Abstract 1446: Effect of PF-03475952, a potent and neutralizing CD44 antibody, on cancer cell apoptosis in vitro and metastasis in two orthotopic models

Effect of PF-03475952, a potent and neutralizing CD44 antibody, on cancer cell apoptosis in vitro and metastasis in two orthotopic models Yuli Wang, Jean wang, Gary Li, Amy Jackson-Fisher, Brett Simmons, Eugenia Kraynov, Christy Ji, Baiyong Li, and David Pocalyko Pfizer Global Research & Development, San Diego, CA 92121 CD44 is a cell surface glycoprotein that has multiple functions. It can act as a receptor for ligands such as hyaluronic acid and osteopontin. Additionally, it can function as co-receptor to modulate the activation of growth factor receptors such as c-met & ERBB. CD44 can also influence cell signaling through interaction with components of the actin cytoskeleton such as the ERM protein. CD44 expression is increased in many types of human cancer. It is also a cell surface marker for cancer stem cells in breast cancer and HCC. In HCC, CD44 overexpression is a frequent event (∼30% based on several reports) and CD44 up regulation is associated with metastasis and poor patient survival. Down regulation of CD44 with RNAi knockdown or neutralizing antibody has been reported to reduce tumor metastasis, recurrence, and growth in different models. PF-03475952 is a fully human IgG2 anti-CD44 monoclonal antibody that was initially developed as a potential therapeutic agent for rheumatoid arthritis. It was shown previously that the PF-03475952 can disrupt the interaction of CD44 with its ligand, hyaluronic acid. The antibody binding induces loss of CD44 from the cell surface, and inhibits LPS-induced cytokine release from various leukocytes. In this report, we evaluated the potential of PF-03475952 as a cancer adjuvant therapy for HCC. HCC is the third most deadly forms of cancer world-wide with frequent early recurrence due to inter and extra hepatic metastasis. The effect of PF-03475952 on cancer metastasis was first demonstrated in an M24met melanoma model. The expression of CD44 and the effects of PF-03475952 on HCC cell lines were then characterized. In vitro, PF-03475952 was able to reduce cell adhesion and promote apoptosis in a CD44-dependent manner. More importantly, PF-03475952 can reduce lung metastasis in a CD44-positive HCC orthotopic model. The study suggested that the CD44 neutralizing antibody, PF-03475952, could be an efficacious agent as adjuvant therapy to prevent cancer metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1446.