Objective
Previous nonclinical studies examining the potential for local immunomodulation to eliminate the need for chronic immunosuppression following alloislets transplantation were all done with a rat sequence of the immunomodulatory protein. In order to identify an appropriate candidate for first in human studies, a new immunomodulatory protein made from humanized versions of the active peptide sequences is being developed. The objective of these studies is to test this humanized version of the immunomodulatory protein for efficacy and safety. The new humanized protein will be tested both in vitro and in vivo and compared with the rat version of the protein in terms of its ability to control immune cell response and proliferation, as well as its ability to return diabetic animals to glycemic control. Additionally, the safety and toxicology profiles of the rat vs. the humanized version of the protein will be examined. The outcome of these studies will form the basis of our first in human clinical trials for iTOL-101.
Background Rationale
A subpopulation of people living with Type 1 Diabetes (T1D) experiences significant inability to control their blood sugar levels even with the use of recombinant human insulin, a condition known as “glycemic instability”. In people with such poorly-controlled (or “brittle”) T1D, unexpected changes in blood sugar levels can occur which can quickly swing between blood sugar levels which are too high (hyperglycemia) and then suddenly too low (hypoglycemia). Long-term problems associated with having hyperglycemia in T1D include microvascular disease and the development of retinopathy, neuropathy, and nephropathy, all of which can lead to other serious clinical conditions (e.g. blindness, autonomic dysfunction, kidney failure, amputations) while the risk for severe hypoglycemic episodes can result in sudden and unexpected seizures, coma, heart attacks, and even death. For these reasons, it is important to find a treatment which allows patients to regain control over their blood sugar levels. Transplanting pancreatic islets has been developed as a treatment for brittle T1D but requires patients to suppress their immune systems medically in order to protect the transplant from rejection. This presents significant medical risks patients which must be balanced against the benefits of glycemic control. Many T1D patients would not be eligible for islet transplantation due to the risks associated with lifelong immunosuppression therefore finding a true cure for T1D would need to eliminate the need for immunosuppression. iTolerance’s technology, iTOL-100, is a chimeric fusion protein on a microgel. The combination with donor pancreatic islets prior to transplantation results in the final product (ITOL-101) that is then implanted onto the omentum. The chimeric fusion protein hides the graft from the recipient’s immune system by killing off the immune cells that would normally attack it. A short term treatment with the tolerance permissive immunosuppressant rapamycin is also given which aids in this “blinding” of the immune system but is rapidly withdrawn. In animal studies grafts have been shown to survive for months without the need for immunosuppression, while restoring glycemic control in the recipient animals. This treatment has the potential to be a true cure for T1D, allowing for a successful cell therapy without the risks associated with life-long immunosuppression.
Description of Project
Type 1 Diabetes Mellitus (T1D) is a serious autoimmune disease in which a patient’s own immune cells attack and kill the insulin producing beta cells within the pancreatic islets, leading to a loss of insulin production and an inability to effectively control a patient’s blood sugar. Without exogenous insulin treatments T1D would be fatal. Islet transplantation has been developed for severe or “brittle” T1D where exogenous insulin treatments are not effective. However, islet transplantation currently requires concurrent life-long recipient immunosuppression which severely limits the large scale applicability the procedure, as the risks of chronic immunosuppression must be balanced against the benefit of better glycemic control. iTolerance has in-licensed a biotechnology comprising a chimeric fusion protein, iTOL-101, which combines an immunomodulatory fusion protein implanted with pancreatic islets into the greater omentum. When tested in diabetic animals treated with a short course of rapamycin immunosuppression (15 days in rodents and 15 days followed by tapering and discontinuation within 90 days in Non-Human Primates), this treatment led to long-term function of the transplanted islets with recovery of glycemic control and in the absence of any further immunosuppression. This treatment could effectively eliminate the need for exogenous insulin for patients with T1D without the risks and side-effects associated with life-long immunosuppression.
Anticipated Outcome
Initial studies to determine if the chimeric fusion protein mixed with pancreatic islets could effectively treat Type 1 Diabetes were done with a rat version of the chimeric fusion protein. While the rat protein and the human protein are very similar (they have very high homology), they are not identical. For human subjects, the use of a human protein would be more appropriate. Therefore, the studies proposed in this grant application are designed to determine if the humanized version of the chimeric fusion protein, which would be the appropriate clinical candidate protein, retains the activity and safety that was seen in early animal studies. The new humanized version of the protein has been made under the strict FDA good manufacturing guidelines and will be tested both in vitro and in vivo (mouse model). We anticipate that in the in vitro model, the humanized version of the chimeric fusion protein will exhibit the same ability to kill immune cells as was previously seen with the rat version of the protein. In the diabetic mouse model we will transplant the humanized chimeric fusion protein with pancreatic islets into the epidydimal fat pad, a site which mimics the greater omentum in larger animals, and anticipate that the animals will regain glycemic control. We base this belief on previous studies where we showed that co-transplantation of the rat chimeric fusion protein with pancreatic islets was able to reverse diabetes and normalize glycemic control in recipient mice.
Relevance to T1D
At present patients with poorly controlled or “brittle” T1D can be considered for pancreatic islet transplantation but the benefits of the procedure and its ability to return them to glycemic control must be balanced against the potential dangers of lifelong immunosuppression. This project is directly relevant to Type 1 Diabetes (T1D) as it looks to test a potential cure for the disease that will allow patients to receive deceased donor pancreatic islets that allow them to return to glycemic control but due to the chimeric fusion protein included, the procedure could be done without the need for lifelong immunosuppression. This would increase the number of patients that could be cured using pancreatic islet transplants which would now only be limited by the number of donor pancreases available.