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

ABSTRACT: Here, we report on a novel bispecific antibody-derivative, designated RTX-CD47, with unique capacity for CD20-directed inhibition of CD47-SIRP? "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.

SUBMITTER: van Bommel PE 

PROVIDER: S-EPMC5749665 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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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.

van Bommel Peter E PE   He Yuan Y   Schepel Ilona I   Hendriks Mark A J M MAJM   Wiersma Valerie R VR   van Ginkel Robert J RJ   van Meerten Tom T   Ammatuna Emanuele E   Huls Gerwin G   Samplonius Douwe F DF   Helfrich Wijnand W   Bremer Edwin E  

Oncoimmunology 20171031 2

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 CD20<sup>pos</sup>/CD47<sup>pos</sup> malignant B-cells, but not of CD20<sup>neg</sup>/CD47<sup>pos</sup> cells, and required  ...[more]

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