Human CLEC9A antibodies deliver Wilms' tumor 1 (WT1) antigen to CD141⁺ dendritic cells to activate naïve and memory WT1-specific CD8⁺ T cells

Objectives: Vaccines that prime Wilms' tumor 1 (WT1)-specific CD8⁺ T cells are attractive cancer immunotherapies. However, immunogenicity and clinical response rates may be enhanced by delivering WT1 to CD141⁺ dendritic cells (DCs). The C-type lectin-like receptor CLEC9A is expressed exclusively by CD141⁺ DCs and regulates CD8⁺ T-cell responses. We developed a new vaccine comprising a human anti-CLEC9A antibody fused to WT1 and investigated its capacity to target human CD141⁺ DCs and activate naïve and memory WT1-specific CD8⁺ T cells. Methods: WT1 was genetically fused to antibodies specific for human CLEC9A, DEC-205 or β-galactosidase (untargeted control). Activation of WT1-specific CD8⁺ T-cell lines following cross-presentation by CD141⁺ DCs was quantified by IFNγ ELISPOT. Humanised mice reconstituted with human immune cell subsets, including a repertoire of naïve WT1-specific CD8⁺ T cells, were used to investigate naïve WT1-specific CD8⁺ T-cell priming. Results: The CLEC9A-WT1 vaccine promoted cross-presentation of WT1 epitopes to CD8⁺ T cells and mediated priming of naïve CD8⁺ T cells more effectively than the DEC-205-WT1 and untargeted control-WT1 vaccines. Conclusions: Delivery of WT1 to CD141⁺ DCs via CLEC9A stimulates CD8⁺ T cells more potently than either untargeted delivery or widespread delivery to all Ag-presenting cells via DEC-205, suggesting that cross-presentation by CD141⁺ DCs is sufficient for effective CD8⁺ T-cell priming in humans. The CLEC9A-WT1 vaccine is a promising candidate immunotherapy for malignancies that express WT1.