1424 BSI-115, a novel anti-V{gamma}9V{delta}2 agonist monoclonal antibody, promotes V{gamma}9V{delta}2 T cell activity against tumor cells

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Background

V9V2, also known as T cell antigen receptor, is composed of a chain including V9 (TRGV9) and C (TRGC) and a chain including V2 (TRDV2) and C (TRDC). V9V2 is expressed on V9V2 T cells which represent 1–5% population of all circulating T cells (~95% of circulating T cells¹), but it can increase to >20–40% in many infections.² V9V2 T cells are activated by ligation of BTN3A1 in a pAg-induced manner.³ V9V2 T cells are pro-inflammatory effector T cell subset and can directly recognize molecules expressed on cancer cells without need of antigen processing and presentation, suggesting that they may exert anti-tumor effects on target cells with reduced or absent expression of MHC class I molecules.⁴ Selective recruitment of V9⁺ T cells by V9/CD123 bispecific antibody induced significant hematological tumor growth inhibition.⁵

Methods

Humanized mice were immunized with recombinant V9V2 protein complex. Protein-based binding assays were used to identify V9V2-positive antibodies followed by cell-based confirmation with V9V2 recombinant cell lines, resulting in the lead candidate – BSI-115. The target binding affinity and specificity of Fc silent BSI-115 were measured by Biacore-based SPR, protein-based ELISA and cell-based FACS. T cell activity of BSI-115 is evaluated in cell-based reporter assay with Jurkat cells overexpressing V9V2 and in a tumor cell killing assay using donor-derived T cells.

Results

Cell binding analysis revealed that BSI-115 binds to Jurkat cells overexpressing either V9V2 or V9V1, indicating that BSI-115 binds to V9 chain specifically, but not V chain. The reporter assay demonstrated that BSI-115 is able to activate NFAT signaling in both V9V2 T cells and V9V1 T cells, and shows higher reporter activity as compared with benchmark antibody. Finally, BSI-115 also exhibited strong cell killing activity and enhanced IFN- release in primary T cell-based tumor killing assay.

Conclusions

BSI-115, a novel anti-V9V2 agonist monoclonal antibody, demonstrates desirable physicochemical and functional characteristics, supporting the initiation of development of T cell engager platform.

References