Model-Based Characterization of the Pharmacokinetics, Target Engagement Biomarkers, and Immunomodulatory Activity of PF-06342674, a Humanized mAb Against IL-7 Receptor-α, in Adults with Type 1 Diabetes.

Autor: Williams JH; Worldwide Research & Development, Pfizer Inc, 10777 Science Center Dr, CB1/1130, San Diego, California, 92121, USA. jason.williams@pfizer.com., Udata C; Worldwide Research & Development, Pfizer Inc, 10777 Science Center Dr, CB1/1130, San Diego, California, 92121, USA., Ganguly BJ; Pfizer Inc, South San Francisco, California, USA.; Lyell Immunopharma, South San Francisco, California, USA., Bucktrout SL; Pfizer Inc, South San Francisco, California, USA.; Parker Institute for Cancer Immunotherapy, San Francisco, California, USA., Joh T; Worldwide Research & Development, Pfizer Inc, 10777 Science Center Dr, CB1/1130, San Diego, California, 92121, USA., Shannon M; Worldwide Research & Development, Pfizer Inc, 10777 Science Center Dr, CB1/1130, San Diego, California, 92121, USA., Wong GY; Worldwide Research & Development, Pfizer Inc, 10777 Science Center Dr, CB1/1130, San Diego, California, 92121, USA., Levisetti M; Worldwide Research & Development, Pfizer Inc, 10777 Science Center Dr, CB1/1130, San Diego, California, 92121, USA.; DNAtrix Therapeutics, San Diego, California, USA., Garzone PD; Pfizer Inc, South San Francisco, California, USA.; Calibr, a division of Scripps Research, La Jolla, California, USA., Meng X; Worldwide Research & Development, Pfizer Inc, 10777 Science Center Dr, CB1/1130, San Diego, California, 92121, USA.
Jazyk: angličtina
Zdroj: The AAPS journal [AAPS J] 2020 Jan 03; Vol. 22 (2), pp. 23. Date of Electronic Publication: 2020 Jan 03.
DOI: 10.1208/s12248-019-0401-3
Abstrakt: 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. 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 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. 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.
Databáze: MEDLINE
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