Combined Therapy of PD-L1 and CD47

Introduction of PD-L1 and CD47

The immunological checkpoint of programmed death-1 (PD-1) and its ligand PD-L1 are renowned for their ability to unleash anti-tumor T-cell immunity, despite the fact that it is suppressed in many tumor types. Another well-known target, CD47, is overexpressed on a variety of malignant cells and functions as an innate inhibitory checkpoint by preventing the phagocytosis of cancer cells and the subsequent activation of innate responses. As a result, tumor cells can avoid being noticed by the body's natural immune system as well as the adaptive immune system. More than 50% of human malignancies express both CD47 and PD-L1, making immune checkpoint molecule targeting in combination treatment an interesting target with promising early results.

Case 1: Bispecific Antibody Harbors Better Anti-tumor Activity

A CD47 and PD-L1-targeting bispecific antibody (BisAb) can inhibit both innate and adaptive immune checkpoint pathways. In comparison to anti-CD47 or anti-PD-L1 antibody treatment alone, the BisAb-based therapy on mice with subcutaneous CT26 tumors results in increased tumor-killing activity in vivo and improves survival rates. The tumor rejection is lessened when an inactive form of BisAb is used. ViSNE analysis of the total T cells in the tumors of BisAb-treated mice reveals that CD8⁺ T cells are more enriched than control cells and that the proportion of Tregs is lower. Both are evidence of a potent antitumor reaction.

Fig.1 Single bispecific antibody shows remarkable antitumor activity than each monoclonal antibody.¹

Case 2: Targeting CD47 and PD-L1 Together in Pancreas Cancer Models

The ability of transplanted MPC-83 cells to normally express CD47 and PD-L1 in vivo is demonstrated by immunofluorescent staining. These mice are then given monoclonal antibodies of anti-CD47 and anti-PD-L1 separately or in combination to assess their anti-tumor effectiveness. In the group receiving combined therapy, the tumor volume is further declining, pointing to a synergistic interaction between these two antibodies. The combined treatment enhanced the fraction of PD-1⁺CD8⁺ T cells in all samples compared to either anti-CD47 or anti-PD-L1 alone, according to flow cell analysis of the lymphocytes isolated from spleen, peripheral blood, and tumor tissue.

Fig.2 Enhanced inhibitory effect of anti-CD47 and anti-PD-L1 is observed when targeting the MPC-83-induced tumor model.²

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References

1. Chen, Shih-Hsun, et al. "Dual checkpoint blockade of CD47 and PD-L1 using an affinity-tuned bispecific antibody maximizes antitumor immunity." Journal for immunotherapy of cancer 9.10 (2021).
2. Pan, Yu, et al. "Single-cell RNA sequencing reveals compartmental remodeling of tumor-infiltrating immune cells induced by anti-CD47 targeting in pancreatic cancer." Journal of hematology & oncology 12 (2019): 1-18.

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