Antagonizing TGF-beta activity with various ectodomains of TGF-beta receptors used in combination or as fusion proteins

• US 20070244042A1
• Filed: 09/28/2005
• Published: 10/18/2007
• Est. Priority Date: 09/28/2004
• Status: Active Grant

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Sun, LuZhe, Hinck, Andrew
• Granted Patent: US 7,795,389 B2
• Time in Patent Office: Days
• US Class Current: 530/350
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 14/71 for growth factors; for growth regulators
• CPC Class Codes: C07K 2319/32 fusions with soluble part of a cell surface receptor, "decoy receptors"

Abstract

Anti-cancer agents and/or transforming growth factor beta (TGF-beta or TGFβ) antagonists are disclosed, where the agents and/or antagonists include a therapeutically effective amount of a combination of therapeutically active portions of sRII and therapeutically active portions of sRIII or a fusion polypeptide or protein comprising therapeutically active portions of sRII and therapeutically active portions of sRIII. Methods for preventing, treating and/or ameliorating the symptoms of cancer are also disclosed based on administering an effective amount of a composition of this invention.

Claims

1. A transforming growth factor beta (TGF-beta or TGFβ

) antagonist composition comprising a therapeutically effective amount of one or more of;

(1) therapeutically active portions of soluble cell surface type II receptors (sRII);

(2) therapeutically active portions of soluble cell surface type III receptors (sRIII);

(3) a fusion polypeptide or protein comprising therapeutically active portions of sRII or synthetic analogs thereof;

(4) a fusion polypeptide or protein comprising therapeutically active portions of sRIII or synthetic analogs thereof;

or (5) a fusion polypeptide or protein comprising therapeutically active portions of sRII and therapeutically active portions of sRIII or synthetic analogs thereof, where the composition includes at least an active portion of sRII and an active portion of sRIII.

2. The composition of claim 1, wherein the composition comprises a therapeutically active portion of sRII and a therapeutically active portion of sRIII.

3. The composition of claim 1, wherein the composition comprises a therapeutically active portion of sRII and a therapeutically active portion of an E domain of sRIII, and/or a therapeutically active portion of an U domain of sRIII.

4. The composition of claim 1, wherein the composition comprises a therapeutically active portion of sRII and a therapeutically active portion of an E domain of sRIII.

5. The composition of claim 1, wherein the composition comprises a therapeutically active portion of sRII and a therapeutically active portion of an U domain of sRIII.

6. The composition of claim 1, wherein the composition comprises a therapeutically active portion of sRII and of a mixture or combination a therapeutically active portion E domain of sRIII and a therapeutically active portion of an U domain of sRIII.

7. The composition of claim 1, wherein the composition comprises a fusion polypeptide or protein including a therapeutically active portion of sRII and a therapeutically active portion of sRIII.

8. The composition of claim 1, wherein the composition comprises a fusion polypeptide or protein including a therapeutically active portion of sRII and a therapeutically active portion of an E domain of sRIII, and/or a therapeutically active portion of an U domain of sRIII.

9. The composition of claim 1, wherein the composition comprises a fusion polypeptide or protein including a therapeutically active portion of sRII and a therapeutically active portion of an E domain of sRIII.

10. The composition of claim 1, wherein the composition comprises a fusion polypeptides or protein including a therapeutically active portion of sRII and a therapeutically active portion of an U domain of sRIII.

11. The composition of claim 1, wherein the composition comprises a fusion polypeptide or protein including a therapeutically active portion of sRII and a mixture or combination of a therapeutically active portion E domain of sRIII and a therapeutically active portion of an U domain of sRIII.

12. The composition of claim 1, wherein the composition comprises a therapeutically active portion of sRII and a fusion polypeptide or protein including and a mixture or combination of a therapeutically active portion E domain of sRIII and a therapeutically active portion of an U domain of sRIII.

13. A transforming growth factor beta (TGF-beta or TGFβ

) anti-cancer composition comprising a therapeutically effective amount of one or more of;

(1) therapeutically active portions of soluble cell surface type II receptors (sRII);

(2) therapeutically active portions of soluble cell surface type III receptors (sRIII);

(3) a fusion polypeptide or protein comprising therapeutically active portions of sRII or synthetic analogs thereof;

(4) a fusion polypeptide or protein comprising therapeutically active portions of sRIII or synthetic analogs thereof;

or (5) a fusion polypeptide or protein comprising therapeutically active portions of sRII and therapeutically active portions of sRIII or synthetic analogs thereof, where the composition includes at least an active portion of sRII and an active portion of sRIII and optionally a non-TGF-beta anti-cancer agent.

14. A method for preventing, treating and/or ameliorating symptoms of cancer comprising the step of administering to an animal including a human a therapeutically effective amount of one or more of:

(1) therapeutically active portions of soluble cell surface type II receptors (sRII);

(2) therapeutically active portions of soluble cell surface type III receptors (sRIII);

(3) a fusion polypeptide or protein comprising therapeutically active portions of sRII or synthetic analogs thereof;

(4) a fusion polypeptide or protein comprising therapeutically active portions of sRIII or synthetic analogs thereof;

or (5) a fusion polypeptide or protein comprising therapeutically active portions of sRII and therapeutically active portions of sRIII or synthetic analogs thereof, where the composition includes at least an active portion of sRII and an active portion of sRIII and optionally a non-TGF-beta anti-cancer agent, where the administrating is selected from the group consisting of oral, intravenous, intra-arterial, direct and mixtures or combinations thereof on a single dose basis, periodic dose basis, intermittent dose basis or mixture or combination of these dose basis thereof.

15. A composition for encoding a TBGb antagonist comprising at least two or a plurality of DNA encoding sequences selected from the group consisting of SEQ ID NO. 5, SEQ ID NO. 7, and SEQ ID NO. 9.

16. A composition comprising at least two or a plurality of amino acid sequences selected from the group consisting of SEQ ID NO. 6, SEQ ID NO. 8, and SEQ ID NO. 10.

17. A method for treating cancer or other human diseases comprising the step of administering an effective amount of a composition comprising at least two or a plurality of DNA encoding sequences selected from the group consisting of SEQ ID NO. 5, SEQ ID NO. 7, and SEQ ID NO. 9 or at least two or a plurality of amino acid sequences selected from the group consisting of SEQ ID NO. 6, SEQ ID NO. 8, and SEQ ID NO. 10 or mixture or combinations thereof.