDCPGACICRGN- Human and
  • Filaggrin 19 306 SHQESTXGXSRGRSGRSG 324 Human Fibrinogen a-chain fragment 20 36 GPXWEXHQSACKDS 50 Human 1
  • Fibrinogen a-chain fragment 580 SKQFTSSTSYNXGDSTFESKS 600 Human 4
  • Fibrinogen b-chain fragment 60 APPPISGGGYXARPAKAAAT 81 Human 3
  • Fibrinogen b-chain fragment 60 APPPISGGGYRAXPAKAAAT 81 Human 4
  • Fibrin a-chain fragment 3 45 181 SCSXALAXEVDLKDY 197 Human
  • BiP fragment 2 63 295 AKRALSSQHQAXIEIESFFE 314 Human a-Enolase fragment 1 64 394 TGAPCXSEXLAK 405 Human a-Enolase fragment 2 65 422 FAGXNFXNPLAK 433 Human a-Enolase fragment 3 66 405 YNQLLXIEEELGSK 419 Human a-Enolase fragment 4 67 256 YDLDFKSPDDPSXYISPDQLADLYK 280 Human
  • fragment 70 190 MKILTEXGYSFTTTAEXEIVRDIKEK 216 Human alpha-2-macroglobulin, fragment 71 705 VGFYESDVMGXGHAR 719 Human alpha-2-macroglobulin, fragment 72 1169 SLNEEAVKKDNSVHWERPQKPK 1190 Human apolipoprotein B- 100, fragment 73 3211 NXNNALDFVTK 3221 Human alpha-2-macroglobulin 74 705 VGFYESDVMGXGHAR 719 Human complement C3 75 1365 VTIKPAPETEKXPQDAK 1381 Human fibronectin 76 977 VFAVSHGXESKPLTAQQTTK 986 Human fibronectin 77 1029 LTVGLTXXGQPR 1039 Human alpha- 1 -antitrypsin 78 158 FLENEDXR 165 Human histone HI .2 79 53 EXSGVSLAALKK 64 Human histone H3.lt
  • Splicing factor 3B subunit 1 84 151 TYMDVMXEQHLTK 163 Mouse
  • Lysine mutant 1 92 CFPKDGRCGIAEFPSXGRSSSYS Human and Aste- raceae

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Abstract

L'invention concerne des nouveaux peptides utilisés pour traiter les maladies auto-immunes, la douleur ou comme outils de diagnostic, lesdits peptides étant formés d'un inhibiteur de la trypsine de tournesol (SFTI) et d'échafaudages peptidiques à base de cyclotide. L'invention concerne également l'utilisation de ces peptides pour atténuer la douleur, en particulier chez les patients souffrant de polyarthrite rhumatoïde, ou comme outil de diagnostic, et une méthode de préparation.
PCT/EP2015/062156 2014-05-30 2015-06-01 Nouveaux peptides à base de sfti et cyclotide WO2015181393A1 (fr)

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CN108948154A (zh) * 2018-05-22 2018-12-07 北京蛋白质组研究中心 一种瓜氨酸修饰肽及其应用
EP3715374A1 (fr) * 2019-03-23 2020-09-30 Ablevia biotech GmbH Composé de séquestration d'anticorps indésirables chez un patient
EP3715375A1 (fr) * 2019-03-23 2020-09-30 Ablevia biotech GmbH Composé pour la prévention ou le traitement de la pré-éclampsie
EP3715376A1 (fr) * 2019-03-23 2020-09-30 Ablevia biotech GmbH Composé pour la prévention ou le traitement de la myasthénie grave
WO2021086259A1 (fr) * 2019-10-30 2021-05-06 Glycoprobe Ab Adsorbant et kit contenant ledit adsorbant dans une colonne
WO2022063892A1 (fr) 2020-09-23 2022-03-31 Ablevia Biotech Gmbh Composé pour augmenter l'efficacité de vecteurs viraux
WO2022063880A1 (fr) 2020-09-24 2022-03-31 Ablevia Biotech Gmbh Composé pour prévenir ou traiter la myasthénie grave
WO2022063882A1 (fr) 2020-09-23 2022-03-31 Ablevia Biotech Gmbh Composé pour la prévention ou le traitement d'affections médiées par des autoanticorps
WO2022063885A1 (fr) 2020-09-23 2022-03-31 Ablevia Biotech Gmbh Composé pour la séquestration d'anticorps anti-peg indésirables chez un patient
WO2022063879A1 (fr) 2020-09-23 2022-03-31 Ablevia Biotech Gmbh Composé pour la séquestration d'anticorps indésirables chez un patient
WO2022063887A1 (fr) 2020-09-23 2022-03-31 Ablevia Biotech Gmbh Composé permettant d'augmenter l'efficacité d'une thérapie de remplacement du facteur viii
WO2023180502A1 (fr) 2022-03-24 2023-09-28 Ablevia Biotech Gmbh Composé pour augmentation de l'efficacité des virus oncolytiques
CN116808172A (zh) * 2023-01-07 2023-09-29 王晓娟 葵花盘脂质体及其在制备降低尿酸和溶解痛风石产品中的应用
US11986536B2 (en) 2019-03-23 2024-05-21 Ablevia Biotech Gmbh Compound for the sequestration of undesirable antibodies in a patient

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WO2014046732A1 (fr) * 2012-09-19 2014-03-27 University Of Southern California Antagonistes de cxcr4 basés sur un cyclotide et présentant une activité anti-vih

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