954 Phosphonate-antibody-drug conjugates: a novel immunostimulatory class of ADCs driving inside-out activation of Vγ9Vδ2 T cells leading to selective tumor cell killing

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Background Gamma delta (γδ) T cells are cytotoxic effectors capable of recognizing and eliminating tumor cells independently of major histocompatibility complex (MHC) presentation. Their presence within tumors correlates with improved clinical outcomes across various cancer types. Vγ9Vδ2 T cells are the dominant γδ T cell subset in human peripheral blood and are uniquely responsive to intracellular phosphoantigens (pAgs) presented by the butyrophilin (BTN)3A/BTN2A complex. Clinical trials have previously been conducted using aminobisphosphonates or synthetic pAgs, either alone or in combination with low-dose interleukin-2 (IL-2); however, these compounds lack tumor specificity and are hindered by an extremely short half-life.Methods To address the lack of tumor targeting and short half-life, we engineered antibody-drug conjugates (ADCs) that selectively deliver phosphonates to tumor cells, enabling inside-out activation of Vγ9Vδ2 T cells. These phosphonate-ADCs consist of a monoclonal antibody directed against a tumor-associated antigen (TAA), linked to a phosphonate payload via a protease-sensitive linker. We applied this strategy to various TAA-targeting antibodies, including anti-CD123, anti-CD20, anti-TROP2 and anti-HER2 directed monoclonal antibodies.Results TAA-positive tumor cell lines pretreated with phosphonate-ADCs effectively triggered Vγ9Vδ2 T cell activation in a BTN3A-dependent manner, resulting in robust cytokine production, degranulation, and tumor cell lysis. Importantly, the fragment crystallizable (Fc) region of the antibody component remained functionally intact, preserving critical effector functions such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Our lead ADC demonstrated favorable stability and was well tolerated in cynomolgus monkeys, with no safety concerns observed. Furthermore, Vγ9Vδ2 T cell activation was successfully replicated with primary patient tumor cells, supporting the translational relevance of this approach.Conclusions Immunostimulatory phosphonate-ADCs represent a novel approach for achieving targeted, physiologically relevant activation of Vγ9Vδ2 T cells by delivering phosphonates directly to tumor cells. This modular platform can be paired with virtually any tumor-targeting monoclonal antibody while preserving Fcγ receptor-mediated effector functions. The resulting dual mechanism, combining the direct anti-tumor activity of the antibody with the immune-activating properties of the phosphonate payload, offers a versatile and potent therapeutic approach. Overall, this platform holds promise not only for targeted cancer immunotherapy but also for potential applications in other disease areas.

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