US RE44,681 E1 · 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 ανβ6, and the responsiveness of patient populations to ανβ6-active compounds and compositions (e.g., antibodies and other ligands that bind ανβ6), 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 ανβ6-active compounds and compositions by examining the expression of ≢νβ6 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 ανβ6 on the surfaces of tumor cells and/or that block one or more components of the TGF-β pathway, particularly in smad4-deficient tumor cells.

Claims41

Dependent claims

A method of inhibiting growth of a cell from a smad4-deficient tumor that is smad4 deficient, comprising:

(a) determining the level of expression of smad4 in a cell from said cancer smad4-deficient tumor;
and
(b) treating a cancer cell that is deficient in smad4 expression the smad4-deficient tumor with one or more an αvβ6 antagonist antibody that selectively binds to the integrin αvβ6 in said cancer cell, wherein said one or more antibody is an antibody from produced by, or a humanized version of an antibody produced by, 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 (deposited under ATCC Accession No. ATCC PTA-3648), 2B1 (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), and 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 smad4-deficient tumor.

1 more element

A method of increasing the responsiveness of a smad4-deficient cancer cell to treatment with a growth-inhibiting chemotherapeutic compounds compound, comprising:

(a) determining the level of expression of smad4 in a cell from said smad4-deficient cancer;
and
(b) treating a the smad4-deficient cancer cell that is deficient in smad4 expression with one or more an αvβ6-antagonist antibodies antibody that selectively bind binds to the integrin αvβ6 in said cancer cell, wherein said one or more antibody is an antibody from produced by, or a humanized verison of an antibody produced by, 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 (deposited under ATCC Accession No. ATCC PTA-3648), 2B1 (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), and 3G9 (deposited under ATCC Accession No. ATCC PTA-3649), or a humanized version thereof
wherein said treatment with said blocking antibodies antibody results in increased responsiveness of said smad4-deficient cancer cell to one or more the growth-inhibiting chemotherapeutic compounds compound as compared to the growth inhibition of said smad4-deficient cancer cell produced by treated with said chemotherapeutic agent compound alone.

1 more element

Dependencies are inferred from the claim text.

Compositions and methods for inhibiting growth of SMAD4-deficient cancers

Life of this patent

Compositions and methods for inhibiting growth of SMAD4-deficient cancers

Life of this patent

Abstract

Claims41