CD47 therapy is considered by the industry as one of the next most important targets in the field of tumor immunity after the PD-1 / L1 era.
With the increasingly mature clinical application of immune checkpoint inhibitors targeting PD-1 / PD-L1, tumors have entered the era of immunotherapy. Although technological progress has promoted the development of chronic cancer, the industry is also constantly looking for new tumor immunotherapy targets to make up for the low response rate of PD-1 / PD-L1 antibody. CD47 therapy is considered by the industry as one of the next most important targets in the field of tumor immunotherapy after PD-1 / L1, which also makes the research competition in this field white hot.
However, recently, the US FDA poured cold water on this field. As an earlier enterprise in the field of CD47, Gilead announced that due to the obvious imbalance between the research groups of suspected accidental serious adverse reactions (susars) reported by researchers, the US FDA has suspended the clinical research of the joint research part of its CD47 monoclonal antibody magrolimab + azacitidine. In this way, the safety of CD47 target drugs is also questioned.
So, is there any development prospect in the field of CD47 treatment? How safe and effective is it? In this regard, Dr. Zhu xiuxuan, President and director of Tianjing biology, said in an interview with the reporter of the 21st Century Business Herald that it is still unknown what caused Gilead’s clinical trial to stop. It also depends on strengthening the understanding of the incident in many ways. This Gilead incident also provides an opportunity for the whole industry to understand, We also hope to know the potential clinical risks of CD47 more clearly when the reasons for the suspension of clinical trials can be further clarified.
popular CD47
CD47 is a glycoprotein widely expressed on the surface of a variety of cancer cells, which is linked to SIRP on the surface of tumor phagocytes α Junctions release “don’t eat me” signals to prevent macrophage phagocytosis. This inhibitory mechanism is also used by entities with high expression of CD47 and hematological malignancies.
The research and development of CD47 is not plain sailing. As early as 2017, tioma (now renamed arch Oncology) announced the termination of a phase I / II clinical trial of its CD47 monoclonal antibody ti-061 in Europe. Subsequently, in 2018, celgene’s CD47 monoclonal antibody cc-90002 failed in the phase I clinical trial. Serious adverse blood reactions are considered to be the root cause of the poor progress of the drug.
Until 2019, forty seven, a cancer immunotherapy company, announced the excellent phase 1b results of its CD47 monoclonal antibody magrolimab combined with azacitidine in the treatment of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) at the 2019 ash conference, which proved the drug formation of this target. Subsequently, gillide spent US $4.9 billion on the acquisition of forty seven in March 2020, pushing the enthusiasm for the research and development of this target drug to the peak.
The research and development of CD47 pathway drugs was once blocked by the safety problems of red blood cells and sectorlets. However, various enterprises have improved the safety problems of this target drug through different strategies such as pre excitation administration, unique epitope antibody screening or antibody molecular design, and have been verified clinically. At present, in addition to gillide, a number of pharmaceutical enterprises, including Cinda biology, Tianjing biology, thinkdi medicine, Yiming Angke and kangfang biology, are laying out CD47.
According to CICC statistics, by the end of 2021, a total of 22 candidate drugs targeting CD47 pathway had registered relevant clinical trials on the NCT registration platform, including 9 anti-CD47 monoclonal antibodies and 2 anti SIRP α Monoclonal antibody, 7 double antibodies and 2 SIRP α Fc fusion protein.
However, at present, there is no target drug listed on CD47, and Xinda biology and Tianjing biology have attracted much attention. Cinda biological IBI 188 is a recombinant human IgG4 monoclonal antibody targeting CD47, which can enhance the phagocytosis of tumor cells by macrophages and promote the cross activation of T cells. The product is in the clinical research on the treatment of high-risk myelodysplastic syndrome at the initial diagnosis; Tianjing biological lezolizumab is an innovative CD47 monoclonal antibody independently developed. Its unique antigen binding epitope can block CD47 and SIRP α And can minimize the combination with normal red blood cells, so as to reduce the occurrence of clinical severe anemia, and lezolizumab does not need pre excitation administration. In September 2020, Tianjing biological authorized its CD47 antibody lemzoparlimab to Alberta with an amount of up to US $1.94 billion.
Dai Wen, head of the great health research group of Huatai Securities Co.Ltd(601688) Research Institute, believes that at present, CD47 is indeed one of the hottest targets in the global market. CD47 related products under development are mainly divided into CD47 monoclonal antibody, double antibody and SIRP α Fusion protein, SIRP α Antibodies, etc. From the perspective of the overall competition pattern, Chinese enterprises Tianjing biology, Jiangsu Hengrui Medicine Co.Ltd(600276) , Xinda biology, etc. have layout. Overall, as the effect of CD47 target on blood tumors is more clear, and the overseas market of blood tumors is wider than that in China, it is more meaningful for local pharmaceutical enterprises to seek opportunities to actively go to sea.
questionable CD47 security
Some researchers believe that with similar broad-spectrum antitumor efficacy, once CD47 drug is successfully approved for marketing, its potential market scale may be comparable to PD-1 However, there is still uncertainty about the future direction, whether it is monoclonal antibody, double antibody, fusion protein or combination. Especially at the end of January 2022, the FDA suspended some clinical trials of magrolimab of Gilead due to unexpected serious adverse reactions, which once again questioned the safety of CD47 target drugs.
However, some insiders believe that this adverse reaction may be more related to the erythrocyte / sectorlet toxicity of magrolimab itself, which does not affect the prospect of the whole CD47 target. Products with better follow-up safety are expected to narrow the progress gap with magrolimab. Gilead also said that at present, no obvious trend of adverse reactions or new safety signals have been found.
Dai Wen believes that the main reason why Gilead suspended the clinical trial this time is that there were more than one death cases during the clinical trial.
Tianjing biology is also concerned about the reasons for the suspension of Gilead clinical trial. According to the 21st Century Business Herald, the reporter learned that Tianjing biological lezolizumab is the product with the fastest clinical progress of CD47 in China. As for the safety of traditional CD47 antibodies, candidate molecules are obtained by screening antibodies targeting unique epitopes. Lezolizumab has a special binding site. Due to the N50 glycosylation of red blood cell CD47, lezolizumab binds worse to red blood cells, but retains the binding ability to tumor sites.
Lezolizumab is currently enrolled in nearly 180 Chinese and foreign patients. It shows good safety in the current clinical study, and most of the traes are grade 1-2. Safety is the differential advantage of lezolizumab.
\u3000\u3000 “Whether the CD47 clinical trial will lead to death, and whether the suspension of Gilead clinical trial is caused by anemia or by thrombocytopenia, there are different opinions at present. We hope to get a more formal reply from FDA as soon as possible. After Gilead incident, we also seriously need to do some more systematic strengthening measures to find drug-related drugs Toxicity may include how to solve it faster if toxicity occurs. ” Dr. Zhu xiuxuan said that in the field of blood tumors, especially in the field of myeloid tumors, CD47 needs to pay more attention to the safety if it is combined with drugs such as azacytidine. As long as the safety performance is better grasped, it will be convenient for the next step in strategy.
is there any prospect of CD47 stopped
Magrolimab’s partial clinical suspension has once again questioned the safety of CD47 target drugs. However, the industry believes that this adverse reaction does not affect the prospect of the whole CD47 target, and the follow-up products with better safety are expected to narrow the progress gap with magrolimab.
Professor Li Jian, chief physician of Hematology Department of Peking Union Medical College Hospital, believes that the effect of PD-1 pathway in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) is very poor. Based on this, CD47 has a broad market prospect. On the one hand, the clinical needs of MDS and AML are the most urgent. At present, there are many innovative therapies such as monoclonal antibody and car-t in the field of myeloma and lymphoma, but at the same time, there is a lack of broad-spectrum field in this field, which also makes CD47 inevitable in this field; On the other hand, the curative effect of CD47 is considerable. From the current efficacy data, the single drug effect of CD47 in AML and MDS is more prominent, and the effective rate has reached 40% – 50%. Therefore, the preliminary data of the therapeutic effect of CD47 pathway drugs in AML and MDS have been preliminarily verified, but whether the final drug verification is successful remains to be read out.
\u3000\u3000 “In addition, the side effects are small. Anemia and thrombocytopenia are not a particularly big problem for patients with myeloid tumors. These patients have very obvious anemia and thrombocytopenia before treatment. Compared with lymphoma and solid tumors, the hematopoietic function of these patients is affected, so the side effects are not particularly critical in this field.” Professor Li Jian believes that combined with the above three points, CD47 is the most promising and worthy of surprise attack in the field of MDS and AML. The future development direction of CD47 is still combination therapy.
A number of clinical trials and real-world studies have shown that blocking PD-L1 alone is not enough to deal with the multiple immune escape mechanism of tumor microenvironment, and other immune checkpoint antagonists need to be combined to improve the benefits of patients. Most of the CD47 targeted drugs under development, whether changing IgG subtype, modifying Fc domain to remove killing effect, reducing / removing erythrocyte binding ability, the efficacy of single drug is still very limited or even ineffective. Therefore, many experts in the industry have pointed out that the combination with PD-L1 inhibitor is one of the natural choices. Considering the production cost, specificity, medication compliance and the possibility of multi drug combination / sequential use in the future, the direct development of bispecific antibodies is an efficient strategy in the long run.
For the future market space of CD47 pathway drugs, CICC analysis believes that AML / MDS is a relatively more confirmed indication of CD47 targeted drugs, with a space of about 15.7 billion yuan. In other hematomas such as non Hodgkin’s lymphoma (NHL), CD47 is the direction of exploration. At present, there are preliminary efficacy data, and the potential of combined therapy in the future needs further data verification. In addition, solid tumor is the ultimate goal of CD47. At present, a variety of drug single drug or combination strategies have shown efficacy in solid tumors, and the combination of CD47 + PD-1 has also shown efficacy in tumor species such as head and neck squamous cell carcinoma (HNSCC). When the concept of CD47 targeted drugs is verified in solid tumors, CD47 is expected to become a new generation of heavy drug targets.
