Objective
Our proposal aims to demonstrate the therapeutic approach of an innovative strategy to modulate diabetogenic T cells and benefit patients with Type 1 Diabetes.
We propose to exploit our discovery that the known immunomodulatory effect of an antagonistic antibody against the costimulatory molecule CD154 is amplified many folds by a specific anti-inflammatory cytokine. In particular, the synergism between these factors promotes the efficient conversion of pathogenic T lymphocytes into Regulatory T cells.
We have two primary objectives:
1. To characterize the suppressive capacity and stability of the Regulatory T cells generated with this novel combination strategy
2. To define the therapeutic potential of an innovative recombinant product that fuses αCD154 with the anti-inflammatory cytokine, forming a bifunctional biologic we refer to as β-Tol.
Overall, our project is designed to define the therapeutic potential of this innovative product and set the stage for more in-depth preclinical studies.
Background Rationale
Type 1 Diabetes (T1D) is an autoimmune disease where the immune system destroys insulin-producing cells in the pancreas. This destruction is primarily caused by specific immune cells, known as T cells, which attack these insulin-producing cells. The onset and progression of T1D are influenced by a mix of genetic, environmental, and immune factors, making the disease complex and challenging to manage.
Recent advancements have led to various strategies that attempt to modulate the immune system to either prevent the onset of the disease or to protect the remaining insulin-producing cells. One significant development is Teplizumab, a drug that targets T cells and has been approved by the FDA to delay T1D onset. This success has renewed interest in immunotherapies that can more effectively and safely control the immune response. However, recently developed treatments have shown limited long-term benefits, highlighting the need for more durable solutions.
One promising area of research involves regulatory T cells (Treg), which help maintain immune balance and prevent autoimmune attacks. Various methods are being explored to increase the number and effectiveness of Treg, including expanding them outside the body and reinfusing them, or using advanced technologies to create Treg that target specific autoimmune responses. However, these methods face challenges like high costs and difficulties in maintaining Treg's stability and function.
Our innovative approach aims to combine the strengths of two research areas to regulate harmful T cells while promoting protective Treg. Our strategy focuses on the CD154 and CD40 molecules, crucial in T1D's autoimmune response. Blocking the interaction between these molecules has shown promise in controlling autoimmunity. We have discovered that combining this blockade with an additional inhibitory molecule enhances the conversion of harmful T cells into protective Tregs. However, this inhibitory molecule cannot be directly used due to its potential side effects and impact on other cells.
To overcome this, we are developing a new drug: β-Tol. It combines a CD154 blocker with an altered version of the inhibitory molecule into a single, targeted therapy. This combination aims to deliver the inhibitory molecule where it's needed, reducing harmful side effects, while also improving effectiveness of the two components. Our research will focus on understanding and optimizing how β-Tol influences immune cells, assessing its stability, and optimizing its design for future clinical use.
β-Tol represents a significant advancement in treating autoimmune diseases like T1D by providing a more targeted, effective, and safer approach. Our studies will pave the way for its clinical translation, offering new hope for managing T1D and potentially other autoimmune conditions.
Description of Project
Type 1 diabetes remains an incurable autoimmune disease that affects millions of people worldwide. It is caused by the immune system’s erroneous attack of the insulin-producing cells in the pancreas. Recent advancements in our understanding of the disease have renewed hope of developing effective treatments. Unfortunately, clinical trials have shown that many new interventions have therapeutic benefits that are limited in their duration. Thus, there is a great need for improved strategies that can safely correct the immune system's malfunction.
Our proposed research focuses on a promising new biologic we refer to as β-Tol. It is a recombinant protein that we believe can act to prevent the immune system from attacking the pancreas by enhancing the body's natural tolerance mechanisms. The core of our approach involves two key components: the blockade of a signaling mechanism that is key for the activation of autoreactive lymphocytes (the CD154/CD40 pathway) and the use of an inhibitory cytokine.
The CD154/CD40 pathway plays a crucial role in activating immune responses that lead to the destruction of pancreatic cells. By blocking this pathway, we can prevent the activation of harmful immune cells. On the other hand, the specific inhibitory cytokine helps to control these immune cells while also turning them into cells that can actively protect the pancreas. However, directly administering this inhibitory cytokine can cause severe side effects due to its widespread action in the body.
To overcome this challenge, we have designed β-Tol, a bifunctional biologic that combines an anti-CD154 antibody with the inhibitory cytokine in a single molecule. This innovative approach ensures that the inhibitory cytokine is delivered specifically to the harmful immune cells, minimizing side effects, while also benefitting from CD154 blockade to enhance the conversion of these cells into protective regulatory cells. The development of β-Tol is possible due to our ongoing collaboration with Dr. Steven Almo’s lab, which specializes in designing multi-functional fusion proteins with highly selective immune modulatory functions.
We aim to further explore the therapeutic properties of the regulatory cells that are induced by the combination of blocking CD154 while additionally providing the inhibitory cytokine. We will use this novel information to provide a benchmark for evaluating the therapeutic efficacy of β-Tol and guide subsequent optimization. Our ultimate goal is to create a safe, effective, and readily translatable treatment for type 1 diabetes that can halt disease progression and restore normal insulin production in patients.
The potential impact of β-Tol is significant, offering a novel approach that promises to be more effective than current treatments and which could represent a valuable alternative to cell-based therapeutic strategies. Our research represents a major step forward in the quest for a cure for type 1 diabetes, and we are committed to translating this innovative therapy from the lab to the clinic.
Anticipated Outcome
We are excited about the potential of our innovative therapeutic approach, β-Tol, to improve treatment for type 1 diabetes. By harnessing the synergy between a key inhibitory cytokine and the blockade of CD154, β-Tol is expected to be more effective than current methods that focus solely on blocking the CD154/40 pathway by creating a lasting change in the balance between the good and bad activities of the immune system. This is a crucial step towards successful clinical applications for type 1 diabetes.
Typically, the beneficial effects of the inhibitory cytokine we use are compromised due to toxicity or inefficacy, which arises from interactions with multiple cell types (unwanted targets) and rapid degradation. Our strategy fuses a protein that blocks CD154 with the inhibitory cytokine, a solution we anticipate will direct the cytokine specifically to T lymphocytes that express CD154, thus enhancing targeting precision and minimizing side effects. With confirmation of the anticipated effect, this approach will streamline the regulatory approval and clinical testing processes since it involves a single molecule.
We also anticipate that β-Tol will offer a dual benefit: unlike methods that aim to reduce autoreactivity by neutralizing the function of harmful cells, our proposed strategy aims to also convert the same harmful cells into regulatory ones that can actively manage the disease. Achieving induction of protective cells in the patient is highly desirable, as it could replace the current expensive and complex therapies that rely on isolating, manipulating, and expanding regulatory cells outside the body.
Moreover, unlike other inhibitory treatments that function at the cost of negatively impacting regulatory cells of the immune system, targeting CD154 has been shown to enhance the modulatory abilities of such cells. We anticipate that β-Tol will offer a stronger and more effective modulation of the immune response compared to said inhibitory strategies.
In summary, our work on β-Tol represents a promising advancement in immunotherapy, with the potential to provide a more effective and streamlined treatment for autoimmune diseases by selectively targeting and modulating the immune system.
Relevance to T1D
Type 1 Diabetes (T1D) is a serious autoimmune disease where the immune system mistakenly attacks and destroys insulin-producing cells in the pancreas. This destruction leads to a lifetime dependence on insulin therapy and constant monitoring of blood sugar levels. Despite advances in treatment, T1D remains incurable and affects millions of people worldwide.
Our proposed project focuses on developing an innovative therapy to address the underlying immune dysfunction in T1D. Current treatments aim to modulate the immune response to protect the insulin-producing cells, but they often provide only temporary benefits. A more durable and targeted approach is needed to effectively manage T1D.
One promising avenue is enhancing the function of regulatory T cells (Treg), which help maintain immune balance and prevent autoimmune attacks. In T1D, the ability of Treg to control harmful cells is somewhat compromised. Various strategies have been explored to restore a proper balance, including expanding Treg outside the body and reinfusing them, or using advanced technologies to create Treg that target specific autoimmune responses. However, these methods face significant challenges, such as high costs and difficulties in ensuring Treg's stability and long-term effectiveness.
Our project proposes a novel strategy that combines the best aspects of existing research to regulate harmful immune cells while promoting protective Treg. We focus on blocking the interaction between two molecules, CD154 and CD40, which play a crucial role in T1D's autoimmune response. Blocking these molecules has shown promise in controlling the activation of harmful cells, but our approach goes a step further by combining this blockade with an additional inhibitory molecule. This additional factor enhances the conversion of harmful immune cells into protective Treg. Unfortunately, its use as a drug is limited by potential side effects.
To overcome this challenge, we are developing a novel product, β-Tol. It fuses a CD154 blocker with variants of the inhibitory molecule into a single, targeted therapy. This combination aims to deliver the inhibitory factor precisely to the harmful immune cells, reducing side effects. Importantly, our preliminary results indicate that this combination offers an additional benefit: the conversion of the same harmful cells into Treg that can actively protect insulin-producing cells in the pancreas. This additional benefit will translate into improving treatment effectiveness. Our research will focus on understanding how β-Tol influences immune cells, assessing its stability, and optimizing its design for future clinical use.
By developing β-Tol, we aim to provide a more targeted, effective, and safer approach to treating T1D. This innovative therapy has the potential to significantly improve the management of T1D, offering new hope for millions of individuals affected by this challenging disease. Our project represents a critical step toward achieving long-term immune regulation and better health outcomes for people with T1D.