Extended Data Figure 3: Pharmacokinetics, pharmacodynamics and efficacy of ABL001.
From: The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1
a, Pharmacokinetic (PK) parameters of ABL001 in mouse, rat and dog after a single dose of ABL001. AUC, area under the curve; BA, bioavailability; CL, clearance; Cmax, maximum concentration observed; IV, intravenous; t1/2term, terminal half-life; PO, oral dosing; Tmax, time at maximum concentration; Vss, volume of distribution. b, Total plasma concentrations and levels of pSTAT5 (Tyr694) in fine needle aspirate samples taken from KCL-22 xenografts were monitored after a single oral administration of ABL001 at doses ranging from 3 to 30 mg kg−1. pSTAT5 (Tyr694) levels were determined using a pSTAT5 (Tyr694) meso scale discovery (MSD) assay with each sample run in duplicate; data are mean ± s.d. Samples are expressed as a percentage of the levels of pSTAT5 (Tyr694) before dosing (t = 0). c, ABL001 efficacy in KCL-22 xenograft tumours was assessed by monitoring tumour volume at doses ranging from 3 to 30 mg kg−1 on either a twice a day (BID) or once a day (QD) dosing schedules. Data are mean ± s.e.m. d, ABL001 efficacy in three patient-derived ALL systemic xenograft models (ALL-7015, AL-7119 and AL-7155) was assessed by FACS monitoring of the percentage of CD45+ cells per live cell in blood samples taken at varying time points after dosing with either 7.5 mg kg−1 BID (group 2) or 30 mg kg−1 BID (group 3) ABL001 for 3 weeks. A control group (group 1) was treated with PBS vehicle. Data are mean ± s.e.m. (n = 6 per group). e, The tolerability of increasing doses of ABL001 dosed on a BID schedule was determined by monitoring mouse body weight 2–3 times per week. Data are mean ± s.e.m. (n = 5 per group).
