Document resource
Background ES009 is a recombinant human IgG4 monoclonal antibody that specifically targets and blocks leukocyte immunoglobulin-like receptor B2 (LILRB2), a transmembrane inhibitory protein predominantly expressed on myeloid lineage cells. LILRB2 broadly binds to multiple ligands, including both classical and non-classical major histocompatibility complex (MHC) class I molecules. By fully blocking LILRB2 interactions with these ligands, ES009 reprograms immunosuppressive M2 macrophages into pro-inflammatory M1 macrophages, alleviates M2-mediated T cell suppression, and reshapes the immunosuppressive tumor microenvironment into one more conducive to anti-tumor immunity. This first-in-human Phase 1 study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of ES009.Methods This open-label, multicenter, non-randomized Phase 1 study (ClinicalTrials.gov ID: NCT06007482) assessed intravenous ES009 in patients with advanced solid tumors who had received and progressed on or were intolerant to standard therapies. Dose escalation followed two designs: an accelerated titration design (ATD) for the first two dose levels (30 mg and 100 mg), followed by a modified toxicity probability interval (mTPI) design for higher doses (300 mg, 800 mg, and 1600 mg). ES009 was administered every three weeks until disease progression, unacceptable toxicity, or other protocol-defined reasons. A Safety Review Committee (SRC) monitored safety data throughout the study.Results Twelve patients with advanced solid tumors—including colorectal cancer, cholangiocarcinoma, non-small cell lung cancer, ovarian cancer, and submandibular gland cancer—were enrolled. No dose-limiting toxicities (DLTs) were observed, and the maximum tolerated dose (MTD) was not reached. Nine patients experienced treatment-emergent adverse events (TEAEs), with six reporting grade 3 TEAEs. Two patients experienced treatment-related adverse events (TRAEs), including diarrhea, nausea, arthralgia, and rash—all grade 1. Arthralgia was considered immune-related. One patient discontinued treatment due to a non-treatment-related craniocerebral injury, and one death occurred due to pneumonia, also unrelated to treatment. In patients receiving ≥300 mg, the half-life (t 1/2) of ES009 ranged from 9.9 to 12.4 days. Full receptor occupancy of LILRB2 was achieved at Ctrough for patients receiving ≥300 mg. Among the eleven patients included in the efficacy analysis, no complete or partial responses were observed. Eight patients achieved stable disease as their best overall response, resulting in a disease control rate of 72.7%.Conclusions ES009 demonstrated a favorable safety and tolerability profile in patients with advanced solid tumors. At dose levels ≥300 mg, ES009 exhibited desirable pharmacokinetic and pharmacodynamic properties. As a monotherapy, ES009 showed preliminary antitumor activity, supporting further clinical development.Trial Registration ClinicalTrials.gov ID: NCT06007482Ethics Approval This study obtained ethics approval from the Bellberry Human Research Ethics Committee, the number/ID of the approval was 2023-06-715. Participants gave informed consent before taking part.