Evolving Antibody Therapies for the Treatment of Type 1 Diabetes

Abstract

Type 1 diabetes (T1D) is widely considered to be a T cell driven autoimmune disease resulting in reduced insulin production due to dysfunction/destruction of pancreatic β cells. Currently, there continues to be a need for immunotherapies that selectively reestablish persistent β cell-specific self-tolerance for the prevention and remission of T1D in the clinic. The utilization of monoclonal antibodies (mAb) is one strategy to target specific immune cell populations inducing autoimmune-driven pathology. Several mAb have proven to be clinically safe and exhibit varying degrees of efficacy in modulating autoimmunity, including T1D. Traditionally, mAb therapies have been used to deplete a targeted cell population regardless of antigenic specificity. However, this treatment strategy can prove detrimental resulting in the loss of acquired protective immunity. Nondepleting mAb have also been applied to modulate the function of immune effector cells. Recent studies have begun to define novel mechanisms associated with mAb-based immunotherapy that alter the function of targeted effector cell pools. These results suggest short course mAb therapies may have persistent effects for regaining and maintaining self-tolerance. Furthermore, the flexibility to manipulate mAb properties permits the development of novel strategies to target multiple antigens and/or deliver therapeutic drugs by a single mAb molecule. Here, we discuss current and potential future therapeutic mAb treatment strategies for T1D, and T cell-mediated autoimmunity.

Keywords: diabetes; immunoregulation; immunotherapy; monoclonal antibodies; self-tolerance.

Figure 1

Type 1 diabetes (T1D) pathogenesis. Cellular events associated with driving T cell-mediated T1D are depicted within the pancreatic lymph node (PLN) and pancreas. Upon initiation of β cell autoimmunity via an ill-defined event, dendritic cells (DC) migrate from the pancreas ferrying islet autoantigens into the PLN. Here, naïve β cell-specific CD4⁺ and CD8⁺ T cells are activated and differentiate into distinct Teff subsets associated with T1D progression including CD8⁺ Tc1, CD4⁺ Th1, Th17, and Tfh. Early indication of ongoing autoimmunity is marked by the detection islet-specific autoantibodies (AutoAbs). Teff traffic into the pancreas and initiate β cell damage, which gradually increases over time prompting nominal insulin production.

Figure 2

mAb therapies to ameliorate type 1 diabetes (T1D). (A, B) Monoclonal antibodies (mAb) treatments can be broadly divided into two categories: depleting mAb or nondepleting (ND)/neutralizing mAb. Some promising mAb treatments are depicted that have been used in either animal models or clinical trials to alter T1D progression. (A) Depleting mAb have been used to target T and B cells in the clinic. Transient depletion of T and B cells delays the progression of β cell autoimmunity. (B) ND mAb have been applied to neutralize cytokines to suppress the proinflammatory milieu of the pancreatic lymph node (PLN) and islets, as well as modulate the properties and activity of various immune effector cells. (C) The relationship between functional β cell mass versus islet inflammation is characterized. Over time, increased chronic islet inflammation results in decreased functional β cell mass, first detected via metabolic abnormalities, and ultimately leading to deficient insulin production, prompting clinical diagnosis of T1D. Individuals at different stages of T1D progression have treated with mAb therapies to alter T1D progression, and in turn (D) prevent diabetes onset, or (E) rescue residual β cell mass after clinical T1D diagnosis. Typically, these clinical trials have used metabolic readouts for β cell function as primary endpoints to determine therapeutic efficacy (C).