Pancreatitis Tx: An Engineered Protein Treatment for Pancreatitis

The Problem

Pancreatitis, or inflammation of the pancreas, occurs in different forms, all of which represent an utterly unmet medical need for which no drug treatments exist that can alleviate patients’ suffering. “Acute pancreatitis” occurs after about 10% of “endoscopic retrograde cholangiopancreatography” (ERCP) operations, a surgical procedure used to address obstructions (such as gallstones) in ducts leading from the pancreas and gall bladder to the small intestine. At least 450,000 such procedures are performed in the US every year, meaning 45,000 people suffer from this complication. “Childhood pancreatitis” encompasses genetic disorders that burden at least 10,000 children and adults in the US. And finally, about 130,000 patients are suffering from “chronic pancreatitis” with often debilitating consequences on their lives.

Our Solution

We have developed the first “disease-modifying” therapy that treats the underlying cause of the disease, not just its symptoms. Common to all forms of pancreatitis is the mis-regulation and accumulation of the digestive enzyme trypsin, which then destroys normal pancreatic tissue. This not only leads to the death of precious pancreas cells, but also causes inflammation at sometimes life-threatening levels.

The Pancreatitis Tx team developed the “Fc-SPINK1” approach using an engineered protein in which two naturally occurring human protein segments are fused together, one being the SPINK1 protein, the body’s natural trypsin inhibitor, and the other the Fc portion of a human antibody molecule. This attachment increases the size of SPINK1, which prevents it from being cleared from the blood circulation by the kidney as rapidly as unmodified SPINK1, and enables it to exhibit an enhanced trypsin-inhibiting effect in the pancreas when applied as a systemic treatment. Fc-SPINK1 inhibits trypsin right where it is produced before it can wreak havoc on pancreatic tissue.

Product Journey

Research on the Fc-SPINK1 pancreatitis treatment has been led by Wyss Core Faculty member Pamela Silver and Jeffrey Way, Lecturer in the Department of Systems Biology and in the Laboratory of Systems Pharmacology at Harvard Medical School. Based on its exceptional potential for creating the first effective treatment that targets the root cause of pancreatitis with life-altering consequences for a large number of patients in desperate need, the project was recognized first in 2021 and again in 2022 as a Wyss Validation Project. Way and Silver formed a team that also included Andrea Geisz, a Research Assistant Professor at Boston University Dental School with expertise in trypsin-mediated diseases and preclinical model systems, and enlisted the help of Wyss Lead Staff Scientist Michael Super with knowledge in the scaled microbial production of engineered therapeutic proteins. More recently, Amazir Jan Bredl and Raghavan Sivaraman have joined the Pancreatitis Tx team.

The team developed a procedure to manufacture the engineered protein, and showed that therapeutic Fc-SPINK1 is effective in a mouse model of acute ERCP-like pancreatitis. Fc-SPINK1 has high selectivity for trypsin, tunable stability in blood plasma, and a desirable safety profile in vivo. As the first therapeutic application, the project currently focuses on ERCP-induced pancreatitis, where Fc-SPINK1 could simply be added in a single prophylactic dose to an infusion of fluids that commonly are administered before surgery. The second application will be for people suffering from chronic pancreatitis, which is often so painful that it cannot be controlled by opiates. The Pancreatitis Tx team is currently scaling up production of the therapeutic protein to be able to manufacture it for clinical use.

Impact

In its efforts to commercialize Fc-SPINK1 as a therapeutic and make it available to patients, the team is consulting with expert physicians including Amit Grover at Boston Children’s Hospital and receiving advice from Wyss Business Development team members Paul Resnick and Alex Li.