Abstract
Abstract C4.4a (LYPD3) is a GPI-anchored cell surface protein with unknown physiological function, although it has been speculated that it might play a role in tumor invasion and metastasis formation. In addition, over-expression of C4.4a correlates with a malignant phenotype and poor prognosis in several cancer indications. As a result of comprehensive gene expression profiling, we report that the C4.4a transcript is being significantly up-regulated in human non-small cell lung cancer (NSCLC) as well as in other tumors compared to the respective normal tissue. This finding was confirmed in IHC studies showing strong C4.4a protein expression on the surface of tumor cells particularly in lung squamous cell carcinoma. Interestingly, a high incidence of C4.4a protein expression was found in a number of additional cancers such as stomach, bladder, colorectal, ovarian, prostate, hepatocellular as well as SCC of the head and neck. In marked contrast to tumors, C4.4a expression in normal tissues is restricted to esophagus, cervix and the outer epithelial layer of skin (stratum spinosum and stratum granulosum). Employing FACS and IHC analyses, several model systems were identified expressing C4.4a in vitro and in vivo. Subsequently, Mab-Zap assays were used to demonstrate efficient internalization of C4.4a in endogenously expressing cells as well as in cells transfected to over-express C4.4a. In summary, the observed strong over-expression of C4.4a in tumors, its very limited expression in normal tissue as well as its ability to rapidly internalize make it a promising target for the generation of antibody-drug conjugates for the treatment of several cancer indications, in particular lung squamous cell carcinoma. Citation Format: Gabriele Leder, Yong-Jiang Cao, Lars Linden, Sven Golfier, Oliver von Ahsen, Claudia Schneider, Joerg Willuda, Kirk McLean, Hans-Dieter Pohlenz, Bertolt Kreft, Karl Ziegelbauer. Target validation of C4.4a (LYPD3) as a target for antibody-drug conjugates for the treatment of squamous cell carcinoma of different origin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-206. doi:10.1158/1538-7445.AM2013-LB-206
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