Objective
Development of a successful curative therapy of type 1 diabetes (T1D) is the ultimate goal of all research activities in the T1D research field. Until now insulin therapy is the only available treatment for patients with T1D. Recently however, research has opened realistic perspectives to establish successful therapies with curative potential, especially when treatment of T1D is started before loss of most of the insulin-producing cells. In this phase of the disease process it is not only possible to stop the aggressive autoimmune destruction of the beta cells mediated through the infiltrating immune cells in the pancreas. Along with this therapeutic restitution of the pancreatic beta cell mass it is possible to fully restore the functional insulin secreting capacity of the beta cells in the islets.
There are two signaling molecules, which have been identified during recent years in the affected pancreatic islets and which have been shown to be the crucial mediators of the dysfunction of the insulin-producing cells. These are the proinflammatory cytokines TNF-alpha and IL-1beta. They are released from the aggressive immune cells, which invade the islets in the pancreas during the disease process and destroy the insulin-producing beta cells. Therefore, combination therapies with antibodies against these two cytokines are highly promising.
The selected antibodies against the two cytokines interact with the cytotoxic disease mediators, when released from the immune cells in the pancreas of the patients with T1D. The result is an inactivation of these proteins, so that they can no longer act as toxins on the insulin-producing beta cells. In a combination therapy with the T cell antibody anti-CD3, which is an indispensable basic component of this antibody combination therapy the destruction of the beta cells is ultimately prevented.
For the study of therapies with curative potential we will use the LEW.1AR1-iddm rat (short name: IDDM rat) model, which is the rat model of human T1D most closely resembling the situation in human T1D. Results obtained in this T1D model are highly reliable and therefore allow the selection of the best antibody based combinations, which can be transferred to the patients with T1D. We envisage that such a translation will be possible without delay since the antibody therapeutics, which we intend to use, are all already approved by the FDA for the treatment of patients with different autoimmune diseases. They have been shown to be safe and without significant side effects, also in the treatment of children and adults. In terms of the therapeutic regimens, we can follow the dosage schemes of the other autoimmune diseases.
Background Rationale
There is general consensus in the scientific community that combination therapies are required in order to achieve this goal since monotherapies have been unable to reach the target of a cure of the disease. Since there is so far no therapy with curative potential available for patients with T1D, it is our aim to open a realistic perspective for such an option by establishing combination treatments with therapeutic antibodies, which efficiently block the beta cell destructive disease process. This therapy will allow a regeneration of the beta cells to a point that sufficient beta cells are available again for insulin production and supply to the organism. It will restore a healthy metabolic state without any symptoms of diabetes.
From previous experiments in our IDDM rat model of human T1D we could already identify one combination of therapeutic antibodies (namely an antibody directed against the cytotoxic proinflammatory cytokine TNF-alpha) plus the immunomodulatory antibody anti-TCR (equivalent to anti-CD3 in humans), which shifts the immune cell repertoire towards a protective antiinflammatory profile. We are highly confident to reach through such a combination therapy our ultimate therapy goal, namely an instantaneous blockage of the beta cell destruction autoimmune process through inactivation of the toxic immune mediators. This will preserve the residual beta cell mass, allowing regeneration of the insulin-producing cells to the point of a return to a normal beta cell mass in the pancreas without any signs of autoimmunity. Based on experiences from previous studies in the IDDM rat and the analyses of the underlying mechanisms now pending, we are highly confident that through such a therapeutic approach we can prevent a relapse of the disease and thereby achieve a long-term curative effect in the treatment of patients with T1D.
Since all three antibodies have already been applied to humans, without observing serious side effects in the dosages to be used, we are confident that the translation to the patients can be executed quickly and without delay.
The studies on the pancreas organs of the IDDM rat model of human T1D with therapeutic antibodies, as they are planned in this proposal, cannot be performed in a study with patients. But the great similarity of this animal model to the human T1D situation makes the successful translation to the patients with T1D possible.
Description of Project
Type 1 diabetes (T1D) is an autoimmune disease for which there is no therapy with curative potential available so far. However, research during recent years has raised hope, so that there is now a realistic option to establish such therapies for children and young adults with T1D. A crucial turning point in this context has been the approval of a novel T cell antibody (teplizumab) for the therapy by the FDA on November 17, 2022. This newly approved so-called anti-CD3 antibody is able to delay T1D manifestation by 25 months in islet-autoantibody positive stage 2 children and young adults. The availability of this anti-CD3 antibody is undoubtedly a huge progress, as it is the first antibody therapy, which has a disease-modifying potential. However, disease manifestation could not be prevented ultimately with this monotherapy. This is in agreement with our published observation in our IDDM rat model of human T1D, in which we could show that the islet infiltration by activated immune cells could not be abolished by monotherapy. This allows the conclusion, that a monotherapy may delay the T1D manifestation, but ultimately exhibits no curative therapeutic potential.
Many experts therefore agree that a combination therapy with sustained curative potential is required. We have established such a combination therapy in the IDDM rat, an autoimmune T1D rat model that is closest in its features to human T1D. In this animal model we can find out with our sophisticated methodologies how to eradicate the beta cell destructive immune cell infiltration in the affected pancreatic islets. Our crucial therapy aim is to obtain again a pancreas with islets that are free of beta cell destroying immune cells. For this purpose, these toxic immune cells must be removed, because they produce and release so-called beta cell toxic cytokines. Only through this approach, we can normalize insulin production and restore normal blood glucose values again.
From our experiments, we know that the T cell antibody, called anti-CD3 in human and anti-TCR in the rat is an indispensable component in each successful therapy combination with curative potential. In addition, however, a 2nd component is required in a successful combination therapy, namely an antibody, which acts through neutralization of the toxic cytokines. In our studies, we could find out that the most effective combination is that of an anti-CD3 antibody plus an anti-TNF-alpha antibody (TNF-alpha = Tumor Necrosis Factor alpha), which restores an immune cell infiltration-free pancreas and normal blood glucose values. This is not surprising, since TNF-alpha is the most toxic cytokine responsible for beta cell destruction in the T1D disease process. Antibodies against other proinflammatory cytokines were not so effective. But in addition, we found out that a triple therapeutic antibody combination, in which an anti-IL-1beta antibody (IL-1beta = Interleukin-1beta) was included additionally as a 3rd antibody is an attractive therapeutic combination; in particular for treatment of T1D patients, where the beta cell mass reduction is already progressed. Treating with this triple combination, we made an amazing observation. This was the only combination therapy, which in our hands fully restored the ultrastructure of the pancreatic islets along with the normalization of the metabolic state. So we can offer through these different schemes a therapeutic option both for stage 2 multiple antibody positive individuals as well as for stage 3 patients in the weeks (4-6) immediately after diabetes manifestation (with serum C-peptide values of around 80 % of normal) and even in the months (4-6) thereafter (with serum C-peptide values of around 50-30 %). We have selected these two combination therapies for our further studies, because they exhibit the most pronounced long-term curative potential.
Anticipated Outcome
The aim of this project proposal is to understand the underlying mechanisms of the different combination therapies. We will identify the best antibody based combination therapies that are optimally effective with respect to a reversal of the autoimmune disease process and the diabetic metabolic state.
This can be a combination of two antibodies for the treatment of patients in stage 2 and early stage 3 of T1D (anti-CD3 antibody plus an anti-TNF-alpha antibody) but also in a combination of three antibodies in stage 3 with progressive beta cell loss (with the 3rd antibody in addition, namely anti-IL-1beta).
These best combinations identified in our preclinical rat model of human T1D through our planned sophisticated RNAseq studies will be made available for an immediate transferal to the patient with T1D. The results obtained with these novel technologies will make it possible, to overcome skepticism, which initially always accompanies the introduction of new therapies. We will design in a final step a treatment schedule (which will address also the individual situation of the patient dependent of the stage of the disease) with respect to dosage and drug administration, which is optimally suited for a comfortable treatment of the patients, in particular in view of the fact that many of them are children and young adults.
Relevance to T1D
The whole project proposal is exclusively targeted to the establishment of T1D therapies with curative potential, which show a sustained treatment success, allowing the individual with diabetes to return to a normal health status without any signs of a diabetic metabolic derangement. This sustained treatment success should not only prevent the development of any kind of diabetic late complications, but also allow the person to lead a normal life without any restrictions such as measurements of blood glucose levels and life-long insulin injections.