The understanding of type 1 diabetes (T1D) has evolved significantly, revealing it to be a complex and heterogeneous disease characterised by multiple endotypes, each driven by distinct biological and clinical pathways. Traditionally, T1D management relied on standardised insulin therapy focused on symptom control rather than targeting the underlying mechanisms.1 It is now recognised that the different endotypes are influenced by factors like age of onset, immune responses, genetic predispositions, and rates of pancreatic β-cell destruction, underscoring T1D's complexity.2,3 This new perspective promotes a need for a tailored treatment approach that aligns with individual disease trajectories, potentially improving therapeutic outcomes.4

T1D typically progresses through three stages. Stage 1 is characterised by the presence of two or more autoantibodies, but with normal blood glucose levels and no symptoms. Stage 2 is marked by the continued presence of autoantibodies along with dysglycaemia, defined as abnormal glucose tolerance or impaired glycaemic control that does not yet meet diagnostic criteria for diabetes, but reflects early β-cell dysfunction and predicts progression to overt diabetes. In contrast, Stage 3 is defined by persistent hyperglycaemia that meets diagnostic criteria for diabetes and is often accompanied by clinical symptoms such as polyuria, polydipsia, weight loss, or fatigue. Approximately 75 % of individuals in stage 2 progress to stage 3 within 4 to 5 years.5

Anti-CD3 monoclonal antibodies have undergone extensive investigation, with various iterations demonstrating differing levels of clinical promise. Otelixizumab, a rat–human chimeric anti-CD3 antibody, was evaluated in multiple trials including DEFEND-1 and DEFEND-2, but its development was halted due to safety concerns; most notably Epstein-Barr virus (EBV) reactivation observed in 75 % of patients, as well as cytokine release syndrome and lymphopenia.6 Importantly, these adverse effects were not observed or were significantly milder and self-limiting with teplizumab, a humanised Fc receptor non-binding anti-CD3 antibody, which demonstrated a more favourable safety and efficacy profile.7 Accordingly, this review focuses on teplizumab, the only anti-CD3 monoclonal antibody to date approved by the U.S. Food and Drug Administration (FDA). Teplizumab's FDA approval in 2022 represents a landmark in T1D immunomodulation as it is the first therapy to delay disease progression from stage 2 to 3 by targeting T1D's autoimmune mechanism.8 Approved for individuals aged eight and older at stage 2, teplizumab binds to CD3 on T-cells, reducing their attack on insulin-producing β-cells, thus preserving insulin production.9,10 Clinical trials demonstrated that a single 14-day infusion course delays progression by three years.8 This delay is life-changing, allowing individuals to remain free from the burdens of daily insulin management and blood glucose fluctuations for longer, potentially reducing the risks of long-term complications associated with early T1D onset. This approval underscores the potential for preventive, immune-targeted approaches in T1D, inspiring further research on personalised, early interventions in diabetes care.5,8 Although teplizumab has been approved by the FDA to delay the onset of T1D in at-risk individuals aged 8 years and older, it has not yet received marketing authorisation from other major regulatory agencies such as the European Medicines Agency (EMA) or the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA). However, teplizumab (PRV-031) has been granted PRIME (PRIority MEdicines) designation by the EMA, offering enhanced regulatory support and a potential accelerated review pathway.11 While formal marketing authorisation in the European Union is still pending, early access or compassionate use pathways have been made available in select European countries, such as Italy. The therapy is also currently under regulatory assessment by the National Institute for Health and Care Excellence (NICE), reflecting growing international momentum to expand access to this first-in-class immunotherapy.12

This commentary aims to identify optimal T1D endotype signatures for teplizumab prevention trials as variability in patient response suggests distinct endotypes impact outcomes. Aligning trials with endotype-specific strategies can establish a new paradigm for T1D management that is grounded in precision medicine and identifies critical areas for future research in discovering the optimal treatment strategies for different T1D endotypes.