Work

548 A phase 1 first-in-human study of ZM008, a novel IgG1 monoclonal antibody targeting LLT1, as monotherapy and combined with toripalimab in patients with advanced solid tumors

Year: 2026

Type: conference-abstract

Abstract: Background ZM008 is a fully human novel monoclonal antibody targeting LLT1–CD161 checkpoint, a key pathway of tumor immune evasion. 1 Disruption of LLT1 – CD161 interaction by ZM008 activates NK and T cells followed by anti tumor effects. Data from preclinical studies established the MOA of ZM008 monotherapy and in combination with anti PD1 antibody.In vivo study – Tumor infiltration of human immune cells and tumor reduction by ZM008 in PC3 xenografted HuNOG EXL.Ex vivo studies with lung and bladder cancer biopsy - tumoroid reduction and immune infiltration after ZM008 monotherapy. Synergy with anti PD1 antibody combination.These data suggest combination of ZM008 and Anti PD1 could activate infiltrated T and NK cells and transform immune suppressive TME into ‘hot’ immune reactive TME.Methods The phase 1 open-label trial is underway to evaluate ZM008 monotherapy and combination therapy with toripalimab in advanced solid tumors. Part 1, stage 1A dose escalation protocol uses 3+3 design to determine the safety and effectiveness of ZM008. ZM008 intravenous dose will start at 0.15 mg/kg and escalating up to 18 mg/kg, Q3W. Extensive protocol amendment was carried out to initiate a parallel and staggered Part 1, stage 1B with escalating dosage of ZM008 combined with 240mg toripalimab, Q3W. The Part 2 includes dose expansion cohorts with ZM008 monotherapy and combination with toripalimab to determine RP2D.The primary study objectives - safety and tolerability of ZM008 as single agent and in combination with Anti PD1, toripalimab. Secondary objectives - measure initial antitumor activity, PK and immunogenicity. Exploratory objectives - pharmacodynamic changes, receptor occupancy, immune and cytokine profiling, ctDNA, paired biopsies and transcriptomics. Key inclusion criteria: histologically confirmed advanced or metastatic NSCLC, TNBC, HNSCC, CRC, prostate cancer, PDAC, biliary tract cancer, high grade serous ovarian cancer, DLBC, RCC, and urothelial cancer, ECOG 0-1, RCC backfill cohorts in Part 1 could be ≤ 2, RECIST v1.1, adequate haematological, hepatic, and renal functions. Key exclusion criteria: uncontrolled brain metastases, any iAEs in prior ICI therapy, uncontrolled cardiovascular disease, history of interstitial lung disease.Results This study is currently recruiting patients at 3 sites in US and, dose escalation in the ZM008 monotherapy cohort 8 has been completed without DLT. Recruitment in the combination arm with ZM008 (2.3 mg/kg) and toripalimab (240 mg) has started.Conclusions Patients are being enrolled at NEXT Oncology sites and Dana Farber Cancer Institute.Trial Registration Clinical trial information: NCT06451497. Research Sponsor: Zumutor Biologics Inc.Reference Mandal T, Gnanasegaran S, Rodrigues G, Kashipathi S, Tiwari A, Dubey AK, Bhattacharjee S, Manjunath Y, Krishna S, Madhusudhan MS, Ghosh M. Targeting LLT1 as a potential immunotherapy option for cancer patients non-responsive to existing checkpoint therapies in multiple solid tumors. BMC Cancer 2024 Nov 7;24(1):1365. doi: 10.1186/s12885-024-13074-z. PMID: 39511540; PMCID: PMC11545609.Ethics Approval Ethics Approval: SALUS IRB approval obtained on 26 March, 2024 for Study protocol number – ZM008-001 with the title: Phase 1 Dose Escalation Trial of ZM008, an Anti-LLT1 Antibody, as Single Agent Followed by Combination with Toripalimab in Patients with Advanced Solid Tumors Compound: Human IgG1 monoclonal antibody Investigational Product Name/Number: ZM008 Sponsor: Zumutor Biologics Inc.

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.0548