Pharmacology and nonclinical development of teplizumab, a first-in-class immunotherapy for delaying the onset of type 1 diabetes.

Teplizumab is a nonmitogenic anti-CD3 monoclonal antibody approved to delay the onset of clinical type 1 diabetes. To address the challenge of the absence of crossreactivity of teplizumab with CD3 of different preclinical species that are typically used in preclinical development, a mouse surrogate of teplizumab (MST) that binds to mouse CD3 and was used in preclinical development to characterize pharmacology, toxicology, and toxicokinetics in mouse models. Teplizumab and MST showed similar binding affinities for human (KD = 2.3 μM) and mouse CD3 (KD = 3.0 μM), respectively. In crossreactivity analyses using human tissues, teplizumab reacted primarily with splenic T-cells. In prediabetic nonobese diabetic mice, administration of MST showed delayed diabetes onset and reduced incidence of diabetes by 30% compared with the control. In toxicity studies, MST-induced decreases in T-lymphocytes were observed. No effects on fertility, reproductive performance, or embryo-fetal development were seen. In the prenatal and postnatal development study reduced fertility in the F1 generation was noted at the highest maternal dose. Although MST-based evaluation may have some limitations, overall, MST served as a valuable scientific alternative for translational understanding of teplizumab pharmacology in mouse model and for toxicological hazard identification of teplizumab. Furthermore, the outlined surrogate-based preclinical evaluation approach may be applicable to other monoclonal antibodies that lack crossreactivity with commonly used preclinical species. SIGNIFICANCE STATEMENT: Teplizumab reacts with human CD3 but not conventional preclinical species and cannot be evaluated in standard preclinical models of biology and safety. To enable preclinical investigation, a mouse surrogate teplizumab (MST) and mouse models were used to evaluate pharmacology and toxicity in support of clinical development. MST demonstrated utility in elucidating pharmacology, biomarker readouts of disease activity, and potential hazards. A similar surrogate-based preclinical strategy may be applicable to other monoclonal antibodies that lack crossreactivity with commonly used preclinical species.