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WO2000059532A1 - Utilisation de domaine de collagene de type iv permettant d'inhiber l'angiogenese et la croissance tumorale - Google Patents

Utilisation de domaine de collagene de type iv permettant d'inhiber l'angiogenese et la croissance tumorale Download PDF

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Publication number
WO2000059532A1
WO2000059532A1 PCT/US2000/008678 US0008678W WO0059532A1 WO 2000059532 A1 WO2000059532 A1 WO 2000059532A1 US 0008678 W US0008678 W US 0008678W WO 0059532 A1 WO0059532 A1 WO 0059532A1
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Prior art keywords
tumor
nci
tissue
angiogenesis
endothelial cell
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WO2000059532A9 (fr
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Peter Brooks
Billy Hudson
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Biostratum Inc
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Biostratum Inc
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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
    • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]

Definitions

  • This invention relates to methods and kits for inhibiting angiogenesis, tumor 5 growth and metastasis, and endothelial cell interactions with the extracellular matrix.
  • Angiogenesis the process of formation of new blood vessels, plays an important role in physiological processes such as embryonic and postnatal 0 development, as well as in wound repair. Formation of blood vessels can also be induced by pathological processes involving inflammation (e.g., diabetic retinopathy and arthritis) or neoplasia (e.g., cancer) (Folkman, 1985, Perspect, Biol. Med., 29, 10). Neovascularization is regulated by angiogenic growth factors secreted by tumor or normal cells as well as the composition of the extracellular matrix and by the activity of
  • a common feature of all solid tumor growth is the requirement for a blood supply. Therefore, numerous laboratories have focused on developing anti-angiogenic compounds based on growth factors and their receptors. While this approach has led to some success, the number of growth factors known to play a role an angiogenesis is large. Therefore, the possibility exists that growth factor antagonists may have only limited use in treating cancer since tumors and associated inflammatory cells likely produce a wide variety of factors that can induce angiogenesis.
  • integrin is expressed most prominently on cytokine -activated endothelial and smooth muscle cells and has been shown to be required for angiogenesis. (Varner et al., Cell Adhesion and Communication 3:367-374 (1995); Brooks et al., Science 264:569-571 (1994)). Based on these findings, a potentially powerful new approach to anti- angiogenic therapy might be to specifically target critical regulatory domains within distinct ECM components.
  • the basement membrane (basal lamina) is a sheet-like extracellular matrix (ECM), which is a basic component of all tissues.
  • ECM extracellular matrix
  • the basal lamina provides for the compartmentalization of tissues, and acts as a filter for substances traveling between tissue compartments.
  • the basal lamina is found closely associated with an epithelium or endothelium in all tissues of an animal including blood vessels and capillaries.
  • the basal lamina components are secreted by cells and then self assemble to form an intricate extra-cellular network. The formation of biologically active basal lamina is important to the development and differentiation of the associated cells.
  • Type IV collagen has been shown to be a major structural component of basement membranes.
  • the protomeric form of type IV collagen is formed as a heterotrimer made up from a number of different subunit chains called ⁇ l(IV) through
  • the type IV collagen heterotrimer is characterized by three distinct structural domains: the non-collagenous (NCI) domain at the carboxyl terminus; the triple helical collagenous domain in the middle region; and the 7S collagenous domain at the amino terminus.
  • NCI non-collagenous
  • the ability to express recombinant ⁇ (IV) NCI domains provides the opportunity to study the effect of specific domains on many biological processes, such as angiogenesis, tumor metastasis, cell binding to basement membranes, and assembly of Type IV collagen molecules.
  • the instant invention provides methods and kits for inhibiting angiogenesis, tumor growth and metastasis, and endothelial cell interaction with the extracellular matrix, each method comprising contacting the tumor, animal tissue, or endothelial cells with antagonists of specific integrin receptors.
  • Figure 1 illustrates the effects of NCI (Hexamer) and 7S domains of Type IV collagen at a 50 ⁇ g/ml concentration on angiogenesis from mouse thoracic aorta organ cultures.
  • Figure 2 illustrates the effects of 7S domain of Type IV collagen on angiogenesis from mouse thoracic aorta organ cultures. The domain concentrations employed in this experiment were 0 ⁇ g/ml (control); 0.5 ⁇ g/ml; 5 ⁇ g/ml and 50 ⁇ g/ml.
  • Figure 3 illustrates the effects of NCI (Hexamer) domain of Type IV collagen on angiogenesis from mouse thoracic aorta organ cultures. The domain concentrations employed in this experiment were 0 ⁇ g/ml (control); 5 ⁇ g/ml and 5 ⁇ g/ml and 50 ⁇ g/ml.
  • Figure 4 are photographs of mouse thoracic aorta segments embedded in Matrigel (EHS basement membrane matrix, Collaborative Biomedical Products, Bedford, MA) at 5 days of culture. Control specimen (0 ⁇ g/ml of NCI (Hexamer) and 7S domains) exhibited growth of microvessels from the cultured tissue into the matrix ( Figure 4A).
  • Control specimen (0 ⁇ g/ml of NCI (Hexamer) and 7S domains) exhibited growth of microvessels from the cultured tissue into the matrix ( Figure 4A).
  • Figure 5 is a graphical representation of data demonstrating the in vivo effect of IV
  • Figure 6 is a graphical representation of data demonstrating that the recombinant ( ⁇ l)
  • NCI monomers inhibit the bFGF-induced increase in angiogenic index in
  • Figure 7 is a graphical representation of demonstrating the dose response effect of
  • Figure 8 is a graphical representation of data demonstrating the dose response effect of
  • Figure 9 is a graphical representation of data demonstrating the dose response effect of
  • Figure 10 is a graphical representation of data demonstrating the effect of recombinant
  • Figure 11 is a graphical representation of data demonstrating the dose response effect
  • Figure 12 is a graphical representation of data demonstrating the effect of recombinant
  • FIG. 13 is a graphical representation of data demonstrating the effect of recombinant
  • Figure 14 is a graphical representation of data demonstrating human endothelial cell
  • Figure 15 is a graphical representation of data demonstrating the effect of soluble ⁇ l
  • Figure 16 is a graphical representation of data demonstrating the effect of isolated recombinant NCI monomers on human endothelial cell migration in vitro.
  • Figure 17 A-F provides the sequences of each type IV collagen ⁇ chain monomer.
  • Figure 18 is a graphical representation of data demonstrating the effect of monoclonal antibodies against various integrins on human endothelial cell adhesion to recombinant
  • Figure 19 is a graphical representation of data demonstrating human endothelial cell
  • Type IV collagen domain encompasses the group of molecules including the non-collagenous NCI domain (Hexamer) and 7S collagenous
  • the invention comprises methods for using Type IV collagen NCI ⁇ -monomers
  • the present invention provides methods and kits for inhibiting angiogenesis in an animal tissue comprising contacting the tumor or animal tissue with an amount effective to inhibit angiogenesis of a polypeptide composition comprising one or more isolated type IV collagen NCI ⁇ chain monomers selected from the group
  • the present invention provides methods and kits for inhibiting tumor growth in tissue comprising contacting the tumor or tissue with an amount effective to inhibit tumor growth of a polypeptide composition comprising one or more
  • isolated type IV collagen NCI ⁇ chain monomers selected from the group consisting of
  • the present invention provides methods and kits for inhibiting tumor metastasis in tissue comprising contacting the tumor or tissue with an amount effective to inhibit metastasis of a polypeptide composition comprising one or more isolated type IV collagen NCI ⁇ chain monomers selected from the group consisting of
  • the present invention provides methods and kits for inhibiting endothelial cell interactions with the extracellular matrix in tissue comprising contacting the tumor or tissue with an amount effective to inhibit endothelial cell interactions with the extracellular matrix of a polypeptide composition comprising one or
  • the NCI -encoding domain of each of the six ⁇ chain cDNAs has been cloned into a vector for recombinant protein expression as previously described (Sado et al., Kidney Intl. 53:664-671 (1998), incorporated by reference herein in its entirety).
  • the vectors are used to stably transfect human kidney 293 cells, which produce the recombinant protein.
  • the DNA and deduced amino acid sequences of the recombinant type IV collagen alpha chain monomers produced as described are shown in Figure 17A-F.
  • the first 17 amino acids correspond to a BM40 signal sequence (which is cleaved from the mature protein), to facilitate protein secretion. All the secreted proteins (ie: mature proteins) start with the sequence APLA followed by the affinity tag, DYKDDDDK at the amino terminus. This tag facilitates purification and identification of the material, and does not interfere with biological activity of the
  • the type IV collagen NCI ⁇ chain monomers can be produced by any method
  • NCI ⁇ chain monomers employed is one that effectively inhibits angiogenesis, tumor growth, tumor metastasis, and/or endothelial cell-extracellular matrix interactions.
  • inhibiting amount of NCI ⁇ chain monomers ranges generally between about 0.01 ⁇ g/kg body weight and about 10 mg/kg body weight, preferably ranging between about 0.05 ⁇ g/kg and about 5 mg/kg body weight.
  • NCI ⁇ chain monomers may be administered by any suitable route,
  • parenteral includes, subcutaneous, intravenous, intraarterial, intramuscular, intrasternal, intratendinous, intraspinal, intracranial, intrathoracic, infusion techniques or intraperitoneally.
  • the NCI ⁇ chain monomers are administered intravenously or subcutaneously.
  • the NCI ⁇ chain monomers may be made up in a solid form (including
  • granules, powders or suppositories or in a liquid form (e.g., solutions, suspensions, or
  • NCI ⁇ chain monomers of the invention may be applied in a variety
  • Suitable solutions for use in accordance with the invention are sterile,
  • NCI ⁇ chain monomers may be subjected to conventional pharmaceutical
  • NCI ⁇ chain monomers are ordinarily combined with
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration.
  • the compounds of this invention may be dissolved in saline, water, polyethylene glycol, propylene glycol, carboxymethyl cellulose colloidal solutions, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.
  • Other adjuvants and modes of administration are well known in the pharmaceutical art.
  • the carrier or diluent may include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
  • the model has been used to study the effects of growth factors and extracellular matrix molecules on the angiogenic response and employs aortic rings cultures in three-dimensional collagen gels under serum-free conditions. These experiments are outlined below.
  • NCI domain was less effective in blocking angiogenesis as compared to that observed in the first experiment ( Figure 1), although it was still effective.
  • Figure 4A-C are photographs of mouse thoracic aorta segments embedded in
  • Matrigel EHS basement membrane matrix, Collaborative Biomedical Products, Bedford, MA
  • the control specimen no domains
  • the control specimen exhibited growth of microvessels from the cultured tissue into the matrix ( Figure 4A).
  • angiogenesis inhibition was observed in tissues cultured in the presence of 50 ⁇ g/ml of 7S ( Figure 4B) and NCI (Hexamer) domain ( Figure 4C).
  • Example 2 Subcutaneous fibrin implant angiogenesis Recombinant human type IV collagen NCI ( ⁇ 3) monomer (Sado et al., Kidney International 53:664-671 (1998)) was injected intravenously in Fisher 344 rats containing fibrin implants surgically placed subcutaneously, a modified version of the method described by Dvorak et al ( Lab. Invest. 57(6):673-686 (1987)). The implants were then removed and directly analyzed using an inverted microscope. The analysis involved counting the number of blood vessels that had grown into the fibrin in the control and experimental group.
  • results are shown as the mean number of blood vessels per implant.
  • the results of this study demonstrate that isolated domains of type IV collagen, including the ⁇ 3 monomer, can significantly inhibit capillary growth in the in vivo fibrin clot
  • NCI ( ⁇ l) monomer 100 ⁇ l of a 1 ⁇ g/ ⁇ l solution; approximately 0.80 mg/kg body
  • Angiogenesis was induced in the CAMs of 10 day old chick embryos with bFGF as described (Brooks et al, Cell 92:391-400 (1998)). Twenty four hours later the
  • PBS sterile phosphate buffered saline
  • Angiogenesis was quantitated by counting the number of angigogenic blood vessel branch points in the confined area of the filter disc.
  • the Angiogenic Index is defined as the number of branch points from experimental treatment minus control treatment.
  • ⁇ l domain showed variable inhibitory activity (0%-50%) throughout the experiments.
  • Example 4 Recombinant NCI domain inhibits melanoma tumor growth in vivo:
  • NCI ⁇ -chain monomers can thus be used alone, or to complement the use of existing anti-tumor agents, in providing enhanced and more effective anti-tumor therapy.
  • Example 5 Immobilized NCI domains support human endothelial cell adhesion
  • endothelial cells In order for new blood vessels to form, endothelial cells must have the capacity to adhere and migrate through the ECM. Moreover, this endothelial cell-ECM interaction may facilitate signal transduction events required for new blood vessel formation. Therefore, since type IV-collagen is an ECM protein which is known to support cell adhesion, we tested the ability of the NCI domains to support endothelial cell attachment.
  • Microtiter plates were coated with 25 ⁇ g/ml of purified NCI domains followed by incubation with 1% bovine serum albumin (BSA) to block non-specific interactions.
  • BSA bovine serum albumin
  • Human endothelial cells ECV304 were then allowed to attach to the immobilized NCI domains for 1 hour.
  • Non-adherent cells were removed by washing and attached cells were quantified by measuring the optical density (O.D.) of crystal violet eluted from attached cells. Data bars represent the mean +/- standard error of the O.D. from triplicate wells.
  • domains from the ⁇ l, ⁇ 2 , ⁇ 3, and ⁇ 6 chains of collagen type IV can mediate human endothelial cell adhesion and/or inhibit endothelial cell adhesion to ECM proteins in vitro, and suggest that the potent anti-angiogenic and anti-tumor activity of the isolated NCI domains is due to disruption of endothelial cell interaction with the extracellular matrix that are necessary for angiogenesis.
  • Each study consisted of an untreated control group and six treatment groups. There were ten animals per treatment group with 40 mice in the control. In each study, all treatment was administered intravenously once every 2 days for 7 doses starting one
  • ⁇ (IV) NCI hexamer were either 100 ⁇ g/mouse or 200 ⁇ g/mouse.
  • the tumor cell inoculum was 1 xlO 6 viable cells. All animals were weighed twice a week throughout the study. Starting one day after the last treatment, 5 mice were periodically sacrificed from each control group to measure pulmonary tumor burden. The experiment was terminated at day 14 when the lungs of the control animals had sufficient tumor mass to provide meaningful evaluation. At that time, the lungs of all remaining animals were excised, weighed, and the number of tumor foci greater than 2 mm in diameter counted.
  • ⁇ v ⁇ 3 receptor can block angiogenesis (U.S. Patent No. 5,766,591), but the instant invention provides the first demonstration of a non-RGD containing antagonist of the
  • antagonists of the ⁇ v ⁇ 5 integrin and the ⁇ 3 ⁇ l integrins can block angiogenesis.
  • the instant invention also provides methods and kits for inhibiting angiogenesis, tumor growth and metastasis, and endothelial cell interaction with the extracellular matrix, each method comprising contacting the tumor, animal tissue, or endothelial cells with antagonists of specific integrin receptors.
  • the methods comprise contacting the tumor, animal tissue, or endothelial cells with one or more of the following polypeptide compositions:
  • angiogenesis can be inhibited by isolated, recombinant domains of type IV collagen, or by antagonists of specific integrin receptors.
  • the present invention is thus broadly applicable to a variety of uses which include inhibition of angiogenesis and treatment of diseases and conditions with accompanying undesired angiogenesis, such as solid and blood-borne tumors including but not limited to melanomas, carcinomas, sarcomas, rhabdomyosarcoma, retinoblastoma., Ewing sarcoma, neuroblastoma, osteosarcoma, and leukemia.
  • the invention is further applicable to treating non-tumorigenic diseases and conditions with accompanying undesired angiogenesis, including but not limited to diabetic retinopathy, rheumatoid arthritis, retinal neovascularization, choroidal neovascularization, macular degeneration., corneal neovascularization, retinopathy of prematurity., corneal graft rejection, neovascular glaucoma., retrolental fibroplasia, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sogrens, acne rosacea, phylectenulosis, syphilis, Mycobacteria infections, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpes simplex infections, Herpes zoster infections, protozoan infections, Kaposi'
  • the invention is also broadly applicable to methods for inhibiting tumor growth and metastasis, reduction of scar tissue formation, reduction of complications due to cell adhesion in organ transplants, and the inhibition of lymphocyte adhesion and mobility.

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Abstract

L'invention concerne des procédés et des kits permettant l'inhibition de l'angiogenèse, de la croissance tumorale et de la métastase ainsi que des interactions des cellules endothéliales avec la matrice extracellulaire. Ce procédé consiste à mettre la tumeur, le tissu animal ou les cellules endothéliales en contact avec une quantité suffisante pour inhiber l'angiogenèse, la croissance tumorale et la métastase ou les interactions des cellules endothéliales avec la matrice extracellulaire d'un antagoniste de récepteurs spécifiques de l'intégrine.
PCT/US2000/008678 1999-04-01 2000-03-31 Utilisation de domaine de collagene de type iv permettant d'inhiber l'angiogenese et la croissance tumorale Ceased WO2000059532A1 (fr)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6358735B1 (en) 1995-06-30 2002-03-19 University Of Kansas Medical Center Method for inhibiting angiogenesis and tumors with the isolated NC1 α3 chain monomer of type IV collagen
US6361994B1 (en) 1995-06-30 2002-03-26 University Of Kansas Medical Center Method for inhibiting angiogenesis and tumors with the isolated NC1 α1 chain monomer of type IV collagen
WO2001051523A3 (fr) * 2000-01-07 2002-08-08 Beth Israel Hospital Proteines et fragments de proteines anti-angiogeniques et leurs procede d'utilisation
US6759047B1 (en) 1998-06-17 2004-07-06 Beth Israel Deaconess Hospital Corp. Anti-angiogenic proteins and methods of use thereof
US6962974B1 (en) 1998-06-17 2005-11-08 Beth Israel Deaconess Medical Center Anti-angiogenic proteins and fragments and methods of use thereof
EP1601372A4 (fr) * 2003-02-20 2006-04-12 Univ New York Peptide clk et peptide slk
US7122517B2 (en) 2001-07-27 2006-10-17 Kansas University Medical Center Crystallized structure of type IV collagen NC1 domain hexamer
US7387779B2 (en) 1998-06-17 2008-06-17 Beth Israel Deaconess Medical Center Anti-angiogenic proteins and fragments and methods of use thereof
US7387998B2 (en) 2003-03-28 2008-06-17 New York University STQ peptides
EP1988915A4 (fr) * 2006-02-03 2009-11-11 Crc For Asthma And Airways Ltd Procede de modulation de l'activite cellulaire et agents a utiliser dans le cadre de celui-ci
US7662783B2 (en) 2003-02-20 2010-02-16 New York University CLK-peptide and SLK-peptide

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US5567609A (en) * 1994-06-30 1996-10-22 University Of Kansas Medical Center Use of isolated domains of type IV collagen to modify cell and tissue interactions
US5766591A (en) * 1994-03-18 1998-06-16 The Scripps Research Institute Methods and compositions useful for inhibition of angiogenesis
WO1999049885A2 (fr) * 1998-03-27 1999-10-07 University Of Kansas Medical Center Utilisation de domaines isoles de collagene du type iv pour modifier des interactions cellulaires et tissulaires

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US5766591A (en) * 1994-03-18 1998-06-16 The Scripps Research Institute Methods and compositions useful for inhibition of angiogenesis
US5567609A (en) * 1994-06-30 1996-10-22 University Of Kansas Medical Center Use of isolated domains of type IV collagen to modify cell and tissue interactions
US5856184A (en) * 1994-06-30 1999-01-05 Yale University Isolated domains of type IV collagen to modify cell and tissue interactions
WO1999049885A2 (fr) * 1998-03-27 1999-10-07 University Of Kansas Medical Center Utilisation de domaines isoles de collagene du type iv pour modifier des interactions cellulaires et tissulaires

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6358735B1 (en) 1995-06-30 2002-03-19 University Of Kansas Medical Center Method for inhibiting angiogenesis and tumors with the isolated NC1 α3 chain monomer of type IV collagen
US6361994B1 (en) 1995-06-30 2002-03-26 University Of Kansas Medical Center Method for inhibiting angiogenesis and tumors with the isolated NC1 α1 chain monomer of type IV collagen
US6432706B1 (en) 1995-06-30 2002-08-13 University Of Kansas Medical Center Method for inhibiting angiogenesis and tumors with the isolated NC1 α6 chain monomer of type IV collagen
US6498140B1 (en) 1995-06-30 2002-12-24 University Of Kansas Medical Center Use of isolated domains of type IV collagen to modify cell and tissue interactions
US6759047B1 (en) 1998-06-17 2004-07-06 Beth Israel Deaconess Hospital Corp. Anti-angiogenic proteins and methods of use thereof
US6962974B1 (en) 1998-06-17 2005-11-08 Beth Israel Deaconess Medical Center Anti-angiogenic proteins and fragments and methods of use thereof
US7387779B2 (en) 1998-06-17 2008-06-17 Beth Israel Deaconess Medical Center Anti-angiogenic proteins and fragments and methods of use thereof
WO2001051523A3 (fr) * 2000-01-07 2002-08-08 Beth Israel Hospital Proteines et fragments de proteines anti-angiogeniques et leurs procede d'utilisation
US7122517B2 (en) 2001-07-27 2006-10-17 Kansas University Medical Center Crystallized structure of type IV collagen NC1 domain hexamer
EP1601372A4 (fr) * 2003-02-20 2006-04-12 Univ New York Peptide clk et peptide slk
US7601694B2 (en) 2003-02-20 2009-10-13 New York University CLK-peptide and SLK-peptide
US7662783B2 (en) 2003-02-20 2010-02-16 New York University CLK-peptide and SLK-peptide
US8133471B2 (en) 2003-02-20 2012-03-13 New York University CLK-peptide and SLK-peptide
US7387998B2 (en) 2003-03-28 2008-06-17 New York University STQ peptides
EP1988915A4 (fr) * 2006-02-03 2009-11-11 Crc For Asthma And Airways Ltd Procede de modulation de l'activite cellulaire et agents a utiliser dans le cadre de celui-ci
EP2468294A1 (fr) * 2006-02-03 2012-06-27 Crc For Asthma And Airways Ltd Procédé de modulation de l'activité cellulaire et agents à utiliser dans celui-ci
US8227419B2 (en) 2006-02-03 2012-07-24 Crc For Asthma And Airways Ltd. Method of treating conditions associated with airway tissue remodeling

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