First-in-human study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of ALPN-101, a dual CD28/ICOS antagonist, in healthy adult subjects

Abstract

ALPN-101 (ICOSL vIgD-Fc) is an Fc fusion protein of a human inducible T cell costimulatory ligand (ICOSL) variant immunoglobulin domain (vIgD) designed to inhibit the cluster of differentiation 28 (CD28) and inducible T cell costimulator (ICOS) pathways simultaneously. A first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ALPN-101 in healthy adult subjects. ALPN-101 was generally well-tolerated with no evidence of cytokine release, clinically significant immunogenicity, or severe adverse events following single subcutaneous (SC) doses up to 3 mg/kg or single intravenous (IV) doses up to 10 mg/kg or up to 4 weekly IV doses of up to 1 mg/kg. ALPN-101 exhibited a dose-dependent increase in exposure with an estimated terminal half-life of 4.3-8.6 days and SC bioavailability of 60.6% at 3 mg/kg. Minimal to modest accumulation in exposure was observed with repeated IV dosing. ALPN-101 resulted in a dose-dependent increase in maximum target saturation and duration of high-level target saturation. Consistent with its mechanism of action, ALPN-101 inhibited cytokine production in whole blood stimulated by Staphylococcus aureus enterotoxin B ex vivo, as well as antibody responses to keyhole limpet hemocyanin immunization, reflecting immunomodulatory effects upon T cell and T-dependent B cell responses, respectively. In conclusion, ALPN-101 was well-tolerated in healthy subjects with dose-dependent PK and PD consistent with the known biology of the CD28 and ICOS costimulatory pathways. Further clinical development of ALPN-101 in inflammatory and/or autoimmune diseases is therefore warranted.

FIGURE 1

ALPN‐101 serum concentration versus nominal time following single IV or SC dosing in part A (a) and repeated IV dosing in part B (b). All doses are IV unless indicated “SC” The concentrations below the lower limit of quantification (LLOQ) before dose administration were treated as “0” and after dose administration were treated as “missing.” In (a), each cohort is presented as n = 4 except 0.012 mg/kg (n = 2), 0.03 mg/kg (n = 3), and 1 mg/kg SC (n = 3). Two subjects (1 in 0.012 mg/kg and 1 in 1 mg/kg SC) were excluded from the summary due to nonspecific enzyme‐linked immunosorbent assay (ELISA) background interference. At 28 days following dose administration, the concentrations for most individuals fell below the LLOQ except at the following dose levels: 3 mg/kg SC (n = 2), 3 mg/kg (n = 4), and 10 mg/kg (n = 4). In (b), each cohort is presented as n = 6 except 1 mg/kg Q2W (n = 5), in which 1 subject was excluded from the summary due to nonspecific ELISA background interference. At 49 days following the first dose administration, the concentrations for most individuals fell below the LLOQ except 1 mg/kg Q1W (n = 2) and 1 mg/kg Q2W (n = 2)

FIGURE 2

ALPN‐101 target saturation on CD4+ cells following single IV or SC dosing in part A (a) and repeated IV dosing in part B (b). Maximum mean target saturation versus single IV doses fitted by a simple binding model (c) and the duration of high target saturation versus single IV doses (d) in part A. All doses are IV unless indicated “SC” The target saturations data at baseline and from subjects on placebo were low (<5%) and are not shown

FIGURE 3

Median SEB‐induced IL‐2 change from baseline versus time profiles following single IV or SC dosing in Part A (a) and repeated dosing in Part B (b). Correlation of estimated PD parameters included maximum effect (c) and duration of effect above or below threshold (d) between target saturation and IL‐2 reduction. All doses are IV unless indicated “SC”. Dotted line represents 95% target saturation in (c) and linear regression line in (d). SEB, Staphylococcus aureus enterotoxin B

FIGURE 4

Anti‐KLH change relative to the baseline versus time profiles after single IV or SC dosing in part A (a, c) and repeated dosing in part B (b, d), displayed as IgG (a, b) and IgM (c, d) anti‐KLH responses. Mean (+SD) anti‐KLH IgG (e) or IgM (f) change from baseline for each treatment groups at indicated time points after dosing. All doses are IV unless indicated “SC” Statistical analysis was performed by one‐way analysis of variance (ANOVA) and unpaired t‐test with Welch’s correction. Statistical significances represent the comparison between placebo and ALPN‐101‐treated groups. * p value 0.033,** p value 0.002. KLH, keyhole limpet hemocyanin