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Mibavademab (previously known as REGN4461), a fully human monoclonal antibody, is being investigated for the treatment of conditions associated with leptin deficiency. Here, we report pharmacokinetics (PKs), pharmacodynamics, and immunogenicity from a phase I study in healthy participants (NCT03530514). In part A, lean or overweight healthy participants were randomized to single‐ascending‐dose cohorts of 0.3, 1.0, 3.0, 10, and 30 mg/kg intravenous (i.v.), or 300 and 600 mg subcutaneous doses of mibavademab or placebo. In part B, overweight or obese participants were randomized to receive multiple doses of mibavademab (15 mg/kg i.v. loading dose and 10 mg/kg i.v. at weeks 3, 6, and 9) or placebo, stratified by body mass index and baseline leptin levels: low leptin (<5 ng/mL) or relatively low leptin (5–8 ng/mL in men and 5–24 ng/mL in women). Fifty‐six and 55 participants completed the single‐ascending‐dose and multiple‐dose parts, respectively. In the single‐ascending‐dose cohorts, mibavademab PKs were nonlinear with target‐mediated elimination, greater than dose‐proportional increases in exposure, and there were no dose‐dependent differences in total soluble leptin receptor (sLEPR) levels in serum over time. Following multiple‐dose administration of mibavademab in participants with leptin <8 ng/mL, lower mean mibavademab concentrations, higher mean total sLEPR concentrations, and larger mean decreases in body weight than in the relatively low leptin cohorts were observed. Baseline leptin was correlated with mibavademab PKs and pharmacodynamics. No treatment‐emergent anti‐mibavademab antibodies were observed in any mibavademab‐treated participant. Results from this study collectively inform further development of mibavademab to treat conditions associated with leptin deficiency. [ABSTRACT FROM AUTHOR]