Identifying Promising Immunomodulators for Type 1 Diabetes (T1D) and Islet Transplantation

Abstract

Type 1 diabetes (T1D) is an autoimmune chronic disorder that damages beta cells in the pancreatic islets of Langerhans and results in hyperglycemia due to the loss of insulin. Exogenous insulin therapy can save lives but does not stop disease progression. Thus, an effective therapy may require beta cell restoration and suppression of the autoimmune response. However, currently, there are no treatment options available that can reverse T1D. Within the National Clinical Trial (NCT) database, a majority of over 3000 trials to treat T1D are devoted to insulin therapy. This review focuses on noninsulin pharmacological therapies, specifically immunomodulators. Many investigational new drugs fall under this category, such as the recently FDA-approved CD3 monoclonal antibody teplizumab to delay the onset of T1D. In total, we identified 39 different immunomodulatory investigational drugs. FDA-approved teplizumab for Stage 2 T1D is discussed along with other immunomodulators that have been tested in Phase 3 clinical trials or higher, including otelixizumab (another anti-CD3 monoclonal antibody), daclizumab (an anti-CD25 monoclonal antibody), ladarixin (CXCR1/2 inhibitor), and antithymocyte globulin (ATG). Immunomodulators also play roles in islet transplantation and cellular therapies like FDA-approved Lantidra. Several immunomodulators involved in Phase 3 clinical studies of islet transplantation are also discussed, including alemtuzumab, basiliximab, etanercept, and reparixin, some already FDA-approved for other uses. These include alemtuzumab, basiliximab, etanercept, and reparixin, some of which have been FDA-approved for other uses. This review provides background, mechanism of action, results of completed trials, and adverse effects as well as details regarding ongoing clinical trials for each of these immunomodulators. Trial Registration: ClinicalTrials.gov identifier: NCT03875729, NCT01030861, NCT00129259, NCT00385697, NCT01280682; NCT03929601, NCT04598893, NCT05757713, NCT00678886, NCT01123083, NCT00064714, NCT00468117, NCT04628481, NCT01106157, NCT02215200, NCT00331162, NCT00679042, NCT01220856, NCT01817959.

Keywords: Type 1 diabetes; autoimmune; immunomodulators; pancreatic beta cell.

Figure 1

Methodology for choosing clinical trials focused on immunomodulators. Using the search term “Type 1 Diabetes Mellitus” as a disease/condition, 3250 clinical trials were identified and subdivided into categories (shown as separate boxes) based on the type of therapeutic intervention: insulin-based therapy (1755 trials), Type 2 diabetes medications (204 trials), other drugs (19 trials related to four unique drugs with potentially direct effects on beta cells that were highlighted in another review (⁣^∗ Source: Ajmal et al. [7])), and immunomodulators (151 trials). Among immunomodulators, only 11 drugs reached Phase 3 or higher in clinical trials related to Type 1 diabetes or organ/islet transplantation (18 trials). One of these 11 immunomodulatory drugs, rituximab, qualified for Phase 3 status, but all trials were either terminated or have not reported any data (NCT01280682; NCT03929601). The remaining 10 drugs formed the focus of this review. Another 1121 trials were listed as “nondrug therapies” because they did not fit into any category but focused on glucose monitoring systems, dietary or educational interventions, behavioral modifications, or other nondrug-based therapeutic interventions (created with Biorender.com).

Figure 2

Graphical representation of the pathogenesis of T1D by immune response and how immunomodulators are involved in the prevention of T cell immune response. This immune response occurs by macrophages and natural killer cells that activate and produce proinflammatory cytokines and trigger insulitis. B cells also contribute to the pathogenesis of T1D and act as antigen-presenting cells (APCs) for antigens. B cells present antigens to autoreactive T cells and mediate pancreatic cell cytotoxicity by major histocompatibility complex. Immunomodulators like daclizumab, teplizumab, otelixizumab, ATG, and ladarixin modulate T cells and natural killer cells and prevent pancreatic beta cell immune response and apoptosis (created with Biorender.com).

Figure 3

A graphical representation of basic steps involved in islet transplantation along with immunosuppressive therapy to help eliminate islet transplantation rejection, graft loss, cell toxicity, and cell death. Pancreatic islets from healthy donors are transplanted into T1D recipients, and a regimen of immunosuppressive drugs is recommended that prevents graft loss and transplantation rejection. Immunomodulators such as etanercept, basiliximab, reparixin, and alemtuzumab are some of the most common drugs that target TNF-alpha, IL-2, CD52+, and CXCL8 receptors, respectively (created with Biorender.com).