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

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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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