Fig. 8: Pharmacokinetics and pharmacodynamics of CYpHER in mice.
From: CYpHER: catalytic extracellular targeted protein degradation with high potency and durable effect
a Designs of CYpHER and control molecules. b NCr nu/nu mice were dosed with 1.5 mg/kg CT-1212-1, CT-1211-1, CT-1222-1, or CT-1232-1 IV. Serum was taken after 10 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 96 h, or 168 h. Three mice per time point were analyzed. Samples were quantitated by ELISA for human Fc domain in technical triplicate. N = 3 mice per time point. Molecules exhibited a normal biphasic distribution curve, and as such, PK parameters were determined by non-compartmental analysis for IV bolus dosing using PKSolver 2.0. c Experimental design for tumor implantation and dosing. Female athymic nude mice (Foxn1nu) were implanted (subcutaneous flank) with 5 ×106 H1975 cells. After 21 days, mice were enrolled and dosed IV on days 0 (enrollment day), 3, and 7. On day 8, tumors from three mice per dosage group were harvested and split for Westerns or for histology. d Western blot of total EGFR and actin. N = 3 mice per condition, all seen in blot. Full blots in Supplementary Fig. 16. e Quantitation of the blots from d. f IHC (hematoxylin/DAB) for total EGFR (top) and Ki67 (bottom) in vehicle, CT-1212-1 450 μg, and CT-1222-1 150 μg groups. Full EGFR fields can be found in Supplementary Fig. 17. g Quantitation of Ki67 positivity, derived from 6-9 regions of interest (ROI) per tumor, three tumors per group, pooled for analysis N (ROI) per sample: Vehicle, 24; CT-1212-1 450 μg, 23; CT-1212-1 150 μg, 22; CT-1212-1 50 μg, 20; CT-1222-1 150 μg, 22; CT-5212-1 150 μg, 21. Two-tailed Welch’s T test vs Vehicle: CT-1212-1 450 μg, P = 0.0192; CT-1212-1, 150 μg, P = 0.0033; CT-1222-1 150 μg, P = 0.0013; CT-1212-1 50 μg and CT-5212-3 150 μg, P > 0.9999. See the Supplementary Data for full statistical breakdown. Each experiment was performed once. Source data are provided as a Source Data file.
