Recently, Antengene Corporation announced that the Phase I clinical trial application (IND) of its global first anti-CD24 monoclonal antibody, ATG-031, had been approved by FDA.
ATG-031, a humanized antibody targeting CD24, can combine with CD24 with a high selectivity, block the binding of CD24 with its ligand Siglec-10, and promote the phagocytosis of tumor cells by macrophages. After ATG-031 mediates the phagocytosis of tumor cells by M2 macrophages, M2 macrophages begin to show the trend of polarization towards anti-tumor M1. ATG-031 has a high anti-tumor efficacy in vivo in animal models, and has a synergistic effect with immune checkpoint inhibitors (ICI) and chemotherapy drugs. And ATG-031 shows a good tolerability in the primate toxicology experiments.
Another "Don't eat me" target: CD24
CD24 (cluster of differentiation 24) is a protein with a small molecular weight expressed on highly glycosylated cell membrane, and is connected with plasma membrane through glycosyl phosphatidyl inositol anchor point. Normally, CD24 is mainly expressed in human immune cells, but it is overexpressed in more than 70% of malignant tumor cells (such as liver cancer, lung cancer, bladder cancer, etc.).
The research shows that through combining with the Ligand-Sialic Acid Binding Ig Like Lectin 10 (Siglec-10) on macrophages, CD24 can release the "Don't eat me" signal that inhibits the phagocytosis of tumor cells by macrophages causing tumor cells to escape immune surveillance. It will help immune effector cells such as macrophages to identify tumor cells by blocking the binding of CD24 with Siglec-10 using antibody targeting CD24 or CD24 receptor fusion protein.
CD47 has to be mentioned when it comes to the "Don't eat me" signal. CD47 is highly expressed in many human hematologic tumor cells, and it will interact with SIRPα on the surface of macrophages and send out a signal of "Don't eat me" to prevent normal cells from being swallowed by macrophages. At the same time, tumor cells will overexpress the CD47 to escape from the immune. It will have an obvious effect on treating tumor to block the CD47-SIRPα pathway. CD47 target was ever regarded as one of the hottest immune checkpoints after PD-1/L1. However, it is difficult to develop CD47 drugs. Famous pharmaceutical companies failed in the development of CD47 target drugs, such as AbbVie and Gilead. This is because the CD47 target itself has insurmountable defects: CD47 is also expressed in red blood cells and platelets, which causes blood toxicity. At present, there is no effective solution to solve the related side effects.
Unlike CD47, CD24 is not expressed in human red blood cells, which will not cause blood-related side effects similar to CD47, with a greater safety window. Thus, CD24 is expected to become a new target of anti-tumor immunotherapy. A popular article published in Nature in 2019 proves that CD24 is another "Don't eat me" signal protein expressed in ovarian cancer and breast cancer cells, making up a large piece of puzzle for the "immune escape" principle of tumor cells.
Drug development targeting CD24
Because of the complex CD24 protein structure and high barriers in R&D, only a few companies are developing the CD24 targeted drugs, such as Antengene Corporation, Pheast, Guangzhou AcroImmune Group, ImmuneOnco and so on.
AcroImmune Group
AcroImmune Group, founded by Chinese scientist Liu Yang and Zheng Pan in 2000, is committed to discovering and developing new immunotherapy for cancer, inflammation and autoimmune diseases. CD24-Siglec10 innate immune checkpoint is discovered firstly by Liu Yang and Zheng Pan's laboratory (Science, 2009). CD24Fc, the first biopharmaceutical product of its self-developed target CD24-Siglec10, was purchased by MSD in 2020. CD24Fc has been performed a safety research in healthy volunteers, and has shown a therapeutic effect...
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