Novel monobody therapy for pancreatic cancer

Novel monobody therapy for pancreatic cancer Abstract The current work is based on the hypothesis that harnessing specific basic elements of TCR CD signaling can enhance anti cancer T cell responses T cell stimulation by antigen induces a conformational change in the CD complex associated with the TCR CD c the earliest molecular event marking productive TCR CD triggering CD c is necessary but not sufficient for optimal CD signaling which additionally requires receptor cross linking As a consequence of CD c a cryptic proline rich sequence PRS in the cytoplasmic domain of CD becomes exposed to interact with adaptor proteins like Nck that contribute to CD signaling Generation of CD c only results from exposure to strong antigens but not to poorly immunogenic antigens like most tumor associated antigens TAAs We recently discovered that a monovalent Fab fragment Mono Fab that binds CD can induce CD c without inducing receptor cross linking and intrinsic signal transduction Such a Mono Fab can enhance T cell responses to weak antigens in vitro and in vivo an effect we call T cell co potentiation Mono Fabs combined with checkpoint inhibition stimulate remarkable anti tumor responses in mouse models Fabs suffer from short serum half life and production issues making them less than ideal for clinical development To address these problems we will construct a monobody form of a humanized anti CD antibody During this Phase I project we will rank order a panel of humanized anti human CD monobodies and evaluate their activity in vitro and in an animal model of pancreatic cancer both alone and in combination with anti PD In Phase II the lead construct and a back up will be further evaluated in tumor models followed by IND enabling studies to support clinical development of this novel therapeutic modality A successful outcome of this work will provide a novel cancer therapy suitable for combination with chemotherapies and other immunotherapeutic agents and likely to enhance many other approaches Narrative Pancreatic cancer is the th leading cause of US cancer deaths Current treatments are ineffective such that of patients will eventually die of their disease Most deaths occur due to the metastatic process by which cancer cells spread to distant sites in the body New therapies that activate the anti tumor potential of the immune system have shown promise in other cancers but have been associated with side effects We have identified a novel means to augment immune system activation which will avoid adverse effects and will be an improved therapy for pancreatic cancer Successful outcome of this work will provide a novel cancer therapy suitable for combination and likely to enhance many other approaches