Objective
The proposed research aims to develop an islet-targeting, beta-cell restorative therapy using mAb43, which specifically homes to pancreatic islets and protects beta cells from autoimmune destruction in a T1D mouse model. The goal is to advance preclinical studies of Isle43, a humanized version of mAb43, to establish proof-of-principle for reversing new-onset T1D and protecting human islet allografts in humanized mice.
Background Rationale
ZnT8 expression in beta cells is dynamically distributed across insulin secretory granules, the cell surface membrane, and the endoplasmic reticulum (ER). During islet inflammation, ER-resident ZnT8 is prone to misfolding, which exacerbates the unfolded protein response in beta cells. When this adaptive response is overwhelmed, it can lead to ER-associated degradation of autoantigens and the hyperexpression of HLA class I molecules, which present autoantigen-derived epitopes to effector T cells. This increased antigen load accelerates T-cell mediated beta-cell destruction. Reducing ZnT8 expression has been shown to enhance the adaptive capacity of human beta cells to pro-inflammatory stress, improving graft stability and insulin secretion in human stem cell-derived beta cells transplanted into immunodeficient mice with preexisting diabetes. These findings suggest that reducing ZnT8 misfolding may help beta cells adapt to islet inflammation in T1D. mAb43, acting as a ZnT8-specific molecular chaperone, alleviates ER protein-folding stress and reduces MHC-I hyperexpression in inflamed mouse islets. Our preliminary studies demonstrate the therapeutic potential of mAb43 in animal studies. The proposed research aims to validate a humanized preclinical candidate, Isle43, for its ability to restore beta-cell function in new-onset T1D and reduce the need for immunosuppressants in human islet transplant.
Description of Project
Type 1 diabetes (T1D) results from the autoimmune destruction of beta cells in pancreatic islets. Current broad-based immunotherapies aim to suppress these autoimmune attacks but often cause long-term or irreversible immune system changes, increasing the risk of infections and malignancies. We propose to develop a beta-cell restorative therapy using a proprietary ZnT8 monoclonal autoantibody (mAb43) that selectively targets pancreatic islets. mAb43 protects and restores beta cell function through two synergistic mechanisms. First, it acts as a molecular chaperone within beta cells, alleviating pathogenic ER stress caused by insulitis, promoting beta-cell recovery through adaptive plasticity. This reduces MHC-I hyperexpression, helping beta cells evade recognition by polyclonal T cells. Second, mAb43 functions as a decoy receptor for B cell receptors, blocking autoreactive B cells from capturing and presenting cell-surface autoantigens to T cells, thereby disrupting the immune cascade leading to T cell-mediated beta cell destruction. Since ZnT8 is a key autoantigen targeted by both autoreactive B and T cells, our prior studies have shown that systemically administered mAb43 homes specifically to pancreatic islets in mice, offering protection against T1D onset, reversing new-onset T1D, and ensuring long-term safety without off-target effects. This proposed research will further evaluate the therapeutic efficacy of humanized mAb43 in reversing new-onset T1D and protecting human islet allografts in humanized mice.
Anticipated Outcome
Isle43 therapy aims to cure patients with new-onset T1D. Upon diagnosis of stage 3 T1D, patients require lifelong insulin therapy. Multiple daily insulin injections in new-onset patients typically induce a temporary recovery of beta-cell function, known as the "honeymoon phase." This phase lasts several months, providing a window for Isle43 to solidify lasting beta-cell restoration while continuing to protect against autoimmune attack. In patients with long-standing T1D, insulin therapy often becomes insufficient for glycemic control, leading to diabetes-related complications and frequent, severe hypoglycemia. Allogeneic islet transplantation with lifelong immunosuppression can help restore glycemic control, but the long-term use of immunosuppressants carries significant toxicity. Isle43 may protect against allograft rejection, reducing the need for immunosuppressants. Additionally, Isle43 could be used as an islet-homing carrier to deliver immunosuppressants, enhancing localized immunosuppression while minimizing systemic toxicity.
Relevance to T1D
Current immunotherapies for T1D are broad-based and pose safety concerns with chronic use. In contrast, Isle43 is an islet-specific, beta-cell restorative therapeutic that targets islet cells without affecting immune cells, making it safe for chronic use to sustain durable protection and functional restoration. In newly diagnosed patients, insulin therapy often induces partial remission by relieving glucose toxicity and reducing beta-cell stress, which decreases antigen load for T cell engagement. However, this "honeymoon period" is temporary, as ongoing islet autoimmunity eventually leads to near-complete beta-cell loss. Early intervention with Isle43 could extend the partial remission provided by insulin therapy. Prolonged Isle43 treatment may even promote spontaneous beta-cell regeneration, gradually reducing the need for insulin and potentially leading to full remission. Even in established T1D, reversing autoimmunity has been shown to restore enough functional beta cells to achieve euglycemia in NOD mice. Isle43 therapy may support the compensatory proliferation of adult beta cells in severely damaged islets by creating a microenvironment conducive to beta cell regeneration.