Abstract
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 (Treg) and effector memory (TEM) cells. PF-06342674 is a humanized monoclonal antibody that binds to and inhibits the function of IL-7Rα. 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. Nonlinear mixed effects models were developed to characterize the pharmacokinetics (PK), target engagement biomarkers, and immunomodulatory activity. PF-06342674 was estimated to have 20-fold more potent inhibitory effect on TEM cells relative to Treg cells resulting in a non-monotonic dose-response relationship for the Treg:TEM ratio, reaching maximum at ~ 3 mg/kg/q2w dose. 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. 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. 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. Furthermore, this analysis serves as an example of mechanistic modeling to support dose selection of a drug candidate in the early phases of development.
Highlights
Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell–mediated destruction of the insulin-Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.California, USA. 4 Present Address: Parker Institute for Cancer Immunotherapy, SanFrancisco, California, USA. 5 Present Address: DNAtrix Therapeutics, San Diego, California, USA. 6 Present Address: Calibr, a division of Scripps Research, La Jolla, California, USA. 7 To whom correspondence should be addressed
The analysis described was carried out utilizing two target engagement biomarkers (total soluble IL-7 receptor measured by enzyme-linked immunosorbent assay (ELISA) and cellular IL-7 receptor occupancy (RO) measured by flow cytometry) and absolute count of two surrogate markers (Treg and the ratio of effector memory (TEM)) measured by flow cytometry
The DR relationship characterizing the effects of PF-06342674 on the Treg:TEM T cell ratio provides evidence that IL-7 receptor-α (IL-7Rα) blockade may shift the balance from autoimmunity towards immune tolerance
Summary
Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell–mediated destruction of the insulin-. Present Address: Parker Institute for Cancer Immunotherapy, San. Francisco, California, USA. Present Address: DNAtrix Therapeutics, San Diego, California, USA. Present Address: Calibr, a division of Scripps Research, La Jolla, California, USA. (e–mail: secreting beta cells, resulting in insulin deficiency and hyperglycemia [1]. 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[2]. Disease 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 [3].
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