Monoclonal antibodies, or antigen-binding fragments thereof, that bind to ERG, and more specifically, to an epitope formed by amino acids 42-66 of ERG3 are disclosed. The monoclonal antibodies can be non-human antibodies (e.g., rabbit or mouse) or humanized monoclonal antibodies having the CDR regions derived from those non-human antibodies. In other embodiments, the monoclonal antibodies are chimeric, having the light and heavy chain variable regions of a non-human ERG antibody. Methods of using the antibodies to detect ERG, or fusion proteins comprising all or part of an ERG polypeptide, such as an ERG polypeptide encoded by a TMPRSS2/ERG, SLC45A3/ERG, or NDRGI /ERG fusion transcript, are also provided, including methods of detecting ERG or ERG fusion events in a clinical setting. The antibodies can also be used to inhibit the activity of ERG or fusion proteins comprising all or part of an ERG polypeptide, such as an ERG polypeptide encoded by a TMPRSS2/ERG, SLC45A3/ERG, or NDRGI /ERG fusion transcript and to treat malignancies associated with overexpression of ERG or an ERG fusion event, such as prostate cancer, Ewing's sarcoma, acute myeloid leukemia, acute T-lymphoblastic leukemia, endothelial cancer, and colon cancer.
