US20030105021A1 - TNF-derived peptides for use in treating oedema - Google Patents

TNF-derived peptides for use in treating oedema Download PDF

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US20030105021A1
US20030105021A1 US09/779,703 US77970301A US2003105021A1 US 20030105021 A1 US20030105021 A1 US 20030105021A1 US 77970301 A US77970301 A US 77970301A US 2003105021 A1 US2003105021 A1 US 2003105021A1
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tnf
peptide
oedema
peptides
amino acids
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Rudolf Lucas
Patrick De Baetselier
Jerome Pugin
Alain Bloc
Lucie Fransen
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Fujirebio Europe NV SA
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Assigned to INNOGENETICS N.V. reassignment INNOGENETICS N.V. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FRANSEN, LUCIE, BLOC, ALAIN, PUGIN, JEROME, DE BAETSELIER, PATRICK, LUCAS, RUDOLF
Priority to US10/162,553 priority Critical patent/US7258861B2/en
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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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/191—Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/525—Tumour necrosis factor [TNF]

Definitions

  • the present invention is based on the finding that peptides derived from a specific domain of tumor necrosis factor-alpha (TNF- ⁇ ) can efficiently be used to treat oedema. More specifically, the present invention relates to the usage of peptides derived from the region of human TNT- ⁇ from Ser 100 to Glu 116 to treat pulmonary oedema. For example, the circularized peptide having amino acid sequence CGQRETPEGAEAKPWYC is shown to be very efficient in inducing oedema resorption.
  • Pulmonary transplantation is shown to be successful in the treatment of patients with end-stage pulmonary disease.
  • pulmonary oedema or edema both terms can be used interchangeably
  • the endothelium plays an essential role in regulating the dynamic interaction between pulmonary vasodilatation and vasoconstriction and is a major target during ischemia/reperfusion and acute respiratory distress syndrome (ARDS)-related lung injury.
  • ARDS acute respiratory distress syndrome
  • TNF tumor necrosis factor-alpha
  • TNF is a pleiotropic cytokine, mainly produced by activated macrophages, that is synthesized as a transmembrane molecule that can be released by metalloproteinases from the cell surface into the circulation (Gearing et al., 1994).
  • TNF has been shown to bind to at least two types of membrane-bound receptors, TNF receptor 1 (55 kD) and TNF receptor 2 (75 kD), that are expressed on most somatic cells, with the exception of erythrocytes and unstimulated T lymphocytes.
  • TNF can be considered as a two-edged sword: indeed, when overproduced, TNF has been shown to be implicated in the pathology of various infectious diseases, such as LPS-induced sepsis (Beutler et al., 1985), cerebral malaria (Grau et al., 1987), as well as treatment-associated mortality in African trypanosomiasis (Lucas et al., 1993).
  • infectious diseases such as LPS-induced sepsis (Beutler et al., 1985), cerebral malaria (Grau et al., 1987), as well as treatment-associated mortality in African trypanosomiasis (Lucas et al., 1993).
  • TNF was shown to be one of the most efficient protective agents against cecal ligation and puncture-induced septic peritonitis in mice and rats (Echtenacher et al., 1990, Alexander et al., 1991; Lucas et al., 1997) and to be implicated in host defense during pneumococcal pneumonia in mice (van der Poll et al., 1997).
  • mice deficient in TNF receptor 1 were shown to be significantly more sensitive to Listeria monocytogenes (Rothe et al., 1993; Pfeffer et al., 1993) and Mycobacterium tuberculosis infection Flynn et al., 1995) as well as against fungal (Steinshamn et al., 1996) and Toxoplasma infections (Deckert-Schluter et al., 1998). Therefore, it becomes clear that apart from its detrimental effects during overproduction or during prolonged chronic secretion, TNF is also one of the most potent protective agents against infections by various pathogens. In this regard, peptides derived from TNF have been suggested to be used as treatment against disease (DE 3841759 to Böhm et al.)
  • TNF receptor 1 Apart from exerting a plethora of effects mediated by the activation of its two types of receptors (TNF receptor 1, 55 kD, and TNF receptor 2, 75 kD), TNF can also mediate receptor-independent activities.
  • the tip domain of TNF is located on the top of its bell-shaped structure and is spatially distinct from its receptor binding sites, that are localized at the base of the trimeric molecule (Lucas et al., 1994). This domain has lectin-like affinity for specific oligosaccharides, such as trimannose and diacetylchitobiose.
  • TNF and the tip peptide of TNF are capable of mediating a trypanolytic activity by interfering with the lysosomal integrity of the trypanosome, a pH-dependent effect probably involving the insertion of TNF into the lysosomal membrane (Magez et al., 1997).
  • mutants of the tip peptide in which three critical amino acids (T(105): E(107); E(110)) were replaced by A were completely unable to mediate this activity (Lucas et al., 1994).
  • triple mTNF A mouse TNF (mTNF) triple mutant, T105A-E107A-E110A (referred to hereafter as triple mTNF), lacks the trypanolytic and lectin-like affinity to oligosaccharides as compared to wild type TNF.
  • the triple mTNF has significantly reduced systemic toxicity as compared to wild-type mTNF in vivo, but retains its penrtonitis-protective effect in a murine model (Lucas et al., 1997).
  • TNF receptor-independent activity of TNF is its membrane-inserting and sodium channel forming capacity (Baldwin et al. 1996). Indeed, others have shown that TNF forms a Na + -channel in an artificial lipid bilayer model, an activity that is pH-dependent, probably because it requires the “cracking” of the trimer, thus exposing hydrophobic residues to the membrane (Kagan et al., 1992).
  • the present invention aims at providing a non-toxic molecule with the same oedema resorption-inducing capacity as TNF. More specifically, the present invention aims at providing non-toxic peptides derived from TNF which can be used to prevent or treat oedema. Moreover, the present invention aims at providing a pharmaceutical composition comprising TNF-derived peptides which induce oedema resorption. In essence, the present invention aims at providing a new medical use of the TNF-derived, trypanocidal peptides as described by Lucas et al. (1994) and fragments and variants thereof.
  • FIG. 1 (A) Current-voltage relationship in murine lung microvascular endothelial cells, preincubation for 30 min with wt mTNF (100 ng/ml) or NES buffer at pH 6 and at pH 7.3. The values represent the means of ⁇ 5 cells ⁇ SEM (*:P ⁇ 0.05). (B) Characteristic current traces of a lung MVEC pretreated with medium (top) or with 100 ng/ml of TNF (bottom) at pH 6.0.
  • FIG. 2 Current-voltage relationship in resident peritoneal macrophages isolated from (A) control and (B) TNFR 1 ⁇ 2 0/ C57BL/6 mice. cells were pretreated for 30 min with medium, wt mTNF (100 ng/ml) or Ltip peptide (100 ⁇ g/ml). The values indicate the means of ⁇ 5 cells ⁇ SEM (*:P ⁇ 0.05).
  • FIG. 3 Effect of amiloride (100 ⁇ M), added for 30 min during the preincubation step, on wt mTNF-induced increase in membrane conductance in MVEC. Comparison of the effect of triple mTNF (100 ng/ml) and wt mTNF (100 ng/ml), upon 30 min preincubation with lung MVEC. Values indicate the means of ⁇ 5 cells ⁇ SEM (*:P ⁇ 0.05).
  • FIG. 4 (A) Effect of Ltip (100 ⁇ g/ml) versus controls in CBA lung MVEC at pH 6 and pH 7.3. (B) Comparison of the effect of 30 min preincubation of MVEC with Ltip peptide, mutTip peptide, and scramblTip peptide at pH 6. Effect of amiloride (100 ⁇ M) added during the preincubation, on Ltip peptide-induced increase in membrane conductance in MVEC. Values indicate the means of ⁇ 5 cells ⁇ SEM (*:P ⁇ 0.05).
  • FIG. 5 Effect of mTNF tip peptide (1 mg/lung) on lung weight change (in g) during an isolated lung perfusion experiment lasting 150 min.
  • FIG. 6 Effect of wild type mTNF ( ⁇ ,1 ⁇ g/lung) or mTNF tip peptide ( ⁇ ,1 mg/lung) versus controls [ ⁇ , NaCl] on lung weight change (in % versus baseline lung weight at 30 min) during isolated lung perfusion experiments after 150 min.
  • Each symbol [ ⁇ , ⁇ or ⁇ ] represents one lung.
  • the present invention relates to the use of a peptide comprising a chain of 7 to 17, preferably a chain of 11 to 16, more preferably a chain of 13 to 15 and most preferably a chain of 14 contiguous amino acids derived from the region of human TNF- ⁇ from Ser 100 to Glu 116 or from the region of mouse TNF- ⁇ from Ser 99 to Glu 115 for the manufacture of a medicament for treating oedema. More specifically the present invention relates to the use of a peptide as described above wherein said chain of 14 contiguous amino acids are chosen from the group consisting of the contiguous amino acid sequences QRETPEGAEAKPWY and PKDTPEGAELKPWY as described by Lucas et al. (1994). The latter sequences are given in the well-known one-letter code for amino acids (the three-letter code is sometimes used further).
  • peptide refers to a polymer of amino acids (aa) derived from the trypanolytic TNF domain having lectin-like affinity as described by Lucas et al. (1994). Moreover, the latter term relates to a polymer of 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17 contiguous amino acids derived from the region of human TNF- ⁇ from Ser 100 to Glu 116 or from the region of mouse TNF- ⁇ from Ser 99 to Glu 115 . The latter TNF regions also refer to the regions shown in FIG. 5, p. 172 of Pennica and Goeddel in Webb and Goeddel, eds. (1987).
  • peptide more specifically relates to a peptide comprising the hexamer TPEGAE of the latter TNF regions or any peptide comprising the corresponding amino acids T, E and E of the latter hexamer which were shown to be three critical amino acids by Lucas et al. (1994). It should be clear that the present invention relates to any peptide derived from the latter TNF regions and does not exclude post-translational modifications of the peptides such as glycosylation, acetylation, phosphorylation, modifications with fatty acids and the like.
  • peptides containing one or more analogues of an aa include unnatural aa's
  • peptides with substituted linkages include mutated versions or natural sequence variations of the peptides, peptides containing disulfide bounds between cysteine residues, as well as other modifications known in the art.
  • the peptides of the present invention are also defined functionally, that is, the present invention relates to any peptide which can be used to treat oedema or which can be used for the manufacture of a medicament for treating oedema.
  • the present invention relates to any molecule, obtained by any method known in the art, with the same or very similar characteristics as the trypanolytic peptides defined by Lucas et al. (1994).
  • the peptides of the present invention can be prepared by any method known in the art such as classical chemical synthesis, as described by Houbenweyl (1974) and Atherton & Shepard (1989), or by means of recombinant DNA techniques as described by Maniatis et al. (1982) and, more specifically, by Lucas et al. (1994).
  • oedema (or edema) relates to any abnormal excess accumulation of (serous) fluid in connective tissue or in a serous cavity.
  • the latter term relates to pulmonary oedema (see also Examples section).
  • the present invention concerns the use of a peptide as described above wherein said peptide is circularized. More specifically, the present invention relates to the use of a peptide as described above, wherein said peptide is circularized by replacing the NH 2 — and COOH-terminal amino acids by cysteine so that a disulfide bridge is formed between the latter cysteines.
  • the present invention concerns the use of a peptide as described above wherein said circularized peptides are chosen from the group consisting of the circularized peptides CGQRETPEGAEAKPWYC and CGPKDTPEGAELIPWYC as described by Lucas et al. (1994).
  • the present invention finally relates to a pharmaceutical composition for treating oedema comprising a peptide as described above.
  • a pharmaceutical composition for treating oedema relates to any composition comprising a peptide as defined above which prevents, ameliorates or cures oedema, in particular pulmonary oedema.
  • a pharmaceutical composition for treating oedema or “a drug or medicament for treating oedema” (both terms can be used interchangeably) relate to a composition comprising a peptide as described above and a pharmaceutically acceptable carrier or excipient (both terms can be used interchangeably) to treat oedema
  • Suitable carriers or excipients known to the skilled man are saline, Ringer's solution, dextrose solution, Hank's solution, fixed oils, ethyl oleate, 5% dextrose in saline, substances that enhance isotonicity and chemical stability, buffers and preservatives.
  • suitable carriers include any carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids and amino acid copolymers.
  • the “medicament” may be administered by any suitable method within the knowledge of the skilled man.
  • the preferred route of administration is parenterally.
  • the medicament of this invention will be formulated in a unit dosage injectable form such as a solution, suspension or emulsion, in association with the pharmaceutically acceptable excipients as defined above.
  • the dosage and mode of administration will depend on the individual.
  • the medicament is administered so that the peptide of the present invention is given at a dose between 1 ⁇ g/kg and 10 mg/kg, more preferably between 10 ⁇ g/kg and 5 mg/kg, most preferably between 0.1 and 2 mg/kg. Preferably, it is given as a bolus dose. Continuous infusion may also be used. If so, the medicament may be infused at a dose between 5 and 20 ⁇ g/kg/minute, more preferably between 7 and 15 ⁇ g/kg/minute.
  • mice Male CBA/J or C57BL/6 mice, as well as male TNFR 1 ⁇ 2 0/0 C57BL/6 mice deficient in TNF receptors (Bruce et al., 1996 ) provided by H. Bluethmann, F. Hoffmann-La Roche, Basel, Switzerland, were used at the age of 8-10 weeks. Their care was in accordance with institutional guidelines.
  • Lung microvascular endothelial cells were isolated from CBA/J mice and characterized as described (Jackson et al., 1990) using magnetic beads (Dynabeads M-450, Dynal, Oslo, Norway), covalently bound to a purified rat-anti-mouse PECAM-1 monoclonal antibody (donated by B. Imhof, University of Geneva).
  • Microvascular lung endothelial cells were resuspended in DMEM containing 2 mM L-glutamine, 100 U/ml penicillin, 10 mg/ml streptomycin, 20% FCS, 40 U/ml heparin and 100 mg/ml endothelial cell growth supplement (Brunschwig Chemie, Basel, Switzerland).
  • TNF and peptides E.coli -derived recombinant murine TNF (further referred as TNF in the text) and an E.coli -derived recombinant (T104A-E106A-E109A) triple TNF mutant (mutTNF) were synthesized as described elsewhere (Lucas et al., 1997). TNF-derived peptides were synthesized with the use of Fmoc-a-amino group protection (Fields et al. 1990), and purified with a C18 reversed-phase high-performance liquid chromatography column.
  • TNF-derived peptides were synthesized: Long tip peptide 99-115 (LTip) GG-CGPKDTPEGAELKPWYC (SEQ ID NO 6) Mutated tip peptide 99-115 (mut- GG-CGPKD A P A GA A LKPWYC (SEQ ID NO 7) Tip) Scrambled tip peptide (scamblTip) GG-CGTKPWELGPDEKPAYC (SEQ ID NO 8) Short tip peptide (STip) CTPEGAEC (SEQ ID NO 9)
  • Electrophysiology Cells were pretreated for 30 min with TNF, mutTNF and tip peptides at 37° C. in a buffer consisting of 145 mM NaCl, 3 mM KCl, 2 mM CaCl 2 , 2 mM MgCl 2 , 10 mM D-glucose, and 10 mM Hepes, and pH-adjusted with NaOH to required value. Cells were then washed with the same buffer pH-adjusted at 7.3, and experiments were performed using the tight-seal, whole-cell recording technique. Currents were recorded with an Axopatch-200A amplifier (Axon Instrument Inc, Foster City, Calif.
  • Liposomes Large unilamellar liposomes were prepared by reverse phase evaporation as previsouly described (Vecsey-Semjen et al, 1996). Liposomes were prepared of either 100% egg phosphatidylglycerol (EPG) or a mixture of EPC and EPG (1:1 W/W) in a buffer containing 100 mM KCl, 20 mM N-[2-Hydroxyethyl] piperazine-N′-[2-ethane-sulfonic acid] (HEPES), pH 7.4 and 1.5 mg/ml of 6-methoxy-N-(3-sulfopropyl)quinolinium (SPQ).
  • EPG egg phosphatidylglycerol
  • HEPES N-[2-Hydroxyethyl] piperazine-N′-[2-ethane-sulfonic acid]
  • SPQ 6-methoxy-N-(3-sulfopropy
  • TNFs and TNF tip peptides Proinflammatory activity of TNFs and TNF tip peptides.
  • Proinflammatory activity of TNF and derived peptides was tested using a bioassay measuring their capacity to induce the surface upregulation of intercellular adhesion molecule (ICAM)-1 in alveolar type II-like epithelial A549 (Pugin et al, 1996). Briefly, A549 cells were plated at confluence in a microtiter plate, and incubated with the various concentrations of TNF, mutTNF, and peptides for 18 hrs at 37° C.
  • IAM intercellular adhesion molecule
  • ICAM-1 surface upregulation of ICAM-1 was detected by direct ELISA on cells using a first anti-ICAM-1 antibody (R&D systems, Abdington, UK), a second donkey-anti mouse IgG-peroxidase conjugated antibody (Jackson), revealed by o-phenylenediamine (Sigma), and stopped by H 2 SO 4 .
  • Optical densities (O.D.) were read at 490 nm, with subtraction of 620 nm O.D. readings.
  • TNF modified the whole cell current in primary murine cells.
  • a 30 min preincubation of resident peritoneal macrophages and lung microvascular endothelial cells with 100 ng/ml of TNF resulted in a significant increase in outward and, to a lesser extent, inward current in the case of microvascular endothelial cells, as measured by means of whole-cell patch clamp, as compared to cells unexposed to TNF (endothelial cells, FIG. 1A; and macrophages, FIG. 2).
  • a reduction in preincubation time (down to 5 min) or in dose of TNF (down to 10 ng/ml) gave similar results (data not shown).
  • mutTNF TNF mutant
  • a mutant (T104A-E106A-E109A) 17 aa circularized peptide (mutTip peptide) and a 17 aa circularized peptide containing the same aa as Ltip peptide in a random sequence (scramblTip peptide) were inactive with regard to the ion channel activity (FIG. 4B). These results indicated that the tip domain of TNF was mediating its membrane conductance increasing activity, and confirmed that residues T104, E106 and E109 were essential for this effect. Ltip peptide was also active in cells deficient in both TNFR-1 and -2 receptors (FIG. 2B).
  • mutTNF did not interact with membranes at neutral pH.
  • brominated lipids have been useful in determining the topology of membrane proteins (Bolen et al., 1990) (Markello et al., 1985) as well as studying the membrane interaction of pore-forming toxins (Gonzalez-Manas et al., 1992) (Van der Goot et al., 1991) (Vecsey-Semjen et al., 1997).
  • TNF contains two tryptophan residues, one at the top of the receptor binding domain and one at the top of the so called tip domain. If the tip of the TNF trimer were to insert into the lipid bilayer, the fluorescence of Trp-113 should be quenched upon insertion into liposomes composed of dioleoylphosphatidylglycerol that had bromines attached at positions 9 and 10 of the acyl chains.
  • tryptophans located at the boundary between the lipid head groups and the acyl chains were succeptible to bromide quenching. We were however unable to see any fluorescence quenching when adding either TNF or mutTNF at acidic pH to vesicles formed of brominated lipids.
  • Lungs of female Whistar rats weighing about 300 g were isolated as described in DeCampos et al. (1993). The lungs were injected intratracheally with either 500 ⁇ l of sterile 9% NaCl, wild type murine TNF (1 ⁇ g/lung) or mTNF tip peptide (Ltip, see above; 1 mg/lung). Subsequently, the lungs were perfused with blood isolated from the same rat. Thirty minutes later, the lungs were injected intratracheally with 2 ml of sterile 9% NaCl solution which leads to a weight increase of about 2 g (FIG. 5). The weight evolution was then followed continuously for 150 min (FIG. 5).
  • tip peptide of mTNF can lead to oedema resorption.
  • the tip peptide in contrast to wt mTNF, does not interact with the TNF receptors and does not lead to an increased expression of adhesion molecules in lung endothelial- and epithelial cells. Consequently, the tip peptide induces less lung toxicity if compared to wt mTNF.
  • Lucas, R. et al. (1997): Generation of a mouse tumor necrosis factor mutant with anti-peritonitis and desensitisation activities comparable to those of the wild type but with reduced systemic toxicity. Infect. Immun 65(6),2006-2010.

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US20110319316A1 (en) * 2009-03-05 2011-12-29 Apeptico Forschung Und Entwicklung Gmbh Method for Preventing and Treating Hyperpermeability
US20130116200A1 (en) * 2010-06-21 2013-05-09 Apeptico Forschung Und Entwicklung Gmbh Treatment of Vascular Complications of Diabetes
CN110613838A (zh) * 2018-06-19 2019-12-27 姜石松 增强细胞通透性的多肽及其应用

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NZ509604A (en) 1998-08-14 2003-05-30 Innogenetics N TNF-derived peptides for use in treating oedema
EP1781323B1 (en) 2004-08-06 2010-02-17 Nycomed GmbH Composition comprising a pulmonary surfactant and a tnf-derived peptide
EP2009023A1 (en) * 2007-06-04 2008-12-31 Rentschler Beteiligungs GmbH Novel peptides and their use for the treatment of edema
AT506150B1 (de) 2007-12-12 2010-01-15 Apeptico Forschung Und Entwick Zyklisches und cystein-freies peptid
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JP6397984B2 (ja) 2014-03-18 2018-09-26 アペプティコ・フォルシュング・ウント・エントヴィックルング・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングＡｐｅｐｔｉｃｏ Ｆｏｒｓｃｈｕｎｇ Ｕｎｄ Ｅｎｔｗｉｃｋｌｕｎｇ Ｇｍｂｈ 乾燥粉末ペプチド医薬
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US20110319316A1 (en) * 2009-03-05 2011-12-29 Apeptico Forschung Und Entwicklung Gmbh Method for Preventing and Treating Hyperpermeability
US20140364358A1 (en) * 2009-03-05 2014-12-11 Apeptico Forschung Und Entwicklung Gmbh Method for Preventing and Treating Hyperpermeability
TWI466679B (zh) * 2009-03-05 2015-01-01 Apeptico Forschung & Entwicklung Gmbh 環化胜肽之用途
US11639368B2 (en) 2009-03-05 2023-05-02 Apeptico Forschung Und Entwicklung Gmbh Method for preventing and treating hyperpermeability
US20130116200A1 (en) * 2010-06-21 2013-05-09 Apeptico Forschung Und Entwicklung Gmbh Treatment of Vascular Complications of Diabetes
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