Preclinical Development of a Therapeutic Antibody for Type-1 Diabetes

Abstract Type 1 diabetes (T1D) is a chronic autoimmune disease that affects approximately 1.5 million Americans, with an estimated economic impact nearing $1 trillion. The disease progresses through three stages: it begins with the presence of autoantibodies and normal blood sugar levels (stage 1), advances to dysglycemia without clinical symptoms (stage 2), and culminates in clinical diabetes (stage 3), where insulin therapy becomes mandatory to manage blood sugar levels and prevent complications. If left untreated, T1D can lead to life-threatening ketoacidosis, while insulin overdose may cause severe hypoglycemia, potentially resulting in loss of consciousness or death if not promptly addressed. Despite advancements in T1D treatment, many patients struggle to meet treatment goals, increasing their risk of long-term complications like cardiovascular disease, kidney damage, nerve damage, and vision impairment. T1D is caused by the autoimmune destruction of insulin- producing beta cells within the pancreatic islets. There is an urgent clinical need for therapies that can simultaneously reverse autoimmunity and restore beta cell function and mass. Currently, Teplizumab, an anti- CD3 monoclonal antibody, is the only approved immunotherapy to delay the onset of clinical T1D in stage 2 patients. However, concerns about broad immune suppression limit its use as a chronic treatment to permanently halt progression from stage 2 to stage 3 T1D. A durable and restorative therapy for T1D remains an unmet need. Islex Therapeutics aims to develop a first-in-class, islet-targeted antibody therapeutic to address this gap. We have identified a novel islet-homing antibody therapy that has demonstrated complete protection and reversal of new-onset T1D in mice without adverse effects during long-term monitoring. The objective of this phase I SBIR application is to establish proof-of-principle for a humanized therapeutic lead by validating its islet-homing capability (Aim 1), its therapeutic efficacy in reversing new-onset diabetes in a mouse model of T1D (Aim 2), and its ability to protect human islets against human T-cell cytotoxicity (Aim 3). The proposed Phase I study will lay the groundwork for Phase II development, focusing on preclinical toxicology studies and antibody drug product manufacturing, ultimately leading to clinical trials in patients with stage 2 and new-onset stage 3 T1D.