WO2019011879A1 - Agent thérapeutique pour le traitement du syndrome de fuite capillaire - Google Patents

Agent thérapeutique pour le traitement du syndrome de fuite capillaire Download PDF

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Publication number
WO2019011879A1
WO2019011879A1 PCT/EP2018/068582 EP2018068582W WO2019011879A1 WO 2019011879 A1 WO2019011879 A1 WO 2019011879A1 EP 2018068582 W EP2018068582 W EP 2018068582W WO 2019011879 A1 WO2019011879 A1 WO 2019011879A1
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amino
carboxylic acid
residue
group
acid
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PCT/EP2018/068582
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Rainer Henning
Petra WUELFROTH
Kai Zacharowski
Peter Petzelbauer
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Rainer Henning
Wuelfroth Petra
Kai Zacharowski
Peter Petzelbauer
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Publication of WO2019011879A1 publication Critical patent/WO2019011879A1/fr

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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
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to the treatment
  • the present invention relates to the field of tumor immunotherapy, more specifically to the prevention of the detrimental sequels of such therapy caused by T-cell cytokine release syndrome elicited by various approaches to tumor immunotherapy.
  • Methods for the prevention of vascular leak triggered, for instance, by T-cell related cytokines in these circumstances are disclosed .
  • Tumors have many mechanisms for immune evasion and for modulating immune response through perturbation of the antigen presenting machinery, DNA repair and replication, tumor microenvironment , inflammation pathways, and checkpoint inhibitors/activators. These immune tolerance mechanisms allow tumors to develop invasive growth.
  • T-cell-engaging immunotherapies include checkpoint inhibitors such as ipilimumab, a CTLA4 specific monoclonal antibody (Lipson et al . , Clin Cancer Res. 2011; 17: 6958- 6962), pembrolizumab (Deeks, Drugs 2016; 76: 375-386) and nivolumab (Johnson et al . , Ther Adv.
  • checkpoint inhibitors such as ipilimumab, a CTLA4 specific monoclonal antibody (Lipson et al . , Clin Cancer Res. 2011; 17: 6958- 6962), pembrolizumab (Deeks, Drugs 2016; 76: 375-386) and nivolumab (Johnson et al . , Ther Adv.
  • CRS cytokine release syndrome
  • CTL019 engineered T-cells composed of an anti-CDl9 single chain variable fragment (scFv) , aCD3( activation domain, and a 4-1BB costimula- tory domain) developed CRS.
  • scFv single chain variable fragment
  • aCD3( activation domain, and a 4-1BB costimula- tory domain developed CRS.
  • scFv single chain variable fragment
  • 4-1BB costimula- tory domain costimula- tory domain
  • the present invention relates to a method for inhibiting, treating and/or preventing a capillary leak syndrome (CLS) or symptoms thereof in a subject treated with a T-cell or NK cell activating agent, said method comprising administering fibrin-derived peptide B Beta 15-42 and/or at least one derivative thereof or a physiologically acceptable salt thereof to said subject.
  • CLS capillary leak syndrome
  • fibrin-derived peptide B Beta 15-42 and/or derivatives thereof can be used to optimize the dosing of T- cell and NK cell activating agents and to exploit their anti-tumor effect to its full extent.
  • Another aspect of the present invention relates to fibrin-derived peptide B Beta 15-42 and/or at least one derivative thereof for use in inhibiting, treating and/or preventing a capillary leak syndrome in a subject treated with a T-cell or NK cell activating agent.
  • a further aspect of the present invention relates to a composition comprising fibrin-derived peptide B Beta 15-42 and/or at least one derivative thereof as defined herein for use in inhibiting, treating and/or preventing a capillary leak syndrome in a subject treated with a T- cell or NK cell activating agent
  • the disruption of the adherence junction between endothelial cells is the hallmark of capillary leak syndrome. This disruption is caused by a rearrangement of the actin skeleton of the endothelial cell and the formation of stress fibres. This disruption can be caused by many effector molecules including cytokines released after activation of T-cells.
  • Symptoms of capillary leak syndrome include elevated hematocrit or hemoglobin readings (with hematocrit levels >40% due to the leak of plasma) , very low blood pressure (profound arterial hypotension, with systolic blood pressure levels ⁇ 90 mm Hg) , albumin deficiency (hypoalbuminemia measuring ⁇ 3.0 g/dL) , partial or generalized edema, cold extremities and a paraprotein in the blood (an MGUS in approximately 80% of cases) .
  • fibrin-derived peptide B Beta 15-42 and/or peptides, peptide derivatives or peptidomimetics act synergistically with the treatment of various cancers with immunologically active agents by allowing to maximize the dose of these agents for optimal anti-tumour efficacy, while avoiding the potentially lethal capillary leak syndrome, preferably caused by stimulation of T-cell related cytokines .
  • the present invention relates to a method for inhibiting, treating and/or preventing a capillary leak syndrome or symptoms thereof in a subject treated with a T-cell or NK cell activating agent, said method comprising administering fibrin-derived peptide B Beta 15-42 and/or at least one derivative thereof or a physiologically acceptable salt thereof to said subject. Fibrin-derived peptide B Beta 15-42 and/or at least one derivative thereof is administered to said subject in a therapeutically effective amount.
  • the present invention relates in another aspect also to a fibrin-derived peptide B Beta 15-42 and/or at least one derivative thereof for use in inhibiting, treating and/or preventing a capillary leak syndrome in a subject treated with a T-cell or NK cell activating agent.
  • the instant invention encompasses methods for inhibiting, treating and/or preventing a cytokine related vascular leak syndrome precipitated by treatment of a cancer patient with an agent that stimulates T-cells to attack and kill tumor cells.
  • fibrin-derived peptide B Beta 15-42 and/or at least one derivative thereof stops or reduces significantly the progress and symptoms of the disorder.
  • the inhibition/reduction may be at least 10%, preferably at least 20%, more preferably at least 50%, compared to a subject suffering from capillary leak syndrome who does not receive therapeutically amounts of fibrin-derived peptide B Beta 15-42 and/or at least one derivative thereof. If the capillary leak syndrome is a result of an increased cytokine secretion within the subject's body (e.g. due to the administration of T-cell activating agents like antibodies) , "inhibition" may also mean that the effect of an increased cytokine secretion is inhibited and/or reduced.
  • This inhibi- tion can for instance be measured by a reduction in ex- travascular lung water using the Picco instrument, by a reduction of the required dose of catecholamines to alleviated critical hypotension or parameter measuring renal function, e.g. creatinin clearance, as well as reduction of cytokine release.
  • treating and “treatment” refer to anything that promotes or enhances the well-being of the subject with respect to the medical treatment of his or her condition. This includes, but is not limited to, a reduction in the frequency or severity of the signs or symptoms of capillary leak syndrome. Since in a preferred embodiment of the present invention fibrin-derived peptide B Beta 15-42 and/or derivatives thereof can be used in subjects suffering from capillary leak syndrome caused by T-cell activating agents like antibodies making the disorder in most or even all cases reversible "treatment” may refer to a reduction of the disorder and/or symptoms thereof to an extent of at least 10%, more preferably at least 20%, preferably at least 30%.
  • B Beta 15-42 refers to the administration or application of fibrin-derived peptide B Beta 15-42 and/or at least one derivative thereof to a subject for the purpose of blocking the onset of capillary leak syndrome.
  • a subject that does not yet meet the clinical criteria or exhibit the symptoms of capillary leak syndrome, but has been treated with a T-cell or NK cell activating agent may be administered B Beta 15-42 and/or at least one derivative thereof to prevent or delay the onset of capillary leak syndrome or reduce the severity of the condition .
  • subject refers to mammals and most preferably to humans.
  • T-cell activating agent is meant to indicate any agent capable of inducing a T- cell or a modified T-cell to enter from a resting state into a state in which the T-cell undergoes the cell cycle or at least parts of it, recognizes a target tumor cell, releases cytokines and is able to kill the target cell.
  • T-cell activating agent induce in T cells or modified T cells those processes required for an immune response.
  • NK cell activating agent is meant to indicate any agent capable of increasing the activity of NK cells.
  • NK cells are usually active cells which show cytotoxic activity and are responsible among others for clearance of cells infected by viruses, senescent cells and malignantly transformed cells (i.e. cancer cells) .
  • the capability of agents to activate NK cells according to the present invention can be tested using methods known in the art (e.g. Nederby L et al . J Immunol Meth 458 (2018) : 21-25) .
  • a "derivative" of fibrin-derived peptide B Beta 15-42 may comprise one or more amino acid changes compared to the wild-type peptide.
  • the first four amino acid residues of the derivative are identical to the wild-type peptide.
  • the N-terminal end of the derivative is preferably a free amino group whereas the C-terminal end may be modified by the addition of organic groups like polyethylene glycol (PEG) .
  • the derivative of the present invention may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid exchanges compared to the wild-type peptide.
  • the derivative may be a monomer, dimer, trimer or tetramer of a modified or wild-type fibrin-derived peptide B Beta 15-42 whereby the monomers of the aforementioned multimers are linked to each other by disulphide bonds of cysteine residues, for instance, or other chemical moieties forming a bridge between the monomers.
  • the derivatives of the present invention exhibit properties for inhibiting, treating and/or preventing a capillary leak syndrome in a subject treated with a T-cell or NK cell activating agent.
  • Fibrin-derived peptide B Beta 15-42 and at least one derivative thereof can be administered in the form of physiologically acceptable nontoxic salts, such as acid addition salts or metal complexes, e.g., with zinc, iron or the like.
  • physiologically acceptable nontoxic salts such as acid addition salts or metal complexes, e.g., with zinc, iron or the like.
  • acid addition salts are hydrochloride, hydrobromide, sulphate, phosphate, male- ate, acetate, citrate, benzoate, succinate, malate, ascorbate, tartrate and the like.
  • the T-cell or NK cell activating agent is administered to a subject in need of an immunotherapy, in particular of a tumor therapy.
  • T-cell or NK cell activating agents are often used. Such agents may include chemotherapeutics as well as antibodies resulting in a T-cell or NK cell activation. These agents are known to result in a significant increase in cytokine secretion, for instance, which may lead to a cytokine "storm". The increased cytokine secretion may result in capillary leak syndrome.
  • the T-cell or NK cell activating agent is administered simultaneously or successively to said fibrin-derived peptide B Beta 15-42 and/or at least one derivative thereof.
  • Tumor immunotherapy agents may include but not only IL 6-blocking antibodies (e.g. tocilizumab) or a corticosteroid.
  • “Simultaneous" administration of active ingredients e.g. a T-cell and/or NK cell activating and fibrin-derived peptide B Beta 15-42 and/or at least one derivative thereof
  • active ingredients e.g. a T-cell and/or NK cell activating and fibrin-derived peptide B Beta 15-42 and/or at least one derivative thereof
  • the active ingredients of the present invention may be administered to a subject "successively" or "sequentially”.
  • the time in between administration of the active ingredients may vary from 1 min to 72 hrs, preferably from 1 min to 48 hrs, more preferably from 5 min to 24 hrs.
  • the fibrin-derived peptide B Beta 15-42 consists of amino acid sequence GHRPLDKKREEAPSLRPAPPPISGGGYR (SEQ ID No. 1) .
  • WO 2009/137851 and WO 2009/137852 disclose derivatives of fibrin-derived peptide B Beta 15-42, which can be used in the method of the present invention.
  • the fibrin-derived peptide B Beta 15-42 derivative has a general formula selected from the group consisting of
  • Xl, X2, X3, X4, X5, ⁇ , X7, ⁇ , ⁇ , XlO, Xll, Xl2, X13, Xl4, Xl5 and Xi6 are independently selected from the group of amino acid residues,
  • Ri is hydrogen or a C1-C10 alkyl group
  • NR2R3 wherein R2 and R3 are independently hydrogen, a C1-C10 alkyl group, or c) a residue -PEG5-6OK, wherein the PEG-residue is linked to the N atom via a spacer, or d) a residue NH-Y1-Z-PEG5-6OK, wherein Yi is a chemical bond or an amino acid residue selected from the group consisting of S, C, K and R, and Z is a spacer by way of which a polyethylene glycol (PEG) - residue is linked, or e) a residue -PEG5-6OK-CO-NR4R5, wherein R4 and R5 are independently hydrogen or a C1-C10 alkyl group, or f) a residue NH-CH (CONH2 ) - (CH 2 ) 4-NH-CO-Y2-PEG5-6OK, wherein
  • X27, X28 and X29 are independently selected from the group consisting amino acid residues or are independently a single bond
  • B is -CO- (CH 2 ) m-Y3- (CH 2 ) m-CO- bound via the CO group to the ⁇ amino group of amino acid residue K, wherein m is an integer from 1 to 4 and Y3 is
  • n is an integer from 1 to 4 and Z is NH or 0,
  • B(2) is a chemical bond or Y
  • B(3) is a chemical bond or R
  • ⁇ is an amino acid residue or a peptidomimetic element, wherein said amino acid residue is selected from the group consisting of L-proline, D-proline, L-hy- droxyproline, D-hydroxyproline, L- (0-benzyl) -hy- droxyproline, D- (O-benzyl) -hydroxyproline, L- (0- tert .
  • Xi5 or Xi6 of formula (I) is an amino acid selected from the group consisting of C and K, which is linked to residue Z-PEG5-6OK via the heteroatom in the side chain, and wherein
  • ORi wherein Ri is hydrogen or a Ci-Cio-alkyl group, or b) NR2R3, wherein R2 and R3 are independently hydrogen or a C1-C10 alkyl group.
  • Xi , Xg , X10, Xi4, X20 and X23 are independently L, I, S, M or A,
  • X2, ⁇ , X7 and X21 are independently E or D,
  • X3, X4, X5 X11 and X22 are independently R or K
  • Xs X12, X24, X25 and X26 are independently A, G, S, or
  • L, Xi3 is I, L or V
  • Xi5 and Xi6 of formula (Ila) , (lib) are independently G, A, S, or C,
  • X27 is G, A or L
  • X28 is Y, F, H or a single chemical bond and X29 is R, K or a single chemical bond.
  • a compound of formula I is preferably selected from the group consisting of GHRPLDKKREEAPSLRPAPPPISGG- GYR-NH2 (SEQ ID No. 9), GHRPLDKKREEAPSLRPAPPPISGGGYRC- (S- CH2-CO-NH-PEG20K ) -OH (SEQ ID No. 10), GHRPLDKKREEAPSLRPAPPPISGGGYRC- (S-CH2-CO-NH-PEG20K ) -amid (SEQ ID No. 11) and GHRPLDKKREEAPSLRPAPPPISGC- ( S-CH 2 -CO-NH-PEG 2 OK) -GYR-amid (SEQ ID No. 12) .
  • a compound of formula Ila is preferably (GHRPLDKKREEAPSLRPAPPPISGCGYR) 2 a Cys25-Cys25 homodimeric cysteine peptide (SEQ ID No. 13).
  • a compound of the formula III is:
  • a compound of formula IV is selected from the group consisting of GHRPLAPSLRPAPPPISGGGYR -OH (SEQ ID No. 17), GHRPLAPSLRPAPPPISGGGYR -NH 2 (SEQ ID No. 18),
  • GHRPLAPSLRPAPPPISGGGYRC- (S-succinimide-PEG 2 0K ) -OH (SEQ ID No. 19) and GHRPLAPSLRPAPPPISGGGYRC- (S-succinimido- PEG20K ) -amide (SEQ ID No. 20).
  • a compound of formula V is selected from the group consisting of GHRPLDKKREEAPSLRPAPPPISGG-OH (SEQ ID No. 21), GHRPLDKKREEAPSLRPAPPPISGG-NH2 (SEQ ID No. 22),
  • GHRPLDKKREEAPSLRPAPPPISGGG-NH2 (SEQ ID No. 24) .
  • a compound of formula VI is selected from the group consisting of GHRPLDK- (IS, 2R) Achc-ISGGGYR (SEQ ID No. 25), GHRPLDK-Acdn-ISGGGYR (SEQ ID No. 26), GHRPLDK- (cis-4-Acha) -ISGGGYR (SEQ ID No. 27) and GHRPLDK-Haic-IS- GGGYR (SEQ ID No . 28) .
  • fibrin-derived peptide B Beta 15-42 as the sole active ingredient or in combination with at least one derivative thereof.
  • fibrin-derived peptide B Beta 15-42 it is possible to administer at least one derivative of fibrin-derived peptide B Beta 15-42 as the sole active ingredient or in combination with fibrin-derived peptide B Beta 15-42.
  • Fibrin-derived peptide B Beta 15-42 and/or at least one derivative thereof may be administered to a subject in need thereof by any means known to be suitable to those skilled in the art, including intravenous, subcutaneous, intramuscular and mucosal administration.
  • a formulation may thus be formulated for administration via the intravenous, subcutaneous, intramuscular and mucosal route.
  • the mucosal route may be exemplified by, but is not limited to, the pulmonary, nasal, sublingual or buccal route.
  • the formulation may be provided as a sterile solution, suspension or an emulsion.
  • the formulation may be applied by means of an injection or an infusion.
  • the formulation may be provided as an aqueous spray and may be applied directly by means of a spray container or an inhalator. Alternatively the formulation may be administered to the mucosa as an aqueous gel.
  • Fibrin-derived peptide B Beta 15-42 and/or at least one derivative thereof may be provided in a liquid or solid form. Both components may be part of a lyophilisate (solid form) which can be combined with a buffer or a physiological salt solution prior administration to a subject. Alternatively, the components may be part of a liquid formulation which may include oils, polymers, vitamins, carbohydrates, amino acids, salts, buffers, albumin, surfactants, or bulking agents. Exemplary carbohydrates include sugar or sugar alcohols such as mono-, di- or polysaccharides, or water-soluble glucans .
  • the saccharides or glucans can include fructose, dextrose, lactose, glucose, mannose, sorbose, xylose, maltose, sucrose, dex- tran, pullulan, dextrin, alpha- and beta-cyclodextrin, soluble starch, hydroxethyl starch and carboxymethyl- cellulose, or mixtures thereof.
  • "Sugar alcohol” is defined as a C4 to Ce hydrocarbon having an -OH group and includes galactitol, inositol, mannitol, xylitol, sorbitol, glycerol, and arabitol. These sugars or sugar alcohols mentioned above may be used individually or in combination.
  • Any physiological buffer may be used, but in some cases can be selected form citrate, phosphate, succinate, and glutamate buffers or mixtures thereof.
  • inventive compounds show an effect at a dose
  • fibrin-derived peptide B Beta 15-42 and/or at least one derivative thereof allows to increase the dose of T-cell and/or NK cell activating agents 1.2-fold up to 10-fold, preferably, 1.5 up to 5 fold, more preferably 1.5 up to 3 fold, because fibrin- derived peptide B Beta 15-42 and its derivatives reduce the side effects caused by both activating agents.
  • the dose of said T-cell or NK cell activating agent administered to a subject within said immunotherapy can be increased when administered simultaneously or successively with fibrin-derived peptide B Beta 15-42 and/or at least one derivative thereof compared to the administration of the T-cell or NK cell activating agent without fibrin-derived peptide B Beta 15-42 and/or at least one derivative thereof .
  • said T-cell activating agent is a checkpoint inhibitor .
  • Checkpoint inhibitor therapy is a form of cancer
  • the therapy uses immune checkpoints which affect immune system functioning. Immune checkpoints can be stimulatory or inhibitory. Tumors can use these checkpoints to protect themselves from immune system attacks . Checkpoint therapy can block inhibitory checkpoints, restoring immune system function.
  • said checkpoint inhibitor is selected from the group consisting of a CTLA4 antagonist, a PDl antagonist and PDL-1 antagonist.
  • fibrin-derived peptide B Beta 15-42 and/or peptides, peptide derivatives or peptidomimetics of the general formulae (I-VI) are administered simultaneously and/or sequentially with a checkpoint inhibitor, exemplified but not limited to an inhibitor to CTLA4 (e.g. ipilimumab) or PD-1 or PDL-1 (e.g. pembrolizumab or nivolumab) .
  • the T- cell activating agent is a bi-specific antibody engaging T-cells to tumor cells comprising at least one binding site for activating molecules on the T-cell surface and at least one binding site for a tumor specific antigen on the tumor cell.
  • the T-cell activating agent is a bi-specific antibody with binding sites for CD3 and CD19.
  • fibrin-derived peptde B Beta 15-42 and/or peptides, peptide derivatives or peptidomimetics of the general formulae (I-VI) are administered simultaneously and/or sequentially with an agent capable of engaging T-cells with tumor cells, exemplified but not limited to a bi-specific antibody targeting CD3 and CD19 (e.g. blinatumomab) .
  • an agent capable of engaging T-cells with tumor cells exemplified but not limited to a bi-specific antibody targeting CD3 and CD19 (e.g. blinatumomab) .
  • the tumor specific antigen is selected from the group consisting of CD19, CD22, BCMA, CD123, Her2, EG- FRvIII, PSCA and GD2.
  • the activating molecule in the T-cell is selected from the group consisting of CD28, 4-1BB, OX40 and ICOS.
  • fibrin-derived peptide B Beta 15-42 and/or peptides, peptide derivatives or peptidomimetics of the general formulae (I- VI) are administered simultaneously and/or sequentially with engineered T-cells carrying a chimeric antigen receptor, which binds to tumor cells, and co-activation receptors required for activation of the T-cell.
  • engineered T-cells carrying a chimeric antigen receptor, which binds to tumor cells, and co-activation receptors required for activation of the T-cell.
  • This is exemplified by but not limited to CTL019, engineered T- cells composed of an anti-CDl9 single chain variable fragment (scFv) , aCD3( activation domain, and a 4-1BB costimulatory domain.
  • a dose of the tumor immunotherapy agent is given in conjunction with fibrin-derived peptide B Beta 15-42 and/or peptides, peptide derivatives or peptidomimetics of the general formulae (I- VI) , which is higher than the dose that can be safely applied without this adjunct treatment because of the elic- itation of potentially lethal capillary leak syndrome.
  • Fibrin-derived peptide BBeta 15-42 and/or peptides, peptide derivatives or peptidomimetics of the general formulae (I-VI) can be given in association with a suitable pharmaceutical carrier and can be dosed by various application route, e.g. by bolus intravenous or subcutaneous injection or by continuous intravenous infusion.
  • Dosage of fibrin derived peptide B Beta 15-42 or peptides, peptide derivatives or peptidomimetics of the general formulae (I-VI) may vary with the particular need of the patient treated. Dosage units may be increased or decreased based on the weight of the patient.
  • the pharmaceutical preparation comprising the agent may be administered at appropriate intervals until the pathological symptoms are reduced or alleviated. These intervals in a particular case will normally depend on the condition of the patient.
  • Another aspect of the present invention relates to fibrin-derived peptide B Beta 15-42 and/or at least one derivative thereof for use in inhibiting, treating and/or preventing a capillary leak syndrome in a subject treated with a T-cell or NK cell activating agent.
  • Yet another aspect of the present invention relates to a composition comprising fibrin-derived peptide B Beta 15-42 and/or at least one derivative thereof as defined herein for use in inhibiting, treating and/or preventing a capillary leak syndrome in a subject treated with a T- cell or NK cell activating agent.
  • composition of the present invention may comprise pharmaceutically acceptable excipients which are usually used to manufacture compositions suited to be administered in a form as defined herein.
  • ECIS Electrometic impedance of endothelial cells is measured using the ECIS system (Applied Biophysics) .
  • Human umbilical cord endothelial cells are seeded on gelatin-coated plates at a density of 12000 cells per well and grown to confluence at 37°C and 5% CO2. After resistance at 4000Hz reaches a stable plateau >1000 ⁇ , CD3 positive T cells isolated from peripheral blood and pre-stimulated with phorbol 12-myristate 13-acetate (PMA) (10 ng/ml) and Ionomycin ( 0.4 ⁇ ) for 6h are added at a concentration of 12000 per well together with FX06 (GHRPLDKKREEAPSLRPAP- PPISGGGYR; SEQ ID No.
  • PMA phorbol 12-myristate 13-acetate
  • Ionomycin 0.4 ⁇

Abstract

La présente invention concerne un procédé d'inhibition, de traitement et/ou de prévention d'un syndrome de fuite capillaire chez un sujet traité avec une cellule T ou un agent d'activation de cellule NK, ledit procédé comprenant l'administration audit sujet d'un peptide B Bêta 15-42 dérivé de la fibrine et/ou d'au moins un dérivé de celui-ci ou d'un sel physiologiquement acceptable de celui-ci.
PCT/EP2018/068582 2017-07-09 2018-07-09 Agent thérapeutique pour le traitement du syndrome de fuite capillaire WO2019011879A1 (fr)

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EP3912679A1 (fr) 2020-05-19 2021-11-24 Johann Wolfgang Goethe-Universität Frankfurt am Main Bbeta pour le traitement de l'endothélite virale

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