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Background ZM008, a fully human IgG1, first-in-class anti LLT1 antibody, disrupts LLT1-CD161 interaction and activates NK mediated immune response. Across various cancers, upregulated LLT1 expression is associated with exhaustive immune markers (PD1, LAG3, TIM3, TIGIT, ICOS) and inversely associated with pro-inflammatory and tumor suppressor signals (LAMP1, PTEN, HLA-E, ULBP1) – indicating immune suppressive ‘Cold tumor’ phenotype. 1 Ex vivo treatment of lung and muscle invasive bladder cancer biopsies with ZM008 showed significant tumor reduction and immune cells infiltration. In addition, ZM008 combinations with Pembrolizumab revealed synergistic anti-tumor effects. Minimum anticipated biological effect level (MABEL) and biological effective dose (BED) were determined by in vitro, in vivo and ex vivo efficacy and safety studies. A Phase 1, open-label, first-in-human study is recruiting patients at 3 US sites to evaluate ZM008 monotherapy and combination with anti PD1 antibody in advanced solid tumors with no standard therapeutic alternative (NCT06451497).Methods The study protocol includes dose-escalation and dose-expansion stages. In dose-escalation, ZM008 monotherapy follows 3+3 standard design from 0.15 mg/Kg to 18 mg/Kg IV Q3W. At BED dose level of 2.3mg/Kg, a staggered parallel arm will start patient recruitment to explore combination of ZM008 with anti PD1 antibody treatments. In dose-expansion, two or more doses of ZM008 will be used to select RP2D and specific cancer indications. The primary study objectives are to determine the safety and tolerability, and to define RP2D of ZM008. Secondary objectives include PK, immunogenicity, pharmacodynamics (PD) changes, and disease response. Exploratory objectives will evaluate PD changes, receptor occupancy, immune and cytokine profiling, ctDNA, and transcriptomics. Major safety parameters will include DLT, nature and severity of TEAE. ORR, CR, PR as per RECISTv1.1 will be assessed. Paired biopsies will measure distribution of immune and tumor cells in the TME as a response to ZM008 treatment. Key inclusion criteria: histologically confirmed advanced or metastatic non-small cell lung, head & neck, pancreatic, biliary, prostate, colorectal, triple-negative breast, urothelial, ovarian, and diffuse large B cell malignancies, ECOG ≤1, measurable disease by RECISTv1.1, adequate hematological, hepatic, and renal functions are required. Key exclusion criteria: uncontrolled brain metastases and any iAEs in prior ICI therapy. Blood and other samples will be collected at baseline and on treatment to analyze for PK, ADA, ctDNA, cytokines and immunophenotyping.Results This study is currently recruiting patients at 3 sites in US and, dose escalation cohort 4 have been completed without DLT.Acknowledgments Research Sponsor: Zumutor Biologics Inc.Trial Registration Clinical trial information: NCT06451497.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 Pembrolizumab in Patients with Advanced Solid Tumors Compound: Human IgG1 monoclonal antibody Investigational Product Name/Number: ZM008 Sponsor: Zumutor Biologics Inc.