WO2001018030A2 - Petits peptides a forte activite anti-angiogenique - Google Patents

Petits peptides a forte activite anti-angiogenique Download PDF

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Publication number
WO2001018030A2
WO2001018030A2 PCT/SG2000/000131 SG0000131W WO0118030A2 WO 2001018030 A2 WO2001018030 A2 WO 2001018030A2 SG 0000131 W SG0000131 W SG 0000131W WO 0118030 A2 WO0118030 A2 WO 0118030A2
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peptide
peptides
pro
angiogenesis
mammalian
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PCT/SG2000/000131
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English (en)
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WO2001018030A3 (fr
Inventor
Rowen Ge
R. Manjunatha Kini
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National University Of Singapore
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Publication of WO2001018030A2 publication Critical patent/WO2001018030A2/fr
Publication of WO2001018030A3 publication Critical patent/WO2001018030A3/fr

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    • 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
    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/71—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
    • 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
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention involves small peptides that function as potent angiogenic inhibitors.
  • the invention relates to small peptides that can be synthesized by enzymatic or chemical methods.
  • the invention relates to use of the small peptides to inhibit angiogenesis, to treat angiogenesis-related diseases and in angiogenesis research.
  • Angiogenesis is the process of new blood vessel formation from pre-existing vessels. It plays important roles in many normal physiological functions such as embryonic development and wound healing (1) . In addition, inappropriate angiogenesis is also associated with various pathological conditions including solid tumor growth and metastasis, rheumatoid arthritis and psoriasis (2) . Many molecules that inhibit tumor angiogenesis have been shown to inhibit tumor growth including antibodies against angiogenic factors, natural and synthetic compounds that inhibit angiogenesis, and the natural angiogenic inhibitors like the angiostatin and endostatin proteins produced by tumor cells (3-8) . Anti- cancer therapy by inhibiting tumor angiogenesis is called anti-angiogenic therapy and has shown great potential as an effective new method for treating cancer, especially solid tumors (9) .
  • Plasminogen is a plasma glycoprotein synthesized mainly in the liver. It is the precursor of the serum protease plasmin that plays important roles in the fibrinolytic system and clot dissolution (10) . At the amino terminus, plasminogen contains five homologous repeats that form looped "kringle" structures held together by disulfide bonds. Plasminogen binds to fibrin through lysine binding sites located on the five kringle domains ( kl through k5) (10) . A naturally occurring fragment of plasminogen containing the first four kringle domains (kl-k4) has been isolated from serum and urine of mice bearing a low metastic Lewis lung carcinoma.
  • This plasminogen fragment has been named angiostatin (equivalent to amino acids 98-440 of murine plasminogen) and is a potent angiogenesis inhibitor that can inhibit endothelial cell proliferation as well as tumor growth and metastasis in mice with no obvious toxicity (5, 6, 11) .
  • reco binant individual kringle domains of human plasminogen produced in E. coli have been found to be able to inhibit endothelial cell proliferation to various degrees with k5 the most potent, followed by kl and k3 (12, 13) .
  • the k5 domain is not present in the naturally existing angiostatin protein.
  • Endostatin is a protein first identified from a hemangioendothelioma cell line in 1997 (17) . It is a 20kDa
  • endostatin functions as a potent angiogenesis inhibitor in vi tro as well as in vivo (17).
  • Systemic administration of endostatin to tumor bearing mice regressed the primary tumor without inducing drug resistance (21) .
  • endostatin was found to be a zinc-binding protein and the zinc-binding is essential for its antiangiogenic activity (22, 23) . Human trials of endostatin are expected to be undertaken.
  • VEGF is a potent endothelial specific mitogen. VEGF functions through two high affinity tyrosine kinase receptors: FLT-1/VEGFR1 and FLK-1/VEGFR2 (26). Both receptors are specifically expressed in endothelial cells. FLT-1 and KDR/FLK-1 stimulate endothelial cell proliferation and migration by binding to these two tyrosine kinase receptors (24). VEGF is also known as vascular permeability factor due to its ability to induce vascular leakage (24). The ligand binding domains of the two receptors as well as the receptor binding sites of VEGF have been studied by site- directed mutagenesis and X-ray crystallography (25, 26, 27, 28).
  • VEGF binds its two receptors through different amino acid contacts (25) .
  • the first three immunoglobulin loops of the FLT-1 receptor seem to be the main area responsible for VEGF binding (29, 30) .
  • the signal transduction triggered by VEGF through its receptors play critical roles in both physiological angiogenesis as well as pathological angiogenesis such as solid tumor growth and metastasis by stimulating embryonic angiogenesis and tumor angiogenesis.
  • An anti-VEGF monoclonal antibody has been shown to inhibit tumor growth in mice by reducing the vessel density of the tumor (14).
  • trans-dominant mutants of both receptors have been shown to inhibit tumor growth in mice (15).
  • proline residues are sometimes found at the ends of the linear sequences that constitute the site of a protein-protein interaction (14, 15). However, the proline residues are not usually present within the interaction site.
  • the invention provides compositions comprising the peptides that are effective in inhibiting undesirable angiogenesis.
  • the invention includes small peptides that have the ability to inhibit bovine aorta endothelial cell proliferation in the presence of basic Fibroblast Growth Factor (bFGF) in vi tro. They can also inhibit angiogenesis in the chick chorioallantoic membrane (CAM) in vivo.
  • the peptides of the invention are typically less than 20 amino acids in length. They preferably contain proline residues at each end or penultimate thereto.
  • Peptides of the invention can be identified within the kringle domains of plasminogen or within the amino acid sequences of endostatin, VEGF, and VEGF receptors, especially FLT-1 and KDR/FLK-1.
  • Some preferred peptides of the invention are named Angio-1, Angio-2, Angio-3, Angio-4 and Angio-5 (SEQ. ID. NOs . 1-3, 11 and 12) according to the plasminogen kringle domains they are derived from.
  • Other preferred peptides are shown in Table 1 (SEQ ID NOS. 29-50).
  • compositions of the anti-angiogenic peptides are also within the scope of the invention.
  • Figure 2 Inhibition of BAE cell proliferation by peptides Angio-2 and Angio- .
  • Figure 3 Inhibition of chick CAM angiogenesis on 4 day embryo by Angio-3 at 120 ug/cover slip.
  • the arrow indicates the inhibition of the growth of new vessels at the site of peptide application.
  • FIG. 1 Inhibition of chick CAM angiogenesis on 4 day embryo by Angio-4 at 120 ug/cover slip. Arrows indicate the inhibition of the growth of new vessels at the site of peptide application.
  • Figure 5 Inhibition of chick CAM angiogenesis on 10 day embryo by Angio-2 at 12 ug/cover slip.
  • Control cover slip containing PBS on 10 day old chick embryo CAM The arrow indicates the position of the control cover slip on CAM.
  • Figure 8 Inhibition of chick CAM angiogenesis in 10 day embryo by Endo-4 at 1.8 ⁇ g/coverslip.
  • FIGS 9A-9B Inhibition of chick CAM angiogenesis in
  • Figure 10 Antiangiogenic effect of peptides in the chick CAM assay. The number of positive inhibitions over the number of CAMs examined for each group are indicated above each bar.
  • Small peptides were designed according to the amino acid sequences of the kringle domains of human plasminogen or from the amino acid sequences of endostatin, VEGF, FLT-1 or KDR/FLK-1 using the "proline bracket model" described in references 14 and 15.
  • the peptides were synthesized using a peptide synthesizer (Applied Biosystems, Inc., model 473A) .
  • the peptides were then purified by typical HPLC methods using a C18 reverse-phase column and eluting with an acetonitrile gradient .
  • Angiostatin-derived peptides of the present invention represent a portion of a kringle domain of plasminogen.
  • the effective portion of a kringle domain is generally residues 30 to 38 or 39 of a kringle domain, numbered as in reference 13. However, it is acceptable to add additional amino acids to this generally effective core peptide. Thus, peptides representing residues 27 to 40 or 41 of a kringle domain would be expected to be effective.
  • Preferred peptides of the invention are derived from human or mouse plasminogen.
  • the exemplified peptides of SEQ. ID. NOs.: 1-3, 11 and 12 represent residues 29-38 or 29-39 of human plasminogen kringle domains (13) .
  • the peptides of the invention preferably range from 8 to 20 amino acids long. Peptides of the invention typically range from 7-20, more typically from 10-15 amino acids in length. The peptides are often about 10 amino acids in length. The peptides are more preferably 8, 9 or 10 residues long, most preferably 10 residues long.
  • the peptides of the invention may contain a single cysteine residue. In such a case, it is desirable that the cysteine residue be derivatized to block disulfide bond formation. Most preferably, peptides of the invention lack cysteine residues altogether.
  • the peptides also preferably contain a pair of proline residues.
  • Each proline residue of the pair is preferably the residue penultimate to a terminus of a peptide, but either or both of the proline residues can be a terminal residue.
  • Imino acids similar to proline, in that their side chains form a ring containing the peptide bonding nitrogen and ⁇ -carbon, and that will "break" an ⁇ -helix or ⁇ -sheet secondary structure, can be substituted for one or more of the proline residues.
  • Exemplary peptides are shown as SEQ. ID. Nos . 1-50. The more preferred peptides are those of SEQ. ID. NOs . 1-3, 11, 12, 29-33, 35-38, 40-41 and 44-50.
  • the peptides of the invention are active in inhibiting angiogenesis in the in vi tro bovine aorta endothelial (BAE) cell proliferation assay with an IC 50 of 20 ⁇ M or less, preferably 5 ⁇ M or less, more preferably 1 ⁇ M or less and most preferably below 0.1 ⁇ M.
  • IC 50 of 20 ⁇ M or less, preferably 5 ⁇ M or less, more preferably 1 ⁇ M or less and most preferably below 0.1 ⁇ M.
  • Much preferred peptides of the invention are active in the in vi tro BAE cell proliferation assay with an IC 50 of about 20 pM.
  • preferred peptides of the invention will exhibit inhibition of angiogenesis in a chick chorioallantoic membrane assay of at least 30% (i.e. inhibition is observed under at least 3 of 10 coverslips applied) at a dose of 50 ⁇ g/coverslip. More preferably at least 50% inhibition is observed at a dose of 25 ⁇ g/coverslip. Most preferably, inhibition in the range of 50-80% is observed for a dose ranging from 10-25 ⁇ g/coverslip.
  • the peptides of the invention encompass peptides that have been derivatized, for example to improve transport across membranes by attachment of hydrophobic groups or that are carboxy-terminal amidated to improve resistance to serum proteases. Methods for accomplishing such derivatizations are known in the art .
  • Formulation of the peptides for administration is standard in the art. It is anticipated that optimization of formulation, dosages and schedule of administration is also standard in the art. Reference 16, especially at parts 4, 5 and 7, provides guidance in these matters.
  • Administration of the peptides for anti-tumor treatment can be by any route, preferably oral, intravenous, intradermal, subcutaneous or aerosol. It is expected that subcutaneous administration is especially effective when anti-metastatic activity is desired (see, reference 6) .
  • the dosage of the peptides will depend upon the therapeutic index of the compound. It is noted that angiostatin has been administered to mice in amounts of 100 mg/kg/day without observable toxicity. Inhibition of metastasis by angiostatin is observed at doses of about 1 mg/kg/day and inhibition of primary tumor growth is observed at about 10 mg/kg/day (6) . Thus, it is expected that effective doses of the peptides of the present invention will be about 0.2 ⁇ g/kg/day to about 2 mg/kg/day for inhibition of metastasis. Preferred dosages are in the 2-200 ⁇ g/kg/day range, most preferred dosages are in the 20-50 ⁇ g/kg/day range. It is expected that the dosage ranges will be about 10- fold higher for inhibition of primary tumor growth.
  • the peptides were tested in an in vi tro bovine aorta endothelial cell (BAE) proliferation assay for their ability to inhibit BAE cell proliferation.
  • BAE vi tro bovine aorta endothelial cell proliferation assay for their ability to inhibit BAE cell proliferation.
  • Cells were plated into 24- well culture plates at 1.25 x IO 4 cells/well in complete SFM- endothelial medium (Gibco, USA) . After 24 h, the medium was removed and various amounts of peptides were added into the wells in 0.5 ml of SFM-endothelial medium without bFGF. After 30 minutes incubation, bFGF was added into each well at a final concentration of 1 ng/ml together with another 0.5 ml of SFM-endothelial medium.
  • Angio-3 inhibited BAE cell proliferation with an IC 50 in a range much lower than the reported nanomolar range of angiostatin protein (5) .
  • Angio-3S a randomly scrambled version of Angio-3 in which the same amino acids present in Angio-3 were put in a random order, completely lost angiogenesis inhibition ability
  • the BAE inhibition assay provides a method for determining the anti- angiogenic activity of peptides.
  • peptides Angio- 3A, -3B, -3C, -3D, -3E and -3F are peptides in which the six amino acids surrounded by the two prolines are individually mutated into alanine. The contribution of each of the six amino acids between the proline residues to the biological activity of Angio-3 can be determined by testing these peptides.
  • peptides Angio-2, Angio-3 and Angio-4 all inhibited BAE cell proliferation, they were also tested in the chick embryo chorioallantoic membrane (CAM) in vivo angiogenesis assay (7).
  • CAM chick embryo chorioallantoic membrane
  • the peptides are coated onto 2-3 mm glass squares cut from microscope cover slips. All three peptides inhibited chick CAM angiogenesis
  • the blood vessels under the cover slip containing all three peptides died and circulation was stopped.
  • the color of the blood changed into dark red instead of the bright red of the circulating blood.
  • Angio-2, Angio-3 and Angio-4, small peptides derived from the sequence of human plasminogen kringle domains 2, 3 and 4 function as potent angiogenesis inhibitors.
  • peptide Angio-3 is more potent in inhibiting BAE cell proliferation compared to angiostatin protein and at least as potent as recombinant angiostatin in inhibiting chick CAM angiogenesis.
  • Cao et al. (12) show that integrity of complete kringle domains is required for anti-angiogenic activity of angiostatin and that a tandem pair of properly folded domains is necessary.
  • Cao et al . (13) also show that, at least with respect to the k5 domain, appropriate disulfide bond formation is necessary for maintaining anti-angiogenic activity.
  • the exemplified small peptides of the invention which (1) do not form complete kringle domains and (2) do not contain any cysteine residues and therefore do not form disulfide bonds, have such high activity.
  • Example 3 Antiangiogenic Activity of Peptides Derived from Endostatin, VEGF and VEGF Receptors
  • Peptides were tested in an in vi tro bovine aorta endothelial cell (BAE) proliferation assay for their ability to inhibit BAE cell proliferation.
  • BAE aorta endothelial cell proliferation assay for their ability to inhibit BAE cell proliferation.
  • Cells were plated into 24-well
  • mVEGF mammalian VEGF sequences
  • fVEGF Zebrafish VEGF
  • hFLTl and hFLT2 Two small peptides, hFLTl and hFLT2, were designed from the second immunoglobulin domain (Ig domain 2) of the extracellular region of FLT-1.
  • the peptide hFLT2 showed very potent angiogenesis inhibition activity on CAM ( Figures 10 and 11).
  • a truncated version of hFLT2 peptide, hFLT2-ll, in which the N-terminal two amino acids have been deleted showed a even more potent antiangiogenic activity comparing to hFLT2 ( Figure 11) .

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Abstract

La présente invention concerne des peptides possédant une forte activité anti-angiogénique. Ces peptides peuvent être administrés sous la forme de compositions pharmaceutiques destinées à la prévention ou au traitement de l'angiogénèse non souhaitée, notamment pour prévenir la formation de métastases tumorales ou inhiber la croissance de tumeurs primaires.
PCT/SG2000/000131 1999-09-03 2000-09-01 Petits peptides a forte activite anti-angiogenique WO2001018030A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SG9904310A SG87828A1 (en) 1999-09-03 1999-09-03 Small peptides having potent anti-angiogenic activity
SG9904310-1 1999-09-03

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WO2001018030A2 true WO2001018030A2 (fr) 2001-03-15
WO2001018030A3 WO2001018030A3 (fr) 2001-09-27

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007116278A2 (fr) * 2006-03-31 2007-10-18 Istituto Nazionale Per La Ricerca Sul Cancro Peptide antiangiogène et ses utilisations thérapeutiques
WO2014037332A1 (fr) * 2012-09-04 2014-03-13 Università Degli Studi Di Torino Inhibiteurs du complexe intégrine alpha6/e-cadhérine et leur utilisation thérapeutique et de diagnostic dans le cancer
CN111344002A (zh) * 2017-08-31 2020-06-26 新加坡保健服务集团 用于治疗视网膜血管生成性疾病的Angio-3

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997015666A1 (fr) * 1995-10-23 1997-05-01 The Children's Medical Center Corporation Compositions therapeutiques anti-angiogenese et procedes associes
WO1997041824A2 (fr) * 1996-05-03 1997-11-13 Abbott Laboratories Nouveaux peptides anti-angiogeniques, polypeptides les codant et procedes d'inhibition de l'angiogenese
WO2000026368A2 (fr) * 1998-10-30 2000-05-11 The Children's Medical Center Corporation Compositions therapeutiques d'endostatine anti-angiogenique

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997015666A1 (fr) * 1995-10-23 1997-05-01 The Children's Medical Center Corporation Compositions therapeutiques anti-angiogenese et procedes associes
WO1997041824A2 (fr) * 1996-05-03 1997-11-13 Abbott Laboratories Nouveaux peptides anti-angiogeniques, polypeptides les codant et procedes d'inhibition de l'angiogenese
US6057122A (en) * 1996-05-03 2000-05-02 Abbott Laboratories Antiangiogenic peptides polynucleotides encoding same and methods for inhibiting angiogenesis
WO2000026368A2 (fr) * 1998-10-30 2000-05-11 The Children's Medical Center Corporation Compositions therapeutiques d'endostatine anti-angiogenique

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007116278A2 (fr) * 2006-03-31 2007-10-18 Istituto Nazionale Per La Ricerca Sul Cancro Peptide antiangiogène et ses utilisations thérapeutiques
WO2007116278A3 (fr) * 2006-03-31 2007-12-21 Istituto Naz Per La Ricerca Su Peptide antiangiogène et ses utilisations thérapeutiques
WO2014037332A1 (fr) * 2012-09-04 2014-03-13 Università Degli Studi Di Torino Inhibiteurs du complexe intégrine alpha6/e-cadhérine et leur utilisation thérapeutique et de diagnostic dans le cancer
CN111344002A (zh) * 2017-08-31 2020-06-26 新加坡保健服务集团 用于治疗视网膜血管生成性疾病的Angio-3
JP2020532586A (ja) * 2017-08-31 2020-11-12 シンガポール ヘルス サービシーズ プライベート リミテッド 網膜血管性疾患の処置のためのａｎｇｉｏ−３
EP3675889A4 (fr) * 2017-08-31 2021-05-12 Singapore Health Services PTE Ltd Angio -3 pour le traitement de maladies angiogéniques rétiniennes
US11266710B2 (en) 2017-08-31 2022-03-08 Singapore Health Services Pte Ltd. Angio-3 for treatment of retinal angiogenic diseases

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WO2001018030A3 (fr) 2001-09-27

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