"Don't Eat Me" Signal: Inventory of CD47 Products Under Development at Home and Abroad

In recent years, the CD47 target has been extremely competitive at home and abroad, and it has become the immune checkpoint with the fastest rise after PD-1/L1.
Unlike PD-1/L1, CD47 mainly helps by inhibiting the phagocytosis of macrophages.
Tumor cells escape
.

At present, most of the products under research for CD47 are monoclonal antibodies, double antibodies and fusion proteins.
They are in clinical phase III at the highest stage of development at home and abroad, including Forty Seven's magrolimab (Hu5F9-G4) and ALX oncology's ALX-148.
Although several drugs have stopped clinical development due to red blood cell toxicity, they have not affected the company's research and development enthusiasm
.

CD47 "Don't Eat Me" Signal Pathway

CD47 "Don't Eat Me" Signal Pathway

As an important "immune checkpoint" molecule of innate immunity, CD47 is widely and highly expressed on the surface of tumor cells, such as ovarian cancer, gastric cancer and non-small cell lung cancer.
It can bind to the signal regulatory protein α (SIRPα) on the surface of macrophages and emit " Don't eat me" signal to avoid immune surveillance
.

A number of pre-clinical studies have confirmed that blocking the CD47-SIRPα interaction can enhance the ability of macrophages to swallow tumor cells in vitro and the anti-tumor immune response in vivo.
It is an effective anti-tumor strategy.
CD47 has also become a post-PD-1/L1 One of the most popular immune checkpoints
.

At present, most of the research on the CD47-SIRPα pathway focuses on monoclonal antibodies, double antibodies and Fc fusion proteins.
Some companies have also begun to explore antibody-conjugated drugs
.

Domestic:

Domestic:

According to the incomplete statistics of research and development customers based on Yaorongyun data, there are about 85 kinds of drugs developed in the global CD47-SIRPα pathway (including the preclinical and drug discovery stages), and about 36 drugs have entered the clinical stage, which are developed by domestic companies.
More than 50%, accounting for half of the country
.

In China, most of the products under research are concentrated in anti-CD47 monoclonal antibodies.
There are 9 clinical-stage drugs, and there are three products in phase II clinical trials, namely Cinda Bio's letaplimab (IBI-188), Zhongshan Kangfang's AK117.
and Tian The lemzoparlimab (TJ-011133) of environmental organisms
.

Tianjing Biological also reached a cooperation with AbbVie on TJ011133 for a maximum of nearly US$3 billion in September 2020, which shows the potential of the CD47 pathway

The most commonly combined target in terms of bi-antibody is PD-L1.
There are already 6 domestic products with PD-L1/CD47 bispecific antibodies, and the fastest progress is IMM-2505 from ImmuneOnco.
In addition, it is combined with CD47.
The targets are also PD-1, HER2, CD19 and CD20.

In terms of the number of products, the company that has developed the most CD47-SIRPα pathway products is ImmuneOnco.
4 products have entered the clinic.
Among them, the CD47/HER2 double antibody IMM2902 was approved for clinical trials by NMPA in July, which is the world's first
.

Next is Cinda Bio, which has 3 clinical products.
Among them, the SIRPα antibody IBI397, which has just been applied for clinical application, is the first of its kind in China
.

Kewang Pharmaceutical is also developing SIRPα antibody.

Fusion protein, domestic Mingang Ke only should the IMM-01 and Shangjian Sheng was SG-404.
And CD20 / CD47 fusion protein Jin Bustamante organism, are in phase I clinical
.

Global: CD47 antibody and SIRPa fusion protein enter clinical phase III

Global: CD47 antibody and SIRPa fusion protein enter clinical phase III

Compared with the domestic phenomenon of anti-CD47 monoclonal antibodies, the distribution of foreign products is relatively balanced.
SIRPα antibody and SIRPα fusion protein have an earlier layout
.

Forty Seven is an early entry of the CD47 antibody.
Magrolimab has entered clinical phase III for the treatment of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML)
.

At the 2019 ASH Annual Meeting, magrolimab combined with azacitidine demonstrated a good therapeutic effect in the phase Ib clinical study for the treatment of MDS and AML.

Forty Seven was acquired by Gilead for a total price of US$4.
9 billion in March 2020
.

Now the clinical research of magrolimab has gradually shifted to solid tumors.

The SIRPα fusion protein is another hot spot in the research and development of the CD47-SIRPα pathway
.

The pioneers of foreign SIRPα fusion protein research and development are mainly Trillium Therapeutics and ALX oncology

The core products of Trillium are TTI-621 and TTI-622.
The Fc regions of the two products are different.
TTI-621 is IgG1 subtype and TTI-622 is IgG4 subtype.
The biggest advantage of the product is that it binds tumor cells CD47 with high affinity.
It does not combine with human red blood cells, which improves the safety of the clinical application of the drug
.

Trillium was acquired by Pfizer for US$2.

ALX oncology's ALX-148 process is faster and has entered clinical phase III
.

Compared with Trillium, the advantage of ALX-148 is that it has turned to the field of solid tumors and has obtained early clinical data in gastric cancer and head and neck cancer

In the field of antibody-conjugated drugs (ADC), currently only the CD47 antibody-conjugated drug SGN-CD47M developed by Seagen has entered the clinical stage and is currently undergoing phase I clinical treatment for advanced solid tumors
.

In addition, Tallac’s TAC-002 is a SIRPα antibody coupled to a TLR9 agonist, developed in cooperation with ALX Oncology, and BYON4228 developed by Byondis.

Overcome CD47 blood toxicity

Overcome CD47 blood toxicity

Although the development prospects of targeting CD47 pathway are broad, it also faces some research bottlenecks that need to be solved urgently.
The main problem lies in various hematological adverse reactions
.
CD47 is not only expressed in tumor cells, but also in most normal cells, such as human red blood cells and platelets
.
When CD47 targeted drugs kill tumor cells, they may "injury" red blood cells and platelets, leading to anemia
.

For example, Celgene's CC-90002 and Surface Oncology's SFR231 both terminated early due to blood adverse reactions and withdrew from clinical trials
.
Therefore, many companies have incorporated safety issues into the molecular design during the R&D process to minimize toxicity issues while improving efficacy
.

Second generation CD47 antibody

Second generation CD47 antibody

The second-generation anti-CD47 monoclonal antibody Hu5F9-G4 developed by Forty Seven.
Using human IgG4 subtype, it reduces the toxicity to normal CD47 expressing cells and has shown good single-agent activity in the phase I clinical trial for the treatment of solid tumors
.
IgG4 subtype is also the design choice for most CD47 monoclonal antibodies
.

However, clinical trial results show that Hu5F9-G4 has reversible side effects, including anemia, hyperbilirubinemia, headache, nausea, and retinal toxicity, which limits the clinical dosage and pharmacodynamics
.

Therefore, Hu5F9-G4 has improved the dosing regimen in the clinic, adopting a stepwise dosing method
.
In the clinical trial of Hu5F9-G4 combined with rituximab in the treatment of diffuse large B-cell lymphoma and follicular lymphoma, the investigator first used a low dose (1 mg/kg) once a week for the purpose of Eliminate senescent red blood cells and induce red blood cell regeneration.
After the standby body is compensatively tolerant to low-dose drugs, a maintenance dose (10-30 mg/kg) is administered once a week to avoid adverse reactions such as anemia
.

The stepwise administration method cannot fundamentally solve the problem of cytotoxicity, so some companies began to screen and develop CD47 antibodies without red blood cell toxicity
.
For example, Tianjing Bio's anti-CD47 monoclonal antibody lemzoparlimab, TG Therapeutics' CD47/CD19 bispecific antibody TG-1801.

Dr.
Zang Jingwu of Tianjing Biologics said in an interview with developers that, unlike the way to reduce blood system side effects through improved dosing regimens, Tianjing Biologics has targeted screening and screening during the early antibody screening process.
Antibodies with weak binding to normal red blood cells
.
Therefore, lemzoparlimab is different from other CD47 antibodies under development.
Its binding force to red blood cells is relatively weak, which can minimize the occurrence of hematological side effects such as anemia, and has the potential to become a best-in-class product
.

Trillium also adopted the same development strategy.
Two SIRPα fusion proteins, TTI-621 and TTI-622, will enhance the phagocytosis of tumors by macrophages in patients with skin T-cell lymphoma, and at the same time will not bind to red blood cell CD47
.

Combination medication

Combination medication

Combination medication is the second strategy
.
In July, ALX Oncology announced the phase Ib clinical data of ALX-148 combined with HER2 antibody trastuzumab and chemotherapy.
In patients with HER2-positive gastric cancer who have received more than two pre-treatments, this combination therapy will give the patients objective The response rate (ORR) reached 72%, and the 12-month overall survival rate was estimated to be 76%
.

Inventory of CD47 drug combination clinical trials in recent years, many companies have added monoclonal antibodies or chemotherapeutics for combination therapy in the later clinical stage
.

Gilead recently initiated phase II clinical trials of magrolimab combined with chemotherapy for triple-negative breast cancer; ALX Oncology also registered ALX-148 combined with trastuzumab, ramucirumab and paclitaxel on the Clinicaltrials.
gov website in August for the treatment of advanced stages.
Phase II/III clinical trial of HER2+ gastric cancer (NCT05002127)
.

Combination therapy will become the focus of CD47's future development, and the indications have also shifted from early hematological tumors to solid tumors.
The clinical value of CD47 still needs to be further explored
.

Among domestic companies, Cinda Biosciences was the one that conducted research on the combination of CD47 antibodies earlier, and in July this year, it facilitated a combination drug transaction
.
Innovent Biotech and Ascent Biopharma have reached a strategic cooperation of US$245 million to develop Ascent Biotech's Bcl-2 inhibitor lisaftoclax (APG-2575) and Innovent Biotech's anti-CD47 monoclonal antibody letaplimab (IBI188) and rituximab.
Clinical research
.

Reference

Reference

[1] Zhu Kongli, Wang Yanping, Song Haiyan.
Application of CD47 molecule in anti-tumor immunity[J].
Chinese Journal of New Drugs and Clinics, 2020.
39(06):335-341.

[1] Zhu Kongli, Wang Yanping, Song Haiyan.
Application of CD47 molecule in anti-tumor immunity[J].
Chinese Journal of New Drugs and Clinics, 2020.
39(06):335-341.

[2] Wang Zhihong, Luo Longlong, Peng Hui.
Research progress of anti-CD47 antibody drugs[J].
International Journal of Pharmaceutical Research, 2019.
46(08):565-570.

[2] Wang Zhihong, Luo Longlong, Peng Hui.
Research progress of anti-CD47 antibody drugs[J].
International Journal of Pharmaceutical Research, 2019.
46(08):565-570.

[3]Guo Ruifeng.
Construction of humanized semi-synthetic nanobody library and development of CD47 nanobody[D].
East China University of Science and Technology, 2021.

[3]Guo Ruifeng.
Construction of humanized semi-synthetic nanobody library and development of CD47 nanobody[D].
East China University of Science and Technology, 2021.