Proof-of-concept study of the CD39-blocking antibody JS019 in eosinophilic-associated disorders Free

Background CD39, an ectonucleotidase that hydrolyzes extracellular ATP to AMP, drives immunosuppressive adenosine accumulation and promotes Th2-dominant inflammation. Preclinical studies have shown that CD39 inhibition reduces eosinophil accumulation and Th2 skewing in murine models. JS019, a fully human IgG1κ monoclonal antibody targeting CD39, has previously been studied in oncology settings. However, its role in treating eosinophilic-associated disorders (EADs) has not been clinically evaluated. Here, we report the first proof-of-concept (PoC) trial of JS019 in patients with EADs.

Methods This study is a prospective, single-center Phase I dose-escalation clinical trial (ChiCTR registry number: CTR20244691) evaluating the safety and efficacy of JS019, a recombinant fully human anti-CD39 monoclonal antibody, in patients with hypereosinophilic syndromes (HES). Eligible participants were adults with eosinophil counts >1.5 × 10⁹/L accompanied by organ involvement, refractory or relapsed after prior treatment, and on stable glucocorticoid therapy (prednisone ≥10 mg/day or equivalent) for ≥1 month prior to screening. Patients with recurrent eosinophilia >0.5 × 10⁹/L during steroid tapering were included, while those with hematologic malignancies were excluded. The primary endpoints were pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity; secondary endpoints included safety and clinical efficacy. Patients received either a single IV dose of JS019 (1, 3, or 5 mg/kg) or repeated 3 mg/kg doses on Days 0, 22, and 50. Clinical symptoms were assessed using the Eczema Area and Severity Index (EASI). Pharmacokinetic half-lives (1 mg/kg: ~8 h; 3 mg/kg: 43 h; 5 mg/kg: 68 h) were used to guide response windows.

Results Five patients received a single infusion of JS019 at 1 mg/kg (n=2), 3 mg/kg (n=2), or 5 mg/kg (n=1), respectively. One patient in the 3 mg/kg dose group received multiple administrations, with the dosing interval adjusted to approximately every 3 weeks based on prior data, resulting in a total of three administrations. The cohort included four males, with a median age of 38 years (range, 26–53) and a median disease duration of 5 years (range, 3–15). All had skin involvement, and one patient had concurrent pulmonary involvement characterized by mild obstructive ventilatory dysfunction and impaired diffusion capacity. All patients were receiving corticosteroids at study entry (median prednisone-equivalent dose: 10 mg/day), and two were also on immunosuppressants. Median baseline eosinophil count was 2.4 × 10⁹/L (range, 1.31–8.38), median EASI score was 7.2 (range, 0.6–10.8), median total IgE was 1987 U/L (range, 53–5000), and median vitamin B12 was 256 pmol/L (range, 166–413).

Following a single infusion of JS019, all patients experienced a marked decline in eosinophil levels within 5 elimination half-lives of the drug. The median absolute reduction in eosinophil count was 2.96 × 10⁹/L (range, 0.92–8.7), with a median percentage reduction of 99% (range, 99.2%–100%). Rash improved in all patients, with a median EASI score reduction of 7.2 (range, 0.6–10.8). Two patients maintained normalized eosinophil levels and symptomatic relief for up to 57 days post-treatment while tapering corticosteroids. Repeated dosing further sustained eosinophil suppression without cumulative toxicity. Notably, blood neutrophil and basophil levels remained stable, suggesting that JS019 selectively targets eosinophils without broader myelosuppression.

JS019 was generally well tolerated. Treatment-related adverse events (AEs) were observed in all patients, predominantly occurring during or shortly after the first infusion of JS019. The most common AEs included abdominal pain (Grade 1, n=2), headache (Grade 2, n=2), vomiting (Grade 1, n=1), diarrhea (Grade 1, n=1) and hypotension (Grade 3, n=1). Most AEs were mild (Grade 1-2) and self-limiting. The single Grade 3 hypotension event was managed by reducing the infusion rate and diluting the drug concentration, allowing completion of the infusion without recurrence. No Grade 4 events or dose-limiting toxicities were observed.

Conclusions This proof-of-concept study demonstrates that CD39 blockade with JS019 induces rapid, selective and sustained eosinophil suppression in patients with eosinophilic-associated disorders, accompanied by early clinical improvements and a favorable safety profile. These results support further clinical development of JS019 in type 2 inflammation beyond oncology.