Tumor-selective blockade of CD47 signaling with a CD47/PD-L1 bispecific antibody for enhanced anti-tumor activity and limited toxicity

Cancer Immunol Immunother. 2021 Feb;70(2):365-376. doi: 10.1007/s00262-020-02679-5. Epub 2020 Aug 6.


CD47, an immune checkpoint receptor frequently unregulated in various blood and solid tumors, interacts with ligand SIPRα on innate immune cells, and conveys a "do not eat me" signal to inhibit macrophage-mediated tumor phagocytosis. This makes CD47 a valuable target for cancer immunotherapy. However, the therapeutic utility of CD47-SIRPα blockade monoclonal antibodies is largely compromised due to significant red blood cell (RBCs) toxicities and fast target-mediated clearance as a result of extensive expression of CD47 on normal cells. To overcome these limitations and further improve therapeutic efficacy, we designed IBI322, a CD47/PD-L1 bispecific antibody which attenuated CD47 activity in monovalent binding and blocked PD-L1 activity in bivalent binding. IBI322 selectively bound to CD47+PD-L1+ tumor cells, effectively inhibited CD47-SIRPα signal and triggered strong tumor cell phagocytosis in vitro, but only with minimal impact on CD47 single positive cells such as human RBCs. In addition, as a dual blocker of innate and adaptive immune checkpoints, IBI322 effectively accumulated in PD-L1-positive tumors and demonstrated synergistic activity in inducing complete tumor regression in vivo. Furthermore, IBI322 showed only marginal RBCs depletion and was well tolerated in non-human primates (NHP) after repeated weekly injections, suggesting a sufficient therapeutic window in future clinical development of IBI322 for cancer treatment.

Keywords: Adaptive immunity; Bispecific antibody; IBI322; Immunotherapy; Innate immunity; Phagocytosis.

MeSH terms

  • Animals
  • Antibodies, Bispecific / pharmacology
  • Antibodies, Bispecific / therapeutic use*
  • B7-H1 Antigen / pharmacology
  • B7-H1 Antigen / therapeutic use*
  • CD47 Antigen / antagonists & inhibitors*
  • Humans
  • Immunotherapy / methods*
  • Mice
  • Mice, Inbred NOD
  • Neoplasms / drug therapy*
  • Neoplasms / pathology


  • Antibodies, Bispecific
  • B7-H1 Antigen
  • CD274 protein, human
  • CD47 Antigen
  • CD47 protein, human