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.