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 in Phase II clinical trial of graft versus-host disease (GVHD) after hematopoietic stem cell transplantation in the preventive treatment for leukemia patients. 

In the treatment of COVID-19 critically ill patients, the Phase III clinical trial code-named SAC-COVID evaluated the safety and effectiveness of CD24Fc in COVID-19 inpatients who need oxygen support. Patients were randomly divided into two groups: standard care + single dose of CD24Fc or standard care + placebo. The results show that: Patients treated with CD24Fc have a 60% greater chance of clinical recovery than patients treated with placebo (P=0.005); The median recovery time of patients treated with CD24Fc is 6 days, while that of placebo group is 10 days; In addition, patients receiving CD24Fc and glucocorticoid (which the average recovery time is 5 days) recover 10 days earlier than patients receiving placebo and glucocorticoid (which the average recovery time is 15 days). 

Besides CD24Fc, AcroImmune Group also designs a next-generation Siglec agonist AI-071 based on its understanding on CD24-Siglec10 signaling pathway. It can effectively regulate the injury to the body which is caused by the inflammatory reaction related to tissue injury according to the signaling pathway targeting CD24-Siglec10, and has a great therapeutic potential for various autoimmune diseases, GvHD, viral pneumonia and other inflammation-related diseases. 

In addition, based on CD24, AcroImmune Group also develops the engineered tumor-specific anti-CD24 antibody ONC-781, chimeric antigen receptor CAR-T ONC-782, bispecific antibody ONC-783 with T cell participation, and antibody conjugate ONC-784. 

Pheast Therapeutics 

One of the R&D targets of Pheast Therapeutics is to develop the CD24 targeted therapy for ovarian cancer, breast cancer and other solid tumors according to CD24 signaling pathway. In addition, the company will also develop target treatment according to the other macrophage checkpoints, overcome the redundant "Don't eat me" signal of tumor, and explore the effect of macrophage checkpoint inhibitor combined with other immunotherapy and targeted therapy. 

ImmuneOnco

While laying out the CD47 target in depth, ImmuneOnco develops a candidate drug (IMM47) in the preparation stage of IND and many candidate drugs (IMM4701 and IMM2547) in discovery and preclinical stage around CD24 target, each of which may become the first drug of its kind to enter the clinical stage in the world. 

At present, the preliminary clinical concept research of CD47 target has been completed in hematologic tumor, and the drug R&D is in the later stage of clinical research. As another "Don't eat me" signal, CD24 expressed in breast cancer and ovarian cancer even exceeds CD47, which is expected to become another popular macrophage checkpoint. In addition, CD24 does not express in red blood cell and will not produce anemia and other blood toxic and side effects, thus, it has a great development prospect in the future. At present, there are not many companies focusing on the R&D of CD24 target in clinical stage, which is a true blue ocean track. 

References:

1. Hotamisligil, G.S., Inflammation, metaflammation and immunometabolic disorders. Nature, 2017. 542(7640): p. 177-185.

2. Pheast Raises $76M in Series A Funding to Train the Immune System to Feast on Cancer. Retrieved April 26, 2022, from https://www.prnewswire.com/news-releases/pheast-raises-76m-in-series-a-funding-to-train-the-immune-system-to-feast-on-cancer-301532492.html.

3. ImmuneOnco Prospectus. Retrieved Mar 26，2023, From https://www1.hkexnews.hk/app/sehk/2023/105261/documents/sehk23032600299_c.pdf.

4. https://medcitynews.com/2022/04/cancer-biotech-pheast-unveils-76m-to-expand-immunotherapys-menu-to-new-targets/.