The destruction of beta cells is a consequence of direct cytotoxicity mediated by beta cell–reactive T cells. Despite the improvements in management of diabetes, there are no approved therapies which modulate the course of disease, and a large proportion of subjects with T1D fail to achieve optimal glycemic control.ĭisease progression in T1D can be quantified as a loss of pancreatic beta cell function over a period of years, approximately 70% of which is prior to appearance of hyperglycemia and glycosuria. The standard-of-care treatment is daily insulin injections in an effort to normalize blood glucose levels throughout the day and ultimately to prevent long-term diabetic complications including diabetic retinopathy, nephropathy, and neuropathy. Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell–mediated destruction of the insulin-secreting beta cells, resulting in insulin deficiency and hyperglycemia. Furthermore, this analysis serves as an example of mechanistic modeling to support dose selection of a drug candidate in the early phases of development. The results provide important insight into the mechanism of IL-7Rα blockade and immunomodulatory activity of PF-06342674 and establish a rational framework for dose selection for subsequent clinical trials of PF-06342674. Doses ≥ 3 mg/kg q2w result in sustained PF-06342674 concentrations higher than the concentration of cellular IL-7 receptor and, in turn, maintain near maximal receptor occupancy over the dosing interval. Target-mediated elimination led to nonlinear PK with accelerated clearance at lower doses due to high affinity binding and rapid clearance of the drug-target complex. PF-06342674 was estimated to have 20-fold more potent inhibitory effect on T EM cells relative to T reg cells resulting in a non-monotonic dose-response relationship for the T reg:T EM ratio, reaching maximum at ~ 3 mg/kg/q2w dose. Nonlinear mixed effects models were developed to characterize the pharmacokinetics (PK), target engagement biomarkers, and immunomodulatory activity. In the current phase 1b study, subjects with type 1 diabetes (T1D) received subcutaneous doses of either placebo or PF-06342674 (1, 3, 8 mg/kg/q2w or 6 mg/kg/q1w) for 10 weeks and were followed up to 18 weeks. PF-06342674 is a humanized monoclonal antibody that binds to and inhibits the function of IL-7Rα. IL-7 receptor-α (IL-7Rα) blockade has been shown to reverse autoimmune diabetes in the non-obese diabetic mouse by promoting inhibition of effector T cells and consequently altering the balance of regulatory T (T reg) and effector memory (T EM) cells.