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.

TCR-like antibodies targeting autoantigen-mhc complexes: a mini-review

“…Although depletion of pathology-driving cells, as in cancer therapy, is a therapeutic option in autoimmunity, TCRL mAb therapy typically aims to reestablish healthy immune balance among cells like CD4+ T eff and T reg cells by non-depleting mechanisms ( Figure 1 ). Here, we propose a few options for future TCRL autoimmune therapeutics, based on advances in TCRL mAb cancer therapies ( 30 , 31 ) and Ab therapies for autoimmune diseases ( 19 , 88 ).…”

“…Antibody treatment can induce target cell apoptosis ( 89 ) or (via Ab Fc region) lead to antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC) ( 88 , 90 ) ( Figures 1A, B ). For example, anti-CD20 mAbs, FDA-approved for RA and primary progressive MS ( 91 , 92 ), appear to work by depletion of CD20+ B cells, including those that present autoantigen to T cells and give rise to autoantibody-producing plasma cells.…”

“…For example, anti-CD20 mAbs, FDA-approved for RA and primary progressive MS ( 91 , 92 ), appear to work by depletion of CD20+ B cells, including those that present autoantigen to T cells and give rise to autoantibody-producing plasma cells. However, unclear long-term benefits and side effects (e.g., lack of vaccine Ab response) of broad B cell elimination are concerns ( 88 ). Alternatively, one may consider engineering a bispecific Ab (BsAb), coupling specificity of anti-CD20 and anti-autoantigen p/MHC for targeted depletion of pathology-related B cells ( Figure 1C ).…”

“…Additionally, autoimmune modulators conjugated to or coupled with TCRL mAbs could facilitate modulator delivery to autoantigen-MHC-II-enriched sites of disease. Such modulators include toxins ( Figure 1D ), immunoregulatory cytokines, and antibodies that neutralize effector molecules or regulate effector cell activity ( 88 ). Cytokines like IL-10 and TGF-β that induce tolerogenic DC ( 95 ) with therapeutic efficacy ( 84 ) might reestablish tolerance at sites harboring auto-APCs ( Figure 1E ).…”

Historical and new insights into pathogenesis of type 1 diabetes (2)

“…We are in an era where immunotherapeutic approaches are being hotly pursued. While several biologicals have been trialled in human type 1 diabetes, recently discussed by Ke and colleagues [7], there have been few immunological interventions that have had a lasting effect when administered after diabetes onset. Most recently, anti‐CD3 (teplizumab) presents exciting promise – when administered in autoantibody‐positive individuals, the onset of overt type 1 diabetes has been delayed [8].…”