CD20-selective inhibition of CD47-SIRPα "don't eat me" signaling with a bispecific antibody-derivative enhances the anticancer activity of daratumumab, alemtuzumab and obinutuzumab.

Here, we report on a novel bispecific antibody-derivative, designated RTX-CD47, with unique capacity for CD20-directed inhibition of CD47-SIRPa“don’teatme”signaling. RTX-CD47 comprises a CD20-targeting scFvantibody fragment derived from rituximab fused in tandem to a CD47-blocking scFv. Single agent treatmentwith RTX-CD47 triggered significant phagocytic removal of CD20pos/CD47posmalignant B-cells, but not ofCD20neg/CD47poscells, and required no pro-phagocytic FcR-mediated signaling. Importantly, treatment withRTX-CD47 synergistically enhanced the phagocytic elimination of primary malignant B cells by autologousphagocytic effector cells as induced by therapeutic anticancer antibodies daratumumab (anti-CD38),alemtuzumab (anti-CD52) and obinutuzumab (anti-CD20). In conclusion, RTX-CD47 blocks CD47“don’teatme”signaling by cancer cells in a CD20-directed manner with essentially no activity towards CD20neg/CD47poscellsand enhances the activity of therapeutic anticancer antibodies directed to B-cell malignancies.