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First-in-Human Study in Healthy Subjects with the Non-Cytotoxic Monoclonal Antibody OSE-127, a Strict Antagonist of the IL-7Rα

ABSTRACT: OSE-127 is a humanized monoclonal antibody targeting the IL-7Rα chain (CD127), under development for inflammatory and autoimmune disease treatment. It is a strict antagonist of the IL-7R pathway, is not internalized by target cells and is non-cytotoxic. Here, a first-in-human, phase I, randomized, double-blind, placebo-controlled, single-center study was carried out to determine the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of OSE-127 administration.Sixty-three healthy subjects were randomly assigned to nine groups: six single ascending dose groups with intravenous (IV) administration (0.002-10 mg/kg), a single subcutaneous treatment group (1 mg/kg), and two double IV injection groups (6 or 10 mg/kg). Subjects were followed during < 146 days. OSE-127’s pharmacokinetic half-life after a single dose increased from 4.6 days (1mg/kg) to 11.7 days (10 mg/kg) and, after a second dose, from 12.5 days (6 mg/kg) to 16.25 days (10 mg/kg). Receptor occupancy was ≥ 95% at doses ≥ 0.02 mg/kg and this saturation level was maintained >100 days after two IV infusions at 10 mg/kg. IL-7 consumption was inhibited by OSE-127 administration, as demonstrated by a decreased IL-7 pathway gene signature in peripheral blood cells and by ex-vivo T-lymphocyte restimulation experiments. OSE-127 was well tolerated, with no evidence of cytokine-release syndrome and no significant alteration of blood lymphocyte counts or subset populations.Altogether, the observed lack of significant lymphopenia or serious adverse events, concomitant with the dose-dependent inhibition of IL-7 consumption by target cells highlight that OSE-127 may show clinical activity in IL-7R pathway-involved diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE224046 | GEO | 2023/02/01

REPOSITORIES: GEO

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Project description:Per- and polyfluoroalkyl substances (PFAS) are persistent pollutants known for their bio-accumulative properties and prevalence in water supplies and household products. Although legacy PFAS, such as perfluorooctanoic acid, are phased out in the U.S. due to public health concerns, a PFAS variant hexafluoropropylene oxide-dimer acid (HFPO-DA) is an emerging replacement. HFPO-DA is a potential neurotoxicant that has been shown to cause dopaminergic neurodegeneration. We investigated the bioaccumulative potential of HFPO-DA and its effects on lifespan, locomotor activity, and brain gene expression in female and male Drosophila melanogaster (fruit flies). Flies were collected less than 4 hours post-eclosion and exposed to 0, 10, 10^2, 10^3, or 10^4 mg/kg/day HFPO-DA. To measure the effect of HFPO-DA on lifespan, surviving flies from each exposure were recorded every 24 hours. Flies were subjected to a negative geotaxis assay at 3, 7, and 14 days of exposure to measure the effects of acute, sub-chronic, and chronic exposures on locomotor ability. To capture HFPO-DA-induced sexually dimorphic gene expression responses in the brain, we sequenced brain-specific mRNA from flies exposed for 3, 7, or 14 days. The Bioconcentration Factor was 0.031 for females, and 0.026 for males. Dose and median lifespan were negatively correlated in both female (R^2 adj = 0.77, p<0.0001) and male flies (R^2 adj = 0.77, p<0.0001). Log-rank Mantel-Cox tests and one-way ANOVAs revealed that median lifespan was reduced in females starting at 10 mg/kg/day and in males starting at 10^2 mg/kg/day (p< 0.01). Acute exposure at 10 mg/kg/day significantly decreased locomotor ability in females (p<0.0001) while acute exposures at 1 mg/kg/day decreased locomotor activity in males (p <0.0001). Among 7500 genes analyzed, pairwise gene expression comparison between controls and treatments identified 2496 differentially expressed genes. While HFPO-DA does not readily bioaccumulate in fruit fly bodies, high-dose exposures have sex-specific effects on lifespan, locomotor ability, and brain gene expression. LOAEL for median lifespan is 10 mg/kg/day in females, and 10^2 mg/kg/day in males. Both locomotor ability and brain gene expression exhibited non-conventional dose-response as seen in other endocrine disrupting chemical exposures.

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First-in-Human Study in Healthy Subjects with the Non-Cytotoxic Monoclonal Antibody OSE-127, a Strict Antagonist of the IL-7Rα

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