Background and Objective <p>Angiopoietin-like 3 (ANGPTL3) increases serum low-density lipoprotein cholesterol and triglyceride by reducing their clearance. SHR-1918 is a monoclonal antibody against ANGPTL3. This study assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of SHR-1918 in healthy subjects.</p> Methods <p>Six dose cohorts (100, 300, 450, 750, 900, and 1200 mg) were planned, each containing 12 healthy subjects randomized (9:3) to receive a single dose of subcutaneous SHR-1918 or placebo. Subjects were followed up to day 148 for the 100-mg cohort and day 190 for the other cohorts.</p> Results <p>A total of 72 subjects were enrolled (SHR-1918, <i>n</i> = 54; placebo, <i>n</i> = 18). SHR-1918 was well tolerated at 100–1200 mg. Treatment-emergent adverse events were comparable between the SHR-1918 (90.7%) and placebo (94.4%) groups. All treatment-emergent adverse events were mild or moderate in severity, with no serious adverse events or treatment-emergent adverse events leading to death. Maximum serum concentration was reached 7.98–10.0 days after injection, and mean half-life was 29.4–53.5 days across the dose range. Serum low-density lipoprotein cholesterol and triglyceride markedly and rapidly decreased upon SHR-1918 administration, whereas those in the placebo group were above baseline at most follow-up visits. The largest median percentage decline in serum low-density lipoprotein cholesterol and triglyceride ranged from − 28.7 to − 49.1% and from − 46.6 to − 82.8%, respectively. For dose levels 300 mg or higher, the low-density lipoprotein cholesterol reduction remained over 30% for 64 days and triglyceride reduction remained over 50% for 85 days.</p> Conclusions <p>SHR-1918 was well tolerated and showed promising efficacy in lipid reduction among healthy subjects.</p> Clinical Trial Registration <p>ClinicalTrials.gov, NCT05432544 (24 June, 2022).</p>