Article Figures & Data
Figures
- Fig. 1.
Mechanism of action of nemvaleukin. (A) Visualization of spatial distance between unfused IL-2 and IL-2R (with native N-termini and C termini labeled). (B) Nemvaleukin selectively engages the intermediate-affinity IL-2R complex that is expressed on subsets of CD8+ T cells and NK cells and is sterically occluded from binding to the high-affinity IL-2R complex that is expressed on CD4+ Tregs.
- Fig. 2.
Mean (+ S.D.) serum concentrations (ng/ml) of nemvaleukin in male cynomolgus monkeys after (A) single intravenous (0.3 mg/kg) or subcutaneous doses (0.3, 1.0 mg/kg) and (B) repeated intravenous (0.1 mg/kg for 5 consecutive days, on days 1–5) or subcutaneous doses (0.5 mg/kg on days 1 and 4). N = 3 per treatment group.
- Fig. 3.
Effect of repeated intravenous (0.1 mg/kg for 5 consecutive days) or subcutaneous (0.5 mg/kg on days 1 and 4) administration of nemvaleukin on (A) total CD8+ T cells and CD56+ NK cells and (B) CD4+ Tregs, and (C) the proportion of cells expressing the cell proliferation marker Ki-67. Data shown are the mean ± S.E. of the mean (S.E.M.) with N = 3 per treatment group. Fold changes were calculated relative to predose levels for individual monkeys.
- Fig. 4.
Effect of repeated intravenous (0.1 mg/kg for 5 consecutive days) or subcutaneous (0.5 mg/kg on days 1 and 4) administration of nemvaleukin on CD8+ T cell subsets in terms of (A) cell numbers and (B) fold change relative to predose levels. Data shown are the mean ± S.E.M. with N = 3 per treatment group.
Tables
- TABLE 1
Potency of nemvaleukin on selected lymphocyte subsets from cynomolgus monkey and human samples (Lopes et al., 2020)
Lymphocyte Population Monkey
EC50
Mean ± S.D.Humana
EC50
Mean ± S.D.nM nM NK cells 0.47 ± 0.22 0.45 ± 0.09 Naïve CD8+ T cells 1.4 ± 0.3 2.2 ± 1.0 Central/transitional memory CD8+
T cells1.3 ± 0.4 1.1 ± 0.1 Effector memory CD8+ T cells 2.0 ± 1.0 1.25 ± 0.4 Terminal effector CD8+ T cells 1.7 ± 0.8 0.93 ± 0.3 Tregs 0.50 ± 0.14 0.59 ± 0.2 ↵aData generated from three separate experiments, each performed in triplicate, and the error represents S.D.
- TABLE 2
PK parameters of nemvaleukin in male cynomolgus monkeys after a single intravenous (0.3 mg/kg) or subcutaneous (0.3 or 1.0 mg/kg) dose
Dose Route Dose Cmax Tmax AUC∞ t1/2 MRT CL Vdss mg/kg ng/ml h ng·h/ml h h ml/h/kg ml/kg Intravenous 0.3 6119 ± 1188 0.083(0.083, 0.083) 28,460 ± 1230 49.5 ± 5.6 12.8 ± 1.9 10.6 ± 0.46 135 ± 16.6 Subcutaneous 0.3 549 ± 208 8 (8, 8) 12,931 ± 3893 61.9 ± 4.6 31.6 ± 4.0 — — Subcutaneous 1.0 1035 ± 133 8 (8, 8) 26,878 ± 2106 37.3 ± 19.4 21.7 ± 2.8 — — N = 3 per treatment group.
Mean (± S.D.) for all parameters except Tmax [median (min, max)].
- TABLE 3
PK parameters of nemvaleukin in male cynomolgus monkeys after repeated intravenous (0.1 mg/kg for 5 consecutive days, on days 1–5) or subcutaneous (0.5 mg/kg on days 1 and 4) doses
Dose route Dose Day Cmax Tmax Ctrough AUCτa AUCt AUCtotal mg/kg ng/ml h ng/ml ng·h/ml ng·h/ml ng·h/ml Intravenous 0.1 1 2575 ± 176 0.083 (0.083, 0.083) <LLOQ 9035 ± 602 9035 ± 602 41,753 ± 2213b 5 2096 ± 80 0.083 (0.083, 0.083) 9.62 ± 1.39 5159 ± 301 5611 ± 429 30,124 ± 1112c Subcutaneous 0.5 1 911 ± 432 8 (8, 8) <LLOQ 17,656 ± 6700 17,656 ± 6700 33,402 ± 9204 4 1006 ± 119 2 (2, 8) 10.0 ± 1.25 15,214 ± 2529 15,746 ± 2601 N = 3 per treatment group, LLOQ = 1.00 ng/ml.
Mean (± S.D.) for all parameters except Tmax [median (min, max)].
↵aτ = 24 hours for intravenous dosing regimen and 72 hours for subcutaneous dosing regimen.
↵bCalculated based on AUC24h,day 1 × 4 + AUCt,day 5.
↵cCalculated based on AUC24h,day 1 + AUC24h,day 5 × 3 + AUCt,day 5.
Data Supplement
- Supplemental Data -
Supplemental Methods
Supplemental Table 1: Antibodies and fluorescent dyes used for determination of pSTAT5 levels in white blood cells from cynomolgus monkeys by flow cytometry
Supplemental Table 2: Markers used to identify immune cell subtypes for pSTAT5 analyses from cynomolgus monkeys
Supplemental Table 3: Antibodies and fluorescent dyes used for phenotyping of white blood cells by flow cytometry in peripheral blood of cynomolgus monkeys
Supplemental Table 4: Markers used to identify immune cell subsets in the peripheral blood of cynomolgus monkeys
Supplemental Fig. 1. Study design and dosing schedules for the (A) single- and (B) repeat-dose studies. Blood samples taken prior to dosing on each day of dose administration.
Supplemental Fig. 2. Effect of repeated i.v. (0.1 mg/kg for 5 consecutive days) or s.c.
Supplemental Fig. 3. Effect of repeated i.v. (0.1 mg/kg for 5 consecutive days) or s.c.
- Supplemental Data -
