hIL-7-hyFc, A Long-Acting IL-7, Increased Absolute Lymphocyte Count in Healthy Subjects

Sang Won Lee, Donghoon Choi, MinKyu Heo, Eui-Cheol Shin, Su-Hyung Park, So Jeong Kim, Yeon-Kyung Oh, Byung Ha Lee, Se Hwan Yang, Young Chul Sung, Howard Lee, Sang Won Lee, Donghoon Choi, MinKyu Heo, Eui-Cheol Shin, Su-Hyung Park, So Jeong Kim, Yeon-Kyung Oh, Byung Ha Lee, Se Hwan Yang, Young Chul Sung, Howard Lee

Abstract

A low lymphocyte count puts immune-compromised patients at risk of mortality. hIL-7-hyFc is a homodimeric interleukin-7 (IL-7), a potent T-cell amplifier, fused to the hybridizing IgD/IgG4 immunoglobulin domain. We performed a randomized, double-blind, placebo-controlled, dose-escalation, phase I study to assess the pharmacokinetic, pharmacodynamic, safety, tolerability, and immunogenicity profiles of hIL-7-hyFc administered s.c. and i.m. to healthy volunteers. Thirty subjects randomly received hIL-7-hyFc or its matching placebo in an 8:2 ratio at 20, 60 μg/kg s.c., or 60 μg/kg i.m. The hIL-7-hyFc was slowly absorbed and its terminal half-life was 63.26 hours after i.m. administration. The hIL-7-hyFc increased absolute lymphocyte count, mostly in T-cells, which peaked 3 weeks after administration and then lasted for several additional weeks. The hIL-7-hyFc was well-tolerated after a single s.c. and i.m. administration. Injection site reaction was the most common treatment-emergent adverse event, which resolved spontaneously without treatment. The hIL-7-hyFc can be developed into a beneficial treatment option for patients with compromised T-cell immunity. This trial was registered at www.clinicaltrials.gov as #NCT02860715.

Conflict of interest statement

D.C., B.H.L., and S.H.Y. are employees of NeoImmuneTech, Inc. M.H., Y.‐K.O., and Y.C. Sung are employees of Genexine, Inc. All other authors declared no competing interests for this work.

© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society of Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Mean serum concentration‐time profiles of interleukin (IL)‐7 after a single subcutaneous or intramuscular administration of hIL‐7‐hyFc. The error bars denote the SDs (● = 20 μg/kg s.c., N = 8; □ = 60 μg/kg s.c., N = 8; ▲ = 60 μg/kg i.m., N = 8).
Figure 2
Figure 2
Time course of mean pharmacodynamic parameters after a single subcutaneous or intramuscular administration of hIL‐7‐hyFc or placebo. (a) Absolute lymphocyte count. (b) Percent change from baseline in absolute lymphocyte count. (c) Absolute T‐cell count. (d) Percent change from baseline in absolute T‐cell count. (e) Absolute B‐cell count. (f) Percent change from baseline in absolute B‐cell count. The error bars denote the SDs. Upper dotted line: 50% change from baseline; middle dotted line: 0% change from baseline; lower dotted line: −50% change from baseline (● = 20 μg/kg s.c., N = 8; □ = 60 μg/kg s.c., N = 8; ▲ = 60 μg/kg i.m., N = 8; ▽ = placebo, N = 6).
Figure 3
Figure 3
Baseline‐corrected pharmacodynamic parameters after a single subcutaneous or intramuscular administration of hIL‐7‐hyFc or placebo. (a) maximum absolute lymphocyte count (ΔEmax), (b) area under the absolute lymphocyte count‐time curve until the last sampling time (ΔAUEC). The error bars represent the standard deviations (*P value < 0.05 vs. placebo; **P value < 0.01 vs. placebo).
Figure 4
Figure 4
Relationships between individual pharmacokinetic parameters vs. pharmacodynamic parameters. (a) maximum concentration (Cmax) of interleukin (IL)‐7 vs. maximum absolute lymphocyte count (ΔEmax), (b) Cmax of IL‐7 vs. absolute lymphocyte count‐time curve until the last sampling time (ΔAUEC), (c) area under the serum concentration vs. time curve (AUC) from time zero to the last measurable time‐point (AUClast) of IL‐7 vs. ΔEmax, (d) AUClast of IL‐7 vs. ΔAUEC of absolute lymphocyte count after a single subcutaneous or intramuscular administration of IL‐7 (● = 20 μg/kg s.c., N = 8; □ = 60 μg/kg s.c., N = 8; ▲ = 60 μg/kg i.m., N = 8).
Figure 5
Figure 5
Percentages of subjects positive on anti‐drug antibody against hIL‐7‐hyFc over time after administration by treatment group. (a) anti‐drug antibody (ADA), (b) neutralizing antibody (nAb).

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