Development of therapeutic anti-STIP1 (stress-induced phosphoprotein 1) antibody for anti-cancer using antibody phage display system

During a systematic search for potential biomarkers of ovarian cancer, we identified that stress-induced phosphoprotein 1 (STIP1) might be used as a biomarker for human ovarian cancer. Subsequently, we established STIP1 ELISA and immunohistochemistry to help detecting ovarian cancer. The combined assays of serum CA125 and STIP1 achieved 100% sensitivity of ovarian cancer detection. These results were published in Molecular and Cellular Proteomics (2010). STIP1 ELISA kits are being produced by internationally renowned, Taiwan-based Abnova Biotechnology Inc. A pilot clinical trial of the use of STIP1 in detecting ovarian cancer was done in 2010, with a grant from the Department of Health, Taiwan (DOH99-TD-I-111-TM013). Under that DOH support, we have achieved the following accomplishments: 1. approval of the US patent 7851230B2 (STIP1 as a biomarker for the detection of human ovarian cancers and endometriosis) on Dec. 14, 2010; 2. elucidation of the functional mechanisms of cancer-secreted STIP1, which was published in the August 2012 issues of Cell Reports (Tsai et al., 2012); 3. identification of STIP1 immunointensities in ovarian cancer tissues as a predicting biomarker for the survival of patients (paper under review); and 4. generation of neutralizing anti-STIP1 antibodies that could be used to counteract the stimulation of cancer cells by secreted STIP1. Afterwards, with the continuous support by Chang Gung Medical Research fund, we have been studying the functions of STIP1 in tumorigenesis and the clinical value of STIP1. We also found that the immunointensity of STIP1 in ovarian cancer was positive correlated with the severity of disease, demonstrating by high STIP1 histoscores in the patients with poor survival (Chao et al., 2013). We have reported that STIP1 was secreted out by tumor tissues and promoted cell proliferation by binding cell surface receptors ALK2, activating the SMAD signaling pathways and stimulated ID3 expression (Wang et al., 2010; Tsai et al., 2012). In addition to neutralizing secreted STIP1, anti-STIP1 antibodies could enter cancer cells and exert cytotoxicity to STIP1-producing cancer cells. More importantly, the efficacy of anti-STIP1 cytotoxicity was positively correlated with the levels of cellular STIP1. Our animal results also showed that STIP1 monoclonal antibody could suppress ovarian cancer cell growth and prolong survival time of mice that were inoculated with mouse ovarian cancer MOSEC cells. These results indicate that STIP1 may be used as therapeutic target to develop antibody against it. Therefore, it is worthy developing antibody therapeutics that target STIP1. The short-term goal of this project is to apply for patents to protect the intellectual property of anti-cancer antibody therapeutics by targeting STIP1. The final goal of this project is the development of all-human, anti-STIP1 antibodies that can be tested in clinical trials of cancer treatment. In this two-year project of translational medical research, we plan to accomplish the following specific aims: 1. to develop single-chain fragment variable (scFv) and human monoclonal antibody (hMAb) against STIP1 using antibody phage display technology, 2. to test therapeutic efficacy of anti-STIP1 scFvs and hMAbs, and 3. to carry out preclinical evaluation (pharmacotoxicology, pharmacokinetics) of the anti-STIP1 scFvs and hMAbs.

Project ID:PG10209-0003
External Project ID:MOHW102-TD-PB-111-NSC106