Abstract 7535: First-in-human phase 1 clinical trial of ZM008, a monoclonal IgG1 targeting LLT1, monotherapy and in combination with pembrolizumab in advanced solid tumors
Authors: Ghosh Maloy , Tiwari Anurag , Dubey Ashvini Kumar , Bhattacharjee Sanghamitra , Manjunath Yogendra , Kashipathi Shalini , Krishna Subith , Mandal Tirtha , Madhusudhan M. S. , Rodrigues Golding 
Published: March 2024

Abstract
Lectin-like transcript 1 (LLT1) interaction with CD161 receptor on NK cells facilitates tumor immune escape. Hence, blocking LLT1-CD161 interaction could potentially activate NK cells and resulted tumor cell cytotoxicity. ZM008 is a first-in-class anti LLT1 monoclonal antibody with promising pre-clinical safety, efficacy data and received IND approval from USFDA. Clinical study will start soon at multiple US sites. TCGA data analysis revealed high LLT1 gene expression in multiple solid cancers BRCA, CHOL, ESCA, GBM, HNSC, KIRC, KIRP, LIHC, LUAD, STAD, SARC. Several immune checkpoint genes PDL1, LAG3, TIM3, TIGIT, ICOS, B7-H3, are positively correlated (p&lt;0.05) with high LLT1 expression. CIBERSORT analysis of immune cells revealed significant presence of Treg and CD33+ immune cells along with IL4, IL10, Arg1 and IDO1 in the TME with high LLT1 expression. Cox regression analysis suggests high LLT1 is a risk factor for survival (p&lt;0.05) in patients with COAD, KICH and KIRC. High TMB and MSI scores were significantly correlated (p&lt;0.05) with LLT1 expression in Colon and Kidney cancers, suggesting plausible biomarker application. Overall, transcriptome data analysis strongly suggests immune repressive gene signatures are prevalent with high LLT1 TMEs in multiple solid cancers. In vitro studies with human PBMC revealed ZM008 activates immune cells by inducing expression of CD69, NKG2D, CD107a, proinflammatory cytokines (IFN-γ, IL2, etc.,) secretion, and tumor cytotoxicity. In MLR assay, ZM008 as a single agent or in combination with Pembrolizumab primed DCs to secrete IFNγ and IL-2 which results in effector NK and T cells activation/proliferation Ex vivo studies with biopsy samples from NSCLC and Bladder Cancer patients showed significant tumor reduction and infiltration of patients’ immune cells with ZM008 monotherapy and ZM008 + pembrolizumab combination. An open label, 3+3 design, multicenter dose escalation phase 1 trial for ZM008 is planned in patients with advanced/metastatic solid tumors with no therapeutic standard alternative to evaluate the safety, tolerability and efficacy of ZM008, as monotherapy and in combination with Pembrolizumab. FIH dosing of 0.15mg/Kg was determined based on MABEL strategy. In silico data analysis showing high LLT1 expression in patients non-responsive to immune checkpoint inhibitor treatments indicate the potential benefit to the patients from ZM008 + pembrolizumab combination treatment. ZM008 treatment will release the immune break, activate the infiltrated immune cells and provide anti tumor effects in solid cancers either as a standalone treatment or combination therapy. Retrospective analysis of patient samples pre and post ZM008 treatment will identify relevant biomarkers for patient recruitment and better prediction of prognosis.
Citation Format: Maloy Ghosh, Anurag Tiwari, Ashvini Kumar Dubey, Sanghamitra Bhattacharjee, Yogendra Manjunath, Shalini Kashipathi, Subith Krishna, Tirtha Mandal, M. S. Madhusudhan, Golding Rodrigues. First-in-human phase 1 clinical trial of ZM008, a monoclonal IgG1 targeting LLT1, monotherapy and in combination with pembrolizumab in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7535.