Claims for Patent: RE44681

Summary for Patent: RE44681

Title:	Compositions and methods for inhibiting growth of SMAD4-deficient cancers
Abstract:	The present invention is in the fields of cell biology, immunology and oncology. The invention relates to the discovery that there is a relationship between the expression levels of the tumor suppressor gene smad4 (also known as dpc4) and integrin .alpha..sub..nu..beta..sub.6, and the responsiveness of patient populations to .alpha..sub..nu..beta..sub.6-active compounds and compositions (e.g., antibodies and other ligands that bind .alpha..sub..nu..beta..sub.6), particularly in cancer cells from such patient populations, more particularly on carcinomas such as pancreatic carcinomas. The invention thus provides methods for determining the responsiveness of tumor cells (particularly those from pancreatic tumors) to such .alpha..sub..nu..beta..sub.6-active compounds and compositions by examining the expression of .sub..nu..beta..sub.6 and smad4 by the tumor cells, as well as methods of diagnosis and treatment/prevention of tumor progression using ligands, including antibodies and molecule drugs, that bind to integrin .alpha..sub..nu..beta..sub.6 on the surfaces of tumor cells and/or that block one or more components of the TGF-.beta. pathway, particularly in smad4-deficient tumor cells.
Inventor(s):	Violette; Shelia M. (Lexington, MA), Koopman; Louise A. (Chestnut Hill, MA)
Assignee:	Biogen Idec MA Inc. (Cambridge, MA)
Application Number:	13/863,646
Patent Claims:	1. A method of inhibiting growth of .[.a cell from.]. a .Iadd.smad4-deficient .Iaddend.tumor .[.that is smad4 deficient.]., comprising: (a) determining the level of expression of smad4 in a cell from said .[.cancer.]. .Iadd.smad4-deficient tumor.Iaddend.; and (b) treating .[.a cancer cell that is deficient in smad4 expression.]. .Iadd.the smad4-deficient tumor .Iaddend.with .[.one or more.]. .Iadd.an .Iaddend..alpha.v.beta.6 antagonist antibody that selectively binds to the integrin .alpha.v.beta.6 .[.in said cancer cell.]., wherein said .[.one or more.]. antibody is an antibody .[.from.]. .Iadd.produced by, or a humanized version of an antibody produced by, .Iaddend.a hybridoma selected from the group consisting of .[.2A1 (deposited under ATCC Accession No. ATCC PTA-3896), 2E5 (deposited under ATCC Accession No. ATCC PTA-3897),.]. 1A8 (deposited under ATCC Accession No. ATCC PTA-3647), 2B10 .Iadd.(.Iaddend.deposited under ATCC Accession No. ATCC PTA-3648), 2B1 .Iadd.(.Iaddend.deposited under ATCC Accession No. ATCC PTA-3646), 1G10 (deposited under ATCC Accession No. ATCC PTA-3898), 7G5 (deposited under ATCC Accession No. ATCC PTA-3899), 8G6 (deposited under ATCC Accession No. ATCC PTA-3645), .Iadd.and .Iaddend.3G9 (deposited under ATCC Accession No. ATCC PTA-3649), .[.or a humanized version thereof.]. wherein said treatment results in the growth inhibition of said .[.cancer cell.]. .Iadd.smad4-deficient tumor.Iaddend.. 2. The method of claim 1, wherein said tumor is a carcinoma. 3. The method of claim 2, wherein said carcinoma is an adenocarcinoma. 4. The method of claim 2, wherein said carcinoma is selected from the group consisting of a pancreatic carcinoma, a colorectal carcinoma, a cervical carcinoma, .Iadd.a .Iaddend.squamous cell carcinoma, a head and neck carcinoma, a liver carcinoma, an ovarian carcinoma and a lung carcinoma. 5. The method of claim 2, wherein said carcinoma is a pancreatic carcinoma. 6. The method of claim .[.4.]. .Iadd.2.Iaddend., wherein said .[.squamous cell.]. carcinoma is an esophageal carcinoma. 7. The method of claim 2, wherein said carcinoma is a colorectal carcinoma. 8. The method of claim 2, wherein said carcinoma is a cervical carcinoma. 9. The method of claim 2, wherein said carcinoma is a head and neck carcinoma. 10. The method of claim 1, wherein said .[.monoclonal.]. antibody is .Iadd.an antibody produced by the hybridoma .Iaddend.3G9 .Iadd.(deposited under ATCC Accession No. ATCC PTA-3649) or a humanized version thereof.Iaddend.. 11. The method of claim 1, wherein said .[.monoclonal.]. antibody is .Iadd.an antibody produced by the hybridoma .Iaddend.8G6 .Iadd.(deposited under ATCC Accession No. ATCC PTA-3645) or a humanized version thereof.Iaddend.. 12. The method of claim 1, wherein said .[.monoclonal.]. antibody is a humanized monoclonal antibody. 13. The method of claim 12, wherein said humanized monoclonal antibody is hu3G9 (BG00011). 14. The method of claim 12, wherein said humanized monoclonal antibody is hu8G6. 15. The method of claim 1, wherein said antibody is conjugated with at least one detectable label. 16. The method of claim 15, wherein said detectable label is selected from the group consisting of a chromogenic label, an enzyme label, a radioisotopic label, a non-radioactive isotopic label, a fluorescent label, a toxic label, a chemiluminescent label, an X-radiographic label, a spin label and a nuclear magnetic resonance contrast agent label. 17. The method of claim 16, wherein said .Iadd.detectable label is a .Iaddend.chromogenic label .[.is.]. selected from the group consisting of diaminobenzidine and 4 hydroxyazo-benzene-2-carboxylic acid. 18. The method of claim 16, wherein said .Iadd.detectable label is an .Iaddend.enzyme label .[.is.]. selected from the group consisting of malate dehydrogenase, staphylococcal nuclease, delta 5 steroid isomerase, yeast alcohol dehydrogenase, alpha glycerol phosphate dehydrogenase, triose phosphate isomerase, peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, .beta. galactosidase, ribonuclease, urease, catalase, glucose 6 phosphate dehydrogenase, glucoamylase and acetylcholine esterase. 19. The method of claim 16, wherein said .Iadd.detectable label is a .Iaddend.radioisotopic label .[.is.]. selected from the group consisting of .[.3H, 111 In, 125I, 131I, 32P, 35S, 14C, 51Cr, 57To, 58Co, 59Fe, 75Se, 152Eu, 90Y, 67Cu, 217Ci, 211At, 212Pb, 47Sc .]. .Iadd..sup.3H, .sup.111In, .sup.125I, .sup.131I, .sup.32P, .sup.35S, .sup.14C, .sup.51Cr, .sup.57To, .sup.58Co, .sup.59Fe, .sup.75Se, .sup.152Eu, .sup.90Y, .sup.67Cu, .sup.217Ci, .sup.211At, .sup.212Pb, .sup.47Sc, .Iaddend.and .[.109Pd .]. .Iadd..sup.109Pd.Iaddend.. 20. The method of claim 16, wherein said .Iadd.detectable label is a .Iaddend.non-radioactive isotopic label .[.is.]. selected from the group consisting of .[.157Gd, 55Mn, 162Dy, 52Tr, 56Fe, 99mTc.]. .Iadd..sup.157Gd, .sup.55Mn, .sup.162Dy, .sup.52Tr, .sup.56Fe, .sup.99mTc, .Iaddend.and .[.112In.]. .Iadd..sup.112In.Iaddend.. 21. The method of claim 16, wherein said .Iadd.detectable label is a .Iaddend.fluorescent label .[.is.]. selected from the group consisting of a .[.152Eu.]. .Iadd..sup.152Eu .Iaddend.label, a fluorescein label, an isothiocyanate label, a rhodamine label, a phycoerythrin label, a phycocyanin label, an allophycocyanin label, a Green Fluorescent Protein (GFP) label, an ophthaldehyde label and a fluorescamine label. 22. The method of claim 16, wherein said .Iadd.detectable label is a .Iaddend.toxic label .[.is.]. selected from the group consisting of a diphtheria toxin label, a ricin label and a cholera toxin label. 23. The method of claim 16, wherein said .Iadd.detectable label is a .Iaddend.chemiluminescent label .[.is.]. selected from the group consisting of a luminol label, an isoluminol label, an aromatic acridinium ester label, an imidazole label, an acridinium salt label, an oxalate ester label, a luciferin label, a luciferase label and an aequorin label. 24. The method of claim 16, wherein said .Iadd.detectable label is an .Iaddend.X-radiographic label .Iadd.that .Iaddend.is barium or cesium. 25. The method of claim 16, wherein said .Iadd.detectable label is a .Iaddend.spin label .Iadd.that .Iaddend.is deuterium. 26. The method of claim 16, wherein said .Iadd.detectable label is a .Iaddend.nuclear magnetic resonance contrast agent label .[.is.]. selected from the group consisting of Gd, Mn and .[.iron.]. .Iadd.Fe.Iaddend.. 27. A method of increasing the responsiveness of a smad4-deficient cancer .[.cell.]. to treatment with a growth-inhibiting chemotherapeutic .[.compounds.]. .Iadd.compound.Iaddend., comprising: (a) determining the level of expression of smad4 in a cell from said .Iadd.smad4-deficient .Iaddend.cancer; and (b) treating .[.a.]. .Iadd.the smad4-deficient .Iaddend.cancer .[.cell that is deficient in smad4 expression.]. with .[.one or more.]. .Iadd.an .Iaddend..alpha.v.beta.6-antagonist .[.antibodies.]. .Iadd.antibody .Iaddend.that selectively .[.bind.]. .Iadd.binds .Iaddend.to the integrin .alpha.v.beta.6 .[.in said cancer cell.]., wherein said .[.one or more.]. antibody is an antibody .[.from.]. .Iadd.produced by, or a humanized verison of an antibody produced by, .Iaddend.a hybridoma selected from the group consisting of .[.2A1 (deposited under ATCC Accession No. ATCC PTA-3896), 2E5 (deposited under ATCC Accession No. ATCC PTA-3897),.]. 1A8 (deposited under ATCC Accession No. ATCC PTA-3647), 2B10 .Iadd.(.Iaddend.deposited under ATCC Accession No. ATCC PTA-3648), 2B1 .Iadd.(.Iaddend.deposited under ATCC Accession No. ATCC PTA-3646), 1G10 (deposited under ATCC Accession No. ATCC PTA-3898), 7G5 (deposited under ATCC Accession No. ATCC PTA-3899), 8G6 (deposited under ATCC Accession No. ATCC PTA-3645), .Iadd.and .Iaddend.3G9 (deposited under ATCC Accession No. ATCC PTA-3649), .[.or a humanized version thereof.]. wherein said treatment with said .[.blocking antibodies.]. .Iadd.antibody .Iaddend.results in increased responsiveness of said .Iadd.smad4-deficient .Iaddend.cancer .[.cell.]. to .[.one or more.]. .Iadd.the .Iaddend.growth-inhibiting chemotherapeutic .[.compounds.]. .Iadd.compound .Iaddend.as compared to the growth inhibition of said .Iadd.smad4-deficient .Iaddend.cancer .[.cell produced by.]. .Iadd.treated with .Iaddend.said chemotherapeutic .[.agent.]. .Iadd.compound .Iaddend.alone. 28. The method of claim 27, wherein said growth-inhibiting chemotherapeutic compound is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, paclitaxel, gemcitabine, adriamycin, melphalan, methotrexate, 5-fluorouracil, etoposide, mechlorethamine, cyclophosphamide, bleomycin, a calicheamicin, a maytansine, a trichothene, CC1065, diphtheria A chain, Pseudomonas aeruginosa exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, an Aleuritesfordii protein, a dianthin protein, a Phytolaca americana protein, .[.momordica.]. .Iadd.Momordica .Iaddend.charantia inhibitor, curcin, crotin, .[.sapaonaria.]. .Iadd.Sapaonaria .Iaddend.officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, a tricothecene, a ribonuclease, and a deoxyribonuclease. 29. The method of claim 28, wherein said growth-inhibiting chemotherapeutic compound is gemcitabine, adriamycin or paclitaxel. .Iadd.30. The method of claim 1, wherein said antibody is an antibody produced by the hybridoma 1A8 (deposited under ATCC Accession No. ATCC PTA-3647) or a humanized version thereof..Iaddend. .Iadd.31. The method of claim 27, wherein said antibody is hu3G9 (BG00011)..Iaddend. .Iadd.32. The method of claim 27, wherein said antibody is hu8G6..Iaddend. .Iadd.33. The method of claim 27, wherein said antibody is an antibody produced by the hybridoma 3G9 (deposited under ATCC Accession No. ATCC PTA-3649) or a humanized version thereof..Iaddend. .Iadd.34. The method of claim 27, wherein said antibody is an antibody produced by the hybridoma 8G6 (deposited under ATCC Accession No. ATCC PTA-3645) or a humanized version thereof..Iaddend. .Iadd.35. The method of claim 27, wherein said antibody is an antibody produced by the hybridoma 1A8 (deposited under ATCC Accession No. ATCC PTA-3647) or a humanized version thereof..Iaddend. .Iadd.36. The method of claim 1, wherein the antibody comprises a heavy chain and a light chain, wherein the heavy and light chains comprise complementarity determining regions (CDRs) 1, 2, and 3 as follows: heavy chain CDR 1 comprising an amino acid sequence set forth in SEQ ID NO.: 3; heavy chain CDR 2 comprising an amino acid sequence set forth in SEQ ID NO.: 9; heavy chain CDR 3 comprising an amino acid sequence set forth in SEQ ID NO.: 15; light chain CDR 1 comprising an amino acid sequence set forth in SEQ ID NO.: 20; light chain CDR 2 comprising an amino acid sequence set forth in SEQ ID NO.: 25; and light chain CDR 3 comprising an amino acid sequence set forth in SEQ ID NO.: 31..Iaddend. .Iadd.37. The method of claim 1, wherein the antibody comprises a heavy chain and a light chain, wherein the heavy and light chains comprise CDRs 1, 2, and 3 as follows: heavy chain CDR 1 comprising an amino acid sequence set forth in SEQ ID NO.: 1; heavy chain CDR 2 comprising an amino acid sequence set forth in SEQ ID NO.: 6; heavy chain CDR 3 comprising an amino acid sequence set forth in SEQ ID NO.: 12; light chain CDR 1 comprising an amino acid sequence set forth in SEQ ID NO.: 18; light chain CDR 2 comprising an amino acid sequence set forth in SEQ ID NO.: 24; and light chain CDR 3 comprising an amino acid sequence set forth in SEQ ID NO.: 28..Iaddend. .Iadd.38. The method of claim 1, wherein the antibody comprises a heavy chain and a light chain, wherein the heavy and light chains comprise CDRs 1, 2, and 3 as follows: heavy chain CDR 1 comprising an amino acid sequence set forth in SEQ ID NO.: 2; heavy chain CDR 2 comprising an amino acid sequence set forth in SEQ ID NO.: 7; heavy chain CDR 3 comprising an amino acid sequence set forth in SEQ ID NO.: 13; light chain CDR 1 comprising an amino acid sequence set forth in SEQ ID NO.: 19; light chain CDR 2 comprising an amino acid sequence set forth in SEQ ID NO.: 24; and light chain CDR 3 comprising an amino acid sequence set forth in SEQ ID NO.: 29..Iaddend. .Iadd.39. The method of claim 27, wherein the antibody comprises a heavy chain and a light chain, wherein the heavy and light chains comprise CDRs 1, 2, and 3 as follows: heavy chain CDR 1 comprising an amino acid sequence set forth in SEQ ID NO.: 3; heavy chain CDR 2 comprising an amino acid sequence set forth in SEQ ID NO.: 9; heavy chain CDR 3 comprising an amino acid sequence set forth in SEQ ID NO.: 15; light chain CDR 1 comprising an amino acid sequence set forth in SEQ ID NO.: 20; light chain CDR 2 comprising an amino acid sequence set forth in SEQ ID NO.: 25; and light chain CDR 3 comprising an amino acid sequence set forth in SEQ ID NO.: 31..Iaddend. .Iadd.40. The method of claim 27, wherein the antibody comprises a heavy chain and a light chain, wherein the heavy and light chains comprise CDRs 1, 2, and 3 as follows: heavy chain CDR 1 comprising an amino acid sequence set forth in SEQ ID NO.: 1; heavy chain CDR 2 comprising an amino acid sequence set forth in SEQ ID NO.: 6; heavy chain CDR 3 comprising an amino acid sequence set forth in SEQ ID NO.: 12; light chain CDR 1 comprising an amino acid sequence set forth in SEQ ID NO.: 18; light chain CDR 2 comprising an amino acid sequence set forth in SEQ ID NO.: 24; and light chain CDR 3 comprising an amino acid sequence set forth in SEQ ID NO.: 28..Iaddend. .Iadd.41. The method of claim 27, wherein the antibody comprises a heavy chain and a light chain, wherein the heavy and light chains comprise CDRs 1, 2, and 3 as follows: heavy chain CDR 1 comprising an amino acid sequence set forth in SEQ ID NO.: 2; heavy chain CDR 2 comprising an amino acid sequence set forth in SEQ ID NO.: 7; heavy chain CDR 3 comprising an amino acid sequence set forth in SEQ ID NO.: 13; light chain CDR 1 comprising an amino acid sequence set forth in SEQ ID NO.: 19; light chain CDR 2 comprising an amino acid sequence set forth in SEQ ID NO.: 24; and light chain CDR 3 comprising an amino acid sequence set forth in SEQ ID NO.: 29..Iaddend.

Details for Patent RE44681

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2026-07-10