Abstract 1557: Characterization of AB154, a humanized anti-TIGIT antibody, for use in combination studies

Abstract

Abstract BACKGROUND: AB154 is a humanized antibody that blocks human TIGIT (T-cell immunoreceptor with Ig and ITIM domains), an inhibitory receptor expressed on natural killer (NK) cells, CD8+ T cells, CD4+ T cells and regulatory T cells (Treg). DNAM-1 (DNAX Accessory Molecule-1) is an activating receptor found on NK cells, monocytes and a subset of T cells that competes with TIGIT for shared ligands CD155 (PVR) and CD112 (Nectin-2), expressed by cancer and antigen-presenting cells. TIGIT blockade prevents binding to its ligands and shifts the immune balance towards a more favorable DNAM-1 interaction. AB154 has the potential to promote sustained immune activation and tumor clearance, particularly in combination with other immunotherapies such as AB122 (α-PD1). METHODS: Binding affinity of AB154 was determined in CHO cells over-expressing human TIGIT and in human T cells. TIGIT blockade was quantified using a TIGIT-expressing reporter gene cell line. TIGIT and PD-1 expression in cancer patient PBMCs and dissociated tumor cells (DTCs) were assessed by flow cytometry. Gene expression of these markers were also derived from TCGA (The Cancer Genome Atlas), GTEX (Genotype-Tissue Expression Project), RNAseq, and by immunohistochemistry in various tumor types and normal tissues. A receptor occupancy (RO) assay was developed using a competing α-TIGIT antibody and validated ex vivo in whole blood leukocytes from healthy donors and cancer patients. RESULTS: AB154 binds to and blocks human TIGIT with sub-nanomolar affinity. Data assembled from TCGA identified tumor types in which expression of TIGIT is greater than PD-1, equivalent to PD-1, or less than PD-1. Expression of TIGIT and CD155 at the protein level was confirmed by IHC. Immunophenotyping performed on dissociated human tumor cells demonstrated strong correlation between TIGIT and PD-1 expression on immune cells. The intensity of TIGIT staining was lowest on conventional CD4+ T cells while its intensity in Treg and CD8+ T cells was 1.5 to 3-fold higher on average. Using flow cytometry, we profiled lymphocyte populations in peripheral whole blood and demonstrated target engagement by AB154 on T cells and NK cells in the low nanomolar range in both healthy and cancer patients (ex vivo). This receptor occupancy assay is being used to monitor target engagement in AB154 dosed patient samples in an ongoing Phase 1 dose escalation study in oncology patients. CONCLUSION: Blockade of multiple immune checkpoint proteins can confer effective and durable responses in the treatment of cancer. The data presented will provide: 1) the basis for selection of tumor types by TIGIT RNA and protein expression profiles, 2) rationale for combining AB154 with AB122 (α-PD-1) in upcoming clinical trials, 3) methodology to evaluate TIGIT receptor occupancy and 4) preliminary PK/PD data from the AB154 Phase 1 dose escalation study in oncology subjects. Citation Format: Amy E. Anderson, Daniel DiRenzo, Susan Lee, Akshata Udyavar, Kimberline Gerrick, Hema Singh, Xiaoning Zhao, Lixia Jin, Lisa Seitz, Nigel P. Walker, Matthew J. Walters, Joanne B. Tan. Characterization of AB154, a humanized anti-TIGIT antibody, for use in combination studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1557.