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

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Here, we report on a novel bispecific antibody-derivative, designated RTX-CD47, with unique capacity for CD20-directed inhibition of CD47-SIRP alpha "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(pos)/CD47(pos) malignant B-cells, but not of CD20(neg)/CD47(pos) 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 CD20(neg)/CD47(pos) cells and enhances the activity of therapeutic anticancer antibodies directed to B-cell malignancies.

Original languageEnglish
Article numbere1386361
Number of pages8
JournalOncoImmunology
Volume7
Issue number2
DOIs
Publication statusPublished - 2018

Keywords

  • bispecific antibody
  • CD47
  • phagocytosis
  • rituximab
  • SIRP
  • STEM-CELLS
  • PHAGOCYTOSIS
  • TARGET
  • SELECTIVITY
  • LYMPHOMA
  • BLOCKADE
  • PROTEIN
  • TUMORS
  • ALPHA

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