Background: PM1003 is a VHH-based anti-PD-L1/4-1BB bispecific antibody. The anti-4-1BB VHH arm binds to a unique epitope at the CRD4 region of 4-1BB, activating 4-1BB signals through cross-linking in the presence of PD-L1 that is often upregulated in the tumor microenvironment, thus avoiding harm to healthy tissues. This is the First In Human study of PM1003. Methods: This study was conducted with a standard 3+3 dose escalation design (Part A: single doses of 0.02, 0.1, 1, 3, 6, and 10 mg/kg for DLT evaluation after 3 weeks followed by Q2W for further administration) and dose expansion (Part B). For Part A, the primary endpoint was safety and tolerability with secondary endpoint of ORR per RECIST 1.1. For Part B, ORR per RECIST 1.1 was the primary endpoint and the secondary endpoints were safety and PK. Results: As of February 9, 2023, a total of 17 subjects have received at least 1 dose of PM1003, including 16 subjects in Part A (3 subjects in each of the 0.02, 0.1, 1, 3 mg/kg dose levels respectively and 4 subjects in 6 mg/kg), and 1 subject in Part B (1 mg/kg Q2W). In Part A, no DLTs were observed up to 6 mg/kg. Of the 17 patients, TRAEs occurred in 15 subjects (88.2%), ≥ Grade 3 TRAEs occurred in 5 subjects (29.4%). No patient discontinued PM1003 administration due to TRAE. The most common TRAEs were anaemia (35.3%), neutrophil count decreased (29.4%), white blood cell count decreased (29.4%), platelet count decreased (29.4%), fatigue (23.5%). 11 subjects completed at least one efficacy evaluation in part A. The median duration of PM1003 exposure was 9.9 weeks (range, 3.1-31.1 weeks). The ORR per RECIST 1.1 was 9.1% with a DCR of 54.5%. Preliminary evidence of antitumor activity has been observed in 1 subject with gastric cancer (1 mg/kg Q2W) who was enrolled after previous surgery, chemotherapy, anti-PD-1 and anti-HER2-ADC treatment, and had a partial response of 87.8% in target lesion reduction during the first efficacy evaluation (7 weeks) after PM1003 treatment. T_1/2 of PM1003 of 1 mg/kg and 3 mg/kg dose level is 6.3 and 12.8 days, respectively. Receptor occupancy of PD-L1 in the 1 mg/kg and 3 mg/kg cohorts reached saturation at 336 hours after the first single dose and maintained at an almost stable state. Conclusions: PM1003 was well-tolerated up to 6 mg/kg and has shown preliminary anti-tumor activity in a patient who was previously treated with multiple drug modalities including anti-PD-1. The dose-escalation at 10 mg/kg and dose expansion are ongoing. Clinical trial information: ChiCTR2100052887.