WO1999026977A1 - Recepteurs 'opg-2' - Google Patents

Recepteurs 'opg-2' Download PDF

Info

Publication number
WO1999026977A1
WO1999026977A1 PCT/US1998/025065 US9825065W WO9926977A1 WO 1999026977 A1 WO1999026977 A1 WO 1999026977A1 US 9825065 W US9825065 W US 9825065W WO 9926977 A1 WO9926977 A1 WO 9926977A1
Authority
WO
WIPO (PCT)
Prior art keywords
opg
receptor
polypeptide
fragment
soluble
Prior art date
Application number
PCT/US1998/025065
Other languages
English (en)
Inventor
Jurg Tschopp
Original Assignee
Biogen, Inc.
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 Biogen, Inc. filed Critical Biogen, Inc.
Priority to AU15356/99A priority Critical patent/AU1535699A/en
Publication of WO1999026977A1 publication Critical patent/WO1999026977A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70575—NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70578—NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Definitions

  • the present invention relates to novel receptors in the TNF family.
  • the novel receptors herein are referred to as OPG-2.
  • the TNF family consists of pairs of ligands and their specific receptors referred to as TNF family ligands and TNF family receptors (Bazzoni and Beutler, 1996).
  • the family is involved in the regulation of the immune system and possibly other non-immunological systems. The regulation is often at a "master switch" level such that TNF family signaling can result in a large number of subsequent events best typified by TNF.
  • TNF can initiate the general protective inflammatory response of an organism to foreign invasion that involves the altered display of adhesion molecules involved in cell trafficking, chemokine production to drive specific cells into specific compartments and the priming of various effector cells.
  • the TNF receptor family is a collection of related proteins that generally consist of an extracellular domain, a transmembrane domain and an intracellular signaling domain.
  • the extracellular domain is built from 2-6 copies of a tightly disulphide bonded domain and is recognized on the basis of the unique arrangement of cysteine residues.
  • Each receptor binds to a corresponding ligand although one ligand may share several receptors.
  • soluble forms of the receptors lacking the transmembrane region and intracellular domain exist naturally.
  • truncated versions of these receptors exist and the soluble inhibitory form may have direct biological regulatory roles.
  • viruses have used this tactic to inhibit TNF activity in their host organisms (Smith, 1994). These receptors can signal a number of events including cell differentiation, cell death or cell survival signals. Cell death signaling often is triggered via relatively direct links to the caspase cascade of proteases e.g. Fas and TNF receptors. Most receptors in this class can also activate NF5 Kappa B controlled events.
  • proteases e.g. Fas and TNF receptors.
  • Most receptors in this class can also activate NF5 Kappa B controlled events.
  • OPG a member of the TNF receptor superfamily has recently been identified.
  • Osteoprotegerin A Novel Secreted Protein Involved in the Regulation of Bone Density, Cell, Vol. 89 309-319, 1997., specifically incorporated herein by reference.
  • OPG inhibits osteoclast maturation and protects bone from both normal osteoclast remodeling and ovariectomy associated bone loss.
  • This protein contains two characterized domains, see infra. It has been found that systemic delivery of OPG via the expression of rat or muring OPG transgenes in mice results in severe yet nonlethal osteopetrosis.
  • the osteopetrotic phenotype caused by OPG overexpression differs significantly from those observed in other mouse osteopetrotic models, whether generated by the disruption of specific genes such as src or fos gene knockouts, or in naturally occurring mouse mutants.
  • the receptors are powerful tools to elucidate biological pathways via their easy conversion to immunoglobulin fusion proteins. These dimeric soluble receptor forms are good inhibitors of events mediated by either secreted or surface bound ligands. By binding to these ligands they prevent the ligand from interacting with cell associated receptors that can signal. Not only are these receptor-Ig fusion proteins useful in an experimental sense, but they have been successfully used clinically in the case of TNF-R-Ig to treat inflammatory bowel disease, rheumatoid arthritis and the acute clinical syndrome accompanying OKT3 administration (Eason et al., 1996; Feldmann et al., 1996; van Dullemen et al., 1995).
  • TNF family of receptors A soluble form of a recently described receptor, osteoprotegerin, can block the loss of bone mass and, therefore, the events controlled by TNF family receptor signaling are not necessarily limited to immune system regulation.
  • Antibodies to the receptor can block ligand binding and hence can also have clinical application. Such antibodies are often very long-lived and may have advantages over soluble receptor-Ig fusion proteins which have shorter blood half-lives.
  • the receptor can be activated either by administration of the ligand, i.e. the natural pathway or some antibodies that can crosslink the receptor are also potent agonists. Antibodies would have an advantage in oncology since they can persist in the blood for long periods whereas the ligands generally have short lifespans in the blood.
  • agonist antibodies could be good weapons in the treatment of cancer.
  • many positive immunological events are mediated via the TNF family receptors, e.g. host inflammatory reactions, antibody production etc. and therefore agonistic antibodies could have beneficial effects in other, non-oncological applications.
  • the inhibition of a pathway may have clinical benefit in the treatment of tumors.
  • the Fas ligand is expressed by some tumors and this expression can lead to the death of Fas positive lymphocytes thus facilitating the ability of the tumor to evade the immune system.
  • inhibition of the Fas system could then allow the immune system to react to the tumor in other ways now that access is possible (Green and Ware, 1997).
  • the receptors are also useful to discover the corresponding ligand as they can serve as probes of the ligand in expression cloning techniques (Smith et al., 1993).
  • the receptors and ligands can form in vitro binding assays that will allow the identification of inhibitory substances. Such substances can form the basis of novel inhibitors of the pathways.
  • OPG-2 is a novel receptor in the TNF family.
  • OPG-2 receptor refers to polypeptides having amino acid sequences which are substantially similar to the native mammalian OPG-2 receptor amino acid sequences, set forth in SEQ. LD. NO 2, and which are biologically active, as defined below, in that they are capable of binding to ligands or transducing a biological signal initiated by an OPG ligand binding to a cell, or cross- reacting with anti- OPG-2 antibodies raised against OPG-2.
  • the terms as used herein include, but are not limited to, analogs or subunits of native proteins having at least 70-90% homology and which exhibit at least some biological activity in common with OPG-2, for example, shortened constructs which retain the ability to bind to a ligand.
  • Various bioequivalent protein and amino acid analogs are described in detail below.
  • the OPG-2 receptors of the invention may be isolated from mammalian tissues and purified to homogeneity, or isolated from cells which contain membrane-bound OPG-2. and purified to homogeneity. Methods for growing cells and isolating cell extracts are well know in the art, as are various cell types and growth and isolation methods. In general, any OPG-2 can be isolated from any cell or tissue expressing this protein using a cDNA probe, isolating mRNA and transcribing the mRNA into cDNA. Thereafter, the protein can be produced by inserting the cDNA into an expression vector, such as a virus, plasmid, cosmid or other expression vector, inserting the expression vector into a cell, and proliferating the resulting cells. The OPG-2 can then be isolated from the medium or cell extract by methods well known in the art. One skilled in the art can readily vary the vectors and cell lines and still obtain the claimed receptors.
  • OPG-2 may be chemically synthesized using the sequences set forth in SEQ.LD.NO.: 2, fragments or portions thereof.
  • OPG-2 is useful in the treatment of osteopenic disorders such as those characterized by excessive osteoclast activity such as primary osteoporosis, Paget's disease of the bone, hypercalcemia of malignancy and osteolytic metastases.
  • the present invention also encompasses DNA sequences which encode OPG-2.
  • the DNA sequence is set forth in SEQ. LD. NO. 1 in comparison with one of two published sequences for OPG-1.
  • the invention relates to sequences that have at least 50% homology with DNA sequences encoding the C terminal receptor binding domain of the ligands and hybridize to the claimed DNA sequences or fragments thereof, and which encode OPG-2 having the sequences identified in SEQ. LD. NO. 2 or the activity of the protein encoded thereby.
  • the invention in certain embodiments furthermore relates to DNA sequences encoding OPG-2 where the sequences are operatively linked to an expression control sequence.
  • Any suitable expression control sequences are useful in the claimed invention, and can easily be selected by one skilled in the art.
  • the invention also contemplates recombinant DNAs comprising a sequence encoding OPG-2 or fragments thereof, as well as hosts with stably integrated OPG-2 sequences introduced into their genome, or possessing episomal elements. Any suitable host may be used in the invention, and can easily be selected by one skilled in the art without undue experimentation.
  • the claimed invention in certain embodiments encompasses recombinant OPG-2.
  • One skilled in the art can readily isolate such recombinant receptors thereby providing substantially pure recombinant OPG-2 polypeptides.
  • Isolated receptors of the invention are substantially free of other contaminating materials of natural or endogenous origin, and contain less than about 10- 15 % by mass of protein contaminants residual of production processes.
  • Mammalian Receptors within the scope of the invention also include, but are not limited to, primate, human, murine, canine, feline, bovine, ovine, equine and porcine
  • OPG-2 Mammalian Receptors can also be obtained by cross species hybridization using a single stranded cDNA derived from the human OPG-2. DNA sequences of the invention can be used as a hybridization probe to isolate Receptor cDNAS from other mammalian cDNA libraries. Derivatives of the Receptors within the scope of the invention also include various structural forms of the proteins of SEQ.LD.NO.: 2 which retain biological activity. For example, a receptor protein may be in the form of acidic or basic salts, or may be in neutral form. Individual amino acid residues may also be modified by oxidation or reduction. OPG-2 derivatives may also be used as immunogens, reagents in a receptor-based immunoassay, or as binding agents for affinity purification procedures of OPG-2 ligands.
  • the present invention also includes OPG-2 with or without associated native- pattern glycosylation.
  • OPG-2 with or without associated native- pattern glycosylation.
  • the glycosylation pattern on the receptor may vary depending on the particular expression system used. For example, typically, expression in bacteria such as E. coli results in a non-glycosylated molecule.
  • OPG-2 derivatives may also be obtained by mutations of the receptors or their subunits.
  • a mutant, as referred to herein, is a polypeptide homologous to a claimed Receptor but which has an amino acid sequence different from the native sequence due to a deletion, insertion or substitution.
  • Bioequivalent analogs of the Receptor proteins of the invention may be constructed by, for example, making various substitutions of residues or sequences or deleting terminal or internal residues or sequences not needed for biological activity. For example, often cysteine residues can be deleted or replaced with other amino acids to prevent formation of unnecessary or incorrect intramolecular disulfide bridges upon renaturation. Other approaches to mutagenesis involve modifications, for example, to enhance expression in the chosen expression system. Soluble Receptors of the invention may comprise subunits which have been changed. Thus, soluble peptides may be produced by truncating the polypeptide. Soluble Receptors of the invention may include any number of well-known leader sequences at the N-terminus.
  • the invention herein provides agents, such as agonists and antagonists, directed against the claimed receptors.
  • the agent comprises a blocking agent that comprises an antibody directed against OPG-2 that inhibits OPG-2 pathway signaling.
  • the antibody is a monoclonal antibody.
  • the claimed invention encompasses antibodies and other agents which act as agonists in the OPG-2 pathways.
  • Inhibitory anti- OPG-2 antibodies and other receptor blocking agents can be identified using screening methods that detect the ability of one or more agents either to bind to OPG-2, or ligands thereto, or to inhibit the effects of OPG-2 signaling on cells.
  • Screen methods that detect the ability of one or more agents either to bind to OPG-2, or ligands thereto, or to inhibit the effects of OPG-2 signaling on cells.
  • One skilled in the art will have knowledge of a number of assays that measure the strength of ligand-receptor binding and can be used to perform competition assays with putative OPG-2 blocking agents.
  • the strength of the binding between a receptor and ligand can be measured using an enzyme-linked immunoadsorption assay (ELIS A) or a radioimmunoassay (RIA).
  • Specific binding may also be measured by flourescently labeling antibody-antigen complexes and performing fluorescence activated cell sorting analysis (FACS), or by performing other such immunodetection methods, all of which are
  • the receptor blocking agents of the invention in one embodiment comprise soluble OPG-2 molecules.
  • the receptor blocking agents of the invention in one embodiment comprise soluble OPG-2 molecules.
  • functional fragments encoding the OPG-2 ligand binding domain can be cloned into a vector and expressed in an appropriate host to produce a modified receptor molecule.
  • Soluble OPG-2 molecules that can compete with native OPG-2 for ligand binding according to the assays described herein can be selected as OPG-2 receptor blocking agents.
  • a soluble OPG-2 comprising amino acid sequences selected from those shown ' herein may be attached to one or more heterologous protein domains ("fusion domains") to increase the in vivo stability of the receptor fusion protein, or to modulate its biological activity or localization.
  • fusion domains heterologous protein domains
  • stable plasma proteins which typically have a half-life greater than 20 hours in the circulation of a mammal— are used to construct the receptor fusion proteins.
  • plasma proteins include but are not limited to: immunoglobulins, serum albumin, lipoproteins, apolipoproteins and transferrin. Sequences that can target the soluble receptors to a particular cell or tissue type may also be attached to the receptor ligand binding domain to create a specifically localized soluble receptor fusion protein.
  • OPG-2 comprising the OPG-2 ligand binding domain may be fused to an immunoglobulin constant region like the Fc domain of a human IgGl heavy chain.
  • Soluble receptor -IgG fusions proteins are common immunological reagents and methods for their construction are well known in the art. (see, e.g. U.S. Patent No. 5, 225, 538).
  • a functional OPG-2 ligand binding domain may be fused to an immunoglobulin (Ig) Fc domain derived from an immunoglobulin class or subclass other than IgGl.
  • Ig immunoglobulin
  • the Fc domains of antibodies belonging to different Ig classes or subclasses can activate diverse secondary effector functions. Activation occurs when the Fc domain is bound by a cognate Fc receptor. Secondary effector functions include the ability to activate the complement system, to cross the placenta and to bind various microbial proteins. The properties of the different classes and subclasses of immunoglobulins are described in the art.
  • Activation of the complement system initiates cascades of enzymatic reactions that mediate inflammation.
  • the products of the complement system have a variety of functions, including binding of bacteria, endocytosis, phagocytosis, cytotoxicity, free radical production and solubilization of immune complexes.
  • the complement enzyme cascade can be activated by the Fc domains of antigen- bound IgGl, IgG3 and Ig M antibodies.
  • the Fc domain of IgG2 appears to be less effective, and the Fc domains of IgG4, IgA, IgD and IgE are ineffective at activating complement.
  • one can select an Fc domain based on whether its associated secondary effector functions are desirable for the particular immune response or disease being treated with the receptor-fusion protein.
  • an especially active Fc domain IgGl
  • an inactive IgG4 Fc domain could be selected.
  • Fc domains that reduce or eliminate binding to Fc receptors and complement activation have been described in the art. These or other mutations can be used, alone or in combination to optimize the activity of the Fc domain used to construct the OPG-2-Fc fusion protein.
  • junction point of the receptor-Ig fusion protein may alter the structure, stability and ultimate biological activity of the soluble OPG-2 fusion protein.
  • One or more amino acids may be added to the C-terminus of the selected OPG-2 fragment to modify the junction point with the selected fusion domain.
  • the N-terminus of the OPG-2 fusion protein may also be varied by changing the position at which the selected OPG-2 DNA fragment is cleaved at its 5' end for insertion into the recombinant expression vector.
  • the stability and activity of each OPG-2 receptor fusion protein may be tested and optimized using routine experimentation and the assays for selecting blocking agents described herein.
  • amino acid sequence variants may also be constructed to modify the affinity of the soluble OPG-2 molecules for their ligands.
  • the soluble molecules of this invention can compete for binding with endogenous receptors. It is envisioned that any soluble molecule comprising an OPG-2 ligand binding domain that can compete with native receptors for ligand binding is a receptor blocking agent that falls within the scope of the present invention.
  • antibodies directed against OPG-2 function as receptor blocking agents.
  • the antibodies of this invention can be polyclonal or monoclonal and can be modified to optimize their ability to block OPG-2 signaling, their bioavailability, stability or other desired traits.
  • Polyclonal antibody sera directed against OPG-2 are prepared using conventional techniques by injecting animals such as goats, rabbits, rats, hamsters or mice subcutaneously with OPG-2, or an OPG-2 -Fc fusion protein in Freund's adjuvant, followed by booster intraperitoneal or subcutaneous injection in incomplete Freund's. Polyclonal antisera containing the desired antibodies directed against OPG-2 can then be screened by conventional immunological procedures.
  • anti-OPG-2 abs can also be made using standard recombinant DNA techniques.
  • "chimeric" antibodies can be constructed in which the antigen binding domain from an animal antibody is linked to a human constant domain. Chimeric antibodies reduce the observed immunogenic responses elicited by animal antibodies when used in human clinical treatments.
  • Human antibodies which can recognize OPG-2 can be synthesized.
  • Human antibodies are chimeras comprising mostly human IgG sequences into which the regions responsible for specific antigen-binding have been inserted, (e.g. WO 94/04679). Animals are immunized with the desired antigen, the corresponding antibodies are isolated, and the portion of the variable region sequences responsible for specific antigen binding are removed. The animal-derived antigen binding regions are then cloned into the appropriate position of human antibody genes in which the antigen binding regions have been deleted. Humanized antibodies minimize the use of heterologous (inter species) sequences in human antibodies, and are less likely to elicit immune responses in the human being treated.
  • anti-OPG-2 antibodies can also be accomplished by making chimeric or humanized antibodies comprising the anti-OPG- 2 variable domains and human constant domains isolated from different classes of immunoglobulins.
  • anti OPG-2 antibodies with increased antigen binding site valencies can be recombinantly produced by cloning the antigen binding site into vectors carrying the human ⁇ chain constant regions.
  • standard recombinant DNA techniques can be used to alter the binding affinities of recombinant antibodies with their antigens by altering amino acid residues in the vicinity of the antigen binding sites.
  • the antigen binding affinity of a humanized antibody can be increased by mutagenesis based on molecular modeling.
  • anti-OPG-2 antibodies may be desirable to increase or decrease the affinity of anti-OPG-2 antibodies for the receptors depending on the targeted tissue type or the particular treatment schedule envisioned. For example, it may be advantageous to treat a patient with constant levels of anti-Receptor antibodies with reduced ability to signal through the pathway for semi-prophylactic treatments. Likewise, inhibitory anti-OPG-2 antibodies with increased affinity for the receptors may be advantageous for short term treatments.
  • antibodies can be used in diagnostic assays.
  • the claimed invention in yet other embodiments encompasses pharmaceutical compositions comprising an effective amount of OPG-2 blocking or activating agent, and pharmaceutically acceptable carriers.
  • the compositions of the invention will be administered at an effective dose to treat the particular clinical condition addressed.
  • Determination of a preferred pharmaceutical formulation and a therapeutically efficient dose regimen for a given application is well within the skill of the art taking into consideration for example, the condition and weight of the patient, the extent of desired treatment and the tolerance of the patient for the treatment. Doses of about 1 mg/kg of a soluble OPG-2 are expected to be suitable starting points for optimizing treatment dosages.
  • Determination of a therapeutically effective dose can also be assessed by performing in vitro experiments that measure the concentration of the blocking or activating agent.
  • the binding assays described herein are useful, as are other assays known in the art.
  • human receptor cDNA sequence of the extracellular domain. If the mouse form is known, human cDNA libraries can be easily screened using the mouse cDNA sequence and such manipulations are routinely carried out in this area. With a human cDNA sequence, one can design oligonucleotide primers to PCR amplify the extracellular domain of the receptor in the absence of the transmembrane and intracellular domains. Typically, one includes most of the amino acids between the last disulfide linked "TNF domain" and the transmembrane domain. One could vary the amount of "stalk" region included to optimize the potency of the resultant soluble receptor.
  • This amplified piece would be engineered to include suitable restriction sites to allow cloning into various C-terminal Ig fusion chimera vectors. Alternatively, one could insert a stop signal at the 3' end and make a truncated form of the receptor without resorting to the use of a Ig fusion chimera approach.
  • the resultant vectors can be expressed in most systems used in biotechnology including yeast, insect cells, bacteria and mammalian cells and examples exist for all types of expression.
  • Various human Fc domains can be attached to optimize or eliminate FcR and complement interactions as desired. Alternatively, mutated forms of these Fc domains can be used to selectively remove FcR or complement interactions or the attachment of N-linked sugars to the Fc domain which has certain advantages. Since OPG-2 is already a soluble receptor it may be possible to simply express the native form of the protein.
  • the above described soluble receptor forms can be used to immunize mice and to make monoclonal antibodies by conventional methods.
  • the resultant mAbs identified by ELISA methods can be further screened for agonist activity either as soluble antibodies or immobilized on plastic in various in vitro cellular assays.
  • the death of the HT29 cell line is a convenient system that is sensitive to signalling through many TNF receptors. If this line does not possess the receptor of interest, that full length receptor can be stably transfected into the HT29 line to now allow the cytotoxicity assay to work. Altematively, such cells can be used in the Cytosensor apparatus to assess whether activation of the receptor can elicit a pH change that is indicative of a signalling event.
  • TNF family receptors signal well in such a format and this method does not require one to know the actual biological events triggered by the receptor.
  • the agonistic mAbs would be "humanized” for clinical use. This procedure can also be used to define antagonistic mAbs. Such mAbs would be defined by the lack of agonist activity and the ability to inhibit receptor-ligand interactions as monitored by ELISA, classical binding or BIAcore techniques.
  • receptor-Ig fusion protein Using the receptor-Ig fusion protein, one can screen other combinatorial libraries for molecules that can bind the receptor directly. These molecules can then be tested in an ELISA formatted assay using the receptor-Ig fusion protein and a soluble form of the ligand for the ability to inhibit the receptor-ligand interaction. This ELISA can be used directly to screen various natural product libraries etc. for inhibitory compounds.
  • the receptor can be transfected into a cell line such as the HT29 line to form a biological assay (in this case cytotoxicity) that can then form the screening assay.
  • Fas-Ligand Privilege and Peril. Proc. Natl. Acad. Sci. USA 94, 5986-5990.
  • CD30 antigen a marker for Hodgkin's lymphoma, is a receptor whose ligand defines an emerging family of cytokines with homology to TNF. Cell 73, 1349-60.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Toxicology (AREA)
  • Immunology (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Zoology (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Cell Biology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne des récepteurs dénommés 'OPG-2' appartenant à la famille des facteurs de nécrose tumorale (TNF).
PCT/US1998/025065 1997-11-24 1998-11-24 Recepteurs 'opg-2' WO1999026977A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU15356/99A AU1535699A (en) 1997-11-24 1998-11-24 Novel receptors opg-2

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US6644697P 1997-11-24 1997-11-24
US60/066,446 1997-11-24
US7489698P 1998-02-17 1998-02-17
US60/074,896 1998-02-17

Publications (1)

Publication Number Publication Date
WO1999026977A1 true WO1999026977A1 (fr) 1999-06-03

Family

ID=26746762

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/025065 WO1999026977A1 (fr) 1997-11-24 1998-11-24 Recepteurs 'opg-2'

Country Status (2)

Country Link
AU (1) AU1535699A (fr)
WO (1) WO1999026977A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999046376A1 (fr) * 1998-03-09 1999-09-16 Basf Aktiengesellschaft Recepteur de la superfamille des recepteurs du facteur de necrose tumorale issu du poumon humain
WO1999050413A2 (fr) * 1998-03-30 1999-10-07 Eli Lilly And Company APPLICATIONS THERAPEUTIQUES DE POLYPEPTIDES mFLINT MURS, OU DE OPG3 EN TANT QUE MEMBRE DE LA SUPERFAMILLE DU RECEPTEUR DU TNF
WO2000037094A2 (fr) * 1998-12-22 2000-06-29 Eli Lilly And Company Applications therapeutiques de polypeptides flint
WO2000047740A2 (fr) * 1999-02-12 2000-08-17 Amgen Inc. Proteines associees au facteur de necrose des tumeurs
WO2001010908A1 (fr) * 1999-08-04 2001-02-15 Amgen Inc. Ntr3, membre de la famille de supergenes recepteurs du tnf
EP1159286A1 (fr) * 1999-03-04 2001-12-05 Human Genome Sciences, Inc. Recepteurs du facteur de necrose tumorale 6 alpha et 6 beta
US6521422B1 (en) 1999-08-04 2003-02-18 Amgen Inc. Fhm, a novel member of the TNF ligand supergene family
US6627199B1 (en) 1999-07-09 2003-09-30 Amgen Inc Isolation, identification and characterization of tmst2, a novel member of the TNF-receptor supergene family
US6764679B2 (en) 1997-09-18 2004-07-20 Genentech, Inc. Antibodies to DcR3 Polypeptide, a TNFR Homolog
US7186800B1 (en) 1997-01-14 2007-03-06 Human Genome Sciences, Inc. Tumor necrosis factor 6α and 6β
US7285267B2 (en) 1997-01-14 2007-10-23 Human Genome Sciences, Inc. Tumor necrosis factor receptors 6α & 6β
US7749960B2 (en) 2001-04-03 2010-07-06 Nestec S.A. Osteoprotegerin in milk

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998030694A2 (fr) * 1997-01-14 1998-07-16 Human Genome Sciences, Inc. RECEPTEURS 6α ET 6β DU FACTEUR DE NECROSE TUMORALE
EP0861850A1 (fr) * 1997-02-04 1998-09-02 Smithkline Beecham Corporation Récepteurs TR4, liés à la nécrose tumorale
WO1999004001A1 (fr) * 1997-07-21 1999-01-28 Zymogenetics, Inc. Recepteur ztnfr-5 du facteur de necrose tumorale
WO1999007738A2 (fr) * 1997-08-06 1999-02-18 Regeneron Pharmaceuticals, Inc. Nouveau recepteur orphelin

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998030694A2 (fr) * 1997-01-14 1998-07-16 Human Genome Sciences, Inc. RECEPTEURS 6α ET 6β DU FACTEUR DE NECROSE TUMORALE
EP0861850A1 (fr) * 1997-02-04 1998-09-02 Smithkline Beecham Corporation Récepteurs TR4, liés à la nécrose tumorale
WO1999004001A1 (fr) * 1997-07-21 1999-01-28 Zymogenetics, Inc. Recepteur ztnfr-5 du facteur de necrose tumorale
WO1999007738A2 (fr) * 1997-08-06 1999-02-18 Regeneron Pharmaceuticals, Inc. Nouveau recepteur orphelin

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SIMONET W ET AL: "Osteoprotegerin: a novel secreted protein involved in the regulation of bone density", CELL, no. 89, 18 April 1997 (1997-04-18), pages 309 309, XP002077048 *

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7534428B2 (en) 1997-01-14 2009-05-19 Human Genome Sciences, Inc. Antibodies to tumor necrosis factor receptors 6α and 6β
US7285267B2 (en) 1997-01-14 2007-10-23 Human Genome Sciences, Inc. Tumor necrosis factor receptors 6α & 6β
US7186800B1 (en) 1997-01-14 2007-03-06 Human Genome Sciences, Inc. Tumor necrosis factor 6α and 6β
US8003386B1 (en) 1997-01-14 2011-08-23 Human Genome Sciences, Inc. Tumor necrosis factor receptors 6α and 6β
US7709218B2 (en) 1997-01-14 2010-05-04 Human Genome Sciences, Inc. Tumor necrosis factor receptors 6α and 6β
US6764679B2 (en) 1997-09-18 2004-07-20 Genentech, Inc. Antibodies to DcR3 Polypeptide, a TNFR Homolog
WO1999046376A1 (fr) * 1998-03-09 1999-09-16 Basf Aktiengesellschaft Recepteur de la superfamille des recepteurs du facteur de necrose tumorale issu du poumon humain
WO1999050413A2 (fr) * 1998-03-30 1999-10-07 Eli Lilly And Company APPLICATIONS THERAPEUTIQUES DE POLYPEPTIDES mFLINT MURS, OU DE OPG3 EN TANT QUE MEMBRE DE LA SUPERFAMILLE DU RECEPTEUR DU TNF
WO1999050413A3 (fr) * 1998-03-30 1999-12-02 Lilly Co Eli APPLICATIONS THERAPEUTIQUES DE POLYPEPTIDES mFLINT MURS, OU DE OPG3 EN TANT QUE MEMBRE DE LA SUPERFAMILLE DU RECEPTEUR DU TNF
WO2000037094A2 (fr) * 1998-12-22 2000-06-29 Eli Lilly And Company Applications therapeutiques de polypeptides flint
WO2000037094A3 (fr) * 1998-12-22 2000-11-09 Lilly Co Eli Applications therapeutiques de polypeptides flint
WO2000047740A3 (fr) * 1999-02-12 2000-12-07 Amgen Inc Proteines associees au facteur de necrose des tumeurs
WO2000047740A2 (fr) * 1999-02-12 2000-08-17 Amgen Inc. Proteines associees au facteur de necrose des tumeurs
EP1159286A4 (fr) * 1999-03-04 2003-01-15 Human Genome Sciences Inc Recepteurs du facteur de necrose tumorale 6 alpha et 6 beta
EP1159286A1 (fr) * 1999-03-04 2001-12-05 Human Genome Sciences, Inc. Recepteurs du facteur de necrose tumorale 6 alpha et 6 beta
US6627199B1 (en) 1999-07-09 2003-09-30 Amgen Inc Isolation, identification and characterization of tmst2, a novel member of the TNF-receptor supergene family
US7320796B2 (en) 1999-07-09 2008-01-22 Amgen Inc. Isolation, identification and characterization of tmst2, a novel member of the TNF-receptor supergene family
US7118863B2 (en) 1999-08-04 2006-10-10 Amgen, Inc. Methods for detecting NTR3 nucleic acids by hybridization
US6852839B2 (en) 1999-08-04 2005-02-08 Amgen, Inc. Fhm, a novel member of the TNF ligand supergene family
US6599716B1 (en) 1999-08-04 2003-07-29 Amgen Inc. Nucleic acids encoding NTR3, a member of the TNF-receptor supergene family
US7544519B2 (en) 1999-08-04 2009-06-09 Amgen Inc. Fhm a novel member of the TNF ligand supergene family: materials and methods for interaction modulators
US6521422B1 (en) 1999-08-04 2003-02-18 Amgen Inc. Fhm, a novel member of the TNF ligand supergene family
WO2001010908A1 (fr) * 1999-08-04 2001-02-15 Amgen Inc. Ntr3, membre de la famille de supergenes recepteurs du tnf
US7749960B2 (en) 2001-04-03 2010-07-06 Nestec S.A. Osteoprotegerin in milk

Also Published As

Publication number Publication date
AU1535699A (en) 1999-06-15

Similar Documents

Publication Publication Date Title
US7402658B2 (en) TRAIN-R: a cysteine-rich member of the TNF-receptor family
US10494416B2 (en) Methods of modulating immune responses using BCMA polypeptide
US6140467A (en) Ligand for herpes simplex virus entry mediator and methods of use
WO1999026977A1 (fr) Recepteurs 'opg-2'
ZA200201201B (en) BAFF receptor (BCMA), an immunoregulatory agent.

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
NENP Non-entry into the national phase

Ref country code: KR

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA