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Compositions against cancer antigen liv-1 and uses thereof

This application is a continuation of U.S. patent application Ser. No. 10/769,612, filed Jan. 29, 2004, which claims the benefit of U.S. Provisional Application No. 60/443,712, filed Jan. 29, 2003, all herein incorporated by reference.

The invention relates to the identification and generation of antibodies that specifically bind to LIV-1 proteins; and to the use of such antibodies and compositions comprising them, in the diagnosis, prognosis, and therapy of cancer.

Zinc plays an essential role in cell growth, and is a cofactor of over 300 enzymes, including enzymes important in angiogenesis and cell remodeling. Vallee, B. L., Auld, D. S., Biochem. 29:5647-5659 (1990). Zinc associates with many macromolecules in cells, including molecular components that act to control growth, apoptosis, development and differentiation. Control of intracellular zinc levels, therefore, may be important in preventing the triggering of a variety of disease states, including cancer.

LIV-1 is a member of the LZT (LIV-1-ZIP Zinc Transporters) subfamily of zinc transporter proteins. Taylor, K. M. and Nicholson, R. I., Biochim. Biophys. Acta 1611:16-30 (2003). Computer analysis of the LIV-1 protein reveals a potential metalloprotease motif, fitting the consensus sequence for the catalytic zinc-binding site motif of the zincin metalloprotease.

The structure of LIV-1 implicates a role for the protein as a zinc-influx transporter protein. Experiments with recombinant LIV-1 localizes the protein to the plasma membrane, similarly concentrated in lamellipodiae as membrane-type metalloproteases. Taylor and Nicholson, supra. Computer analysis predicts six to eight transmnembrane domains, a long extracellular N terminus, a short extracellular C terminus, as well as the consensus sequence for the catalytic zinc-binding site of metalloproteases. LIV-1 distribution studies indicates primary expression in breast, prostate, pituitary gland and brain tissue. Taylor and Nicholson, supra.

The LIV-1 protein has also been implicated in certain cancerous conditions, e.g. breast cancer and prostate cancer. The detection of LIV-1 is associated with estrogen receptor-positive breast cancer, McClelland, R. A., et al., Br. J. Cancer 77:1653-1656 (1998), and the metastatic spread of these cancers to the regional lymph nodes. Manning, D. A. et al., Eur. J. Cancer 30A:675-678 (1994). Antibodies useful for diagnosis, prognosis, and effective treatment of cancer, including metastatic cancer, would be desirable. Accordingly, provided herein are compositions and methods that can be used in diagnosis, prognosis, and therapy of certain cancers.

The present invention provides anti-LIV-1 antibodies that are useful for making conjugated antibodies for therapeutic purposes. For example, the anti-LIV-1 antibodies of the invention are useful as selective cytotoxic agents for LIV-1 expressing cells. In some embodiments, the antibodies of the present invention are therapeutically useful in persons diagnosed with cancer and other proliferative conditions, including benign proliferative conditions. In one aspect the antibodies of the present invention can be used to treat proliferative conditions of the prostate or breast including, for example, prostate cancer or breast cancer.

The present invention provides antibodies that competitively inhibit binding of proteins encoded by vectors containing some or all of the sequence associated with LIV-1 (Hs.79136). In some embodiments the antibodies are further conjugated to an effector component. The effector component can be a label (e.g., a fluorescent label, an effector domain e.g. MicA) or can be a cytotoxic moiety (e.g., a radioisotope or a cytotoxic chemical). An exemplary cytotoxic chemical is auristatin-E. In other embodiments the antibodies can be used alone to inhibit tumor cell growth.

The antibodies of the invention can be whole antibodies or can be antibody fragments. In some embodiments the immunoglobulin is a humanized antibody. An exemplary antibody of the invention is defined by CDRs.

The invention further provides immunoassays using the immunoglobulins of the invention. These methods involve detecting a cancer cell in a biological sample from a patient by contacting the biological sample with an antibody of the invention. The antibody is typically conjugated to a label such as a fluorescent or other label.

The invention also provides double-stranded ribonucleic acids that bind to mRNA encoded by the LIV-1 nucleic acid of SEQ ID NO:1. The double-stranded ribonucleic acids may cover the length of the target mRNA, or may be short double-stranded ribonucleic acids complementary to tile target mRNA, e.g. siRNA.

The invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and the antibody or double stranded ribonucleic acid of the invention. In these embodiments, the antibody can be further conjugated to an effector component. The effector component can be a label (e.g., a fluorescent label) or can be a cytotoxic moiety (e.g., a radioisotope or a cytotoxic chemical). An exemplary cytotoxic chemical is auristatin-E. The antibodies in the pharmaceutical compositions can be whole antibodies or antibody fragments. In some embodiments the inuunoglobulin is a humanized antibody.

The invention also provides methods of inhibiting proliferation of a prostate cancer-associated or breast cancer-associated cell. The method comprises contacting the cell with an antibody or double-stranded ribonucleic acid of the invention. In most embodiments, the cancer cell is in a patient, typically a human. The patient may be undergoing a therapeutic regimen to treat metastatic or benign prostate cancer or breast cancer or may be suspected of having prostate cancer or breast cancer.