Background: The B- and T-lymphocyte attenuator (BTLA) is an inhibitory receptor expressed on B, T and NK cells. Icatolimab (TAB004 or JS004) is a humanized IgG4 monoclonal antibody (mAb) with a hinge mutation (S228P) that binds BTLA and blocks its interaction with its ligand HVEM. In preclinical studies, icatolimab monotherapy suppressed tumor growth in murine tumor models using human BTLA knock-in mice. In this first-in-human dose-escalation study, we report the preliminary safety and efficacy of icatolimab as a single agent in patients with advanced solid tumors. Methods: Eligible patients with advance solid tumors refractory to standard therapies were enrolled in this study. Icatolimab was administered at escalating doses of 0.3, 1, 3 and 10 mg/kg intravenously Q3W and followed by dose expansion in 3 and 10 mg/kg cohorts until disease progression or intolerable toxicity. Dose-limiting toxicity (DLT) was evaluated by a safety monitoring committee. Study objectives included safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity. Results: A total of 25 patients with solid tumor were enrolled in the Part A of this phase I study (NCT04137900). The median age was 62 (range 32-85) years with 16 (64%) male patients. Patients were heavily pretreated with a median of 4 prior lines of therapy. Fifteen (60%) patients received and progressed upon prior anti-PD-1/L1 therapy. By the data cutoff date of December 31, 2021, the median follow-up was 32 weeks. No DLT was observed. 24 (96%) patients experienced treatment emergent adverse event (TEAEs), with 7 (28%) experienced grade 3 TEAEs. No grade 4 or 5 TEAE occurred. The incidence or severity of AE was not associated with the dose. The most common TEAEs were fatigue (32%), abdominal pain (20%), diarrhea (16%), arthralgia (16%), aspartate aminotransferase increased (16%), constipation (16%), and contusion (16%). One (4%) TEAE led to discontinuation of study drug. Four (16%) patients experienced immune related AE. Among 19 evaluable patients by the cutoff date, 1 confirmed PR (melanoma) and 6 SD were observed as assessed by the investigator per RECIST v1.1. The response was still ongoing over 12 months in the melanoma patient who had progressed upon prior nivolumab and BRAF/MEK inhibitors treatments. BTLA receptor was fully occupied in the 3 and 10 mg/kg cohorts. The mean elimination half-life of icatolimab was 7.5 to 19.2 days in four dose cohorts. Biomarker analysis indicated co-expression of HVEM and CD8 was associated with favorable response. Conclusions: Icatolimab monotherapy were well tolerated in all doses evaluated and showed preliminary clinical efficacy as a monotherapy. Icatolimab in combination with toripalimab (anti-PD-1) for the treatment of patients with advanced solid tumors is currently ongoing. Clinical trial information: NCT04137900.