Antigen-loaded antibodies

Guillaume Wassmer, PhD

Acute myeloid leukemia (AML) accounts for 80% of acute leukemia cases in adults and results from the accumulation of immature malignant myeloid cells at the expense of healthy differentiated counterparts. The treatment options for AML remain limited. While a moderate therapy success has been observed in patients below the age of 65, about 70% of older patients succumb to the disease within one year after diagnosis. Therefore, the search for more therapeutic options in AML is imperative.

Our laboratory has developed a platform for efficient delivery of immunodominant viral epitopes to tumor cells. The approach is based on antigen-armed antibodies (AgAbs) that carry antigens from the Epstein-Barr virus (EBV). With the help of this strategy, malignant cells become visible for the immune system and are targeted by EBV-specific CD4+ cytotoxic T cells. Indeed, AgAbs bind to surface molecules expressed by the malignant cells and provoke receptor-mediated endocytosis. As a result, viral peptides included in the AgAbs are shuttled into the endosomal compartments of the target cells, where the epitopes can be processed for MHC class II-restricted presentation on the cell surface. In EBV-positive individuals, circulating memory virus-specific cytotoxic CD4+ T cells recognize the MHCII-bound peptides on the surface of tumor cells and mediate cell lysis.

We have developed AgAbs that specifically target AML and leukemia stem cells. This approach makes sense because a high percentage of AML cells express functional MHC-II molecules and up-regulate several specific membrane receptors. Our preliminary experiments suggest that the AgAb strategy in AML is promising. Indeed, AgAbs can eliminate primary AML cells in vitro and ex vivo. Moreover, this therapeutic approach conferred a strong survival advantage in a murine AML model.