Antibodies against GPR64 and uses thereof

#The invention relates to the identification and generation of antibodies that specifically bind to GPR64 proteins; and to the use of such antibodies and compositions comprising them in the diagnosis, prognosis and therapy of cancer.

#Ovarian cancer is the sixth most common cancer in women, accounting for 6% of all female cancers. It ranks fifth as the cause of cancer death in women. The American Cancer Society predicts that there will be about 23,100 new cases of ovarian cancer in this country in the year 2000 and about 14,000 women will die of the disease. Because many ovarian cancers cannot be detected early in their development, they account for a disproportionate number of fatal cancers, being responsible for almost half the deaths from cancer of the female genital tract; more deaths than any other reproductive organ cancer.

#Most patients with epithelial ovarian cancer, the predominant form, are asymptomatic in early-stage disease and usually present with stage III or IV disease. Their five-year survival is less than 25%, with lower survival among African-American women. The minority of patients discovered with early-stage disease have a five-year survival rate of 80%-90% (Parker, S. L. et. al. Cancer statistics, 1997. CA 1997:47:5-27).

#FIG. 1 depicts the nucleotide and amino acid sequences of GPR64 (SEQ ID NOs: 1 and 2)

#FIG. 2 depicts the nucleotide and amino acid sequences of VH and VL regions of the five anti-GPR64 antibodies: GPR64-1, -16, -18, -20 and -48. (SEQ ID NOs: 3-22)

#FIG. 3 depicts plots of 4-day growth assay data showing that GPR64 expression down-modulation by RNAi in cell proliferation in GPR64 expressing cancer cells.

#The present invention provides novel reagents and methods for treatment, diagnosis and prognosis for certain cancers using antibodies against GPR64. In particular, the present invention provides anti-GPR64 antibodies that are particularly useful as selective cytotoxic agents for GPR64 expressing cells.

#Epitope mapping of antibodies showing high affinity binding can be carried out through competitive binding analyses well-known in the art and described further below. Using this methodology, antibodies recognizing a number of individual epitopes can be identified. The antibodies are then assessed for GPR64 dependent cell death in vitro. Using these methods antibodies that promote significant cell death can be identified

#As used herein, “antibody” includes reference to an immunoglobulin molecule immunologically reactive with a particular antigen, and includes both polyclonal and monoclonal antibodies. The term also includes genetically engineered forms such as chimeric antibodies (e.g. humanized murine antibodies) and heteroconjugate antibodies (e.g., bispecific antibodies). The term “antibody” also includes antigen binding forms of antibodies, including fragments with antigen-binding capability (e.g., Fab′, F(ab′)2, Fab, Fv and rIgG. See also, Pierce Catalog and Handbook, 1994-1995 (Pierce Chemical Co., Rockford, Ill.). See also, e.g., Kuby, J., Immunology, 3rd Ed., W.H. Freeman & Co., New York (1998). The term also refers to recombinant single chain Fv fragments (scFv). The term antibody also includes bivalent or bispecific molecules, diabodies, triabodies, and tetrabodies. Bivalent and bispecific molecules are described in, e.g., Kostelny et al. (1992) J Immunol 148:1547, Pack and Pluckthun (1992) Biochemistry 31:1579, Hollinger et al., 1993, supra, Gruber et al. (1994) J Immunol: 5368, Zhu et al. (1997) Protein Sci 6:781, Hu et al. (1996) Cancer Res. 56:3055, Adams et al. (1993) Cancer Res. 53:4026, and McCartney, et al. (1995) Protein Eng. 8:301.