The WFDC2 (HE4/HE4a) gene product is a member of a family of stable 4-disulfide core proteins. HE4 is a secreted and glycosylated protein that was first observed in human epididymis tissue (human epididymis protein 4; HE4) and is overexpressed in certain cancers, including ovarian cancers. Characterization of the HE4/HE4a proteins and nucleic acids have been reported, for example, in Kirchhoff C, Habben I, Ivell R, Krull N (March 1992). “A major human epididymis-specific cDNA encodes a protein with sequence homology to extracellular proteinase inhibitors”. Biol Reprod 45 (2): 350-7 Schummer M, Ng W V, Bumgarner R E, Nelson P S, Schummer B, Bednarski D W, Hassell L, Baldwin R L, Karlan B Y, Hood L (December 1999). “Comparative hybridization of an array of 21,500 ovarian cDNAs for the discovery of genes overexpressed in ovarian carcinomas”. Gene 238 (2): 375-85; Kirchhoff C (1998). “Molecular characterization of epididymal proteins.” Rev. Reprod. 3 (2): 86-95; Kirchhoff C, Osterhoff C, Habben I, et al. (1990). “Cloning and analysis of mRNAs expressed specifically in the human epididymis.” Int. J. Androl. 13 (2): 155-67; Hellström I, et al; Cancer Res. 2003 Jul. 1; 63(13):3695-700. Over-expression of HE4/HE4a in cancer cells suggests that this protein and its various isoforms can be a useful biomarker for detecting cancer and for identifying patients having an increased likelihood of having cancer. Methods and composition relating to the use of molecular markers such as HE4/HE4a have been reported previously, including U.S. Pat. No. 7,270,960; US20100311099; US20080020473; US20070286865; US20100047818; US20090104684; and US20030108965, the contents of each of which are incorporated herein in their entirety.
HE4/HE4a proteins have been reported to have different isoforms due to alternative splicing as well as different glycoforms from different patterns of glycosylation. In light of the above, a need exists in the art for compositions and binding agents (e.g. antibodies) that are capable of detecting over-expression of biomarkers such as HE4a, their variants, splice isoforms and glycoforms for the diagnosis of cancer.
USPTO Backgrounds
USPTO Backgrounds