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Antibody-adjuvant conjugates elicit robust myeloid activation and durable anti-tumor immunity

Despite the presence of antigen-presenting myeloid cells in the tumor microenvironment during tumorigenesis, the immune system generally fails to mount an effective anti-tumor response. Recent findings in the Engleman lab revealed that simultaneous intra-tumoral delivery of tumor-binding antibodies and certain immune stimuli can induce myeloid cell uptake, processing and presentation of a wide range of tumor antigens to T cells, resulting in tumor-eradicating immunity in syngeneic mouse models. We aimed to understand the cellular and molecular mechanisms underlying this approach and further develop it for potential clinical use by designing and constructing antibody-adjuvant conjugates (AACs). Unlike separately administered components, such conjugates have the potential to deliver precise antibody-adjuvant ratios to the tumor microenvironment following intra-tumoral or systemic delivery. In vitro experiments revealed that AACs are able to potently activate human primary myeloid cells, leading to increased co-stimulatory receptor expression and production of pro-inflammatory cytokines, superior to that induced by the mixture of components. Furthermore, stimulation with the AAC induces dendritic cell differentiation and prolonged cellular survival. CyTOF-based analysis of intracellular signaling in human primary PBMCs revealed a unique signaling signature of the AACs compared to the mixture of components, suggesting a novel biological mechanism by which the AACs stimulate myeloid cells in a toll like receptor (TLR) and Fc receptor (FcR) dependent manner. Finally, we demonstrated in vivo activity in a murine tumor model, in which treatment with an AAC led to tumor clearance. These results provide a strong basis for AACs as a therapeutic technology platform as well as rationale for evaluating the safety and efficacy of these AACs in clinical trials.