WO1997035607A1 - Methods of tissue induction using a combination of bone morphogenetic protein and parathyroid hormone-related peptide - Google Patents
Methods of tissue induction using a combination of bone morphogenetic protein and parathyroid hormone-related peptide Download PDFInfo
- Publication number
- WO1997035607A1 WO1997035607A1 PCT/US1997/004162 US9704162W WO9735607A1 WO 1997035607 A1 WO1997035607 A1 WO 1997035607A1 US 9704162 W US9704162 W US 9704162W WO 9735607 A1 WO9735607 A1 WO 9735607A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- bmp
- proteins
- composition
- pthrp
- compositions
- Prior art date
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
- A61K38/29—Parathyroid hormone (parathormone); Parathyroid hormone-related peptides
-
- 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
- A61K38/18—Growth factors; Growth regulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
Definitions
- the present invention relates to novel methods and compositions for repairing, reducing or preventing damage to cartilage and cartilaginous tissue.
- the methods and compositions may further be useful for the induction and maintenance of cartilaginous tissue formation, wound healing and cartilage and other tissue repair. These methods and compositions may also be useful for augmenting the activity of bone morphogenetic proteins.
- the present application relates to the use of compositions comprising an osteogenic or cartilage- inducing member of the transforming factor beta [TGF-3] superfamily of proteins, such as a bone morphogenetic protein [BMP], in combination with parathyroid hormone-related peptide [PTHrP].
- the compositions are useful for induction and maintenance of cartilaginous tissue, such as articular cartilage.
- BMPs Bone Morphogenetic Proteins
- BMP-2 has been shown to be able to induce the formation of new cartilage and/or bone tissue in vivo in a rat ectopic implant model, see United States Patent No. 5,013,649; in mandibular defects in dogs, see Toriumi et al. , Arch. Otolarvngol Head Neck Sure.. 117: 1101-1112 (1991); in femoral segmental defects in sheep, see Gerhart et al. , Trans Orthop Res Soc. 16: 172 (1991).
- BMP-4, -6 and -7 Other members of the BMP family have also been shown to have osteogenic activity, including BMP-4, -6 and -7, see Wozney, Bone Morphogenetic Proteins and Their Gene Expression, in Cellular and Molecular Biology of Bone, pp. 131-167 (Academic Press, Inc. 1993). BMP proteins have also been shown to demonstrate inductive and/or differentiation potentiating activity on a variety of other tissues, including cartilage, tendon, ligament, neural tissue.
- Parathyroid hormone-related peptide (PTHrP) is a protein which is known exist in at least three isoforms of 139, 141 and 173 amino acids. [Karaplis et al. , Genes & Development. 8:277-289 (1994).
- PTHrP is highly homologous to the N- terminal fragment of parathyroid hormone (PTH), and binds the same receptor as PTH. PTHrP appears to play a substantial role in calcium metabolism by an autocrine/paracrine mechanism, and also appears to regulate embryonal development, vascular tone and nutrition. Tsukazaki et al. , Calcif Tissue Int 57: 196-200 (1995). It has recently been shown that mice deficient in PTHrP exhibit abnormal cartilage maturation, indicating that PTHrP is an essential factor for chondrocyte development and maturation. In Tsukazaki, it is reported that PTHrP expression in articular cartilage varies in intensity and localization during development, while the PTH/PTHrP receptor is highly expressed in the growth plate and in articular cartilage.
- compositions useful for inducing cartilaginous tissue formation in a patient in need of same comprising one or more protein members of the transforming growth factor- ? (TGF-/3) superfamily together with parathyroid hormone related peptide (PTHrP), or an equivalent PTH- like polypeptide.
- TGF-/3 transforming growth factor- ?
- PTHrP parathyroid hormone related peptide
- the compositions of the invention comprise at least one protein member of the bone morphogenetic protein (BMP) family and parathyroid hormone related peptide (PTHrP).
- the composition comprises a bone morphogenetic protein is selected from the group consisting of BMP-2, BMP-4, BMP-5, BMP-7, BMP-12 and BMP-13 together with PTHrP or an equivalent PTH-like polypeptide.
- the compositions comprise BMP-2, BMP-13, heterodimers of BMP-2 and BMP- 13 or combinations of the above, and PTHrP or an equivalent PTH-like polypeptide; especially preferred BMPs are BMP-2 and BMP- 13.
- the compositions may further comprise one or more additional members of the BMP subfamily of proteins.
- the PTHrP used is PTHrPl-34, a truncated peptide comprising the first 34 amino acids of the N-terminal portion of PTH.
- the compositions comprise BMP-2 and one or more additional proteins selected from the group consisting of BMP-4, BMP-5, BMP-7, BMP- 12 and BMP-13; or BMP- 13 and one or more additional proteins selected from the group consisting of BMP-2, BMP-4, BMP-5, BMP-7 and BMP- 12 together with PTHrP 1-34, PTHrP or another PTH-like polypeptide.
- the present invention relates to methods for inducing the formation and maintenance of cartilage in a patient, for example a patient suffering from arthritis, particularly osteoarthritis, or a patient with an articular cartilage defect or other cartilaginous tissue defect, said method comprising administering to said patient an effective amount of the above compositions.
- the method of the present invention relates to a method for treating articular cartilage defects or damage in a patient in need of same, said method comprising administering to said patient an effective amount of the above compositions.
- the invention further relates to methods for inducing the formation of cartilage and cartilaginous tissue comprising administering to a patient a composition comprising a member of the TGF-/3 superfamily of proteins and Parathyroid hormone-related peptide (PTHrP).
- the methods and compositions of the present invention are thus useful for repairing, reducing or preventing damage to cartilage and cartilaginous tissue.
- the methods and compositions may further be useful for the induction and maintenance of cartilaginous tissue formation, wound healing and cartilage and other tissue repair.
- cartilaginous tissue such as articular cartilage, the meniscus, and the articular surfaces of developing bone, or for the treatment of diseases or defects of cartilaginous tissue, such as arthritis, particularly osteoarthritis.
- the methods and compositions of the present invention comprise a combination of one or more proteins from the transforming growth factor-0 superfamily with one or more parathyroid hormone-related peptides.
- the transforming growth factor- ? superfamily is a well-characterized family of proteins involved in cellular proliferation and differentiation of cells into various tissues.
- Members of the TGF- J superfamily are generally dimeric in structure, comprising two monomeric units which are produced by proteolytic cleavage from a larger precursor protein, of which the processed monomer represents the carboxyl terminal portion.
- the dimeric TGF-/3 proteins generally have molecular weights of approximately 20,000 to 35,000 and share a common cysteine pattern in the mature protein region. See, for example, Sporn et al.
- the TGF-/3 superfamily includes several subgroups beside TGF- ⁇ l through - ⁇ 5, are the bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), the inhibins, as well as GDNF and Mullerian inhibitory substance and other structurally related proteins.
- BMPs bone morphogenetic proteins
- GDFs growth and differentiation factors
- GDNF Mullerian inhibitory substance and other structurally related proteins.
- the TGF- ⁇ superfamily also includes proteins from other species, which have been characterized and are highly conserved compared to die mammalian TGF- ⁇ s, including Vgl (Xenopus), see for example, Weeks and Melton, CeH, 51 :861-867 (1987); Dpp, Screw and 60A (Drosophila), see for example Padgett et al., Nature (London). 325:81-84 (1987); Doctor et al. , Dev. Biol. 151:591-505 (1992); and more recently identified proteins including Univin (sea urchin), Dorsalin-1 (chicken) and Radar (Zebrafish).
- Other factors which may be effectively used in the composition include synthetic molecules or fragments of a TGF-3 superfamily member which are able to bind to a TGF-/3 receptor molecule.
- BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7 are disclosed, for instance, in United States Patents 5,108,922; 5,013,649; 5,116,738; 5, 106,748; 5, 187,076; and 5, 141,905; BMP-8, disclosed in PCT publication WO91/18098; BMP-9, disclosed in PCT publication WO93/00432; BMP- 10, disclosed in PCT application WO94/26893; BMP-11, disclosed in PCT application WO94/26892; BMP- 12 and BMP-13, disclosed in PCT application WO 95/16035, or BMP-15, disclosed in co- pending patent application, serial no.
- TGF- ⁇ proteins which may be useful in the present invention include BIP, disclosed in WO94/01557; and MP52, disclosed in PCT application WO93/16099. Methods for production of heterodimeric proteins comprising two distinct monomeric units, each comprising the amino acid sequence of one of the above TGF-3 proteins, are described in WO93/09229. The disclosures of all of the above applications are hereby incorporated by reference.
- PTHrP Parathyroid hormone-related peptide
- PTHrP is closely related in structure to parathyroid hormone.
- PTHrP is known to exist in at least three isoforms of 139, 141 and 173 amino acids.
- PTHrP is highly homologous to the N-terminal fragment of parathyroid hormone (PTH), and binds the same receptor as PTH.
- the nucleotide and amino acid sequences of the PTHrP gene from rat, mouse and human are known and may be used to produce PTHrP-like polypeptides useful in the present invention. [See Karaplis et al. , Mol. Endocrin.
- PTHrP 1-34 which comprises the first 34 amino acids of PTHrP, is used in one preferred embodiment of the present invention.
- PTH-like polypeptides which are equivalent to PTHrPl-34 in their ability to enhance survival of chondrocytes.
- PTH-like polypeptides may include, for example, PTH, whether of human, porcine, bovine or other mammalian origin; variants of PTH, such as those described in Wingender et al. , United States Patent 5,455,329; Wingender et al. , United States Patent 5,457,047; and Schluter et al. , United States Patent 5,457,092, and the references cited therein; as well as variants of the above in which one or more amino acids of PTH has been deleted from the carboxy and/or amino terminal portions of the molecule.
- the disclosures of the above publications are hereby incorporated by reference.
- PTH, PTHrP and the above variants may be produced via recombinant DNA engineering using the known sequences of the PTH and PTHrP proteins, or may be isolated by purification.
- the methods and compositions of the present invention may comprise simultaneous or sequential administration of at least two active agents, a TGF- ⁇ protein and a parathyroid hormone-related peptide, to a patient or site in need of cartilage repair, formation or maintenance.
- active agents may be encapsulated or otherwise maintained in contact with a carrier which provides for slow release of the agent.
- the methods and compositions may comprise the active agents in a weight ratio of from about 90: 10, to about 10:90.
- the active agents are present in a weight ratio of about 70:30 to 30:70.
- compositions of the invention may comprise, in addition to a TGF- ⁇ protein and a parathyroid hormone-related peptide, other therapeutically useful agents including growth factors such as epidermal growth factor (EGF), transforming growth factor- ⁇ , activins, inhibins, platelet derived growth factor (PDGF), fibroblast growth factor (FGF), and fibroblast growth factor-4 (FGF-4), parathyroid hormone (PTH) , leukemia inhibitory factor (LIF/HILDA/DI A) , and insulin-like growth factors (IGF-I and IGF-II). Portions of these agents may also be used in compositions of the present invention.
- the compositions may also include an appropriate matrix for instance, for supporting the composition and providing a surface for cartilage or for other connective tissue growth. The matrix may provide slow release of the protein and/or the appropriate environment for presentation thereof.
- the methods and compositions of the present invention employ proteins which are able to induce cartilaginous tissue or other tissue formation in circumstances where such tissue is not normally formed, and has application in the healing of cartilage, for example articular cartilage tears, deformities and other cartilage defects in humans and other animals.
- Such methods and compositions employing cartilaginous tissue inducing proteins may have prophylactic use in preventing damage to cartilaginous tissue, as well as use in the improved fixation of cartilage to bone or other tissues, and in repairing defects to cartilage tissue.
- De novo cartilaginous tissue formation induced by a composition of the present invention contributes to the repair of congenital, trauma induced, or other cartilage defects of other origin, and is also useful in surgery for attachment or repair of cartilage.
- the methods and compositions of the invention may also be useful in the treatment of arthritis and other cartilage defects.
- the methods and compositions of the present invention can also be used in other indications wherein it is desirable to heal or regenerate cartilage tissue.
- Such indications include, without limitation, regeneration or repair of injuries to the articular cartilage.
- the methods and compositions of the present invention may provide an environment to attract cartilage-forming cells, stimulate growth of cartilage-forming cells or induce differentiation of progenitors of cartilage-forming cells and chondrocytes.
- compositions and methods of the present invention may also be useful for treating cell populations, such as embryonic cells or stem cell populations, to enhance or enrich the growth, survival and/or differentiation of the cells into chondrocytes or other cell types.
- cell populations such as embryonic cells or stem cell populations
- the compositions and methods of the present invention may be used to treat chondrocytic cell lines, such as articular chondrocytes, in order to maintain chondrocytic phenotype and survival of the cells.
- the treated cell populations may be useful for gene therapy applications.
- the proteins useful in the methods of the present invention are useful for inducing the formation, maintenance and survival of chondrocytes and/or cartilaginous tissue. It is contemplated that these proteins may have the ability to induce the formation of other types of tissue, such as tendon and ligament, as well.
- the cartilaginous tissue-inducing methods and compositions provided herein also may include factors encoded by the sequences similar to those of naturally-occurring TGF- ⁇ proteins, into which modifications are naturally provided (e.g. allelic variations in the nucleotide sequence which may result in amino acid changes in the polypeptide) or deliberately engineered. For example, synthetic polypeptides may wholly or partially duplicate continuous sequences of the amino acid residues of BMP-2 or BMP- 13.
- cartilaginous tissue growth factor polypeptides of naturally-occurring BMP-2 or BMP- 13 may possess cartilaginous or other tissue growth factor biological properties in common therewith. Thus, they may be employed as biologically active substitutes for naturally-occurring cartilaginous tissue inducing polypeptides in therapeutic methods and compositions.
- the proteins useful in the present invention, or the DNA sequences encoding therefor, may be engineered to provide one or more additional cysteine residues to increase potential dimer formation, particularly for forming dimers of the TGF- ⁇ proteins.
- the resulting DNA sequence would be capable of producing a "cysteine added variant" of the protein.
- Production of "cysteine added variants" of proteins is described in United States Patent 5,166,322, the disclosure of which is hereby incorporated by reference.
- Other specific mutations of the sequences of cartilaginous tissue inducing proteins described herein involve modifications of glycosylation sites. These modifications may involve O-linked or N-linked glycosylation sites.
- the absence of glycosylation or only partial glycosylation results from amino acid substitution or deletion at asparagine-linked glycosylation recognition sites.
- the asparagine-linked glycosylation recognition sites comprise tripeptide sequences which are specifically recognized by appropriate cellular glycosylation enzymes. These tripeptide sequences may be asparagine-X-threonine, asparagine-X- serine or asparagine-X-cysteine, where X is usually any amino acid except proline.
- a variety of amino acid substitutions or deletions at one or both of the first or third amino acid positions of a glycosylation recognition site (and/or amino acid deletion at the second position) results in non-glycosylation at the modified tripeptide sequence.
- bacterial expression of protein will also result in production of a non-glycosylated protein, even if the glycosylation sites are left unmodified.
- the methods of the present invention for inducing cartilaginous tissue formation may comprise administering to a patient an effective amount of a composition comprising one or more protein members of the transforming growth factor- ⁇ (TGF- ⁇ ) superfamily together with parathyroid hormone related peptide (PTHrP), or an equivalent PTH-like polypeptide.
- TGF- ⁇ transforming growth factor- ⁇
- PTHrP parathyroid hormone related peptide
- the methods of the present invention for inducing cartilaginous tissue formation may comprise heterodimers comprised of two distinct monomeric units, each of which has the amino acid sequence of a member of the TGF- ⁇ superfamily, together with PTHrP, or an equivalent PTH-like polypeptide.
- the compositions of the invention comprise one or more members of the bone morphogenetic protein (BMP) family, together with PTHrP or an equivalent PTH-like polypeptide.
- BMP bone morphogenetic protein
- the composition comprises a bone morphogenetic protein selected from the group consisting of BMP-2, BMP-4, BMP-5, BMP-7, BMP-12 and BMP-13, or heterodimers of the above, together with PTHrP or an equivalent PTH-like polypeptide.
- the composition comprises BMP-2, BMP-13, heterodimers of BMP-2 and BMP- 13 or combinations of the above, and PTHrP or an equivalent PTH-like polypeptide.
- compositions may optionally comprise one or more additional proteins which are members of the TGF- ⁇ superfamily, preferably of the BMP family of proteins.
- the composition comprises BMP-2 and one or more additional proteins selected from the group consisting of BMP-4, BMP-5, BMP-7, BMP-12, BMP- 13 and heterodimers of the above; or BMP- 13 and one or more additional proteins selected from the group consisting of BMP-2, BMP-4, BMP-5, BMP-7, BMP- 12 and heterodimers of the above; each together with PTHrP or an equivalent PTH-like polypeptide.
- these compositions may be used to induce the formation, maintenance and survival of chondrocytes and/or cartilaginous tissue or other tissue.
- compositions may also be used for articular cartilage repair, wound healing and other tissue repair, such as skin repair. It is further contemplated that proteins of the invention may increase neuronal survival and therefore be useful in transplantation and treatment of conditions exhibiting a decrease in neuronal survival. Compositions and methods of the invention may further be useful for induction and repair of other tissue, including wound healing.
- more than one protein of the TGF- ⁇ superfamily may be used together with PTHrP to enhance the induction, maintenance and differentiation of one or more cell and/or tissue types, including cartilaginous tissue.
- a composition comprising both BMP-2 and BMP- 13 implanted together with PTHrP may give rise to both bone and cartilaginous tissue.
- Such a composition may be useful for treating defects of the junction between cartilage and bone, causing cartilage and bone to form simultaneously at contiguous anatomical locations, and may therefore be useful for regenerating tissue at the site of cartilage attachment to bone.
- wound healing such as skin healing and related tissue repair.
- wounds include, but are not limited to burns, incisions and ulcers. (See, e.g. PCT Publication WO84/01106 for discussion of wound healing and related tissue repair).
- the methods and compositions of the invention further comprise heteromolecules comprised of different TGF- ⁇ moieties , in combination with PTHrP or an equivalent PTH-like polypeptide.
- the heteromolecule is a heterodimer, for example, of two monomers each comprising the amino acid sequence of a BMP protein.
- a method and composition of the invention may comprise a disulfide linked dimer comprising a BMP-2 protein subunit and a subunit from one of the other BMP proteins described above.
- the present invention comprises compositions and methods employing a heterodimer wherein one subunit comprises the amino acid sequence of BMP-2, and one subunit comprises an amino acid sequence for a bone morphogenetic protein selected from the group consisting of BMP-3, BMP-4, BMP- 5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13 orBMP- 15.
- Further embodiments may comprise a heterodimer of other disulfide bonded TGF- ⁇ moieties, including VGR-2, MP52, MIS, activin and TGF- ⁇ .
- the heterodimer may comprise one subunit comprising the amino acid sequence of BMP-2 or BMP-13, and the other subunit may comprise the amino acid of activin.
- compositions of the present invention may be combined with other agents beneficial to the treatment of the defect, wound, or tissue in question.
- compositions and methods of the invention may act in concert with or perhaps synergistically with administration of other related proteins and growth factors.
- Further therapeutic methods and compositions of the invention therefore comprise a therapeutic amount of at least one of the BMP proteins, whether homodimeric or heterodimeric, in combination with PTHrP or an equivalent PTH- like polypeptide, and other growth factors.
- the preparation and formulation of such physiologically acceptable protein compositions having due regard to pH, isotonicity, stability and the like, is within the skill of the art.
- the therapeutic compositions are also presently valuable for veterinary applications due to the lack of species specificity in TGF- ⁇ proteins. Particularly domestic animals and thoroughbred horses in addition to humans are desired patients for such treatment with the compositions of the present invention.
- the therapeutic method includes administering the composition topically, systemically, or locally as an injectable and/or implant or device.
- the therapeutic composition for use in this invention is, of course, in a pyrogen-free, physiologically acceptable form.
- the composition may desirably be encapsulated or injected in a viscous form for delivery to the site of tissue damage.
- Topical administration may be suitable for wound healing and tissue repair.
- Therapeutically useful agents other than the proteins which may also optionally be included in the composition as described above, may alternatively or additionally, be administered simultaneously or sequentially with the composition in the methods of the invention.
- the compositions of the present invention may be used in conjunction with presently available treatments for cartilage injuries, such as suture (e.g.
- the suture, allograft or autograft may be soaked in the compositions of the present invention prior to implantation. It may also be possible to inco ⁇ orate the protein or composition of the invention onto suture materials, for example, by freeze-drying.
- compositions of the present invention may include an appropriate matrix and/or sequestering agent as a carrier.
- the matrix may support the composition or provide a surface for cartilaginous tissue formation and/or other tissue formation.
- the matrix may provide slow release of the protein and/or the appropriate environment for presentation thereof.
- the sequestering agent may be a substance which aids in ease of administration through injection or other means, or may slow the migration of protein from the site of application.
- a carrier material is based on biocompatibility, biodegradability, mechanical properties, cosmetic appearance and interface properties.
- the particular application of the compositions will define the appropriate formulation.
- Potential matrices for the compositions may be biodegradable and chemically defined. Further matrices are comprised of pure proteins or extracellular matrix components. Other potential matrices are nonbiodegradable and chemically defined.
- Preferred matrices include collagen-based materials, including sponges, such as Helistat * (Integra LifeSciences, Plainsboro, N.J.), or collagen in an injectable form, as well as sequestering agents, which may be biodegradable, for example hyaluronic acid derived.
- Biodegradable materials such as cellulose films, or surgical meshes, may also serve as matrices. Such materials could be sutured into an injury site, or wrapped around the cartilage.
- polymeric matrices including polymers of poly (lactic acid), poly(glycolic acid) and copolymers of lactic acid and glycolic acid. These matrices may be in the form of a sponge, or in the form of porous particles, and may also include a sequestering agent. Suitable polymer matrices are described, for example, in WO93/00050, the disclosure of which is incorporated herein by reference.
- Preferred families of sequestering agents include blood, fibrin clot and/or cellulosic materials such as alkylcelluloses (including hydroxyalkylcelluloses), including methylcellulose, ethylcellulose , hydroxyethylcellulose , hydroxypropylcellulose, hydroxypropyl-methylcellulose, and carboxymethylcellulose, the most preferred being cationic salts of carboxymethylcellulose (CMC).
- alkylcelluloses including hydroxyalkylcelluloses
- CMC carboxymethylcellulose
- Other preferred sequestering agents include hyaluronic acid, sodium alginate, poly(ethylene glycol), polyoxyethylene oxide, carboxyvinyl polymer and poly(vinyl alcohol).
- the amount of sequestering agent useful herein is 0.5-20 wt%, preferably 1-10 wt% based on total formulation weight, which represents the amount necessary to prevent desorbtion of the protein from the polymer matrix and to provide appropriate handling of the composition, yet not so much that the progenitor cells are prevented from infiltrating the matrix, thereby providing the protein the opportunity to assist the activity of the progenitor cells.
- Additional optional components useful in the practice of the subject application include, e.g.
- cryogenic protectors such as mannitol, sucrose, lactose, glucose, or glycine (to protect the protein from degradation during lyophilization), antimicrobial preservatives such as methyl and propyl parabens and benzyl alcohol; antioxidants such as EDTA, citrate and BHT (butylated hydroxytoluene); and surfactants such as poly(sorbates) and poly(oxyethylenes); etc.
- compositions of the invention may be employed in methods for treating a number of cartilage defects, such as the regeneration of cartilaginous tissue in areas of cartilage damage, to assist in repair of tears of cartilage tissue, and various other types of tissue defects or wounds.
- these methods entail administering to a patient needing such cartilaginous tissue or other tissue repair, a composition comprising an effective amount of an osteogenic or cartilage-inducing member of the transforming factor beta [TGF- ⁇ ] superfamily of proteins, such as a bone morphogenetic protein [BMP], preferably BMP-2, BMP-4, BMP-5, BMP-7, BMP- 12 and BMP-13, in combination with parathyroid hormone-related peptide [PTHrP] or an equivalent PTH-like polypeptide.
- BMP bone morphogenetic protein
- PTHrP parathyroid hormone-related peptide
- the methods may entail administration of a heterodimeric protein in which each of the monomers comprises the amino acid sequence of an osteogenic or cartilage-inducing member of the TGF ⁇ superfamily of proteins, such as a BMP, particularly, BMP-2, BMP-4, BMP-5, BMP-7, BMP-12 and BMP-13, in combination with PTHrP or an equivalent PTHrP-like polypeptide.
- each of the monomers is selected from the group consisting of BMP-2, BMP-4, BMP-5, BMP-7, BMP-12 and BMP-13.
- a further aspect of the invention is a therapeutic method and composition for inducing or maintaining chondrocytes or cartilaginous tissue, for repairing cartilaginous tissue, for repairing cartilage as well as treating arthritis and other conditions related to arthritis or cartilage defects.
- Such compositions comprise a therapeutically effective amount of one or more osteogenic or cartilaginous tissue inducing proteins, such as BMP-2 or BMP-13, in combination with PTHrP or an equivalent PTH-like polypeptide, in admixture with a pharmaceutically acceptable vehicle, carrier or matrix.
- the dosage regimen will be determined by the attending physician considering various factors which modify the action of the composition, e.g.
- the dosage may vary with the type of matrix used in the reconstitution and the types of additional proteins in the composition.
- the addition of other known growth factors, such as IGF-I (insulin like growth factor I), to the final composition, may also affect the dosage.
- Progress can be monitored by periodic assessment of chondrocyte survival, cartilaginous tissue formation, or cartilaginous tissue growth and/or repair.
- the progress can be monitored by methods known in the art, for example, X-rays, arthroscopy, histomorphometric determinations and tetracycline labeling.
- the following examples illustrate practice of the present invention in using the compositions and methods described above.
- the methods are useful for producing, recovering and maintaining chondrocytes and/or human cartilaginous tissue inducing protein, employing the methods and compositions of cartilaginous tissue inducing proteins and PTHrP and equivalent PTH-like polypeptides.
- the examples demonstrate the invention with respect to BMP-2 and PTHrP 1-34, with minor modifications within the skill of the art, the same results may be attainable with other TGF- ⁇ proteins, particularly other BMPs, as well as equivalent PTH-like polypeptides.
- PTHrP was tested for its effect on cell lines derived from El 3 mouse limb buds either alone or in combination with BMP-2.
- Cells were grown to confluence in DME medium supplemented with 10% fetal calf serum (FCS). At confluence, cells were transferred to DME medium supplemented with 1 % FCS and cultured for 1 , 2, 4 or 8 days in the presence of either BMP-2 (100 ng/ml), PTHrPl-34 (100 ng/ml)(Peninsular Laboratories Ine). or a combination of BMP-2 and PTHrPl-34.
- FCS fetal calf serum
- tissue specific mRNAs for cartilage proteoglycan core protein, collagen type II and decorin
- bone osteocalcin, alkaline phosphatase and collagen type I
- hypertrophic cartilage collagen type X
- Treatment of limb bud cells with a combination of BMP-2 and PTHrPl-34 induced and maintained expression of proteoglycan core protein and collagen type II.
- Expression of osteocalcin, collagen type I, alkaline phosphatase and collagen type X were all strongly inhibited by treatment with the combination of BMP-2 and PTHrPl-34, compared with treatment with BMP-2 alone.
- PTHrPl-34 alone did not induce expression of any of these RNAs.
- Example 2 Cartilage Induction Using BMP and PTHrP Combinations of other BMPs and PTHrPl-34 are tested for their effect on cell lines derived from E13 mouse limb buds as described in Example 1 above.
- Cells are grown to confluence on medium containing DME supplemented with 1 % fetal calf serum.
- the cells are treated with (a) BMP, such as BMP-13, alone; (b) PTHrP alone; or (c) combinations of BMP and PTHrP; in varying doses from less than 1 ng/ml up to about 5.0 x 10 3 ng/ml.
- histologic and Northern analyses are performed for expression of cartilage and bone markers as described in Example 1 above.
- Example 3 Full Thickness Articular Cartilage Repair Model A full thickness articular cartilage defect model in the femoral-patellar joint of adult rabbits is used to evaluate the ability of the combination of BMPs and PTHrP to affect cartilage and bone repair.
- Adult New Zealand White rabbits are anesthetized and prepared for sterile surgery.
- a 3 x 3 mm defect through articular cartilage and into underlying subchondral bone is drilled into the patellar groove of the knee joint.
- the defect is either left empty, filled with collagen sponge (controls), or with collagen sponge soaked with 10 ⁇ g rhBMP-2 alone, PTHrP alone, another BMP protein alone, or a combination of BMP and PTHrP (experimental).
- the incision is closed and animals are allowed free movement within their cages for 4 weeks. After 4 weeks the animals are humanely euthanatized and the articular cartilage/subchondral bone defect is evaluated histologically for tissue architecture, quantity and quality of repair tissue. Northern analysis is performed for additional phenotyping.
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP97916010A EP0906120B1 (en) | 1996-03-26 | 1997-03-17 | Compositions comprising a combination of bone morphogenetic protein and parathyroid hormone-related peptide |
AU23290/97A AU727312B2 (en) | 1996-03-26 | 1997-03-17 | Methods of tissue induction using a combination of bone morphogenetic protein and parathyroid hormone-related peptide |
JP9534452A JP2000507944A (en) | 1996-03-26 | 1997-03-17 | Tissue induction method using a combination of bone morphogenetic protein and parathyroid hormone-related peptide |
AT97916010T ATE219685T1 (en) | 1996-03-26 | 1997-03-17 | COMPOSITIONS CONTAINING A COMBINATION OF BONE MORPHOGENETIC PROTEIN AND PARATHYROID-LIKE PEPTIDE |
DE69713597T DE69713597T2 (en) | 1996-03-26 | 1997-03-17 | COMPOSITIONS CONTAINING A COMBINATION OF BONE MORPHOGENETIC PROTEIN AND PARATHYROID-LIKE PEPTIDE |
FI981916A FI981916A (en) | 1996-03-26 | 1998-09-08 | Methods for causing tissue formation using a combination of a bone morphogenetic protein and a peptide-like parathyroid hormone |
NO984345A NO984345D0 (en) | 1996-03-26 | 1998-09-18 | Method of Tissue Induction Using a Combination of Bone Morphogenic Protein and Parathyroid Hormone-Related Peptide |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/622,101 | 1996-03-26 | ||
US08/622,101 US5700774A (en) | 1996-03-26 | 1996-03-26 | Compositions comprising bone morphogenic proteins and truncated parathyroid hormone related peptide, and methods of inducing cartilage by administration of same |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997035607A1 true WO1997035607A1 (en) | 1997-10-02 |
Family
ID=24492945
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1997/004162 WO1997035607A1 (en) | 1996-03-26 | 1997-03-17 | Methods of tissue induction using a combination of bone morphogenetic protein and parathyroid hormone-related peptide |
Country Status (12)
Country | Link |
---|---|
US (2) | US5700774A (en) |
EP (1) | EP0906120B1 (en) |
JP (1) | JP2000507944A (en) |
KR (1) | KR19990087489A (en) |
AT (1) | ATE219685T1 (en) |
AU (1) | AU727312B2 (en) |
CA (1) | CA2249212A1 (en) |
DE (1) | DE69713597T2 (en) |
FI (1) | FI981916A (en) |
NO (1) | NO984345D0 (en) |
OA (1) | OA10885A (en) |
WO (1) | WO1997035607A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999018991A1 (en) * | 1997-10-14 | 1999-04-22 | Smith & Nephew Plc | Materials and methods relating to cartilage repair |
WO2002013865A1 (en) * | 2000-08-16 | 2002-02-21 | Chugai Seiyaku Kabushiki Kaisha | Agents for ameliorating symptoms caused by joint diseases |
US6994990B1 (en) | 1997-11-28 | 2006-02-07 | Curis, Inc. | Active modified hedgehog proteins |
JP2007077165A (en) * | 1999-07-21 | 2007-03-29 | Omeros Corp | Solution and method for inhibition of pain, inflammation and cartilage degradation |
Families Citing this family (76)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU674500B2 (en) | 1991-11-04 | 1997-01-02 | Genetics Institute, Llc | Recombinant bone morphogenetic protein heterodimers, compositions and methods of use |
US5942496A (en) | 1994-02-18 | 1999-08-24 | The Regent Of The University Of Michigan | Methods and compositions for multiple gene transfer into bone cells |
US6551618B2 (en) | 1994-03-15 | 2003-04-22 | University Of Birmingham | Compositions and methods for delivery of agents for neuronal regeneration and survival |
US5906827A (en) * | 1994-06-03 | 1999-05-25 | Creative Biomolecules, Inc. | Matrix for the manufacture of autogenous replacement body parts |
US6897297B1 (en) * | 1997-12-03 | 2005-05-24 | Curis, Inc. | Hydrophobically-modified protein compositions and methods |
US6171340B1 (en) | 1998-02-27 | 2001-01-09 | Mcdowell Charles L. | Method and device for regenerating cartilage in articulating joints |
EP1557427A3 (en) * | 1998-04-30 | 2005-10-19 | Curis, Inc. | Hedgehog protein conjugate |
DE69911609T2 (en) | 1998-07-13 | 2004-07-01 | University Of Southern California, Los Angeles | PROCESS FOR ACCELERATING THE GROWTH AND HEALING OF BONES AND CARTILES |
US6916783B2 (en) * | 1998-07-13 | 2005-07-12 | University Of Southern California | Methods for accelerating bone and cartilage growth and repair |
US7067144B2 (en) * | 1998-10-20 | 2006-06-27 | Omeros Corporation | Compositions and methods for systemic inhibition of cartilage degradation |
US6727224B1 (en) * | 1999-02-01 | 2004-04-27 | Genetics Institute, Llc. | Methods and compositions for healing and repair of articular cartilage |
US6197061B1 (en) | 1999-03-01 | 2001-03-06 | Koichi Masuda | In vitro production of transplantable cartilage tissue cohesive cartilage produced thereby, and method for the surgical repair of cartilage damage |
EP2305324B1 (en) | 1999-03-25 | 2014-09-17 | Metabolix, Inc. | Medical devices and applications of polyhydroxyalkanoate polymers |
US6315992B1 (en) | 1999-06-30 | 2001-11-13 | Tissuegene Co. | Generating cartilage in a mammal using fibroblasts transfected with a vector encoding TGF-β-1 |
US7338655B1 (en) | 1999-06-30 | 2008-03-04 | Tissuegene, Inc. | Gene therapy using TGF-β |
US7687462B2 (en) * | 1999-10-05 | 2010-03-30 | The Regents Of The University Of California | Composition for promoting cartilage formation or repair comprising a nell gene product and method of treating cartilage-related conditions using such composition |
US6770078B2 (en) | 2000-01-14 | 2004-08-03 | Peter M. Bonutti | Movable knee implant and methods therefor |
US7635390B1 (en) | 2000-01-14 | 2009-12-22 | Marctec, Llc | Joint replacement component having a modular articulating surface |
US6702821B2 (en) * | 2000-01-14 | 2004-03-09 | The Bonutti 2003 Trust A | Instrumentation for minimally invasive joint replacement and methods for using same |
US7708741B1 (en) | 2001-08-28 | 2010-05-04 | Marctec, Llc | Method of preparing bones for knee replacement surgery |
AU2002335747B2 (en) | 2001-09-15 | 2009-01-29 | Rush University Medical Center | Stratified cartilage tissue and methods to engineer same |
AU2002337807A1 (en) * | 2001-10-04 | 2003-04-14 | Massachusetts Institute Of Technology | Effect of bone morphogenetic proteins on engineered cartilage |
US20030165473A1 (en) * | 2001-11-09 | 2003-09-04 | Rush-Presbyterian-St. Luke's Medical Center | Engineered intervertebral disc tissue |
CA2472472A1 (en) * | 2002-01-10 | 2003-07-24 | Osteotrophin Llc | Treatment of bone disorders with skeletal anabolic drugs |
JP4033400B2 (en) * | 2002-03-12 | 2008-01-16 | ティシュージーン,インク | Cartilage regeneration using chondrocytes and TGF-β |
US7431922B2 (en) * | 2002-03-29 | 2008-10-07 | Tissuegene, Inc. | Bioadhesive directed somatic cell therapy |
US7005127B2 (en) * | 2002-03-29 | 2006-02-28 | Tissuegene, Inc. | Mixed-cell gene therapy |
AU2003280130B2 (en) | 2002-06-28 | 2009-06-11 | Centocor, Inc. | Mammalian CH1 deleted mimetibodies, compositions, methods and uses |
AU2003259765B2 (en) * | 2002-08-13 | 2009-01-22 | Wyeth | Peptides as solubilizing excipients for transforming growth factor Beta proteins |
US20050209142A1 (en) * | 2002-11-20 | 2005-09-22 | Goran Bertilsson | Compounds and methods for increasing neurogenesis |
US7837690B2 (en) | 2003-01-15 | 2010-11-23 | Biomet Manufacturing Corp. | Method and apparatus for less invasive knee resection |
US7887542B2 (en) | 2003-01-15 | 2011-02-15 | Biomet Manufacturing Corp. | Method and apparatus for less invasive knee resection |
US7789885B2 (en) | 2003-01-15 | 2010-09-07 | Biomet Manufacturing Corp. | Instrumentation for knee resection |
US8551100B2 (en) | 2003-01-15 | 2013-10-08 | Biomet Manufacturing, Llc | Instrumentation for knee resection |
EP1613267A2 (en) * | 2003-03-27 | 2006-01-11 | Children's Hospital Medical Center | Use of fgf- 18 protein, target proteins and their respective encoding nucleotide sequences to induce cartilage formation |
US7067123B2 (en) | 2003-04-29 | 2006-06-27 | Musculoskeletal Transplant Foundation | Glue for cartilage repair |
US7901457B2 (en) | 2003-05-16 | 2011-03-08 | Musculoskeletal Transplant Foundation | Cartilage allograft plug |
US7488348B2 (en) | 2003-05-16 | 2009-02-10 | Musculoskeletal Transplant Foundation | Cartilage allograft plug |
CN1878565B (en) | 2003-09-12 | 2011-01-12 | 惠氏公司 | Injectable calcium phosphate solid rods and pastes for delivery of osteogenic proteins |
US7488324B1 (en) | 2003-12-08 | 2009-02-10 | Biomet Manufacturing Corporation | Femoral guide for implanting a femoral knee prosthesis |
US8697139B2 (en) | 2004-09-21 | 2014-04-15 | Frank M. Phillips | Method of intervertebral disc treatment using articular chondrocyte cells |
US7837740B2 (en) | 2007-01-24 | 2010-11-23 | Musculoskeletal Transplant Foundation | Two piece cancellous construct for cartilage repair |
WO2006081379A1 (en) * | 2005-01-26 | 2006-08-03 | Wyeth | Use of sfrps as markers of bmp activity |
CA2597605A1 (en) | 2005-02-16 | 2006-08-24 | The Regents Of The University Of California | Pharmaceutical compositions for treating or preventing bone conditions |
US7695479B1 (en) | 2005-04-12 | 2010-04-13 | Biomet Manufacturing Corp. | Femoral sizer |
US7815926B2 (en) | 2005-07-11 | 2010-10-19 | Musculoskeletal Transplant Foundation | Implant for articular cartilage repair |
WO2007011610A2 (en) * | 2005-07-18 | 2007-01-25 | Acologix, Inc. | Protein formulation for promoting hard tissue formation |
WO2007035778A2 (en) | 2005-09-19 | 2007-03-29 | Histogenics Corporation | Cell-support matrix and a method for preparation thereof |
US8070752B2 (en) | 2006-02-27 | 2011-12-06 | Biomet Manufacturing Corp. | Patient specific alignment guide and inter-operative adjustment |
US9907659B2 (en) | 2007-04-17 | 2018-03-06 | Biomet Manufacturing, Llc | Method and apparatus for manufacturing an implant |
US8603180B2 (en) | 2006-02-27 | 2013-12-10 | Biomet Manufacturing, Llc | Patient-specific acetabular alignment guides |
US9918740B2 (en) | 2006-02-27 | 2018-03-20 | Biomet Manufacturing, Llc | Backup surgical instrument system and method |
US9345548B2 (en) | 2006-02-27 | 2016-05-24 | Biomet Manufacturing, Llc | Patient-specific pre-operative planning |
US10278711B2 (en) | 2006-02-27 | 2019-05-07 | Biomet Manufacturing, Llc | Patient-specific femoral guide |
US7780672B2 (en) | 2006-02-27 | 2010-08-24 | Biomet Manufacturing Corp. | Femoral adjustment device and associated method |
US9173661B2 (en) | 2006-02-27 | 2015-11-03 | Biomet Manufacturing, Llc | Patient specific alignment guide with cutting surface and laser indicator |
US9113971B2 (en) | 2006-02-27 | 2015-08-25 | Biomet Manufacturing, Llc | Femoral acetabular impingement guide |
US8591516B2 (en) | 2006-02-27 | 2013-11-26 | Biomet Manufacturing, Llc | Patient-specific orthopedic instruments |
US8407067B2 (en) | 2007-04-17 | 2013-03-26 | Biomet Manufacturing Corp. | Method and apparatus for manufacturing an implant |
US9289253B2 (en) | 2006-02-27 | 2016-03-22 | Biomet Manufacturing, Llc | Patient-specific shoulder guide |
US9339278B2 (en) | 2006-02-27 | 2016-05-17 | Biomet Manufacturing, Llc | Patient-specific acetabular guides and associated instruments |
US20150335438A1 (en) | 2006-02-27 | 2015-11-26 | Biomet Manufacturing, Llc. | Patient-specific augments |
US7695520B2 (en) | 2006-05-31 | 2010-04-13 | Biomet Manufacturing Corp. | Prosthesis and implementation system |
US9795399B2 (en) | 2006-06-09 | 2017-10-24 | Biomet Manufacturing, Llc | Patient-specific knee alignment guide and associated method |
JP5579445B2 (en) * | 2007-01-22 | 2014-08-27 | オルソトロフィックス インコーポレイテッド | Peptide compositions and methods for promoting cartilage formation |
US8435551B2 (en) | 2007-03-06 | 2013-05-07 | Musculoskeletal Transplant Foundation | Cancellous construct with support ring for repair of osteochondral defects |
CA2717725A1 (en) | 2008-03-05 | 2009-09-11 | Musculoskeletal Transplant Foundation | Cancellous constructs, cartilage particles and combinations of cancellous constructs and cartilage particles |
US8513193B2 (en) | 2008-10-13 | 2013-08-20 | University Of Rochester | Protecting and repairing cartilage and musculoskeletal soft tissues |
KR20220100999A (en) | 2008-11-25 | 2022-07-18 | 코오롱 티슈진 인크. | Primed cell therapy |
US8530420B2 (en) * | 2008-12-16 | 2013-09-10 | Kaohsiung Medical University | Treatment of arthritis with parathyroid hormone |
US9968376B2 (en) | 2010-11-29 | 2018-05-15 | Biomet Manufacturing, Llc | Patient-specific orthopedic instruments |
US9241745B2 (en) | 2011-03-07 | 2016-01-26 | Biomet Manufacturing, Llc | Patient-specific femoral version guide |
EP2875125B1 (en) * | 2012-07-20 | 2018-10-24 | Alfred C. Kuo | Methods for producing cartilage and bone |
US10077420B2 (en) | 2014-12-02 | 2018-09-18 | Histogenics Corporation | Cell and tissue culture container |
JP2020506926A (en) * | 2017-02-01 | 2020-03-05 | ザ・ジョンズ・ホプキンス・ユニバーシティ | Parathyroid hormone and regeneration of degenerative disc disease |
US10722310B2 (en) | 2017-03-13 | 2020-07-28 | Zimmer Biomet CMF and Thoracic, LLC | Virtual surgery planning system and method |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5118667A (en) * | 1991-05-03 | 1992-06-02 | Celtrix Pharmaceuticals, Inc. | Bone growth factors and inhibitors of bone resorption for promoting bone formation |
Family Cites Families (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5108922A (en) * | 1986-07-01 | 1992-04-28 | Genetics Institute, Inc. | DNA sequences encoding BMP-1 products |
US5187076A (en) * | 1986-07-01 | 1993-02-16 | Genetics Institute, Inc. | DNA sequences encoding BMP-6 proteins |
US5106748A (en) * | 1986-07-01 | 1992-04-21 | Genetics Institute, Inc. | Dna sequences encoding 5 proteins |
US5543394A (en) * | 1986-07-01 | 1996-08-06 | Genetics Institute, Inc. | Bone morphogenetic protein 5(BMP-5) compositions |
US5013649A (en) * | 1986-07-01 | 1991-05-07 | Genetics Institute, Inc. | DNA sequences encoding osteoinductive products |
ZA874681B (en) * | 1986-07-01 | 1988-04-27 | Genetics Inst | Novel osteoinductive factors |
US5459047A (en) * | 1986-07-01 | 1995-10-17 | Genetics Institute, Inc. | BMP-6 proteins |
US5457092A (en) * | 1987-07-30 | 1995-10-10 | Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) | Methods of promoting bone growth in mammals comprising administration of modified parathyroid hormone |
JPH03504201A (en) * | 1989-02-23 | 1991-09-19 | ゲゼルシャフト・フュア・ビオテクノロギッシェ・フォルシュンク・ミット・ベシュレンクテル・ハフツング (ゲー・ベー・エフ) | DNA sequences encoding PTH variants, PTH variants, expression vectors, bacterial hosts, compositions for use and treatment |
WO1991018098A1 (en) * | 1990-05-16 | 1991-11-28 | Genetics Institute, Inc. | Bone and cartilage inductive proteins |
US5364839A (en) * | 1990-06-18 | 1994-11-15 | Genetics Institute, Inc. | Osteoinductive pharmaceutical formulations |
ATE142460T1 (en) * | 1991-06-21 | 1996-09-15 | Genetics Inst | MEDICINAL PRODUCTS CONTAINING OSTEOGENIC PROTEINS |
WO1993000432A1 (en) * | 1991-06-25 | 1993-01-07 | Genetics Institute, Inc. | Bmp-9 compositions |
AU674500B2 (en) * | 1991-11-04 | 1997-01-02 | Genetics Institute, Llc | Recombinant bone morphogenetic protein heterodimers, compositions and methods of use |
UA48105C2 (en) * | 1992-02-12 | 2002-08-15 | Біофарм Гезельшафт Цур Біотехнологішен Ентвіклунг Вон Фармака Мбх | DNA FRAGMENT CODING THE PROTEIN OF THE FAMILY TGF-в (VERSIONS), RECOMBINANT DNA MOLECULE (VERSIONS), CELL-HOST (VERSIONS), METHOD FOR OBTAINING THE PROTEIN OF THE FAMILY TGF-в (VERSIONS), PHARMACEUTICAL COMPOSITION (VERSIONS), ANTIBODY OR AN ANTIBODY FRAGMENT (VERSIONS), CDNA MOLECULE (VERSIONS) |
IL106278A0 (en) * | 1992-07-13 | 1993-11-15 | Sumitomo Metal Ind | Bone formation-inducing protein |
EP1439190A1 (en) * | 1993-01-12 | 2004-07-21 | The Johns Hopkins University School Of Medicine | Growth differentiation factor-5 |
US5808007A (en) * | 1993-01-12 | 1998-09-15 | The Johns Hopkins University School Of Medicine | Growth differentiation factor-3 |
EP0678101A4 (en) * | 1993-01-12 | 1997-07-16 | Univ Johns Hopkins Med | Growth differentiation factor-9. |
DK0690873T3 (en) * | 1993-03-19 | 2003-09-29 | Univ Johns Hopkins Med | Growth Differentiation Factor-8 |
DK0698094T3 (en) * | 1993-05-12 | 2004-05-03 | Inst Genetics Llc | BMP-11 compositions |
ATE265529T1 (en) * | 1993-05-12 | 2004-05-15 | Inst Genetics Llc | BMP-10 COMPOSITIONS |
CA2165776A1 (en) * | 1993-07-09 | 1995-01-19 | Se-Jin Lee | Growth differentiation factor-6 |
EP0717633A4 (en) * | 1993-07-09 | 1998-05-20 | Univ Johns Hopkins Med | Growth differentiation factor-7 |
ATE319823T1 (en) * | 1993-12-07 | 2006-03-15 | Inst Genetics Llc | BMP-12, BMP-13 AND TENDON-INDUCING COMPOSITIONS CONTAINING SAME |
-
1996
- 1996-03-26 US US08/622,101 patent/US5700774A/en not_active Expired - Lifetime
-
1997
- 1997-03-17 WO PCT/US1997/004162 patent/WO1997035607A1/en not_active Application Discontinuation
- 1997-03-17 CA CA002249212A patent/CA2249212A1/en not_active Abandoned
- 1997-03-17 DE DE69713597T patent/DE69713597T2/en not_active Expired - Lifetime
- 1997-03-17 EP EP97916010A patent/EP0906120B1/en not_active Expired - Lifetime
- 1997-03-17 JP JP9534452A patent/JP2000507944A/en active Pending
- 1997-03-17 KR KR1019980706917A patent/KR19990087489A/en not_active Application Discontinuation
- 1997-03-17 AU AU23290/97A patent/AU727312B2/en not_active Ceased
- 1997-03-17 AT AT97916010T patent/ATE219685T1/en active
- 1997-09-10 US US08/926,942 patent/US5846931A/en not_active Expired - Lifetime
-
1998
- 1998-09-08 FI FI981916A patent/FI981916A/en not_active IP Right Cessation
- 1998-09-18 NO NO984345A patent/NO984345D0/en not_active Application Discontinuation
- 1998-09-25 OA OA9800179A patent/OA10885A/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5118667A (en) * | 1991-05-03 | 1992-06-02 | Celtrix Pharmaceuticals, Inc. | Bone growth factors and inhibitors of bone resorption for promoting bone formation |
Non-Patent Citations (3)
Title |
---|
HOLLNAGEL ET AL: "PARATHYROID HORMONE (PTH) AND PTH/PTHRP-RECEPTOR MEDIATED STIMULATION OF OSTEOCHONDROGENIC DEVELOPMENT IN BMP-TRANSFECTED C3H10T1/2 MESENCHYMAL PROGENITOR CELLS TAKES PLACE DURING THE EARLY COMMITMENT PERIOD", CALCIFIED TISSUE INTERNATIONAL, vol. 56, no. 5, May 1995 (1995-05-01), pages 430, XP000676748 * |
KATAGIRI ET AL: "BONE MORPHOGENETIC PROTEIN-2 CONVERTS THE DIFFERENTIATION PATHWAY OF C2C12 MYOBLASTS INTO THE OSTEOBLAST LINEAGE", THE JOURNAL OF CELL BIOLOGY, vol. 127, no. 6PT1, December 1994 (1994-12-01), pages 1755 - 1766, XP000676744 * |
ZHENG ET AL: "WHAT'S NEW IN THE ROLE OF CYTOKINES ON OSTEOBLAST PROLIFERATION AND DIFFERENTIATION", PATHOLOGY RESEARCH AND PRACTICE, vol. 188, no. 8, December 1992 (1992-12-01), pages 1104 - 1121, XP000676745 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999018991A1 (en) * | 1997-10-14 | 1999-04-22 | Smith & Nephew Plc | Materials and methods relating to cartilage repair |
US6994990B1 (en) | 1997-11-28 | 2006-02-07 | Curis, Inc. | Active modified hedgehog proteins |
JP2007077165A (en) * | 1999-07-21 | 2007-03-29 | Omeros Corp | Solution and method for inhibition of pain, inflammation and cartilage degradation |
WO2002013865A1 (en) * | 2000-08-16 | 2002-02-21 | Chugai Seiyaku Kabushiki Kaisha | Agents for ameliorating symptoms caused by joint diseases |
Also Published As
Publication number | Publication date |
---|---|
AU727312B2 (en) | 2000-12-07 |
OA10885A (en) | 2003-02-18 |
FI981916A0 (en) | 1998-09-08 |
NO984345L (en) | 1998-09-18 |
EP0906120B1 (en) | 2002-06-26 |
EP0906120A1 (en) | 1999-04-07 |
AU2329097A (en) | 1997-10-17 |
NO984345D0 (en) | 1998-09-18 |
JP2000507944A (en) | 2000-06-27 |
DE69713597T2 (en) | 2003-02-20 |
KR19990087489A (en) | 1999-12-27 |
CA2249212A1 (en) | 1997-10-02 |
ATE219685T1 (en) | 2002-07-15 |
FI981916A (en) | 1998-09-08 |
US5700774A (en) | 1997-12-23 |
US5846931A (en) | 1998-12-08 |
DE69713597D1 (en) | 2002-08-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5700774A (en) | Compositions comprising bone morphogenic proteins and truncated parathyroid hormone related peptide, and methods of inducing cartilage by administration of same | |
US5902785A (en) | Cartilage induction by bone morphogenetic proteins | |
Chubinskaya et al. | Regulation of osteogenic proteins by chondrocytes | |
US5409896A (en) | TGF-β composition for inducing bone growth | |
EP0527787B1 (en) | Method of predisposing mammals to accelerated tissue repair | |
US6287816B1 (en) | BMP-9 compositions | |
EP2374870B1 (en) | Composition comprising an osteogenic protein selected from the group consisting of OP-2, OP-3, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-9, BMP-10, BMP-11, BMP-15, BMP-3B, DPP, Vg-1, Vgr-1, 60A protein, GDF-1, GDF-2, GDF-3, GDF-6, GDF-7, GDF-8, GDF-9, GDF-10, and GDF-11 for use in repairing a defect locus in nonarticular cartilage | |
AU660182B2 (en) | Bone growth factors and inhibitors of bone resorption for promoting bone formation | |
US5364839A (en) | Osteoinductive pharmaceutical formulations | |
US7875590B2 (en) | Injectable solid hyaluronic acid carriers for delivery of osteogenic proteins | |
Vukičević et al. | Discovery and clinical applications of bone morphogenetic proteins | |
US6492493B2 (en) | Bone morphogenetic protein (BMP)-17 and BMP-18 compositions | |
KR20000036012A (en) | Bone morphogenetic protein-16 (bmp-16) compositions | |
US9050300B2 (en) | Surgical applications for BMP binding protein | |
Bostrom et al. | Biologics in bone healing | |
CA2438934A1 (en) | Chondrogenic potential of human bone marrow-derived cd105+ cells by bmp | |
McKinney et al. | A Bone Regeneration Study: Transforming Growth Factor-β: 1: and Its Delivery | |
JP3931353B2 (en) | Wound healing agent | |
Puleo | Biotherapeutics in orthopaedic medicine: accelerating the healing process? | |
JPH07316066A (en) | Wound healing agent | |
Chiba et al. | Histological study of effect of bone morphogenetic protein derived from bovine tooth on periosteum in rats |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU CA CN HU JP KR NO RU |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 1019980706917 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 981916 Country of ref document: FI |
|
ENP | Entry into the national phase |
Ref document number: 2249212 Country of ref document: CA Ref country code: CA Ref document number: 2249212 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1997916010 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1997916010 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1019980706917 Country of ref document: KR |
|
WWG | Wipo information: grant in national office |
Ref document number: 1997916010 Country of ref document: EP |
|
WWR | Wipo information: refused in national office |
Ref document number: 1019980706917 Country of ref document: KR |