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WO1996011269B1 - Tie-2 ligands, methods of making and uses thereof - Google Patents

Tie-2 ligands, methods of making and uses thereof

Info

Publication number
WO1996011269B1
WO1996011269B1 PCT/US1995/012935 US9512935W WO9611269B1 WO 1996011269 B1 WO1996011269 B1 WO 1996011269B1 US 9512935 W US9512935 W US 9512935W WO 9611269 B1 WO9611269 B1 WO 9611269B1
Authority
WO
WIPO (PCT)
Prior art keywords
ligand
tie
nucleic acid
receptor
human
Prior art date
Application number
PCT/US1995/012935
Other languages
French (fr)
Other versions
WO1996011269A2 (en
WO1996011269A9 (en
Filing date
Publication date
Priority claimed from US08/319,932 external-priority patent/US5643755A/en
Priority claimed from US08/348,492 external-priority patent/US5879672A/en
Priority claimed from US08/373,579 external-priority patent/US5650490A/en
Priority claimed from US08/418,595 external-priority patent/US5814464A/en
Priority to CZ19971025A priority Critical patent/CZ292453B6/en
Priority to AU41295/96A priority patent/AU711111B2/en
Priority to DE69520149T priority patent/DE69520149T2/en
Priority to HK98105155.3A priority patent/HK1005944B/en
Priority to MX9702530A priority patent/MX9702530A/en
Priority to US08/817,318 priority patent/US6433143B1/en
Priority to EP95939501A priority patent/EP0784683B1/en
Priority to AT95939501T priority patent/ATE199259T1/en
Priority to NZ296638A priority patent/NZ296638A/en
Priority to CA2202028A priority patent/CA2202028C/en
Priority to PL95319586A priority patent/PL184642B1/en
Priority to ES95939501T priority patent/ES2154354T3/en
Application filed filed Critical
Priority to HU9800160A priority patent/HU221422B1/en
Priority to JP51267296A priority patent/JP4054375B2/en
Priority to DK95939501T priority patent/DK0784683T3/en
Priority to EP96910769A priority patent/EP0821728B1/en
Priority to DE69633121T priority patent/DE69633121T2/en
Priority to CA2216963A priority patent/CA2216963C/en
Priority to AT96910769T priority patent/ATE273384T1/en
Priority to AU53871/96A priority patent/AU715621B2/en
Priority to PCT/US1996/004806 priority patent/WO1996031598A1/en
Priority to JP53053796A priority patent/JP4122056B2/en
Priority to HK98109175.1A priority patent/HK1008230B/en
Publication of WO1996011269A2 publication Critical patent/WO1996011269A2/en
Publication of WO1996011269A9 publication Critical patent/WO1996011269A9/en
Publication of WO1996011269B1 publication Critical patent/WO1996011269B1/en
Priority to NO19971557A priority patent/NO322643B1/en
Priority to FI971406A priority patent/FI120313B/en
Priority to US09/442,717 priority patent/US6627415B1/en
Priority to GR20010400568T priority patent/GR3035717T3/en

Links

Abstract

The present invention provides for an isolated nucleic acid molecule encoding a human TIE-2 ligand. In addition, the invention provides for a receptor body which specifically binds a human TIE-2 ligand. The invention also provides an antibody which specifically binds a human TIE-2 ligand. The invention further provides for an antagonist of human TIE-2. The invention also provides for therapeutic compositions as well as a method of blocking blood vessel growth, a method of promoting neovascularization, a method of promoting the growth or differentiation of a cell expressing the TIE-2 receptor, a method of blocking the growth or differentiation of a cell expressing the TIE-2 receptor and a method of attenuating or preventing tumor growth in a human.

Claims

-68-AME DED CLAIMS[received by the International Bureau on 21 May 1996 (21.05.96); original claims 1-60 replaced by amended claims 1-69 (9 pages)]
1. An isolated nucleic acid molecule encoding a TIE-2 ligand.
2. An isolated nucleic acid molecule according to claim 1 wherein the nucleic acid sequence is:
(a) the nucleic acid sequence comprising the coding region of the human TIE-2 ligand as set forth in Figure 4 or Figure 5;
(b) a nucleic acid sequence that hybridizes under moderately stringent conditions to the nucleic acid sequence of (a) and which encodes a TIE-2 ligand that binds TIE-2 receptor; or
(c) a nucleic acid sequence which, but for the degeneracy of the genetic code, would hybridize to a nucleic acid sequence of (a) or (b), and which encodes a TIE-2 ligand that binds TIE-2 receptor.
3. An isolated nucleic acid molecule according to claim 2 wherein the encoded TIE-2 ligand is a TIE-2 agonist.
4. An isolated nucleic acid molecule according to claim 1 wherein the nucleic acid sequence is
(a) the nucleic acid sequence comprising the coding region of the human TIE-2 ligand as set forth in Figure 6;
(b) a nucleic acid sequence that hybridizes under moderately stringent conditions to the nucleic acid sequence of (a) and which encodes a TIE-2 ligand that binds TIE-2 receptor; or
(c) a nucleic acid sequence which, but for the degeneracy of the genetic code would hybridize to a nucleic acid sequence of (a) or (b), and which encodes a TIE-2 ligand that binds TIE-2 receptor.
N:70494A(PCT)/DMG:AB:ao May 1996 -69-
5. An isolated nucleic acid molecule according to claim 4 wherein the encoded TIE-2 ligand is a TIE-2 antagonist.
6. A nucleic acid molecule which is degenerate of a sequence of claim 2 or 4 and encodes a ligand that binds the TIE-2 receptor.
7. A nucleic acid molecule which hybridizes under moderately stringent conditions to a sequence encoding a TIE-2 ligand as set out in Figure 4, 5 or 6.
8. A vector which comprises a nucleic acid molecule of any one of the preceding claims.
9. A vector according to claim 8 wherein the nucleic acid molecule is operatively linked to an expression control sequence capable of directing its expression in a host cell.
10. A vector according to claim 8. or 9 which is a plasmid.
11. A plasmid according to claim 10 designated pJFE14 encoding TIE-2 ligand (ATCC Accession No. 75910).
12. A plasmid according to claim 10 designated pBluescript KS encoding human TIE-2 ligand 2 (ATCC Accession No. 75963).
13. A vector according to claim 8 or 9 designated as gtIO encoding hTIE- 2 ligand 1 (ATCC Accession No. 75928).
14. An isolated TIE-2 ligand substantially free of other proteins.
N:70494A(PCT)/DMG:AB:ao May 1996 -70-
15. An isolated TIE-2 ligand according to claim 14 encoded by a nucleic acid molecule according to claim 1.
16. An isolated TIE-2 ligand according to claim 14 encoded by a nucleic acid according to claim 2 or 3.
17. An isolated TIE-2 ligand according to claim 14 encoded by a nucleic acid according to claim 4 or 5.
18. A host-vector system for the production of a ligand according to any one of claims 14 to 17 which comprises a vector according to any one of claims 8 to 13 in a host cell.
19. A host-vector system according to claim 18 wherein the host cell is a bacterial, yeast, insect or mammalian cell.
20. A host vector system comprising the host vector system of claim 18 or 19 and a nucleic acid encoding the TIE-2 receptor.
21. A method of producing a ligand as defined in any one of claims 14 to 17 which comprises growing cells of a host-vector system according to any one of claims 18 to 20 under conditions permitting production of the ligand, and recovering the ligand so produced.
22. An antibody which specifically binds the ligand of any one of claims 14 to 17.
23. An antibody according to claim 22 which is a monoclonal antibody.
24. A receptorbody which specifically binds the ligand of any one of claims 14 to 17.
N:70494A(PCT)/DMG:AB:ao May 1996
mWED SHEEI (ARTICLE 19 -71-
25. An isolated nucleic acid molecule encoding a receptorbody according to claim 24.
26. A vector comprising a nucleic acid molecule according to claim 25.
27. A vector according to claim 26 which is a plasmid.
28. A plasmid according to claim 27 designated vTIE-2 receptorbody (ATCC Deposit VR2484).
29. A conjugate comprising a ligand according to any one of claims 14 to 17 and, conjugated thereto, a cytotoxic agent.
30. A conjugate according to claim 29 wherein the cytotoxic agent is a radioisotope or toxin.
31. A pharmaceutical composition comprising a TIE-2 ligand according to any one of claims 14 to 17 and a pharmaceutically acceptable carrier.
32. A pharmaceutical composition comprising an antibody according to claim 22 or 23 and a pharmaceutically acceptable carrier.
33. A pharmaceutical composition comprising a receptorbody according to claim 24 and a pharmaceutically acceptable carrier.
34. A pharmaceutical composition comprising a conjugate according to claim 29 or 30 and a pharmaceutically acceptable carrier.
35. A ligand according to any one of claims 14 to 17, an antibody according to claim 22 or 23, a receptorbody according to claim 24, a conjugate according to claim 29 or 30, or a composition according to any
N.70494A(PCT)/DMG:AB:ao May 1996 -72- one of claims 31 to 34 for use in a method of treatment of the human or animal body, or in a method of diagnosis.
36. A ligand according to claim 16 for use in a method of treatment of the human or animal body.
37. A ligand according to claim 17 for use in a method of treatment of the human or animal body.
38. An antibody or receptorbody according to claim 35, which antibody or receptorbody specifically binds the ligand of claim 16, for use in a method of blocking blood vessel growth in a mammal.
39. An antibody or receptorbody according to claim 38 for use in a method wherein the mammal is a human.
40. A ligand according to claim 36 for use in a method of promoting neovascularization in a mammal.
41. A ligand according to claim 40 for use in the promotion of wound healing.
42. A ligand according to claim 40 for use in the treatment of ischemia.
43. A TIE-2 antagonist for use in a method of inhibiting TIE-2 ligand activity in a mammal.
44. An antagonist according to claim 43 which is an antibody capable of specifically binding TIE-2 receptor.
N:70494A(PCT)/DMG:AB:ao May 1996 -73-
45. An antibody according to claim 43 which is an antibody according to claim 22 or 23.
46. An antagonist according to claim 43 which is a receptorbody according to claim 24.
47. An antagonist according to claim 43 which is a ligand according to claim 17.
48. An antagonist according to any one of claims 43 to 47 for use in a method wherein the mammal is a human.
49. An antagonist according to any one of claims 43 to 48 for use in a method of attenuating or preventing tumour growth in a human.
50. A method of maintaining a TIE-2 receptor expressing cell in culture, which method comprises administering to the TIE-2 receptor expressing cell an effective amount of the ligand of claim 16.
51. A method according to claim 50 wherein the TIE-2 receptor expressing cell is an endothelial cell.
52. A method of identifying a TIE-2 receptor antagonist comprising contacting cells expressing the TIE-2 receptor with: a) a test compound; and b) a ligand according to claim 16 or 17; under conditions permitting binding of the ligand to the receptor and determining whether the test compound is capable ofinterfering with the binding of the ligand to the receptor.
N:70494A(PCT)/DMG:AB:ao May 1996
53. A polypeptide produced by the method of claim 21.
54. A nucleic acid according to claim 1 or 25, substantially as hereinbefore described with reference to any one of the foregoing Examples.
55. A vector according to claim 8 or 26, substantially as hereinbefore described with reference to any one of the foregoing Examples.
56. A ligand according to any one of claims 14 to 17, substantially as hereinbefore described with reference to any one of the foregoing Examples.
57. A host-vector system according to claim 18, substantially as hereinbefore described with reference to any one of the foregoing Examples.
58. A method according to claim 21 , 50 or 52, substantially as hereinbefore described with reference to any one of the foregoing Examples.
59. An antibody according to claim 22 or 35, substantially as hereinbefore described with reference to any one of the foregoing Examples.
60. A receptorbody according to claim 24 or 35, substantially as hereinbefore described with reference to any one of the foregoing Examples.
61. A conjugate according to claim 29 or 35, substantially as hereinbefore described with reference to any one of the foregoing Examples.
N:70494A(PCT)/DMG:AB:ao May 1996 -75-
62. A composition according to any one of claims 31 to 35, substantially as hereinbefore described with reference to any one of the foregoing Examples.
63. A TIE-2 antagonist according to claim 43, substantially as hereinbefore described with reference to any one of the foregoing Examples.
64. A ligandbody which specifically binds the TIE-2 receptor or the receptorbody of claim 24, 35 or 60.
65. A ligandbody which comprises a TIE-2 ligand fused to an immunoglobulin constant region.
66. The ligandbody of claim 65 wherein the TIE-2 ligand is TIE-2 ligand 1 or TIE-2 ligand 2 and the immunoglobulin constant region is the Fc portion of human lgG1.
67. A ligandbody according to any one of claims 64 to 66 for use in a method of treatment of the human or animal body, or in a method of diagnosis.
68. A method of treating a human or animal subject comprising administering to the subject an effective amount of a ligand according to any one of claims 14 to 17, an antibody according to claim 22 or 23, a receptorbody according to claim 24, a conjugate according to claim 29 or 30, a composition according to any one of claims 31 to 34, or a ligandbody according to any one of claims 64 to 67.
N:70494A(PCT)/DMG:AB:ao May 1996 -76-
69. A method according to claim 68, the method being as defined in any one of claims 38 to 49, or 67.
N:70494A(PCT)/DMG:AB:ao May 1996
WENDED SHEET (MiTICLE 19)
PCT/US1995/012935 1994-10-07 1995-10-06 Tie-2 ligands, methods of making and uses thereof WO1996011269A2 (en)

Priority Applications (27)

Application Number Priority Date Filing Date Title
DK95939501T DK0784683T3 (en) 1994-10-07 1995-10-06 TIE-2 ligands, methods of forming them and their applications
JP51267296A JP4054375B2 (en) 1994-10-07 1995-10-06 TIE-2 ligand, methods for making and using the same
HU9800160A HU221422B1 (en) 1994-10-07 1995-10-06 Tie-2 ligands, recombinant methods of making and uses thereof
EP95939501A EP0784683B1 (en) 1994-10-07 1995-10-06 Tie-2 ligands, methods of making and uses thereof
AT95939501T ATE199259T1 (en) 1994-10-07 1995-10-06 TIE-2 LIGANDS, METHOD FOR THE PRODUCTION THEREOF, AND THEIR APPLICATIONS
DE69520149T DE69520149T2 (en) 1994-10-07 1995-10-06 TIE-2 LIGANDE, METHOD FOR THEIR PRODUCTION, AND THEIR APPLICATIONS
HK98105155.3A HK1005944B (en) 1994-10-07 1995-10-06 Tie-2 ligands, methods of making and uses thereof
MX9702530A MX9702530A (en) 1994-10-07 1995-10-06 TIE-2 LINKS, PREPARATION METHODS AND USES THEREOF.
US08/817,318 US6433143B1 (en) 1994-10-07 1995-10-06 Tie-2 ligands
CZ19971025A CZ292453B6 (en) 1994-10-07 1995-10-06 Isolated nucleic acid molecule encoding a human TIE-2 ligand and use thereof
AU41295/96A AU711111B2 (en) 1994-10-07 1995-10-06 Tie-2 ligands, methods of making and uses thereof
NZ296638A NZ296638A (en) 1994-10-07 1995-10-06 Ligands which bind to tie-2 (tyrosine kinase with ig and egf homology domains) receptors
CA2202028A CA2202028C (en) 1994-10-07 1995-10-06 Tie-2 ligands, methods of making and uses thereof
PL95319586A PL184642B1 (en) 1994-10-07 1995-10-06 Isolated nucleic acid molecule encoding TIE-2 ligand, vector containing the isolated nucleic acid molecule, isolated and purified TIE-2 ligand, host-vector system, method of producing isolated and purified TIE-2 ligand, antibody, ligand body, conjugate, pharmaceutical composition, the use of an antibody, the use of an isolated and purified ligand, an in vitro method of maintaining the expression of the TIE-2 receptor in culture, a method of identifying a TIE-2 receptor antagonist, the body of the receptor, an isolated nucleic acid molecule encoding the body of the receptor, a vector containing an isolated nucleic acid molecule encoding the body of the receptor a pharmaceutical composition containing the body of the PL receptor
ES95939501T ES2154354T3 (en) 1994-10-07 1995-10-06 LIGANDOS TIE-2, METHODS TO OBTAIN THEM AND ITS USES.
EP96910769A EP0821728B1 (en) 1995-04-06 1996-04-05 Tie-2 ligands, methods of making and uses thereof
PCT/US1996/004806 WO1996031598A1 (en) 1995-04-06 1996-04-05 Tie-2 ligands, methods of making and uses thereof
JP53053796A JP4122056B2 (en) 1995-04-06 1996-04-05 TIE-2 ligand, methods for making and using the same
HK98109175.1A HK1008230B (en) 1995-04-06 1996-04-05 Tie-2 ligands, methods of making and uses thereof
DE69633121T DE69633121T2 (en) 1995-04-06 1996-04-05 TIE-2 LIGANDS, MANUFACTURING METHOD AND USE
AU53871/96A AU715621B2 (en) 1995-04-06 1996-04-05 TIE-2 ligands, methods of making and uses thereof
CA2216963A CA2216963C (en) 1995-04-06 1996-04-05 Tie-2 ligands, methods of making and uses thereof
AT96910769T ATE273384T1 (en) 1995-04-06 1996-04-05 TIE-2 LIGANDS, PRODUCTION METHOD AND USE
NO19971557A NO322643B1 (en) 1994-10-07 1997-04-04 Isolated nucleic acid molecule encoding TIE-2 ligand, TIE-2 ligand, method of preparation and use thereof, and antibody to the TIE-2 ligand.
FI971406A FI120313B (en) 1994-10-07 1997-04-04 TIE-2 ligands, methods of making them and using them
US09/442,717 US6627415B1 (en) 1995-04-06 1999-11-18 TIE-2 ligands, methods of making and uses thereof
GR20010400568T GR3035717T3 (en) 1994-10-07 2001-04-06 Tie-2 ligands, methods of making and uses thereof

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
US08/319,932 US5643755A (en) 1994-10-07 1994-10-07 Nucleic acid encoding tie-2 ligand
US08/319,932 1994-10-07
US08/330,261 US5521073A (en) 1994-10-07 1994-10-27 TIE-2 ligand, and method of making
US08/330,261 1994-10-27
US08/348,492 US5879672A (en) 1994-10-07 1994-12-02 Tie-2 ligand 1
US08/348,492 1994-12-02
US35350394A 1994-12-09 1994-12-09
US08/353,503 1994-12-09
US08/373,579 1995-01-17
US08/373,579 US5650490A (en) 1994-10-07 1995-01-17 Tie-2 ligand 2
US08/418,595 US5814464A (en) 1994-10-07 1995-04-06 Nucleic acids encoding TIE-2 ligand-2
US08/418,595 1995-04-06

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US08/418,595 Continuation US5814464A (en) 1994-10-07 1995-04-06 Nucleic acids encoding TIE-2 ligand-2

Related Child Applications (5)

Application Number Title Priority Date Filing Date
US08/817,318 A-371-Of-International US6433143B1 (en) 1994-10-07 1995-10-06 Tie-2 ligands
PCT/US1996/004806 Continuation WO1996031598A1 (en) 1995-04-06 1996-04-05 Tie-2 ligands, methods of making and uses thereof
US10/179,615 Division US7063840B2 (en) 1994-10-07 2002-06-24 TIE-2 ligands, methods of making and uses thereof
US10/179,820 Division US20030166858A1 (en) 1999-09-16 2002-06-24 TIE-2 ligands, methods of making and uses thereof
US10/179,744 Division US20020173627A1 (en) 1999-09-16 2002-06-24 TIE-2 ligands, methods of making and uses thereof

Publications (3)

Publication Number Publication Date
WO1996011269A2 WO1996011269A2 (en) 1996-04-18
WO1996011269A9 WO1996011269A9 (en) 1996-06-06
WO1996011269B1 true WO1996011269B1 (en) 1996-08-22

Family

ID=27559710

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1995/012935 WO1996011269A2 (en) 1994-10-07 1995-10-06 Tie-2 ligands, methods of making and uses thereof

Country Status (22)

Country Link
US (4) US5814464A (en)
EP (1) EP0784683B1 (en)
JP (1) JP4054375B2 (en)
CN (1) CN1230536C (en)
AT (1) ATE199259T1 (en)
AU (1) AU711111B2 (en)
CA (1) CA2202028C (en)
CZ (1) CZ292453B6 (en)
DE (1) DE69520149T2 (en)
DK (1) DK0784683T3 (en)
ES (1) ES2154354T3 (en)
FI (1) FI120313B (en)
GR (1) GR3035717T3 (en)
HU (1) HU221422B1 (en)
IL (4) IL115517A (en)
MX (1) MX9702530A (en)
NO (1) NO322643B1 (en)
NZ (1) NZ296638A (en)
PL (1) PL184642B1 (en)
PT (1) PT784683E (en)
WO (1) WO1996011269A2 (en)
ZA (1) ZA958444B (en)

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