WO2001072829A2 - Peptides blocking vascular endothelial growth factor (vegf)-mediated angiogenesis, polynucleotides encoding said peptides and methods of use thereof - Google Patents
Peptides blocking vascular endothelial growth factor (vegf)-mediated angiogenesis, polynucleotides encoding said peptides and methods of use thereof Download PDFInfo
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- WO2001072829A2 WO2001072829A2 PCT/IB2001/000577 IB0100577W WO0172829A2 WO 2001072829 A2 WO2001072829 A2 WO 2001072829A2 IB 0100577 W IB0100577 W IB 0100577W WO 0172829 A2 WO0172829 A2 WO 0172829A2
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- peptide
- vegf
- seq
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- 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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- 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
-
- 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
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0815—Tripeptides with the first amino acid being basic
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
- G01N33/6845—Methods of identifying protein-protein interactions in protein mixtures
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/475—Assays involving growth factors
Definitions
- PEPTIDES BLOCKING VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF)-MEDIATED ANGIOGENESIS, POLYNUCLEOTIDES ENCODING SAID PEPTIDES AND METHODS OF USE THEREOF.
- Angiogenesis the formation of blood vessels by sprouting from pre- existing ones, is essential for the growth of solid tumors beyond 2-3 mm in diameter and for tumor metastasis (Folkman, 1995; reviewed in Bouck et al, 1996).
- the generation of new capillaries involves a multistep process, which includes the dissolution of the membrane of the originating vessel, the endothelial cell migration and proliferation, and formation of a new vascular tube (Cliff, 1963; Schoefl, 1963; Ausprunck and Folkman, 1977). Suppression of any one of these steps would inhibit the formation of new vessels and therefore affect tumor growth and generation of metastases.
- endothelial cells are genetically stable and therefore unlikely to mutate into drug-resistant variants (Young, 1989; Kerbel, 1991; Boehm et al, 1997). Since they line the inside of blood vessels, they are easily accessible to circulating drugs. This feature suggests that anti-angiogenic therapies targeting endothelial cells may provide a promising mechanism for cancer treatment.
- VEGF Vascular Endothelial Growth Factor
- VPF Vascular Endothelial Growth Factor
- VPF Vascular Endothelial Growth Factor
- VEGF was purified initially from the conditioned media of follicu- lostellate cells and from a variety of tumor cell lines (Ferrara et al, 1989; Plouet et al, 1989; Myoken et al, 1991). It is a member of the cystine-knot family of growth factors, which also includes PDGF (Platelet Derived Growth Factor). Recently, a number of VEGF structural homologs have been identified: VEGF-B, VEGF-C, VEGF-D and Placenta Growth Factor (P1GF) (Klagsbrun and D'Amore, 1996; reviewed in Ferrara, 1999). The human gene encoding VEGF is organized into eight exons, separated by seven introns.
- VEGF ⁇ 65 which lacks the residues encoded by exon 6, is the mature and active form of VEGF. It binds to heparin and cell surface heparan sulfate proteoglycans, and can be expressed as a free or as a cell membrane bound form (Houck et al, 1992).
- VEGF vascular endothelial growth factor
- Flt-1 orVEGFR-1 fins-like tyrosine kinase- 1
- KDR/Flk-l or VEGFR-2 kinase domain receptor
- Flt-1 binds VEGF with 50-fold higher affinity than KDR (De Vries et al, 1992), most of the VEGF angiogenic properties (mitogenicity, chemotaxis, and induction on morphological changes) are mediated by interaction with KDR (Waltenberger et al, 1994). Therefore, the interaction between VEGF and KDR is the most appropriate to interrupt in order to inhibit angiogenesis.
- New agonists and antagonists for cell membrane receptors have been successfully identified using this process (Cwirla et al, 1990; Cortese et al, 1996), for example, RGD containing peptides that bind either the GPIIb/IIIa receptor on platelets (O'Neil et al., 1992) or the 5 1 integrin (Koivunen et al, 1993).
- the selected peptides were able to antagonize integrin-mediated cell adhesion.
- the present inventors have -identified peptides blocking the binding of VEGF to KDR.
- a random peptide library displayed on filamentous phages was screened using two parallel strategies. In the first, the peptide repertoire was screened with cells expressing recombinant KDR (Plouet et al, 1997) and in the second, with a monoclonal antibody raised against VEGF. Since this antibody blocked VEGF-dependent endothelial cell proliferation, we postulated that its antigen binding site mimics all or part of the VEGF interaction surface with KDR.
- ATWLPPR SEQ ID NO:l
- ATWLPPR SEQ ID NO:l
- CHO-KDR cells express a functional KDR
- A Scatchard analysis of VEGF binding. The ratio of bound to free VEGF molecules (B/F) was plotted against bound VEGF concentration.
- B Effect of heparin. VEGF binding to CHO-KDR cells was measured in the presence of various amounts of heparin
- C Effect ofPlGF. VEGF (100 ng/ml) binding to CHO-KDR cells was tested in absence (white bars) or presence (black bars) of heparin (1.8 ⁇ g/ml), and compared to P1GF (50 ng/ml) or to PBS (control). Data correspond to the mean and standard deviations of triplicate samples. All binding experiments were performed twice and gave similar results.
- Fig. 2 Selected phage-displayed peptides bind to KDR specifically in ELISA. Clones selected by KDR binding (10 13 pfu/ml) (A) or by anti-VEGF antibody binding (10 12 pfu/ml) (B) were compared with M13 phage particles (control). Results are representative of three independent assays.
- Peptides selected by KDR binding (A) or by anti-VEGF binding (B) were tested in competition with VEGF for binding to CHO-KDR cells at the concentration of 2,1 10 "4 M and in the presence of heparin (1.8 ⁇ g/ml). Data represent the means and standard deviations of triplicate samples. Similar results were obtained in three independent experiments.
- VI can abolish VEGF binding to KDR.
- Various concentrations of VEGF (A) or of VI peptide (B) were tested in competition with radioactive- labelled VEGF for binding to CHO-KDR cells.
- As a uninhibitory control, V5 was tested in the same conditions. Data represent the mean and standard deviations of triplicate samples. Similar results were obtained in two different experiments.
- CPAE cell growth was measured after 24h of incubation in presence of synthetic peptides selected by antibody binding (A) or by KDR binding (B) and compared with untreated cultures. Data represent means and standard deviations of proliferation inhibition for triplicates and are represen- tative of three independent experiments.
- Fig. 7. inhibits the proliferation of human endothelial cells induced by VEGF or by AIA in a dose dependent manner.
- HUAE cell cultures were grown in presence of VEGF (A) or anti-idiotypic antibodies (B), and were supplemented daily with various concentrations of VI or V5. Cells were counted after 5 days. Data are means of proliferation inhibition percentages for triplicate samples.
- Fig. 8. VI acts specifically on endothelial cells. CPAE and NIH 3T3 fibroblasts were cultured with or without VI peptide, and the changes in cell proliferation were measured after 24h. Data represent the means and standard deviations of proliferation inhibition percentages for triplicate samples, and similar results were obtained in two independent experiments.
- VI inhibits corneal angiogenesis in vivo.
- the neovasculariza- tion in implants containing VI, V5, or PBS (vehicle), in the presence or absence of VEGF was assessed 12 days after insertion in rabbit corneal pockets: A) a representative picture of each implant group, B) angiogenic score means and standard errors measured for eight implant groups.
- Fig. 10 Displacement curves of 125 I-VEGF 165 binding to CHO-KDR transfected cells by the VI derivatives.
- the experiment was performed by incubating cells (500,000 cell/well) during 3 hours at +4°C with 125 I-VEGF (Amersham Fr) at a final concentration of 7 pM and increasing concentration of the different peptides analogues (0 to 500 ⁇ g/ml) in a final volume of 0.3 ml in the presence of heparin (1 ⁇ g/ml).
- the non specific binding was established in the presence of VEGF 165 (R&D system UK) at a final concentration of 3 nM.
- Fig. 11 Comparison of the displacement curves of 125 I-VEGF165 binding to CHO-KDR transfected cells by the peptides VI, A9, A10 and A7. Experimen- tal conditions are indicated in the legend of Fig. 10.
- Fig. 12 Displacement curves of 125 I-VEGF 165 binding to CHO-KDR transfected cells by the peptides Al l obtained by the substitution of the 6 amino acids upstream to arginine by alanine. Experimental conditions are indicated in the legend of Fig. 10. Fig. 13. Effect of VI (400 ⁇ g/ml) VEGF165 induced HUVEC proliferation. Various concentrations of VEGF 165 were added during 96 hours.
- Fig. 14 Effect of VI on the binding of 125 I VEGF 165 to VEGF R2 (KDR)/Fc Chimera (R&D UK). The disulfide linked homodimeric protein were immobilized on the surface of Immulon polystyrene well (Dynatech VA). VEGF was incubated overnight at +4°C. After 3 washings, the bound radio activity was measured.
- Fig. 15 A and B (A) Displacement curves of 125 I-VEGF 165 binding to CHO-KDR transfected cells by VEGF 165 at increasing concentrations, in the presence of either saline (open circles) or 50 ⁇ g/ml VI (closed circles). (B) Scatchard representation.
- Fig. 16 A and B (A & B) Scatchard representation of 125 I-VEGF 165 to control HUV-EC cells. (C) Scatchard representation of I25 I-VEGF165 to HUV-EC cells in the presence of VI 40 ⁇ g/ml. Experimental conditions are indicated in the legend of Fig. 10.
- Fig. 17 Heparin effect on binding of 125 I VEGF 165 to transfected CHO cell in the presence of either saline (open circles) or VI peptide (closed circles) at a final concentration of 50 ⁇ g/ml. Experimental conditions are indicated in the legend of Fig. 10.
- Fig. 18 Displacement curves of 125 I-VEGF 165 binding to MDA MB cells by increasing concentrations of VI. Experimental conditions are indicated in the legend of Fig. 10. Fig. 19. Cross linking of 125 I VEGF 165 (160pM) to HUV-EC cells. 1:
- peptides capable of interacting with VEGF covers any peptide or chemical product capable of inducing or modulating the activity of VEGF.
- the activity of inhibiting VEGF properties involved in angiogenesis is a peptide or chemical product capable of inducing or modulating the activity of VEGF.
- inhibitor includes any measurable reproducible reduction in the interaction of VEGF and KDR or anti-VEGF; angiogenesis; symptoms of diseases correlated to angiogenesis; or any other activities VEGF may mediate.
- an effective amount of a compound for treating a disorder is an amount that is sufficient to ameliorate, or in some manner reduce a symp- torn or stop or reverse progression of a condition. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
- treatment means any manner in which the symptoms or pathology, of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.
- amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.
- "consisting essentially of, in relation to amino acid sequence of a protein or peptide is a term used hereinafter for the purposes of the specification and claims to refer to a conservative substitution or modification of one or more amino acids in that sequence such that the tertiary configuration of the protein or peptide is substantially unchanged.
- Constant substitutions is defined by aforementioned function, and includes substitutions of amino acids having substantially the same charge, size, hydrophilicity, and/or aromaticity as the amino acid replaced. Such substitutions, known to those of ordinary skill in the art, include glycine-alanine-valine; isoleucine-leucine; tryptophan-tyrosine; aspartic acid-glutamic acid; arginine-lysine; asparagine-glutamine; and serine-threonine.
- Modification in relation to amino acid sequence of a protein or peptide, is defined functionally as a deletion of one or more amino acids which does not impart a change in the conformation, and hence the biological activity, of the protein or peptide sequence.
- amino acids are: alanine (A), cysteine (C), aspartic acid (D), glutamic acid (E), phenylalanine (F), glycine (G), histidine (H), isoleucine (I), lysine (K), leucine (L), methionine (M), asparagine (N), proline (P), glutamine (Q), arginine (R), serine (S), threonine (T), valine (V), tryptophan (W), and tyrosine.
- Nle L-norleucine
- Aabu .aminobutyric acid
- Hphe L-homophenylalanine
- Nva L-norvaline
- Dala D-alanine
- Dcys D-cysteine
- Dasp D-aspartic acid
- Dglu D-glutamic acid
- Dphe D-phenylalanine
- Dhis D-histidine
- Dile D-isoleucine
- Dlys D-lysine
- Dleu D-leucine
- Dmet D-methionine
- Dasn D-asparagine
- Dpro D-proline
- Dgln D-glutamine
- Darg D-arginine
- Dser D-serine
- Dthr D-threonine
- Dval D-valine
- Dtrp D-tryptophan
- Dtyr D-tryptophan
- Dtyr D-tryptophan
- Nmala L-N-methylalanine
- Nmcys L-N-methylcysteine
- Nmglu L-N-methylglutamic acid
- Nmphe L-N-methylphenylalanine
- Nmhis L-N-methylhistidine
- Nmlys L-N-methyllysine
- Nmleu L-N-methylleucine
- Nmmet L-N-methylmethionine
- Nmasn L-N-methylasparagine
- Nmchexa N-methylcyclohexylalanine
- Nmgln L-N-methylglutamine
- Nmarg L-N-methylarginine
- Nmser L-N-methylserine
- Nmthr L-N-methylthreonine
- Nmval L-N-methylvaline
- nucleic acid sequencing encoding a protein or peptide as disclosed herein may be modified slightly in sequence (e.g., substitution of a nucleotide in a triplet codon), and yet still encode its respective gene product of the same amino acid sequence.
- expression vector refers to an oligonucleotide which encodes the peptide of the invention and provides the sequences necessary for its expression in the selected host cell.
- Expression vectors will generally include a transcriptional promoter and terminator, or will provide for incorporation adjacent to an endogenous promoter.
- Expression vectors will usually be plasmids, further comprising an origin of replication and one or more selectable markers. However, expression vectors may alter- natively be viral recombinants designed to infect the host, or integrating vectors designed to integrate at a preferred site within the host's genome.
- viral recombinants are Adeno-associated virus (AAV), Adenovirus, Herpesvirus, Poxvirus, Retrovirus, and other RNA or DNA viral expression vectors known in the art. Examples of other expression vectors are disclosed in Molecular Cloning: A Laboratory Manual Second Edition, Sambrook, Fritsch, and Maniatis, Cold Spring Harbor Laboratory Press, 1989.
- AAV Adeno-associated virus
- Adenovirus Herpesvirus
- Herpesvirus Herpesvirus
- Poxvirus Herpesvirus
- Retrovirus RNA or DNA viral expression vectors known in the art.
- other expression vectors are disclosed in Molecular Cloning: A Laboratory Manual Second Edition, Sambrook, Fritsch, and Maniatis, Cold Spring Harbor Laboratory Press, 1989.
- the peptide of the present invention can be produced by a known chemical synthesis method (see, for example, a liquid phase synthesis method, a solid phase synthesis method, etc.; Izumiya, N., Kato, T., Aoyagi, H., Waki, M., "Basis and Experiments of Peptide Synthesis", 1985, Maruzen Co., Ltd.) based on that sequence.
- the peptide of the present invention may contain one or more protected amino acid residues.
- the protected amino acid is an amino acid whose functional group or groups is/are protected with a protecting group or groups by a known method and various protected amino acids are commercially available.
- the protecting group for the ⁇ -amino group of an amino acid is Boc (t-butyloxycarbonyl) or Fmoc (9-fluorenylmethyloxycarbonyl).
- the protecting group for the guanidino group of arginine (Arg) is Tos (tosyl), NO.sub.2 (nitro), Mtr (4-methoxy-2,3,6-trimethylbenzenesulfonyl) or Pmc (2,2,5, 7,8-pentamethyl- chroman-6-sulfonyl).
- the protecting group for the ⁇ -amino group of lysine (Lys) is Z (benzyloxycarbonyl) or Cl.Z (2-cholorobenzyloxycarbonyl), Boc, or Npys (3-nitro-2-pyridinesulfenyl).
- the protecting group for the imidazolyl group of histidine (His) is Tos, Z, Pac (phenacyl), Bom (benzyloxymethyl), Dnp (dinitrophenyl), or Trt (trityl).
- the protecting group for the mercapto group of cysteine (Cys) is Bzl (benzyl), MBzl (4-methoxybenzyl), 4-MeBzl (4-methylbenzyl), Acm (acetamidomethyl), Trt, Npys, t-Bu (t-butyl), or t-BuS (t-butylthio).
- Preferred are MBzl, 4-MeBzl, Trt, Acm, and Npys.
- the protecting group for the hydroxyl group of tyrosine (Tyr) is Bzl, Cl.sub.2. Bzl (2,6-dichlorobenzyl), or t-Bu or the hydroxyl group of Tyr may be non-protected.
- the protecting group for the indole group of tryptophan (T ⁇ ) is CHO (formyl) or the indole group of T ⁇ may be non-protected.
- the protecting group for the thiomethyl group of methionine (Met) is methyl sulfoxide or the thiomethyl group of Met may be non-protected.
- the protecting group for the hydroxyl group of serine (Ser) and threonine (Thr) is Bzl or t-Bu.
- the protecting group for the carboxyl group of aspartic acid (Asp) and glutamic acid (Glu) is OBzl (benzyl ester), OtBu (t-butyl ester), OcHex (cyclohexyl ester), OPac (phenacyl ester), etc.
- the protecting group for the carbamide group of asparagine (Asn) and glutamine (Gin) is Trt or Xan (xanthyl).
- each protective group be selected appropriately from those known per se depending on the conditions of peptide synthesis.
- the binding of the protected amino acid is achieved by usual condensation methods, for example, a DCC (dicyclohexylcarbodiimide) method, a DIPCDI (diiso- propylcarbodiimide) method (Tartar, A., et al.; J. Org. Chem., 44, 5000 (1979)), an activated ester method, a mixed or symmetric acid anhydride method, a carbonyldiimidazole method, a DCC-HONSu (N-hydroxysuccinimide) method (Weygand, F., et al., Z.
- the condensation reaction is usually carried out in an organic solvent such as dichloromethane, dimethylformamide (DMF), N-methylpyrrolidone (NMP) and the like or a mixed solvent composed of them.
- organic solvent such as dichloromethane, dimethylformamide (DMF), N-methylpyrrolidone (NMP) and the like or a mixed solvent composed of them.
- the eliminating reagent for the protective group of ⁇ -amino group there can be used trifluoroacetic acid/dichloromethane, HCl/dioxane, piperidine/DMF or piperidine/NMP, etc. and these are selected appropriately depending on the kind of the protecting group.
- the degree of progress of condensation reaction in each stage of synthesis can be examined by the method of E. Kaiser, et al. [Anal. Biochem., 34, 595 (1970)] (ninhydrin reaction). As described above, a protected peptide resin having a desired amino acid sequence can be obtained.
- TFMSA trifluoromethanesulfonic acid
- TMSOTf trimethylsilyl triflate [Fujii, N., et al.; J. Chem. Soc, Chem. Commun., 274 (1987)]
- TMSBr trimethylsilylbromide [Fujii, N., et al.; Chem. Pharm. Bull., 35, 3880 (1987)]
- trifluoroacetic acid, or the like can eliminate the resin and protecting group simultaneously.
- the above-described eliminating reagent is selected appropriately depending on the strategy used (Boc or Fmoc) and the kinds of the resin and the protecting group.
- the peptide of the present invention can be produced by a series of the methods described above.
- the peptide of the present invention can be produced by producing a polynucleotide (DNA or RNA) which corresponds to the amino acid sequence of the peptide of the present invention and producing a peptide by a genetic engineering technique using the polynucleotide.
- Polynucleotide coding sequences for amino acid residues are known in the art and are disclosed for example in Molecular Cloning: A Laboratory Manual Second Edition. Sambrook, Fritsch, and Maniatis, Cold Spring Harbor Laboratory Press, 1989.
- the peptide of the present invention thus produced can be purified by isolation/purification methods for proteins generally known in the field of protein chemistry. More particularly, there can be mentioned, for example, extraction, recrystalli- zation, salting out with ammonium sulfate, sodium sulfate, etc., centrifugation, dialysis, ultrafiltration, adso ⁇ tion chromatography, ion exchange chromatography, hydrophobic chromatography, normal phase chromatography, reversed-phase chromatography, gel filtration method, gel permeation chromatography, affinity chromatography, electrophoresis, countercurrent distribution, etc. and combinations of these.
- the peptide of the present invention which is produced can be hydro- lyzed with an acid, for example, hydrochloric acid, methanesulfonic acid or the like and its amino acid composition can be examined by a known method. By this, it can be presumed whether or not the peptide of the present invention is produced correctly. More strictly, the amino acid sequence of the produced peptide is determined by a known amino acid sequence determination method (for example, Edman degradation technique, etc.) to confirm whether the peptide of the present invention is produced correctly.
- the peptide of the present invention includes a form of a salt thereof.
- the peptide of the present invention is particularly useful as a medicine and hence the salt of the peptide is preferably a pharmaceutically acceptable salt.
- the peptide of the present invention may form a salt by addition of an acid.
- the acid include inorganic acids (such as hydrochloric acid, hydro- bromic acid, phosphoric acid, nitric acid, and sulfuric acid) or organic carboxylic acids (such as acetic acid, propionic acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, and salicylic acid ), acidic sugars such as glucuronic acid, galacruronic acid, gluconic acid, ascorbic acid, etc., acidic polysaccharides such as hyaluronic acid, chondroitin sulfates, alginic acid, or organic sulfonic acids (such as methanesulfonic acid, and p-toluenesulfonic acid), and the like.
- these salts preferred is a pharmaceutically acceptable salt.
- the peptide of the present invention may form a salt with a basic substance.
- the salt include, for example, pharmaceutically acceptable salts selected from salts with inorganic bases such as alkali metal salts (sodium salt, lithium salt, potassium salt, etc.), alkaline earth metal salts, ammonium salts, and the like or salts with organic bases, such as diethanolamine salts, cyclohexylamine salts, and the like.
- the pharmaceutically acceptable carrier which can be used in the present invention is not limited particularly and includes an excipient, a binder, a lubri- cant, a colorant, a disintegrant, a buffer, an isotonic agent, a preservative, an anesthetic, and the like which can be used in a medical field.
- the medicine of the present invention can be applied by any suitable administration method depending on the pu ⁇ ose of treatment and selected from injection (subcutaneous, intracutaneous, intravenous, intraperitoneal, etc.), eye dropping, instilla- tion, percutaneous administration, oral administration, inhalation, and the like.
- the dosage form such as injectable preparations (solutions, suspensions, emulsions, solids to be dissolved when used, etc.), tablets, capsules, granules, powders, liquids, liposome inclusions, ointments, gels, external powders, sprays, inhalating powders, eye drops, eye ointments, suppositories, pessaries, and the like can be selected appropriately depending on the administration method, and the peptide of the present invention can be accordingly formulated.
- Formulation in general is described in Chapter 25.2 of Comprehensive Medicinal Chemistry, Volume 5, Editor Hansch et al, Pergamon Press 1990.
- the dose of the medicine of the present invention should be set up indi- vidually depending on the pu ⁇ ose of administration (prevention, maintenance (prevention of aggravation), alleviation (improvement of symptom) or cure); the kind of disease; the symptom, sexuality and age of patient; the administration method and the like and is not limited particularly.
- Antibodies which react specifically with the inventive peptides are also included in the present invention. Methods of generating antibodies directed to a specific peptide fragment are known in the art. Examples of such methods are disclosed in Antibodies, A Laboratory Manual, Harlow and Lane, Cold Spring Harbor Press, 1988, herein inco ⁇ orated by reference.
- KDR-expressing cells were obtained by trans- fecting glycosaminoglycan-deficient pgsA 745 Chinese hamster ovary (CHO) cells (Esko, 1991) with the psV-7d expression vector (Plouet et al, 1997).
- CHO cells and CHO-KDR cell line were grown routinely in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% (v/v) fetal calf serum, 50 units/ml penicillin, 50 ⁇ g/ml strepto- mycin, and 2 mM L-glutamine.
- DMEM Dulbecco's modified Eagle's medium
- CPAE Calf pulmonary artery endothelial cells
- CNRS UPR 9079, Villejuif, France were kindly provided by Dr. Binetruy (CNRS UPR 9079, Villejuif, France) and grown in minimum Eagle medium (MEM) supplemented with 20 % (v/v) fetal calf serum, 50 units/ml penicillin, 50 ⁇ g/ml streptomycin, and 2 mM L-glutamine.
- HUAE Human Umbilical Artery Endothelial Cells
- EGM EGM medium supplemented with antibiotics and 15% (v/v) fetal calf serum.
- Stock HUAE cultures were maintained by addition of 1 ng/ml VEGF every other day.
- the NIH3T3 fibroblast cell line was grown routinely in MEM medium supplemented with antibiotics and 10% (v/v) fetal calf serum.
- ELISA of the phage-displayed peptide binding to CHO-KDR cells Exponentially growing CHO-KDR cells were seeded in 96-well microtiter plates at 7x10 4 cells/well and left overnight at 37°C. Cells were fixed with paraformaldehyde (4% in PBS) for 15 min at room temperature and washed with PBS. Wells were then filled with PBS-Glycine 0.2%, kept for 15 min at room temperature and then washed with PBS. Phage particles (10 12 or 10 13 /ml) were added to each well and incubated 2 h at room temperature. Wells were washed with PBS and the amount of bound phage was detected with peroxidase-conjugated anti-M13 phage serum (Pharmacia Biotech, Uppsala, Sweden).
- CHO-KDR cells were seeded in 24-well plates at a density of 5x10 5 cells/well After 24 h, subconfluent plates were transferred at 4°C, and all subsequent operations were done at 4°C. Cells were washed twice with PBS, and incubated with 125 I-VEGF (30 000 cpm, Amersham, Buckinghamshire, UK) in binding buffer (DMEM medium supplemented with 20 mM Hepes, pH 7.4, and 2 mg/ml gelatine).
- binding buffer DMEM medium supplemented with 20 mM Hepes, pH 7.4, and 2 mg/ml gelatine
- VEGF vascular endothelial growth factor
- heparin Sigma, St Louis, MO
- placenta growth factor PIGF, R & D Systems, Minneapolis, MN
- peptides Neosystem, France
- CPAE cells were plated into 96-well tissue culture plates at a density of 500 cells/well After 24 h, various concentrations of anti-VEGF antibody were added. The cells were cultured for an additional day and cell proliferation was measured using the Cell proliferation ELISA kit from Boerhinger (Indianapolis, IN). Cells were incubated with BrdU for 4 h at 37°C, and the inco ⁇ oration of BrdU in newly synthetized DNA was quantified by immunoassay as described by the manufacturer. To investigate the peptide effect, after 24 h of CPAE cell growth, 2.1x10 " ⁇ synthetic peptides were added daily to the culture medium.
- HUAE cells were seeded at 5,000 cells/well in 12 well plates in medium containing 2 ng /ml VEGF or 100 ng/ml immunopurified KDR anti-idiotypic antibodies (Ortega et al, 1997), and supplemented daily with various concentrations of VI or V5 peptide. Cells were trypsinized and counted after 5 days using a Coulter counter.
- Neovascularization was assessed on day 12 by direct examination with a slit lamp and scored according to a 4 grade scale (grade 1 : less than 1mm long neovessels, grade 2: 1 mm long neovessels, grade 3: 1 to 2 mm long neovessels, grade 4: neovessels extending to the implant). Means and standard deviations were determined on 8 implant groups for each condition. RESULTS
- CHO-KDR cells express a VEGF binding KDR
- a receptor that we could use to perform panning techniques.
- CHO cells expressing a recombinant KDR at their membrane surface were tested for their ability to bind VEGF in a variety of conditions.
- Figure IA shows that the dissociation constant of VEGF on CHO-KDR cells was 334 pM. Heparin was able to increase the binding of VEGF to CHO-KDR cells, the optimal concentration being 1.8 ⁇ g/ml ( Figure IB) and PIGF was not modifying VEGF binding to CHO-KDR cells ( Figure 1C).
- Figure IB Heparin was able to increase the binding of VEGF to CHO-KDR cells, the optimal concentration being 1.8 ⁇ g/ml
- Figure 1C PIGF was not modifying VEGF binding to CHO-KDR cells
- Table I DNA sequence of the peptides selected by binding to CHO- KDR cells or to the anti-VEGF antibody.
- Calf Pulmonary Aortic Endothelial cells were used as model cells for VEGF-dependent proliferation.
- the anti-VEGF antibody exerted a dose-dependent inhibitory activity on the proliferation on these cells, and a complete abolition of cell division was achieved in presence of 30 ⁇ g/ml of antibody. At the same concentration, this antibody had no inhibitory effect on the growth of NIH3T3 fibroblast cells (not shown).
- the peptide library was then screened by binding to the anti-VEGF antibody. At the end of the selection, 24 clones were isolated and analyzed. DNA sequencing showed that seven independent peptides had been selected (VI to V7) with no consensus motifs, although a LPP motif was found in two of them (VI and V6) (Table I). When tested for binding to KDR by ELISA on CHO-KDR cells, all the selected clones gave strong ELISA signals, confirming that they were able to bind the cell receptor ( Figure 2B). Further, they showed higher reactivity than the peptides selected by KDR binding, using phage concentrations ten times lower. This suggests that they had a higher affinity for the receptor. Interestingly, the best reactivities were observed for VI and V6.
- Group A was composed of four clones and was characterized by the motif YX(I T)(M/P)P (SEQ ID NO: 15), the tyrosine residue always occurring in the first position.
- Group B was characterized by a longer motif HSSLQPRXL (SEQ ID NO: 16).
- VI inhibits the binding of VEGF to KDR
- VI could nearly block VEGF binding at a 320 M concen- tration, its IC 50 being estimated estimated at 8x10 "5 M.
- V5 tested in same conditions did not modify VEGF binding.
- the other peptides binding the anti-VEGF antibody did not show any inhibitory effect of VEGF binding to KDR at this concentration (data not shown).
- VI specifically inhibits the proliferation of vascular endothelial cells
- VI suppressed the mito- genic activity of VEGF in a dose dependent manner, whereas V5 had no inhibitory effect.
- KDR anti-idiotypic antibodies AIA were generated and found to be selective agonists for KDR, since they promoted endothelial cell proliferation in vitro (data not shown).
- Figure 7B shows that unlike V5, VI could suppress the AIA- dependent cell proliferation, indicating that the VI effect was mediated by a direct interaction with KDR.
- VI inhibits corneal angiogenesis in vivo
- a rabbit corneal pocket assay was used to determine whether VI could inhibit angiogenesis in vivo.
- the neovascularization in corneal implants containing VEGF in the presence or absence of peptides was measured ( Figures 9A and 9B).
- VI and V5 did not improve the generation of new blood vessels.
- VEGF induced a significant angiogenic response, which was not modified by the addition of V5. This stimulatory effect was totally abolished by VI, demonstrating that VI could inhibit VEGF-induced corneal angiogenesis.
- Table III Structure of peptides obtained by systematic replacement of one amino-acid by alanine.
- Table IV Effect (CI 50 ) of the replacement of each amino acid by a L-alanine residue (AlaScan) on binding of VEGF to CHO-KDR transfected cells.
- C-Specificity of C-terminal arginine To determine the specificity of the C-terminal arginine residue its substitution by lysine (A9) and the suppression of this residue (A 10), (Table V), have been studied.
- Displacement curves of 125 I-VEGF 165 binding to CHO-KDR transfected cells by the peptide analogues A10 showed that C-terminal region arginine residue deletion significantly reduced the peptide efficiency.
- the substitution of arginine by lysine (A9) also reduced the peptide efficiency showing that the effect of this arginine residue was not due only to its positive electric charge, (Fig. 11).
- VI Human umbilical vein endothelial cell
- VI was not able to inhibit VEGF binding to VEGF R2 (KDR)/Fc Chimera (Fig. 14).
- VI inhibited the binding of 125 I VEGF165 to VR2 expressed by transfected CHO cells.
- the scatchard binding analysis showed the presence of high affinity specific receptors. This affinity is lowered in the presence of VI (Figs. 15 A and B).
- HUV-EC the cells were incubated with VEGF at increasing concentrations, in the presence of either saline or VI peptide. Scatchard analysis of radioligand receptor binding showed the presence of specific receptors for I VEGF 165 on the surface of HUV-EC cell line with a Kd of 117 and 2300 pM. VI inhibited only the VEGF binding to high affinity receptors, (see Figs. 16 A, B and C).
- VEGF 165 The binding of VEGF 165 to transfected CHO cell is agonized heparin- dependent in a concentration range of 10 to 1000 ng/ml VI inhibited this heparin agonistic effect, (see Fig. 17) F Inhibitory effect of VI on 12S I VEGF165 binding to MDA-MB 231 cells :
- the cross-linking of 125 I VEGF 165 to HUV-EC cells showed two labeled 125 I-VEGF-receptor complexes.
- the 240-260 kDa complex could correspond to the VEGF-R2-2EGF165 complex and the 160-170 kDa complex could conespond to the
- VEGF is different from other growth factors because it acts as an endothelial cell specific mitogen during angiogenesis (Plouet et al, 1989; Leung et al, 1989; Fenara, 1993).
- Previous studies have shown that blocking the VEGF- VEGF receptor pathway using antibodies results in murine and human tumor regression (Kim et al, 1993; Cheng et al, 1996).
- We report here the identification of peptides antagonist for VEGF by use of a phage-displayed peptide library.
- bFGF basic fibroblast factor
- VEGF is a secreted endothelial cell-specific mitogen whose receptors are expressed almost exclusively on vascular endothelial cells and is therefore of greater therapeutic interest (Millauer et al, 1993; Peters et al, 1993).
- VEGF antagonists we used a 7-mer random peptide library displayed on bacteriophage Ml 3 and performed two selections, one based on binding to KDR, and the other on binding to an anti-VEGF blocking antibody. This allowed us to compare the sequences selected by the two strategies, and to identify residues responsible for the antagonist activity.
- PIGF did not modify VEGF binding to KDR expressing cells (Terman et al, 1994).
- the reactivity of the peptides selected for KDR binding was relatively low, and only one of them could compete with VEGF for KDR binding at concentrations in the 10 "4 M range.
- VI vascular endothelial growth factor-KDR
- ATWLPPR VI peptide
- Soker et al. 1998 have identified a new receptor for VEGF which is expressed by endothelial cells and tumor cells.
- NRP-1 a receptor for the collapsin/semaphorin family that mediates neuronal cell guidance.
- NRP-1 When co-expressed in cells with KDR, NRP-1 enhanced the binding of VEGF to KDR. Conversely, inhibition of VEGF binding to NRP-1 inhibited its binding to KDR and its subsequent mitogenic activity on endothelial cells. In fact, NRP-1 might be acting as a co-receptor that enhances the VEGF-induced activities mediated by KDR.
- VI reacts specifically with KDR, we tested the binding of VI to KDR in competition with KDR anti-idiotypic antibodies. We found that VI was able to block the proliferation of endothelial cells induced by these antibodies, showing that its inhibitory effect was due to a specific interaction with KDR.
- V6 which shared the LPP motif in common with VI, significantly inhibited the proliferation of endothelial cells but it did not affect the binding of VEGF to KDR.
- the K4 peptide contained a motif LPA and could partially inhibit VEGF binding to KDR, but had a minor effect on endothelial growth. This suggests that the presence of an alanine residue instead of a proline may account for its lack of reactivity, and that the LPP motif is essential for peptide antagonist activity.
- Angiogenesis is involved in a variety of human diseases.
- the VEGF/KDR interaction has been shown to play a role in cancer, but also in diabetic retmopathy (Pierce et al, 1995), psoriasis (Detmar et al, 1994), hemangioblastoma (Wizigmann-Voos et al, 1995), and Kaposi's sarcomas in AIDS patients (Albini et al, 1996).
- identification of VEGF antagonists may have potential applications in the treatment of a variety of human diseases.
- small molecules are prefened since reduced size make them more amenable to translation into organic molecules.
- Peptides provide leading molecules for the design of unexpensive drugs that can be administered orally.
- ATWLPPR peptide is an effective antagonist of VEGF and an inhibitor of angiogenesis.
- This peptide could be a potent inhibitor of tumor angiogenesis, and could have a more general interest in diseases in which angiogenesis is involved.
- in vivo anti-tumor chemotherapy assays using this peptide must be investigated.
- the invention also relates to the ATWLPPR peptide for use in inhibiting angiogenesis and/or in treating a disease selected in the group consisting of cancer, diabetic retinopathy, psoriasis, hemangioblastoma, and Kaposi's sarcoma.
- a disease selected in the group consisting of cancer, diabetic retinopathy, psoriasis, hemangioblastoma, and Kaposi's sarcoma.
- the vascular endothelial growth factor family identification of a fourth molecular species and characterization of alternative splicing of R ⁇ A. Molecular Endocrinol, 5, 1806- 1814.
- Vascular endothelial growth factor is a secreted angiogenic mitogen. Science, 246, 1306-1309.
- VEGF Vascular endothelial cell growth factor
- Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor.
- VEGF receptor subtypes KDR and FLTl show different sensitivities to heparin and placenta growth factor. Growth factor, 11, 187-195. • Tisher, E., Mitchell, R., Hartman, T., Silva, M., Gospodarowicz, D., Fiddes, J.C. and Abraham, J.A. (1991) The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J. Biol. Chem., 266, 11947-11954.
Abstract
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Also Published As
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US20050019826A1 (en) | 2005-01-27 |
CA2404528A1 (en) | 2001-10-04 |
WO2001072829A3 (en) | 2002-04-04 |
JP2003528632A (en) | 2003-09-30 |
US20020068697A1 (en) | 2002-06-06 |
EP1268544A2 (en) | 2003-01-02 |
AU4445601A (en) | 2001-10-08 |
US20030171289A1 (en) | 2003-09-11 |
US6559126B2 (en) | 2003-05-06 |
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