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At the end of 2018, Celgene understated the monotherapy of CD47 monoclonal antibody CC-90002 for the treatment of acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). On the day of the suspension of the CC-90002 trial, shares in other CD47 companies such as Trillium, Forty Seven, and Surface Oncology all fell. However, after a short-term share price shock, the market value of Forty Seven, which owns First-in-class CD47 monoclonal antibody 5F9, quickly recovered and remained at around $500 million.

 

On March 25, 2019, another American biotechnology company, Arch Oncology, which focused on the study of new drugs for CD47, announced that it has completed a $50 million Series B round of financing to promote a single-agent Phase I clinical trial of its new CD47 antibody, AO-176. It is worth noting that this round of investors, in addition to several well-known biomedical professional investment funds, also attracted Roche’s winds with strong biopharmaceutical research and development background.

 

Although Celgene’s anti-CD47 introduced from Inhibrx has been clinically dissected in Phase I, but since 2017, many pharmaceutical giants are still vying to arrange CD47 related projects, CD47/SIRPα as a post-PD-1/PD-L1 study. The most rapidly progressing tumor immunological checkpoints still have great appeal in clinical applications.

The biological mechanism of CD47 target is more complicated, but CD47 has become a tumor immunotherapy target on the basis of theory. CD47 is highly expressed in many cancer cells, and its signaling pathway has become a highlight of target therapy in recent years. Since CD47, which is highly expressed on tumor cells, binds to the macrophage surface receptor SIRPɑ, it transmits a “Don’t Eat Me” signal to counteract the “eat me” signal on the tumor cells, thereby shielding the phagocytic function of macrophages. Therefore, if a monoclonal antibody or the like is used to block the CD47/SIRPα signaling pathway, the phagocytosis of tumor cells by macrophages can be restored.

As a target of a new generation of tumor immunotherapy, CD47 can cause a mechanism of action of innate and adaptive immune responses, which has been repeatedly confirmed in clinical trials, and has significant activity in blood and solid tumor suppression in single drug tests. For example, the use of Trillium’s TTI-621 monotherapy in patients with cutaneous T-cell lymphoma enhances the phagocytosis of macrophages by tumors, as well as the tendency of T cells to attack cancer cells. CD47 mAb 5F9 also showed monotherapy activity in a solid phase I trial of Forty Seven.

 

Security issues worthy of attention

Forty Seven, Celgene (Inhibrx), Surface Oncology and other companies as pioneers in the development of CD47 target-related antibody drugs, also found and reported a series of safety issues in clinical research, making the safety of CD47 target issues widely concerned.

CD47 is involved in maintaining the balance of red blood cells in the body. On the surface of aging red blood cells, due to the increase in the “eat me” signal such as calreticulin on the cell surface, the “eat me” signal exceeds the CD47 “don’t eat me” signal, which promotes the phagocytosis of aging red blood cells by macrophages. CD47 dominates the clearance and balance of red blood cells in the body. This means that while CD47 treatments kill tumor cells, they may accidentally injure red blood cells, leading to anemia.

The first generation of CD47 mAbs, such as Celgene’s CC-90002 and Surface Oncology’s SFR231, attempt to solve this problem by selecting antibodies with low in vitro red blood cell agglutination activity. However, in actual clinical trials, the anemia and pharmacokinetic sinking effect (PK sink effect) is still unresolved, showing that red blood cell agglutination is not the main cause of anemia.

The situations discussed above are very common in the development of innovative drugs. Many of the target-related efficacy and safety issues are also solved by the second generation of molecules after trial and error and empirical precipitation of the first generation of drug molecules (that is, for the entire industry). CD47 may also No exception.

There are several strategies for reducing the ability of CD47 drugs to bind to red blood cells. The most effective one is to design CD47 antibodies that reduce or eliminate red blood cell binding. Arch Oncology’s product AO-176 is such an antibody. According to the information disclosed by the company, the monoclonal antibody can selectively bind tumor cells without binding to red blood cells. Although the specific test data is not disclosed, the drug-making properties of AO-176 monotherapy should be one of the main considerations when Roche Ventures conducts due diligence. If the patent search reveals two other monoclonal antibodies that selectively bind to tumor cells without substantially binding to red blood cells from Phanes Therapeutics. Two unrelated companies have the same results, suggesting that it is feasible to reduce CD47 drugs for red blood cell binding strategies.

In theory, CD47 on the surface of red blood cells and CD47 on the surface of tumor cells may have different conformations, or bind different intracellular and cell surface proteins. In addition, the membrane topographic conformation and membrane fluidity of the two-sided foveal red blood cells are different from those of the spherical tumor cells. If properly designed, CD47 antibodies may not bind to CD47 on their surface due to the special membrane structure of red blood cells.

Numerous research companies have also incorporated safety issues into molecular design research. These companies have developed second-generation CD47 antibodies based on their predecessors and have made great progress. It is foreseeable that the next generation of CD47 monoclonal antibody that does not bind or less bind red blood cells will eliminate or reduce side effects such as anemia, and provide more treatments for cancer patients, while preserving the efficacy of such new drugs in clinical trials. .

 

The imagination of CD47 double antibody

The unique potential of CD47 monoclonal antibody is that it can overcome the cancer cell inhibition of innate immune system macrophages and open up a new way for tumor immunotherapy. A recent clinical trial of a tumor-specific site injection by Trillium showed that blockade of CD47 may cause the immune system to recognize tumor cell-specific antigens, thereby enhancing T cell attack on cancer cells. If this result is confirmed in a larger clinical trial in the next step, the combination of CD47 monoclonal antibody and PD-1 or PD-L1 monoclonal antibody will greatly increase the efficiency of their single drug.

Similarly, CD47 monoclonal antibody may also bring unexpected surprises to cancer treatment if it is combined with some selective tumor immunotherapy targets. The newly concluded AACR 2019 also announced the development direction of the CD47 target. Three posters on the CD47 target were presented at the global anticancer drug development event. Two of them are second-generation monoclonal antibodies that do not bind or less bind red blood cells, and one is a double-resistant variety. The monoclonal antibody is OA-176 of ArchOncology and GenSci-059 of GeneScience, and the double antibody is anti-CD47 / Methothelin of Novimmune.

 

In conclusion, the second generation CD47 antibody has the potential to exceed PD-1 and PD-L1 mAb, either as a single drug or a combination drug or even a double antibody. Good things are going to be worn, and we look forward to this day coming soon.

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