Clinical Development of an N-cadherin Antibody to Target Cancer Stem Cells

Metastatic disease and the castration resistance remain tremendous challenges in the treatment of prostate cancer. New targeted treatments, such as the anti-testosterone medication enzalutamide, have improved the survival of men with advanced disease, but a majority develops treatment resistance. The field of cancer stem cells hypothesizes that treatment resistance emerges because stem cells are inherently resistant to our current therapies and eventually repopulate tumors. One mechanism by which cancer stem cells resist therapy is through acquisition of an epithelial to mesenchymal transition (EMT), a phenomenon of normal development used by cancers to survive and metastasize. Our laboratory has shown that prostate cancers undergo an EMT that leads to invasion, metastasis and treatment resistance. N-cadherin, a critical regulator of EMT, is expressed in most castration resistant prostate cancers (CRPC) and is sufficient to promote treatment resistance. We therefore developed antibodies against N-cadherin, which are able to inhibit growth, metastasis and progression of prostate cancers in vivo. The goal of this translational application is to move this promising treatment from the laboratory to the clinic by making the antibody human, making it bind more strongly, and then testing it for toxicity, behavior and anti-tumor activity. At the completion of this project, we will be poised to manufacture this lead molecule and move expeditiously to Phase I clinical studies. At this juncture in the project, we have made our two original lead antibodies into human ones that would not elicit an immune response in patients. We have begun to test these “humanized” antibodies and they appear to retain the properties of the mouse ones from which they were derived. We have also generated additional candidate antibody drugs through screening of a library containing millions of candidate antibodies. We have narrowed these candidates down to approximately 9, and are continuing to work to prioritize these based on activity. Finally, we have begun the process of maturing these lead candidates to bind more tightly to N-cadherin, the target, hypothesizing that this will further improve the efficacy of these drugs moving forward. Over the coming months, we will finalize selection of 2-3 lead antibodies and begin testing them in animal experiments as the next step toward realizing the goal of testing them in patients.

Metastatic disease and castration resistance remain tremendous challenges in the treatment of prostate cancer. New targeted treatments, such as the anti-testosterone medication enzalutamide, have improved the survival of men with advanced disease, but a majority develops treatment resistance. The field of cancer stem cells hypothesizes that treatment resistance emerges because stem cells are inherently resistant to our current therapies and eventually repopulate tumors. One mechanism by which cancer stem cells resist therapy is through acquisition of an epithelial to mesenchymal transition (EMT)., a phenomemon of normal development used by cancers to survive and metastasize. Our laboratory has shown that prostate cancers undergo an EMT that leads to invasion, metastasis and treatment resistance. N-cadherin, a critical regulator of EMT, is expressed in most castration resistant prostate cancers and is sufficient to promote treatment resistance. We therefore developed antibodies against N-cadherin, which are able to inhibit growth, metastasis and progression of prostate cancers. The goal of this translational application is to move this promising treatment from the lab to the clinic by making the antibody human, making it bind more strongly and then testing it for toxicity, behavior and anti-tumor activity. At the completion of the project, we will be poised to manufacture this lead molecule and move expeditiously to Phase I clinical studies. At this junction, we have made our two original lead antibodies into human ones. We have also developed a third new fully human antibody that binds to a different region of the protein. We have confirmed that the three antibodies are all active in vitro, inhibiting invasion as well as sphere formation , a key property of cancer stem cells. We have performed initial in vivo experiments demonstrating that that the human antibodies retain the anti-tumor activity of the mouse antibodies from which they were derived. We have selected a lead antibody and a backup and are n the process of creating stable cell lines to produce these antibodies for pre-clinical testing, including assessment of toxicity.