Novel targeted therapeutic for advanced metastatic disease

Novel targeted therapeutic for advanced metastatic disease Abstract Despite improved targeted therapies lung cancer remains the leading cause of cancer related mortality worldwide The five year survival rate for advanced stage lung cancer is less than largely due to metastasis to the CNS Around of patients diagnosed with either small cell lung cancer SCLC or non small cell lung cancer NSCLC will develop metastatic brain lesions Therapeutics that specifically target the metastatic process are needed The role of K channels in tumorigenesis has been recognized for over a decade In particular the two pore domain channel KCNK exerts a tumorigenic and pro metastatic effect in several models Furthermore KCNK is over expressed from to andgt fold in of breast and of lung tumors In xenograft models tumor cells over expressing KCNK are typically aggressive In the xenograft model a dominant negative mutant of KCNK abolishes its K channel activity and abrogates its oncogenic function without any effect on normal cell growth These data support the hypothesis that KCNK promotes tumor growth and may be a therapeutic target in KCNK expressing malignancies Despite these data suggesting the potential for therapeutics directed against KCNK a lack of specific reagents has hindered both research and preclinical studies We have identified a monoclonal antibody to the extracellular loop domain of KCNK and have demonstrated its high specificity and high affinity for the KCNK channel This mAb inhibits the proliferation and viability of KCNK cancer cell lines in vitro Most importantly for the present work monoclonal antibodies to KCNK potently inhibited the initiation growth and metastatic spread of tumors in human xenograft and syngeneic mouse models These observations instruct the overall goal of this project to develop a monoclonal antibody therapy targeting tumors expressing KCNK In Phase I we will generate a humanized and Fc enhanced form of murine anti KCNK mAb Y We will evaluate binding specificity in vitro functional activity and in vivo anti tumor activity of huY This innovative therapeutic humAb will be the safest and most effective treatment for KCNK tumors with particular application to advanced stage lung cancer and breast cancer Demonstration of a humAb with a nanomolar Kd high specificity for KCNK and in vivo anti tumor activity will merit submission of a Phase II application Phase II work will focus on obtaining the preclinical data necessary for submission of an IND Initial CMC work pharmacokinetics and toxicology as well as expanded animal studies will be performed Narrative Despite improved targeted therapies cancer remains an intractable health problem Most deaths occur due to the metastatic process by which cancer cells spread to distant sites in the body A potassium ion channel KCNK has been reported to be a factor in tumor growth and metastasis We have identified the first monoclonal antibody specific to KCNK and have demonstrated activity in cell culture and in animal models of human cancer We will develop a humanized version of this antibody and evaluate its potential as a therapeutic for cancer