TARGETED BINDING AGENTS DIRECTED TO a5 1 AND USES THEREOF

Abstract

The invention relates to targeted binding agents against α5β1 and uses of such agents. More specifically, the invention relates to fully human monoclonal antibodies directed to α5β1. The described targeted binding agents are useful in the treatment of diseases associated with the activity and / or overproduction of α5β1 and as diagnostics.

Description

BACKGROUND OF THE INVENTION[0001]1. Field of the Invention[0002]The invention relates to targeted binding agents against the target antigen α5β1 integrin (α5β1) and uses of such agents. In some embodiments, the invention relates to fully human monoclonal antibodies directed to α5β1 and uses of these antibodies. Aspects of the invention also relate to hybridomas or other cell lines expressing such targeted binding agents or antibodies. The described targeted binding agents and antibodies are useful as diagnostics and for the treatment of diseases associated with the activity and / or overexpression of α5β1.[0003]2. Description of the Related Art[0004]The integrin superfamily includes at least 24 family members consisting of heterodimers that utilize 18 alpha and 8 beta chains (Hynes, (2002) Cell 110: 673-87). This family of receptors is expressed on the cell surface and mediates cell-cell and cell-extracellular matrix interactions that regulate cell survival, proliferation, migration, ...

AI Technical Summary

Benefits of technology

[0018]In another embodiment, the targeted binding agent binds α5β1 with a KD less than about 400, 300, 200, or 100, 75, 60, 50, 40, 30, 20, 10, or 5 pM as measured in a monovalent affinity assay. Monovalent affinity may be measured in a BIACORE® assay in which soluble receptor is flowed over immobilized antibody. In comparison with a bivalent affinity assay, the KD as reported by a monovalent affinity assay is much less likely to be affected by experimental artefacts and is thus able to report a KD much closer to the true monovalent affinity of the antibody. In a bivalent affinity assay, the density of immobilized receptor influences the extent to which single antibody molecules bind twice and / or rebind immobilized receptor as they are flowed over. As such, in a bivalent affinity assay, the density of receptor can directly affect the reported KD. Thus, a monovalent affinity assay provides a much more biologically-relevant measurement of affinity.

[0021]In one embodiment of the invention, the targeted binding agent is an antibody. In one embodiment of the invention, the targeted binding agent is a monoclonal antibody. In one embodiment of the invention, the targeted binding agent is a fully human monoclonal antibody. In another embodiment of the invention, the targeted binding agent is a fully human monoclonal antibody of the IgG1, IgG2, IgG3 or IgG4 isotype. In another embodiment of the invention, the targeted binding agent is a fully human monoclonal antibody of the IgG2 isotype. This isotype has reduced potential to elicit effector function in comparison with other isotypes, which may lead to reduced toxicity. In another embodiment of the invention, the targeted binding agent is a fully human monoclonal antibody of the IgG1 isotype. The IgG1 isotype has increased potential to elicit ADCC in comparison with other isotypes, which may lead to improved efficacy. The IgG1 isotype has improved stability in comparison with other isotypes, e.g. IgG4, which may lead to improved bioavailability, or improved ease of manufacture or a longer half-life. In one embodiment, the fully human monoclonal antibody of the IgG1 isotype is of the z, za or f allotype.

[0083]In one embodiment treatment of a neoplastic disease comprises inhibition of tumour growth, tumour growth delay, regression of tumour, shrinkage of tumour, increased time to is regrowth of tumour on cessation of treatment, increased time to tumour recurrence, slowing of disease progression.

[0095]In some embodiments, the targeted binding agents or antibodies as disclosed herein can be modified to enhance their capability of fixing complement and participating in complement-dependent cytotoxicity (CDC). In other embodiments, the targeted binding agents or antibodies can be modified to enhance their capability of activating effector cells and participating in antibody-dependent cytotoxicity (ADCC). In yet other embodiments, the targeted binding agents or antibodies as disclosed herein can be modified both to enhance their capability of activating effector cells and participating in antibody-dependent cytotoxicity (ADCC) and to enhance their capability of fixing complement and participating in complement-dependent cytotoxicity (CDC).

[0097]In certain embodiments, the half-life of a targeted binding agent or antibody as disclosed herein and of compositions of the invention is at least about 4 to 7 days. In certain embodiments, the mean half-life of a targeted binding agent or antibody as disclosed herein and of compositions of the invention is at least about 2 to 5 days, 3 to 6 days, 4 to 7 days, 5 to 8 days, 6 to 9 days, 7 to 10 days, 8 to 11 days, 8 to 12, 9 to 13, 10 to 14, 11 to 15, 12 to 16, 13 to 17, 14 to 18, 15 to 19, or 16 to 20 days. In other embodiments, the mean half-life of a targeted binding agent or antibody as disclosed herein and of compositions of the invention is at least about 17 to 21 days, 18 to 22 days, 19 to 23 days, 20 to 24 days, 21 to 25, days, 22 to 26 days, 23 to 27 days, 24 to 28 days, 25 to 29 days, or 26 to 30 days. In still further embodiments the half-life of a targeted binding agent or antibody as disclosed herein and of compositions of the invention can be up to about 50 days. In certain embodiments, the half-lives of antibodies and of compositions of the invention can be prolonged by methods known in the art. Such prolongation can in turn reduce the amount and / or frequency of dosing of the antibody compositions. Antibodies with improved in vivo half-lives and methods for preparing them are disclosed in U.S. Pat. No. 6,277,375; and International Publication Nos. WO 98 / 23289 and WO 97 / 3461.

[0101]The serum half-life of proteins comprising Fc regions may be increased by increasing the binding affinity of the Fc region for FcRn. In one embodiment, the Fc variant protein has enhanced serum half life relative to comparable molecule.

Problems solved by technology

Knockout of the primary α5β1 ligand, fibronectin, also results in a similar embryonic lethality as a result of a failure to form vasculature.

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