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

• Main Authors: Peter E. van Bommel, Yuan He, Ilona Schepel, Mark A. J. M. Hendriks, Valerie R. Wiersma, Robert J. van Ginkel, Tom van Meerten, Emanuele Ammatuna, Gerwin Huls, Douwe F. Samplonius, Wijnand Helfrich, Edwin Bremer
• Format: Article
• Language: English
• Published: Taylor & Francis Group 2018-02-01
• Series: OncoImmunology
• Subjects: bispecific antibody; cd47; phagocytosis; rituximab; sirpα
• Online Access: http://dx.doi.org/10.1080/2162402X.2017.1386361
• ISSN: 2162-402X

Here, we report on a novel bispecific antibody-derivative, designated RTX-CD47, with unique capacity for CD20-directed inhibition of CD47-SIRPα “don't eat me” signaling. RTX-CD47 comprises a CD20-targeting scFv antibody fragment derived from rituximab fused in tandem to a CD47-blocking scFv. Single agent treatment with RTX-CD47 triggered significant phagocytic removal of CD20pos/CD47pos malignant B-cells, but not of CD20neg/CD47pos cells, and required no pro-phagocytic FcR-mediated signaling. Importantly, treatment with RTX-CD47 synergistically enhanced the phagocytic elimination of primary malignant B cells by autologous phagocytic 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't eat me” signaling by cancer cells in a CD20-directed manner with essentially no activity towards CD20neg/CD47pos cells and enhances the activity of therapeutic anticancer antibodies directed to B-cell malignancies.