CA2348773A1 - Functional antagonists of hedgehog activity - Google Patents
Functional antagonists of hedgehog activity Download PDFInfo
- Publication number
- CA2348773A1 CA2348773A1 CA002348773A CA2348773A CA2348773A1 CA 2348773 A1 CA2348773 A1 CA 2348773A1 CA 002348773 A CA002348773 A CA 002348773A CA 2348773 A CA2348773 A CA 2348773A CA 2348773 A1 CA2348773 A1 CA 2348773A1
- Authority
- CA
- Canada
- Prior art keywords
- antagonist
- hedgehog
- polypeptide
- residue
- isolated
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
- 239000005557 antagonist Substances 0.000 title claims abstract 66
- 241000289669 Erinaceus europaeus Species 0.000 title claims abstract 37
- 230000000694 effects Effects 0.000 title claims 2
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract 38
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract 38
- 102000003693 Hedgehog Proteins Human genes 0.000 claims abstract 28
- 108090000031 Hedgehog Proteins Proteins 0.000 claims abstract 28
- 230000001419 dependent effect Effects 0.000 claims abstract 10
- 238000000034 method Methods 0.000 claims abstract 5
- 101000606317 Drosophila melanogaster Protein patched Proteins 0.000 claims abstract 4
- 102000012850 Patched-1 Receptor Human genes 0.000 claims abstract 3
- 238000011191 terminal modification Methods 0.000 claims abstract 2
- 229920001184 polypeptide Polymers 0.000 claims 37
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 claims 13
- 230000011664 signaling Effects 0.000 claims 10
- 108091028043 Nucleic acid sequence Proteins 0.000 claims 9
- 241000051107 Paraechinus aethiopicus Species 0.000 claims 7
- 238000003556 assay Methods 0.000 claims 7
- 235000018102 proteins Nutrition 0.000 claims 7
- 102000004169 proteins and genes Human genes 0.000 claims 7
- 108090000623 proteins and genes Proteins 0.000 claims 7
- 125000000539 amino acid group Chemical group 0.000 claims 6
- 210000004027 cell Anatomy 0.000 claims 6
- 235000018417 cysteine Nutrition 0.000 claims 6
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims 6
- 210000004899 c-terminal region Anatomy 0.000 claims 5
- 102000002260 Alkaline Phosphatase Human genes 0.000 claims 4
- 108020004774 Alkaline Phosphatase Proteins 0.000 claims 4
- 238000004519 manufacturing process Methods 0.000 claims 4
- 108091033319 polynucleotide Proteins 0.000 claims 4
- 102000040430 polynucleotide Human genes 0.000 claims 4
- 239000002157 polynucleotide Substances 0.000 claims 4
- 230000006698 induction Effects 0.000 claims 3
- 101100522123 Caenorhabditis elegans ptc-1 gene Proteins 0.000 claims 2
- 108010065129 Patched-1 Receptor Proteins 0.000 claims 2
- 235000001014 amino acid Nutrition 0.000 claims 2
- 150000001413 amino acids Chemical class 0.000 claims 2
- 230000002401 inhibitory effect Effects 0.000 claims 2
- 230000004048 modification Effects 0.000 claims 2
- 238000012986 modification Methods 0.000 claims 2
- 238000008940 Alkaline Phosphatase assay kit Methods 0.000 claims 1
- 230000004568 DNA-binding Effects 0.000 claims 1
- 229920002307 Dextran Polymers 0.000 claims 1
- 102000005720 Glutathione transferase Human genes 0.000 claims 1
- 108010070675 Glutathione transferase Proteins 0.000 claims 1
- 108060003951 Immunoglobulin Proteins 0.000 claims 1
- 239000002202 Polyethylene glycol Substances 0.000 claims 1
- 230000003213 activating effect Effects 0.000 claims 1
- 230000002730 additional effect Effects 0.000 claims 1
- 125000003275 alpha amino acid group Chemical group 0.000 claims 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims 1
- 238000009396 hybridization Methods 0.000 claims 1
- 230000002209 hydrophobic effect Effects 0.000 claims 1
- 102000018358 immunoglobulin Human genes 0.000 claims 1
- 230000035772 mutation Effects 0.000 claims 1
- 229920001223 polyethylene glycol Polymers 0.000 claims 1
- 230000017854 proteolysis Effects 0.000 claims 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
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
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
Abstract
Variants of hedgehog protein that contain N-terminal modifications are described that can block hedgehog function; thus allowing these variants to serve as functional antagonists. These peptides have a primary amino acid sequence lacking the ability to elicit a hedgehog-dependent response in C3H 10T1/2 cells but having the ability to bind to the hedgehog receptor, patched-1. Methods for producing such functional antagonists and methods of using the funtional antagonists are also described.
Claims (46)
1. An isolated, functional antagonist of a hedgehog polypeptide, the antagonist characterized in that the antagonist can bind to a hedgehog receptor, but does not induce a hedgehog-dependent signaling response.
2. The isolated antagonist of claim 1, wherein the antagonist is characterized in that it does not induce a hedgehog-dependent signaling response in an assay selected from the group of assays consisting of: an alkaline phosphatase induction assay in cells; a ptc-1 expression assay in C3H10T1/2 cells; a gli-1 expression assay in C3H10T1/2 cells; and a patched-1 protein induction assay in C3H10T1/2 cells
3. The isolated antagonist of claim 1, wherein the antagonist is a hedgehog polypeptide that has an N-terminal cysteine residue altered from a residue corresponding to residue Cys-1 of a mature hedgehog polypeptide to a residue that does not correspond to residue Cys-1 of the mature hedgehog polypeptide.
4. The isolated antagonist of claim 3, lacking an N-terminal cysteine corresponding to Cys-1 of the mature hedgehog polypeptide.
5. The isolated antagonist of claim 3, wherein the antagonist includes an N-terminal extension moiety having an element that corresponds to a Cys-1 of the mature hedgehog polypeptide.
6. The isolated antagonist of claim 3, wherein the antagonist includes an N-terminal extension moiety having an element that replaces a Cys-1 of the mature hedgehog polypeptide.
7. The isolated antagonist of claim 3, wherein the antagonist is missing no greater than about 12 amino acids beginning from an N-terminal cysteine corresponding to a Cys-1 of the mature hedgehog polypeptide.
8. The isolated antagonist of claim 3, wherein the antagonist has a mutation of the N-terminal cysteine to another amino acid residue.
9. The isolated antagonist of claim 8, wherein the another amino acid is a polar or charged amino acid residue.
10. The isolated antagonist of claims 8 or 9, wherein the another amino acid residue is a serine residue.
11. The isolated antagonist of claim 3, wherein the antagonist further includes a modification to a C-terminal end of the antagonist.
12. The antagonist of claim 11, wherein the antagonist is missing no greater than about 11 amino acid residues from the C-terminal end.
13. The antagonist of claim 11, wherein the modification comprises a polypeptide linked to the C-terminal end, the polypeptide having an amino acid sequence unrelated to the antagonist polypeptide.
14. The antagonist of claim 13, wherein the polypeptide linked to the antagonist is selected from the group consisting of a glutathione-S-transferase, a DNA
binding domain, a polymerase activating domain, a histidine tag, and an immunoglobulin or portion thereof.
binding domain, a polymerase activating domain, a histidine tag, and an immunoglobulin or portion thereof.
15. The antagonist of claim 11, wherein the C-terminal modification comprises a hydrophobic moiety linked to the C-terminal end.
16. The isolated antagonist of claim 1, wherein the N-terminal cysteine is in a modified form and corresponds to Cys-1 of the mature hedgehog polypeptide.
17. The isolated antagonist of claim 15, wherein the N-terminal cysteine is in an oxidized form.
18. The isolated antagonist of claim 3, wherein the Cys-1 of the mature hedgehog polypeptide is selected from the group consisting of (a) Cys-1 of mature Sonic hedgehog polypeptide; (b) Cys-1 of mature Indian hedgehog polypeptide; and (c) Cys-1 of mature Desert hedgehog polypeptide.
19. An isolated, Sonic hedgehog antagonist of Sonic, Desert, or Indian hedgehog polypeptide, wherein the antagonist comprises a Sonic hedgehog polypeptide characterized in that the antagonist can bind to a Sonic, Desert, or Indian hedgehog-responsive receptor, but cannot induce a Sonic, Desert, or Indian hedgehog-dependent signaling response.
20. The isolated antagonist of claim 19, wherein the Sonic hedgehog polypeptide has an N-terminal cysteine residue altered from a residue corresponding to residue Cys-1 of a mature Sonic hedgehog polypeptide to a residue that does not correspond to residue Cys-1 of the mature Sonic hedgehog polypeptide.
21. An isolated, Desert hedgehog antagonist of Desert, Sonic, or Indian hedgehog polypeptide, wherein the antagonist comprises a Desert hedgehog polypeptide characterized in that the antagonist can bind to a Desert, Sonic, or Indian hedgehog-responsive receptor, but cannot induce a Sonic, Indian or Desert hedgehog-dependent signaling response.
22. The isolated antagonist of claim 21, wherein the Desert hedgehog polypeptide has an N-terminal cysteine residue altered from a residue corresponding to residue Cys-1 of a mature Desert hedgehog polypeptide to a residue that does not correspond to residue Cys-1 of the mature Desert hedgehog polypeptide.
23. An isolated, Indian hedgehog antagonist of Indian, Desert, or Sonic hedgehog polypeptide, wherein the antagonist comprises an Indian hedgehog polypeptide characterized in that the antagonist can bind to an Indian, Desert ,or Sonic hedgehog-responsive receptor, but cannot induce an Indian, Desert, or Sonic hedgehog-dependent signaling response.
24. The isolated antagonist of claim 23, wherein the Indian hedgehog polypeptide has an N-terminal cysteine residue altered from a residue corresponding to residue Cys-1 of a mature Indian hedgehog polypeptide to a residue that does not correspond to residue Cys-1 of the mature Indian hedgehog polypeptide.
25. An isolated, functional antagonist of a hedgehog polypeptide, selected from the group of polypeptides consisting of SEQ ID NOS: 5, 6, 7, 8, 9 and 11.
26. An isolated, functional antagonist of a hedgehog polypeptide, the antagonist having the following properties:
(i) the isolated antagonist binds a hedgehog receptor; and (ii) the isolated antagonist blocks alkaline phosphatase (AP) induction by mature hedgehog protein when tested in an AP assay.
(i) the isolated antagonist binds a hedgehog receptor; and (ii) the isolated antagonist blocks alkaline phosphatase (AP) induction by mature hedgehog protein when tested in an AP assay.
27. The isolated antagonist of claim 26, wherein the hedgehog receptor is patched-1.
28. The isolated antagonist of claim 26 having the additional property of being unable to induce ptc-1 and gli-1 expression.
29. The isolated antagonist of claim 26, comprising a hedgehog polypeptide lacking an N-terminal cysteine corresponding to Cys-1 of a mature Sonic hedgehog.
30. An isolated DNA sequence encoding, upon expression, the functional antagonist of claims 1, 19, 21 or 23.
31. The DNA sequence of claim 30, wherein the DNA sequence encodes a hedgehog polypeptide that is a member of the vertebrate hedgehog family.
32 A DNA sequence encoding a functional antagonist of a hedgehog polypeptide, the DNA sequence comprising a polynucleotide selected from the group consisting of:
(a) SEQ ID NOS.: 16 and 17;
(b) a polynucleotide that hybridizes to any of the foregoing sequences under standard hybridization conditions and that encodes a protein having the activity of a functional antagonist of a hedgehog polypeptide; and {c) a polynucleotide that codes on expression for a protein encoded by any of the foregoing polynucleotide sequences.
(a) SEQ ID NOS.: 16 and 17;
(b) a polynucleotide that hybridizes to any of the foregoing sequences under standard hybridization conditions and that encodes a protein having the activity of a functional antagonist of a hedgehog polypeptide; and {c) a polynucleotide that codes on expression for a protein encoded by any of the foregoing polynucleotide sequences.
33. The DNA sequence of claim 32, wherein the DNA sequence encodes a hedgehog polypeptide that is at least 60% homologous to a polypeptide of the group selected from polypeptide SEQ ID NOS: 1-9 and 11.
34. A vector comprising the DNA sequence of claim 30.
35. A host cell containing the vector of claim 34.
36. A functional antagonist of a hedgehog polypeptide encoded by the DNA
sequence contained within the vector of claim 34.
sequence contained within the vector of claim 34.
37. A therapeutic composition comprising the polypeptide of claims 1, 19, 21, 23, or 26 in an acceptable carrier.
38. A method of making a functional hedgehog antagonist comprising altering an N-terminal cysteine residue of a mature hedgehog polypeptide from a residue corresponding to residue Cys-1 of mature Sonic hedgehog to a residue that does not correspond to residue Cys-1 of mature Sonic hedgehog.
39. The method of claim 38, wherein the step of altering comprises exposing hedgehog polypeptide to proteolysis.
40. A method of making a functional hedgehog antagonist protein comprising expressing protein from the host cell of claim 35 and purifying the protein.
41. A method of making a functional hedgehog antagonist protein comprising modifying a hedgehog polypeptide at an N-terminal cysteine residue of the hedgehog polypeptide.
42. A method of making a functional hedgehog antagonist protein comprising modifying a hedgehog polypeptide at an amino acid residue that is other than an N-terminal cysteine residue of the hedgehog polypeptide.
43. A method of inhibiting hedgehog-dependent signaling in a subject, comprising administering to the subject the composition of claim 37 in an amount sufficient to inhibit hedgehog-dependent signaling in the subject
44. A method of inhibiting hedgehog-depending signaling in a subject, comprising administering to the subject the vector of claim 34, in an amount sufficient to inhibit hedgehog-dependent signaling in the subject.
45. The isolated antagonist of claim 3, wherein a moiety is linked to an amino acid residue of the antagonist, the moiety selected from the group consisting of polyethylene glycol and dextran.
46. The antagonist of claim 1, wherein the hedgehog-dependent signaling response is measured in a C3H10T1/2 alkaline phosphatase assay.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10670398P | 1998-11-02 | 1998-11-02 | |
| US60/106,703 | 1998-11-02 | ||
| PCT/US1999/025700 WO2000025725A2 (en) | 1998-11-02 | 1999-11-02 | Functional antagonists of hedgehog activity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2348773A1 true CA2348773A1 (en) | 2000-05-11 |
| CA2348773C CA2348773C (en) | 2010-04-13 |
Family
ID=22312815
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2348773A Expired - Fee Related CA2348773C (en) | 1998-11-02 | 1999-11-02 | Functional antagonists of hedgehog activity |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US8410061B2 (en) |
| EP (1) | EP1133519B1 (en) |
| JP (1) | JP4574012B2 (en) |
| AT (1) | ATE404583T1 (en) |
| AU (1) | AU765485B2 (en) |
| CA (1) | CA2348773C (en) |
| DE (1) | DE69939327D1 (en) |
| IL (2) | IL142905A0 (en) |
| WO (1) | WO2000025725A2 (en) |
Families Citing this family (31)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4669968B2 (en) | 1997-02-10 | 2011-04-13 | プレジデント アンド フェローズ オブ ハーバード カレッジ | Methods for regulating hematopoiesis and angiogenesis |
| EP1034269A1 (en) * | 1997-11-28 | 2000-09-13 | Roche Diagnostics GmbH | An active hedgehog-protein-mutant, a process for its preparation and its use for pharmaceutical purposes |
| US6897297B1 (en) * | 1997-12-03 | 2005-05-24 | Curis, Inc. | Hydrophobically-modified protein compositions and methods |
| IL146842A0 (en) * | 1999-06-01 | 2002-07-25 | Biogen Inc | Polymer conjugates of hedgehog proteins and uses |
| ES2233383T3 (en) * | 1999-06-08 | 2005-06-16 | Lorantis Limited | THERAPEUTIC USE OF A HEDGEHOG SIGNALING ROAD IHIBITOR. |
| AU2005203058C1 (en) * | 1999-11-05 | 2009-07-02 | Curis, Inc. | Hedgehog fusion proteins and uses |
| CA2390166C (en) | 1999-11-05 | 2011-03-22 | Biogen, Inc. | Hedgehog fusion proteins and uses |
| US8168178B2 (en) | 1999-11-30 | 2012-05-01 | Curis, Inc. | Methods and compositions for regulating lymphocyte activity |
| WO2001098344A2 (en) * | 2000-06-16 | 2001-12-27 | Curis, Inc. | Angiogenesis-modulating compositions and uses |
| US7498304B2 (en) | 2000-06-16 | 2009-03-03 | Curis, Inc. | Angiogenesis-modulating compositions and uses |
| US8044259B2 (en) * | 2000-08-03 | 2011-10-25 | The Regents Of The University Of Michigan | Determining the capability of a test compound to affect solid tumor stem cells |
| US6984522B2 (en) | 2000-08-03 | 2006-01-10 | Regents Of The University Of Michigan | Isolation and use of solid tumor stem cells |
| WO2002011752A1 (en) * | 2000-08-04 | 2002-02-14 | Takeda Chemical Industries, Ltd. | Use of gli1 gene |
| US7708998B2 (en) | 2000-10-13 | 2010-05-04 | Curis, Inc. | Methods of inhibiting unwanted cell proliferation using hedgehog antagonists |
| CA2425356C (en) | 2000-10-13 | 2015-10-06 | Curis, Inc. | Hedgehog antagonists, methods and uses related thereto |
| US7663017B2 (en) | 2003-07-30 | 2010-02-16 | Institut Pasteur | Transgenic mice having a human major histocompatability complex (MHC) phenotype, experimental uses and applications |
| CA2561221C (en) | 2004-03-26 | 2016-09-20 | Curis, Inc. | Rna interference modulators of hedgehog signaling and uses thereof |
| PL1978993T3 (en) | 2005-10-31 | 2017-07-31 | Oncomed Pharmaceuticals, Inc. | Compositions and methods for treating cancer based on human fzd receptors |
| EP1945754B1 (en) | 2005-10-31 | 2014-07-23 | The Regents Of The University Of Michigan | Compositions and methods for treating and diagnosing cancer |
| US7723477B2 (en) | 2005-10-31 | 2010-05-25 | Oncomed Pharmaceuticals, Inc. | Compositions and methods for inhibiting Wnt-dependent solid tumor cell growth |
| US8026354B2 (en) | 2005-11-23 | 2011-09-27 | Institut Pasteur | Recombinant plasmodium falciparum merozoite surface proteins 4 and 5 and their use |
| WO2008092002A2 (en) | 2007-01-24 | 2008-07-31 | The Regents Of The University Of Michigan | Compositions and methods for treating and diagnosing pancreatic cancer |
| MX2011003183A (en) | 2008-09-26 | 2011-04-21 | Oncomed Pharm Inc | Frizzled-binding agents and uses thereof. |
| SG10201609290PA (en) | 2009-08-25 | 2016-12-29 | Abraxis Bioscience Llc | Combination therapy with nanoparticle compositions of taxane and hedgehog inhibitors |
| TWI535445B (en) | 2010-01-12 | 2016-06-01 | 安可美德藥物股份有限公司 | Wnt antagonists and methods of treatment and screening |
| NZ602700A (en) | 2010-04-01 | 2014-10-31 | Oncomed Pharm Inc | Frizzled-binding agents and uses thereof |
| CA2887711A1 (en) | 2012-10-23 | 2014-05-01 | Oncomed Pharmaceuticals, Inc. | Methods of treating neuroendocrine tumors using wnt pathway-binding agents |
| AU2014212081A1 (en) | 2013-02-04 | 2015-08-13 | Oncomed Pharmaceuticals, Inc. | Methods and monitoring of treatment with a Wnt pathway inhibitor |
| US9168300B2 (en) | 2013-03-14 | 2015-10-27 | Oncomed Pharmaceuticals, Inc. | MET-binding agents and uses thereof |
| WO2015036405A1 (en) | 2013-09-10 | 2015-03-19 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for diagnosing and treating basal cell carcinoma |
| US9814703B2 (en) | 2013-11-14 | 2017-11-14 | The Board Of Trustees Of The Leland Stanford Junior University | Methods for treating cancer by activation of BMP signaling |
Family Cites Families (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5789543A (en) * | 1993-12-30 | 1998-08-04 | President And Fellows Of Harvard College | Vertebrate embryonic pattern-inducing proteins and uses related thereto |
| US6610656B1 (en) * | 1993-12-30 | 2003-08-26 | President And Fellows Of Harvard College | Method of promoting chondrocyte differentiation with hedgehog related polypeptides |
| US7060450B1 (en) * | 1993-12-30 | 2006-06-13 | President And Fellows Of Harvard College | Screening assays for agonists and antagonists of the hedgehog signaling pathway |
| US6884775B1 (en) * | 1993-12-30 | 2005-04-26 | President And Fellows Of Harvard College | Methods and compositions for regulating skeletogenic formation |
| US6271363B1 (en) * | 1993-12-30 | 2001-08-07 | President & Fellows Of Harvard College | Nucleic acids encoding hedgehog proteins |
| US6261786B1 (en) * | 1993-12-30 | 2001-07-17 | Imperial Cancer Res. Technology | Screening assays for hedgehog agonists and antagonists |
| US6165747A (en) * | 1993-12-30 | 2000-12-26 | President & Fellows Of Harvard College | Nucleic acids encoding hedgehog proteins |
| US20030186357A1 (en) * | 1993-12-30 | 2003-10-02 | Philip W. Ingham | Vertebrate embryonic pattern-inducing proteins, and uses related thereto |
| EP0773995A4 (en) | 1994-02-25 | 1997-07-16 | Univ Columbia | Dna encoding the vertebrate homolog of hedgehog, vhh-1, expressed by the notochord, and uses thereof |
| AU742972B2 (en) | 1996-09-20 | 2002-01-17 | President And Fellows Of Harvard College | Hedgehog interacting proteins and uses related thereto |
| US5759811A (en) * | 1996-11-13 | 1998-06-02 | The Regents Of The University Of California | Mutant human hedgehog gene |
| AU8173098A (en) * | 1997-06-27 | 1999-01-19 | Ontogeny, Inc. | Neuroprotective methods and reagents |
| US6287558B1 (en) | 1997-08-01 | 2001-09-11 | Biohybrio Technologies Llc | Devices containing cells or tissue and an agent that inhibits damage by a host cell molecule |
| US6639051B2 (en) * | 1997-10-20 | 2003-10-28 | Curis, Inc. | Regulation of epithelial tissue by hedgehog-like polypeptides, and formulations and uses related thereto |
| JP4289788B2 (en) * | 1997-12-03 | 2009-07-01 | バイオジェン・アイデック・エムエイ・インコーポレイテッド | Hydrophobically modified protein composition and production method |
| US6897297B1 (en) * | 1997-12-03 | 2005-05-24 | Curis, Inc. | Hydrophobically-modified protein compositions and methods |
| DE69942063D1 (en) * | 1998-09-11 | 2010-04-08 | Curis Inc | ANTAGONISTS OF 'HEDGEHOG' AND 'PATCHED' INHIBITING THE GROWTH AND THE DIFFERENTIATION OF CELLS AND TISSUES, AS WELL AS THEIR USES |
| IL146842A0 (en) * | 1999-06-01 | 2002-07-25 | Biogen Inc | Polymer conjugates of hedgehog proteins and uses |
-
1999
- 1999-11-02 DE DE69939327T patent/DE69939327D1/en not_active Expired - Lifetime
- 1999-11-02 JP JP2000579170A patent/JP4574012B2/en not_active Expired - Fee Related
- 1999-11-02 AU AU21445/00A patent/AU765485B2/en not_active Ceased
- 1999-11-02 WO PCT/US1999/025700 patent/WO2000025725A2/en active IP Right Grant
- 1999-11-02 CA CA2348773A patent/CA2348773C/en not_active Expired - Fee Related
- 1999-11-02 AT AT99965744T patent/ATE404583T1/en not_active IP Right Cessation
- 1999-11-02 IL IL14290599A patent/IL142905A0/en unknown
- 1999-11-02 EP EP99965744A patent/EP1133519B1/en not_active Expired - Lifetime
-
2001
- 2001-05-01 IL IL142905A patent/IL142905A/en not_active IP Right Cessation
-
2002
- 2002-06-05 US US10/164,282 patent/US8410061B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2348773C (en) | 2010-04-13 |
| DE69939327D1 (en) | 2008-09-25 |
| AU2144500A (en) | 2000-05-22 |
| JP4574012B2 (en) | 2010-11-04 |
| JP2002534060A (en) | 2002-10-15 |
| IL142905A (en) | 2009-12-24 |
| ATE404583T1 (en) | 2008-08-15 |
| AU765485B2 (en) | 2003-09-18 |
| EP1133519B1 (en) | 2008-08-13 |
| WO2000025725A2 (en) | 2000-05-11 |
| US20030166543A1 (en) | 2003-09-04 |
| IL142905A0 (en) | 2002-04-21 |
| US8410061B2 (en) | 2013-04-02 |
| EP1133519A2 (en) | 2001-09-19 |
| WO2000025725A3 (en) | 2000-11-30 |
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