Abstract 4254: ADT-010, a novel immunomodulatory antibody that harnesses the anti-tumor properties of tissue-resident Vδ1 γδ T cells

Background: Recent studies have highlighted the contribution of gamma delta (γδ) T cells in the immune response to cancer, and their infiltration in tumors is a positive prognostic factor. Vδ1 T cells are the most abundant γδ T cells in epithelial tissues including the gut and skin and form a significant proportion of tumour infiltrating lymphocytes (TILs) in a number of solid tumour indications. Tissue-resident cytotoxic Vδ1 γδ T cells are of particular interest in immunotherapy approaches for their role in recognising and eradicating cancer cells, providing new avenues for antibody tissue-based immunological intervention. Vδ1 γδ T cells combine features of innate and adaptive immunity: in contrast to αβ T cells that rely on antigen-presentation via MHC, γδ T cells recognize and kill transformed cells by direct recognition of a pattern of stress associated ligands expressed on their surface, opening up a potential range of cold tumours with decreased or impaired tumour antigen presentation. Adaptate’s first-in-class approach is to harness the specific anti-tumour properties of Vδ1 T cells using activating immunomodulatory antibodies. Methods: Adaptate’s ADT-010 is a first-in-class, fully human, monoclonal antibody which selectively recognizes and binds to the Vδ1 TCR leading to Vδ1 T cell activation. ADT-010 was selected via high-stringency antigen binding using a human phage display library. To elucidate its mechanism of action, the binding and functional activity of ADT-010 was evaluated on expanded skin-derived Vδ1 T cells in vitro. Results: ADT-010 specifically enhanced the Vδ1 killing of cancer cells whilst sparing healthy non-diseased cells. The functional activity of ADT-010 on expanded skin-derived Vδ1 T cells was investigated in the presence or absence of tumour cells. ADT-010 mediated activation of Vδ1 T cells in the presence of target tumour cells was demonstrated through TCR downregulation, CD107a and CD25 upregulation, and enhanced anti-tumour cytotoxicity. Taken together the data indicates that Vδ1 TCR engagement on γδ T cells by ADT-010 results in their full activation and enhanced cytotoxicity only in the presence of target tumour cells. Conclusions: Despite recent advances in immune therapies in oncology, there currently remains a significant unmet need for effective and safe treatments for solid tumours. The challenges of treating such tumours which include infiltration into the tumour tissue and discrimination between healthy and tumour