Preexisting Autoantibodies Predict Efficacy of Oral Insulin to Cure Autoimmune Diabetes in Combination With Anti-CD3

Abstract

We have previously developed a combination therapy (CT) using anti-CD3 monoclonal antibodies together with islet-(auto)antigen immunizations that can more efficiently reverse type 1 diabetes (T1D) than either entity alone. However, clinical translation of antigen-specific therapies in general is hampered by the lack of biomarkers that could be used to optimize the modalities of antigen delivery and to predict responders from nonresponders. To support the rapid identification of candidate biomarkers, we systematically evaluated multiple variables in a mathematical disease model. The in silico predictions were validated by subsequent laboratory data in NOD mice with T1D that received anti-CD3/oral insulin CT. Our study shows that higher anti-insulin autoantibody levels at diagnosis can distinguish responders and nonresponders among recipients of CT exquisitely well. In addition, early posttreatment changes in proinflammatory cytokines were indicative of long-term remission. Coadministration of oral insulin improved and prolonged the therapeutic efficacy of anti-CD3 therapy, and long-term protection was achieved by maintaining elevated insulin-specific regulatory T cell numbers that efficiently lowered diabetogenic effector memory T cells. Our validation of preexisting autoantibodies as biomarkers to distinguish future responders from nonresponders among recipients of oral insulin provides a compelling and mechanistic rationale to more rapidly translate anti-CD3/oral insulin CT for human T1D.

MECHANISMS IN ENDOCRINOLOGY: Insulin and type 1 diabetes: immune connections

“…In order to identify mice most likely to benefit from CT, they used a validated mathematical model of murine T1D pathophysiology (T1D PhysioLab Platform) (36) for defining suitable biomarkers that could differentiate responders from nonresponders and that are translatable into human trials. They showed that animals that best responded to this CT had elevated IAAs before therapy (35). These results are consistent with human data obtained in a post hoc analysis of the Diabetes Prevention Trial of T1D (DPT-1) (37), showing that patients with the highest IAA titers responded better (i.e.…”

“…This shift also applied to different epitopes derived from PI. Indeed, new-onset T1D patients preferentially displayed T-cell reactivities against the leader sequence epitope PPI [6][7][8][9][10][11][12][13][14] , whereas the B-chain epitope PI [33][34][35][36][37][38][39][40][41][42] was predominantly recognized in long-standing patients (63).…”

“…IAA detection could also inform decisions for recruiting subjects into insulin-based clinical trials, as suggested by Mamchak et al (35). These authors treated NOD mice with a combined therapy (CT) comprising a short-course anti-CD3 mAb treatment and oral insulin therapy.…”

IL-7 receptor α blockade, an off-switch for autoreactive T cells

“…Indeed, certain combination therapies in T1D are not only capable of reverting disease in animal models but bear the potential to significantly reduce drug toxicity (14). It has been shown that the dose of a systemic immunomodulator, such as anti-CD3, can be greatly reduced when combined with an antigen-specific approach (19,20). Thus, when crafting a cure for T1D, we should embrace various techniques, and the reports by Lee et al (2) and Penaranda et al (3) have added an interesting device to the toolbox to do so.…”

Clinical Potential of Antigen-Specific Therapies in Type 1 Diabetes

“…Optimization of clinical translation could center on biomarker discovery and validation. We recently demonstrated that the presence of insulin autoantibodies prior to treatment with oral insulin/anti-CD3 combination therapy predicts efficacy in the NOD mouse [37]. To adequately apply potential immune biomarkers such as regulatory cytokine responses to islet antigens [38][39][40] or autoreactive T cell frequencies [41], in future trials, we need to better understand how these immune markers vary per individual during the natural course of T1D development and progression.…”