Objective
Immune therapies such as teplizumab have had efficacy on modifying the progression of Type 1 diabetes in those at risk and those with disease but this an other treatments have had limited sustained efficacy. The underlying hypothesis, that we plan to test in this proposal, is that to have lasting efficacy, the combination of an agent like teplizumab, which can modulate the pathogenic immune response acutely, followed by a more specific therapy that can target antigen specific T cells and maintain their non-responsiveness is needed. The objective of this proposal is to test the combination of anti-CD3 mAb under experimental conditions that mimic what is seen in patients at risk or with Type 1 diabetes, with nanoparticles that are coated with MHC molecules with diabetes antigenic peptides and a second ligand. The second ligand is designed to delete or render in active the diabetes antigen specific T cells.
Background Rationale
Immune therapies, such as teplizumab, have been able to modify the progression of Type 1 diabetes. However, they tend to work well in the short term and lose their efficacy over time. The reasons for the loss of efficacy are not clear. Possibilities include recovery of pathogenic T cells from a precursor compartment or loss of the activity of the immune therapy. To have lasting therapeutic efficacy, therefore, we plan to combine anti-CD3 mAb with nanoparticles that contain MHC molecules that contain peptides from diabetes antigens and a second ligand that may delete or render diabetes antigen specific T cells inactive. This type of combinatorial approach avoids the risks of long term global immune suppression.
Description of Project
Immune therapies, such as teplizumab (anti-CD3 mAb) have been able to modify the progression of beta cell loss in patients with and at risk for Type 1 diabetes. However, the effects of these treatments have not been permanent. Retreatment is an option but long term treatment with broadly suppressive immune therapies is not an option for patients. This proposal is designed to develop a combination of agents that can induce and maintain protection from Type 1 diabetes protection. It is built on mechanistic studies from clinical studies and preclinical models that have identified features of T cells that are associated with protection from disease. Our strategy combines an effective therapy to break the accelerated progression of disease followed by an antigen specific therapy that selectively modulates pathologic T cells. Specifically we plan to combine anti-CD3 mAb with nanoparticles bearing relevant MHC molecules loaded with antigenic peptides and costimulatory ligands that are recognized by pathogenic T cells in order to eliminate or silence these cells. We plan to determine the optimal design of the nanoparticles that can induce elimination or sustain exhaustion of CD8+ T cells that recognize diabetes antigens. We will test these particles in vitro and in vivo using NOD mice that are treated with suboptimal doses of anti-CD3 mAb to model the occurrence of disease in patients. We will identify when the combination of agents should optimally be given and how they change the autoimmune repertoire including those cells that are thought to be responsible for recurrent diabetes. Our studies combine the use of an agent with extensive clinical experience in Type 1 diabetes with a new modality that is already in clinical trials. If successful, this combination of agents would lead to a strategy to arrest the disease and sustain protection from disease without broad immune suppression.
Anticipated Outcome
We anticipate that the combination of anti-CD3 mAb with the appropriate nanoparticles will delete or render antigen specific T cells non-responsive. It is likely that we will need to test a number of ligands for their ability to modify T cells in vivo and the duration of their efficacy may depend on their biologic activity. We do not know whether it will be better to administer the nanoparticles before, with, or after anti-CD3 mAb but this will have importance for developing this approach for treating patients.
Relevance to T1D
Immune therapies offer the possiblity of preventing progression of Type 1 diabetes. If they do this in those at risk, the patients may not develop the clinical disease. In patients already diagnosed with T1D this may prevent the complete loss of beta cell function which has clinical benefits. To do this, however, the immune therapy needs to have lasting benefits which has been a challenge. Moreover, not all patients respond to certain immune therapies suggesting that additional ways of treatment are needed. The approach that we are developing may extend the efficacy of teplizumab which has been shown to delay progression of Type 1 diabetes in those at risk and to reduce the loss of beta cell function in those with T1D. If effective, our studies will lead to Phase I trials to test nanoparticles in patients with T1D and we anticipate combination trials to start afterwards, since we also anticipate that teplizumab will receive approval for delay or prevention of T1D. Finally, this therapy may be very effective in the setting of islet transplantation where non-responsivess may be induced not only to the islet graft but also to recurrent T1D.