PD-1/PD-L1-inhibiting
antibodies have shown disappointing efficacy in patients with refractory
ovarian cancer (OC). Apparently, OC cells exploit nonoverlapping immunosuppressive mechanisms to evade the immune system. In this respect, the CD73-adenosine inhibitory immune checkpoint is of particular interest, as it rapidly converts pro-inflammatory
ATP released from
cancer cells to immunosuppressive
adenosine (
ADO). Moreover,
cancer-cell-produced
ADO is known to form a highly immunosuppressive extra-tumoral 'halo' that chronically inhibits the anticancer activity of various immune effector cells. Thus far, conventional CD73-blocking
antibodies such as oleclumab show limited clinical efficacy, probably due to the fact that it indiscriminately binds to and blocks CD73 on a massive surplus of normal cells. To address this issue, we constructed a novel bispecific antibody (bsAb) CD73xEpCAM that inhibits CD73 expressed on the OC cell surface in an
EpCAM-directed manner. Importantly, bsAb CD73xEpCAM showed potent capacity to inhibit the CD73
enzyme activity in an
EpCAM-directed manner and restore the cytotoxic activity of
ADO-suppressed anticancer T cells. Additionally, treatment with bsAb CD73xEpCAM potently inhibited the proliferative capacity of OC cells and enhanced their sensitivity to
cisplatin,
doxorubicin,
5FU, and ionizing radiation. BsAb CD73xEpCAM may be useful in the development of
tumor-directed immunotherapeutic approaches to overcome the CD73-mediated immunosuppression in patients with refractory OC.