US5912224A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Methods and compositions for enhancing cellular response to TGF-β ligands
Assignee: General Hospital Corp
•
Filing: 1997-02-21
•
Granted: 1999-06-15
•
Expires: 2017-02-21
Abstract
Abstract The present invention concerns the TGF- beta receptor-mediated signaling pathway. The invention is based on the unexpected finding that TGF- beta receptor-mediated signaling is inhibited by the cytoplasmic interactor FKBP12. The invention further concerns methods and pharmaceutical compositions for enhancing cellular response to TGF- beta ligands. A screening assay is also provided for identifying macrolide potentiators capable of binding FKBP12 and thereby blocking FKBP12-inhibition of TGF- beta receptor-mediated signaling.
Inventors
- 👤 Patricia K. Donahoe
- 👤 Tongwen Wang
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-07 21:51
CPC Classifications
C; C07; C07K; C07K14/00; C07K14/435; C07K14/705; C07K14/71; A; A61; A61K; A61K31/00; A61K31/33; A61K31/395; A61K31/435; A61K31/4353; A61K31/436; A61K38/00; A61K38/16; A61K38/17; A61K38/18; A61K38/1841; A61K38/1875; A61K38/22; C07K14/46; C07K14/47; C07K14/4701; C07K14/4702; G; G01; G01N; G01N33/00; G01N33/48; G01N33/50; G01N33/68; G01N33/6872
Claims Analysis
Total Claims: 33
Claim 1
Independent Claim
82 words
A method for potentiating a cellular response, comprising: (a) administering to cells which express a receptor of a Transforming Growth Factor-beta (TGF-β) family ligand an effective amount of a TGF-β family ligand to induce the receptor-mediated cellular response; and (b) administering to said cells an effective amount of a macrolide which is a naturally occurring or synthetic FK506 or rapamycin derivative, lacks or has reduced immunosuppressive activity as compared to FK506 or rapamycin, respectively, and binds FKBP12 to potentiate the cellular response.
Claim 2
Independent Claim
82 words
A method for potentiating a cellular response, comprising: (a) administering to cells which express a receptor of a Transforming Growth Factor-beta (TGF-β) family ligand an effective amount of a TGF-β family ligand to induce the receptor-mediated cellular response; and (b) administering to said cells an effective amount of a macrolide which is a naturally occurring or synthetic FK506 or rapamycin derivative, lacks or has reduced immunosuppressive activity as compared to FK506 or rapamycin, respectively, and binds FKBP12 to potentiate the cellular response.
Claim 3
Dependent Claim
12 words
The method of claim 1, wherein said macrolide is a FK506 antagonist.
Claim 4
Dependent Claim
92 words
The method of claim 2, wherein said FK506 antagonist has the following formula: ##STR3## wherein R 1 is selected from the group consisting of H, alkyl, aryl and acyl, R 2 is selected from the group consisting of H and --OR 5 , such that R 5 is selected from the group consisting of H, alkyl, aryl and acyl, R 3 is selected from the group consisting of --CH 2 -- and --CH 2 CH 2 --, and R 4 is selected from the group consisting of H, alkyl, acyl and aryl.
Claim 5
Dependent Claim
60 words
The method of claim 2, wherein said FK506 antagonist has the following formula: ##STR4## wherein R 1 is selected from the group consisting of H and --CH 3 , R 2 is selected from the group consisting of H and --OH, and R 3 is selected from the group consisting of --CH 2 -- and --CH 2 CH 2 --.
Claim 6
Dependent Claim
11 words
The method of claim 2, wherein said FK506 antagonist is 15-O-desmethyl-FK520.
Claim 7
Dependent Claim
11 words
The method of claim 2, wherein said FK506 antagonist is L-685,818.
Claim 8
Dependent Claim
24 words
The method of claim 1, wherein said receptor is selected from the group consisting of R1, R2, R3, R4, ALK3, ALK6, Sax and Tkv.
Claim 9
Dependent Claim
24 words
The method of claim 2, wherein said receptor is selected from the group consisting of R1, R2, R3, R4, ALK3, ALK6, Sax and Tkv.
Claim 10
Dependent Claim
55 words
The method of claim 7, wherein said TGF-β family ligand is selected from the group consisting of TGF-β1, TGF-β2, TGF-β3, TGF-β4, TGF-β5, Mullerian Inhibiting Substance (MIS), an inhibin, an activin, a bone morphogenetic protein, the Vgr-1 gene product, the decapentaplegic gene product, growth differentiation factor (GDF)-1, GDF-2, GDF-3, GDF-4, GDF-5, GDF-6, GDF-7, GDF-8 and GDF-9.
Claim 11
Dependent Claim
55 words
The method of claim 8, wherein said TGF-β family ligand is selected from the group consisting of TGF-β1, TGF-β2, TGF-β3, TGF-β4, TGF-β5, Mullerian Inhibiting Substance (MIS), an inhibin, an activin, a bone morphogenetic protein, the Vgr-1 gene product, the decapentaplegic gene product, growth differentiation factor (GDF)-1, GDF-2, GDF-3, GDF-4, GDF-5, GDF-6, GDF-7, GDF-8 and GDF-9.
Claim 12
Dependent Claim
18 words
The method of claim 9, wherein said TGF-β family ligand and said macrolide are administered to a patient.
Claim 13
Dependent Claim
18 words
The method of claim 10, wherein said TGF-β family ligand and said macrolide are administered to a patient.
Claim 14
Dependent Claim
10 words
The method of claim 11, wherein said patient is human.
Claim 15
Dependent Claim
10 words
The method of claim 12, wherein said patient is human.
Claim 16
Dependent Claim
19 words
The method of claim 13, wherein said TGF-β family ligand is administered before, after, or simultaneously with said macrolide.
Claim 17
Dependent Claim
19 words
The method of claim 14, wherein said TGF-β family ligand is administered before, after, or simultaneously with said macrolide.
Claim 18
Dependent Claim
57 words
The method of claim 15, wherein said TGF-β family ligand and said macrolide are administered for an effect selected from the group consisting of treatment of an ulcer, prevention or reduction of formation of scar tissue caused by ocular trauma, treatment of psoriasis, inhibition of growth of a gynecological tumor, and inhibition of growth of ocular melanoma.
Claim 19
Dependent Claim
57 words
The method of claim 16, wherein said TGF-β family ligand and said macrolide are administered for an effect selected from the group consisting of treatment of an ulcer, prevention or reduction of formation of scar tissue caused by ocular trauma, treatment of psoriasis, inhibition of growth of a gynecological tumor, and inhibition of growth of ocular melanoma.
Claim 20
Dependent Claim
46 words
The method of claim 15, wherein said TGF-β family ligand and said macrolide are administered for an effect selected from the group consisting of promotion of proliferation of connective tissue or soft tissue for wound healing and promotion of healing or growth of bone or cartilage.
Claim 21
Dependent Claim
46 words
The method of claim 16, wherein said TGF-β family ligand and said macrolide are administered for an effect selected from the group consisting of promotion of proliferation of connective tissue or soft tissue for would healing and promotion of healing or growth of bone or cartilage.
Claim 22
Independent Claim
78 words
A method for potentiating a cellular response, comprising: (a) administering to a patient having cells which express a receptor of a Transforming Growth Factor-beta (TGF-β) family ligand an effective amount of a TGF-β family ligand to induce the receptor-mediated cellular response; and (b) administering to said patient a FK506 antagonist which binds FKBP12 but lacks or has reduced immunosuppressive activity as compared to FK506, wherein said antagonist is administered in an amount effective to potentiate the cellular response.
Claim 23
Independent Claim
78 words
A method for potentiating a cellular response, comprising: (a) administering to a patient having cells which express a receptor of a Transforming Growth Factor-beta (TGF-β) family ligand an effective amount of a TGF-β family ligand to induce the receptor-mediated cellular response; and (b) administering to said patient a FK506 antagonist which binds FKBP12 but lacks or has reduced immunosuppressive activity as compared to FK506, wherein said antagonist is administered in an amount effective to potentiate the cellular response.
Claim 24
Dependent Claim
23 words
The method of claim 21, wherein said TGF-β family ligand is selected from the group consisting of TGF-β1, TGF-β2, TGF-β3, TGF-β4 and TGF-β5.
Claim 25
Dependent Claim
14 words
The method of claim 21, wherein said TGF-β family ligand is Mullerian Inhibiting Substance.
Claim 26
Dependent Claim
11 words
The method of claim 22, wherein said FK506 antagonist is 15-O-desmethyl-FK520.
Claim 27
Dependent Claim
11 words
The method of claim 23, wherein said FK506 antagonist is 15-O-desmethyl-FK520.
Claim 28
Dependent Claim
11 words
The method of claim 22, wherein said FK506 antagonist is L-685,818.
Claim 29
Dependent Claim
11 words
The method of claim 23, wherein said FK506 antagonist is L-685,818.
Claim 30
Dependent Claim
23 words
The method of claim 25, wherein said TGF-β family ligand and said FK506 antagonist are administered to inhibit growth of a gynecological tumor.
Claim 31
Dependent Claim
23 words
The method of claim 27, wherein said TGF-β family ligand and said FK506 antagonist are administered to inhibit growth of a gynecological tumor.
Claim 32
Dependent Claim
22 words
The method of claim 25, wherein said TGF-β family ligand and said FK506 antagonist are administered to inhibit growth of ocular melanoma.
Claim 33
Dependent Claim
22 words
The method of claim 27, wherein said TGF-β family ligand and said FK506 antagonist are administered to inhibit growth of ocular melanoma.
References Cited (Backward Citations)
US4885171A
Cited
US5011687A
Cited
US5008240A
Cited
US5436228A
Cited
US5310880A
Cited
US5387589A
Cited
US5286730A
Cited
WO1994021634A1
Cited
WO1995001801A1
Cited
WO1995006649A1
Cited
US5411940A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 2002-06-14 | 2002-12-14 | 2003-06-15 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2006-06-14 | 2006-12-14 | 2007-06-15 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2010-06-14 | 2010-12-14 | 2011-06-15 | $7700.00 | Window Closed / Lapsed |