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WO1993010810A1 - Regeneration des os - Google Patents

Regeneration des os Download PDF

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Publication number
WO1993010810A1
WO1993010810A1 PCT/US1992/010214 US9210214W WO9310810A1 WO 1993010810 A1 WO1993010810 A1 WO 1993010810A1 US 9210214 W US9210214 W US 9210214W WO 9310810 A1 WO9310810 A1 WO 9310810A1
Authority
WO
WIPO (PCT)
Prior art keywords
igf
bone
growth factor
fgf
acidic
Prior art date
Application number
PCT/US1992/010214
Other languages
English (en)
Inventor
Samuel E. Lynch
Harry N. Antoniades
Original Assignee
Institute Of Molecular Biology, Inc.
President And Fellows Of Harvard College
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institute Of Molecular Biology, Inc., President And Fellows Of Harvard College filed Critical Institute Of Molecular Biology, Inc.
Priority to JP5510253A priority Critical patent/JPH07504160A/ja
Publication of WO1993010810A1 publication Critical patent/WO1993010810A1/fr

Links

Classifications

    • 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
    • A61K38/22—Hormones
    • A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to bone and periodontal regeneration.
  • composition which is known for this use is a combination of platelet derived growth factor (PDGF) and insulin-like growth factor I (IGF-l), described in U.S. Patent No. 4,861,757.
  • Growth factors are polypeptide hormones which stimulate a defined population of target cells. As multifunctional hormone-like molecules, they may stimulate or inhibit cell proliferation as well as affect cell function, depending on the state of differentiation of the target cell and the combination of other signal peptides present.
  • growth factors include PDGF, IGF's, transforming growth factor beta (TGF-/3) , transforming growth factor alpha (TGF- ⁇ ) , epidermal growth factor (EGF) and acidic or basic fibroblast growth factor (aFGF or bFGF) .
  • IGF-l alone has also been studied for its effects on bone growth.
  • IGF-I somatomedin C
  • IGF-I platelet- derived growth factor-BB
  • PDGF-BB platelet- derived growth factor-BB
  • Hock et al (Endocrinology 1988; 122:254-60) found that IGF-I stimulates primarily pre-osteoblast replication in vitro and that collagen and bone matrix synthesis is stimulated independently of cell replication. Canalis et al (J. Cell. Phvsiol. 1989; 140:530-537) reported that PDGF-BB opposed the stimulatory effect of IGF-I on collagen synthesis, IGF-I prevented the PDGF effect on collagen degradation and that PDGF-BB and IGF-I had additive effects on calvarial DNA synthisis.
  • FGF fiberblast growth factor
  • bFGF did not significantly alter 3 Hy- thymidine incorporation in bone fracture calluses (Joyce et al 1991) .
  • bFGF has been reported to enhance mitogenesis in fetal calvarial bone cultures but did not simulate differentiated function of osteoblasts directly (Canalis et al J. Clin. Invest. 1988; 81:1572).
  • aFGF has the same reported biological effects on bone as bFGF but generally requires higher concentrations (Canalis J____ Clin. Invest. 1987; 79:52-58). Both aFGF and bFGF tend to decrease matrix synthesis in the fetal rat calvarial model (Canalis et al 1989) .
  • bFGF has also been reported to enhance the capacity of bone marrow cells to form bone-like nodules in vitro (Noff et al F.E.B.S. Letters 1989; 250:619-21). Both aFGF and bFGF increased DNA synthesis in cells cultured from parietal bones while bFGF was a more potent stimulator of alpha 1 Type 1 procollagen mRNA (McCarthy et al Endocrinology 1989; 125:2118-26).
  • the present invention provides novel methods for stimulating and enhancing bone and periodontal regeneration.
  • the methods of the invention employ IGF's, preferably IGF-I, and acidic or basic (a or b respectively) FGF.
  • IGF's preferably IGF-I, and acidic or basic (a or b respectively) FGF.
  • the invention aids in regeneration, at least in part, by promoting the growth of bone, cementum, and ligament by stimulating protein and collagen synthesis. Bone regeneration using the invention is more effective than that achieved in the absence of treatment (i.e. without applying exogenous agents) or by treatment with similar levels of purified IGF-I or purified FGF's alone.
  • a mammal e.g., a human patient
  • a composition that includes purified acidic or basic FGF and purified IGF-I.
  • the two factors can be applied sequentially, close enough in time to effect synergistic bone regeneration.
  • the composition is prepared by combining, in a pharmaceutically acceptable carrier substance, e.g., commercially available inert gels, polymers or liquids (e.g., saline supplemented with albumin or methyl cellulose) , purified acidic or basic FGF and an IGF, e.g. IGF-I (which are commercially available) .
  • a pharmaceutically acceptable carrier substance e.g., commercially available inert gels, polymers or liquids (e.g., saline supplemented with albumin or methyl cellulose)
  • purified acidic or basic FGF and purified IGF-I are combined in a weight ratio of between 100:1 and 1:250. More preferably the purified FGF and IGF-I are combined in a weight ratio of between 50:1 and 1:100. Most preferably the FGF and IGF-I are combined in a weight ration of between 10:1 and 1:50.
  • FGF or IGF acidic or basic FGF or IGF which, prior to mixing with the other growth factor, is 90% or greater, by weight, FGF or IGF, i.e., is substantially free of other proteins, lipids, and carbohydrates with which it is naturally associated.
  • a purified protein preparation will generally yield a single major band on a polyacrylamide gel for each subunit of IGF or acidic or basic FGF.
  • the purified a or b FGF or IGF used in the compositions of the invention is pure as judged by amino- ter inal amino acid sequence analysis.
  • the purified a or b FGF and IGF may be obtained by purifying them from natural sources e.g. brain or plasma, respectively, by recombinant DNA technology, or by chemical synthesis.
  • - ⁇ IGF and FGF we mean naturally derived, recombinant, and synthesized materials of mammalian, preferably primate, origin; most preferably, the primate is a human, but can also be a chimpanzee or other primate.
  • a method of making recombinant a and b FGF and analogues thereof is dislcosed in EP 88311099.1.
  • IGF's are commercially available from Amgen Corporation' (Thousand Oaks, California) and Kabi (Sweden) .
  • a and b FGF are commercially available from R & D Systems (Minneapolis, MN) and AmGen Corporation.
  • FGF and IGF include active fragments and analogs thereof which mediate biological activity through their respective receptors. Analogs which are presently unknown may be made and tested for this purpose. Testing of these analogs for efficacy is routine, and may be easily accomplished by conventional methods, e.g. radioreceptor assays. Suitable analogs are disclosed in EP 88311099.1. While IGF-I is preferred, IGF-II or IGF-III may also be used in the invention.
  • compositions of the invention are formed by combining an IGF with a or b FGF using known mixing methods or by attaching these proteins to polymers.
  • the composition is prepared by combining the two growth factors in a pharmaceutically acceptable carrier substance, e.g., commercially available inert gels, polymers or liquids (e.g., saline polymers supplemented with albumin or methyl cellulose) .
  • a pharmaceutically acceptable carrier substance e.g., commercially available inert gels, polymers or liquids (e.g., saline polymers supplemented with albumin or methyl cellulose) .
  • the purified growth factors are combined in a weight ratio of between 100:1 and 1:250 more preferably from 50:1 to 1:100, and most preferably from 10:1 to 1:50 aFGF or bFGF to IGF.
  • regenerating bone of a mammal is accomplished by administering to the patient, preferably by local administration to the area of injured or depleted bone, an effective amount of a composition of the invention.
  • Systemic administration can also be used.
  • a preferred dosage of the composition is about 0.1-1000 ⁇ g, more preferably l-100 ⁇ g, of biologically active growth factors/cm 2 of the area of injured or depleted bone.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Stimulation et amélioration de la régénération des os et du pariodonte par l'utilisation du facteur de croissance semblable à l'insuline (IGF) et du facteur de croissance de fibroblaste basique ou acide (FGF).
PCT/US1992/010214 1991-11-27 1992-11-24 Regeneration des os WO1993010810A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP5510253A JPH07504160A (ja) 1991-11-27 1992-11-24 骨の再生

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US799,375 1977-05-23
US79937591A 1991-11-27 1991-11-27

Publications (1)

Publication Number Publication Date
WO1993010810A1 true WO1993010810A1 (fr) 1993-06-10

Family

ID=25175741

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1992/010214 WO1993010810A1 (fr) 1991-11-27 1992-11-24 Regeneration des os

Country Status (3)

Country Link
JP (1) JPH07504160A (fr)
CA (1) CA2123803A1 (fr)
WO (1) WO1993010810A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0677294A4 (fr) * 1993-08-25 1998-02-04 Kaken Pharma Co Ltd Remede contre les affections periodontiques.
WO1998019700A1 (fr) * 1996-11-01 1998-05-14 Genentech, Inc. Traitement des cellules des poils auditifs de l'oreille interne
US6046164A (en) * 1993-08-25 2000-04-04 Kaken Pharmaceutical Co., Ltd. Therapeutic agent for diseases of periodontal tissue
US6156728A (en) * 1996-11-01 2000-12-05 Genentech, Inc. Treatment of inner ear hair cells
EP1284748A4 (fr) * 2000-05-03 2005-02-16 Gropep Ltd Traitement de tissus conjonctifs endommages
US10071182B2 (en) 2014-10-14 2018-09-11 Samuel E. Lynch Methods for treating wounds

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0298723A1 (fr) * 1987-07-07 1989-01-11 California Biotechnology, Inc. Facteurs de croissance de fibroblaste recombinants

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0298723A1 (fr) * 1987-07-07 1989-01-11 California Biotechnology, Inc. Facteurs de croissance de fibroblaste recombinants

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
J. CLIN. INVEST., Volume 84, Number 2, issued August 1989, pp. 640-646, LYNCH et al., "Growth Factors in Wound Healing". *
J. ENDOCRINOL. INVEST., Volume 12, issued 1989, CANALIS et al., "Growth Factors and the Skeletal System", pages 577-584. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0677294A4 (fr) * 1993-08-25 1998-02-04 Kaken Pharma Co Ltd Remede contre les affections periodontiques.
US6046164A (en) * 1993-08-25 2000-04-04 Kaken Pharmaceutical Co., Ltd. Therapeutic agent for diseases of periodontal tissue
WO1998019700A1 (fr) * 1996-11-01 1998-05-14 Genentech, Inc. Traitement des cellules des poils auditifs de l'oreille interne
US6156728A (en) * 1996-11-01 2000-12-05 Genentech, Inc. Treatment of inner ear hair cells
US6653279B1 (en) 1996-11-01 2003-11-25 Genentech, Inc. Treatment of inner ear hair cells
US6927204B2 (en) 1996-11-01 2005-08-09 Genentech, Inc. Treatment of inner ear hair cells
EP1284748A4 (fr) * 2000-05-03 2005-02-16 Gropep Ltd Traitement de tissus conjonctifs endommages
US10071182B2 (en) 2014-10-14 2018-09-11 Samuel E. Lynch Methods for treating wounds

Also Published As

Publication number Publication date
CA2123803A1 (fr) 1993-06-10
JPH07504160A (ja) 1995-05-11

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