Bispecific T cell engagers for the treatment of pancreatic ductal adenocarcinoma

---Project Summary/Abstract ---- Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer. Poor survival rates are largely due to the late stage at which PDAC is diagnosed and a lack of effective therapies. The long-term goal of this research program is to discover new immunotherapeutic approaches for the treatment of PDAC. Preliminary studies by our group and others have shown that the Anterior Gradient-2 (AGR2) protein, a member of the protein disulfide isomerase (PDI) family, is induced during PDAC oncogenesis and highly expressed in andgt;90% of PDAC patients. AGR2 has intracellular oxidative folding function and is also released from the cell where it localizes to the surface of PDAC cells and is shed into the tumor microenvironment. We hypothesize that AGR2 is an actionable target for the development of PDAC targeted immunotherapies and will test that theory using a new immunotherapy drug candidate. In preliminary studies we generated a proprietary anti-AGR2 single chain antibody fragment (scFv) by phage display screening and constructed a bispecific T-cell engager (BiTE) that binds to AGR2 and CD3, which is a subunit of the T cell receptor complex. We found that BiTE engagement stimulates T cell receptor signaling, T cell activation/proliferation, and T cell induced killing of AGR2-positive PDAC cells in cellular models. The specific objectives of this study are: (1) to improve the AGR2 binding affinity of our scFv via affinity maturation, and (2) to demonstrate high potency T cell dependent killing of PDAC cells by an optimized BiTE molecule in vitro and in genetically engineered mouse models (GEMMs) of PDAC. These aims are built on clear rationale from the existing literature and strong preliminary data. This work is innovative because we will investigate the activity and mechanism of a new immunotherapy drug candidate for the treatment of PDAC, which is a cancer in need of new therapies. In addition we expect that this study will reveal new methods and mechanisms for generating an anti-tumor immune response in PDAC, for which existing immunotherapies have thus far been ineffective.Narrative (Relevance)) ---------------------------- Pancreatic cancer is one of the deadliest cancers and effective therapies are lacking. We have developed an immunotherapy approach to target the Anterior Gradient-2 (AGR2) protein, which is highly expressed in pancreatic tumors. Our strategy relies on a Bispecific T-cell Engager (BiTE) that activates immune cells in pancreatic tumors and causes an anti-tumor immune response. We anticipate that these studies will reveal new ways of treating pancreatic cancer in preclinical models of cancer, setting the stage for clinical development and the delivery of a new treatment regimen to patients in need.