CD47 meets PD-L1, mutual achievement and exploration of infinite possibilities!

CD47 and PD-L1 are related to immunosuppression in many types of tumors; CD47 and PD-L1 are both regulated by the proto-oncogene MYC.
Immunotherapy represented by the immune checkpoint PD-1/PD-L1 antibody has penetrated The first to third-line treatments for a variety of common tumors have broad market prospects and are of important strategic significance in the product pipeline of pharmaceutical companies
.
The potential combination possibility makes PD-1/PD-L1 antibody the cornerstone of supporting the future layout of pharmaceutical companies in the oncology field
.
As early as a few years ago when the PD-1/PD-L1 antibody just emerged, leading companies have begun to find the next potential target, or plan to match the PD-1/PD-L1 antibody with a "partner", hoping to The single-drug response rate is limited (10%~35%), and drug resistance or recurrence gradually appears during continuous treatment
.
As a natural immune checkpoint, CD47 can bind to the signal-regulated protein α (SIRPα) on the surface of macrophages in the tumor microenvironment and send out a "dont eat me" signal to avoid immune surveillance
.
Therefore, CD47 has naturally become a very attractive target
.
Foreign companies such as Forty Seven, Trillium, and domestic companies such as ImmuneOnco and Tianjing Biotechnology have entered the game.
Through continuous improvement of technical details, they have gradually reduced the "injury" of CD47-targeted drugs on red blood cells and platelets, and their safety has been significantly improved
.
Both PD-L1 and CD47 are highly expressed in tumor cells and can be simultaneously regulated by MYC
.
MYC expressed by tumor cells can regulate the tumor microenvironment by acting on innate and acquired immune cells and cytokines.
Activation of MYC can up-regulate the expression of CD47 and PD-L1 (MYC can directly act on the promoters of CD47 and PD-L1 , And then regulate the expression level of its mRNA and protein), which in turn leads to immunosuppression and tumor proliferation [1]
.
Many scientific research institutions have verified the idea of ​​blocking CD47 and PD-L1 for tumor immunotherapy at the animal level.
At the same time, pharmaceutical companies are constantly improving the molecular design of this idea according to the characteristics of the target.
On the one hand, it can reduce a single target.
To reduce the side effects, on the other hand, it specifically acts on the tumor microenvironment through the synergistic enrichment effect
.
Take the preclinical research data of CD47/PD-L1 bispecific antibody published by Pfizer as an example.
Its bi-antibody adopts Knob-Into-Hole design to prevent the mismatch of two heavy chains, while adopting common light chain technology to prevent heavy and light chain errors.
Match
.
In order to reduce the binding of the antibody to normal cells expressing CD47, the antibody is designed to have a high affinity for PD-L1 and a low affinity for CD47 (0.
227 nM VS 59.
5 nM)
.
At the same time, in order to increase the efficacy of the antibody, IgG1 subtype is used, which has effects such as ADCP and ADCC [2]
.
The high binding of bispecific antibodies to PD-L1 allows it to selectively bind to cells expressing PD-L1 in the tumor microenvironment, and further reduces the binding to red blood cells
.
In the mouse model, the therapeutic effect of the CD47/PD-L1 double antibody is significantly better than that of the monoclonal antibody, and is better than the combination therapy of the two monoclonal antibodies
.
The CD47/PD-L1 double antibody activates CD8+ T cells and increases the number of CD8+ T cells in the tumor.
It can also activate some natural immune pathways, such as Toll-like receptor related pathways
.
Double antibody therapy up-regulates the expression of TAM (tumor-associated macrophages) antigen processing and presentation related genes, and regulates cDC1, cDC2 and mregDC cells
.
When there are multiple potential solutions to a problem, it means that the pattern is undetermined and everyone who enters the game has a chance
.
In order to achieve the purpose of blocking CD47 and PD-1/PD-L1 at the same time, each company, based on its own resources, separately develops the combination of CD47-targeted drugs and PD-1/PD-L1 inhibitors, or directly develops bispecifics Antibody
.
Most clinical studies of the project are still in the early stages, and currently the published data are limited
.
It is necessary to accumulate more clinical results to judge which is better
.
For CD47 double antibodies that have entered the clinical stage, the mainstream choice is the combination of PD-L1 and CD47, except for the combination of PD-1 and CD47 selected by Hans Biotech
.
*In addition, domestic Nanjing Shenghe, Biotech, Immune Onco and Tianjing Biotechnology have also deployed CD47/PD-L1 double antibodies, which are in the pre-clinical stage and will soon enter clinical trials.
HX-009 HX009 is produced by Hansi Biotech The developed CD47/PD-1 bispecific antibody has been carried out in both phase I and phase II clinical trials in Australia and China
.
HX009 can increase the phagocytosis of macrophages by blocking CD47, activate the immune response of CD8+ T cells, and reactivate T cells by blocking PD-1
.
A phase I clinical study of HX009 in Australia aims to evaluate the safety and tolerability of HX009 injection in patients with advanced solid tumors, as well as pharmacokinetic (PK) characteristics, and use RECIST 1.
1 criteria to evaluate its use in solid tumors The preliminary anti-tumor efficacy of the above
.
The data shows that as of April 2021, the 7 dose groups in Australia have completed the dose escalation enrollment, and a total of 21 patients have been enrolled in the group.
No dose-limiting toxicity and maximum tolerated dose, safety and tolerability have been observed.
Good
.
Among the 20 patients who completed at least one tumor assessment: 3 patients (15%) achieved partial remission (PR), with an objective response rate (ORR) of 15%; 7 patients (35%) achieved stable disease (SD), The disease control rate (DCR) is 50%
.
6MW3211 6MW3211 is an innovative drug independently researched and developed by Maiwei Biologics using the bispecific/bifunctional antibody development platform.
It has obtained NMPA and FDA clinical approvals in July 2021 and August 2021, and has started international multi-center phase I clinical trials.
Research
.
Two humanized antibodies with highly homologous light chain amino acid sequences were transformed by co-light chain technology to construct an anti-PD-L1/CD47 bispecific antibody with a structure similar to the natural antibody [3]
.
One side of Fab binds to PD-L1, blocks the combination of PD-L1 and PD1, eliminates the immunosuppression of PD-1 signaling pathway, restores the immune function of T cells to find and attack tumor cells; combined with PD-L1, 6MW3211 is in The tumor tissue is enriched, and the other side of the Fab targets CD47 to block its binding to SIRP-α, relieve the CD47-mediated immunosuppressive signal, thereby more effectively relieve the immunosuppression in the tumor microenvironment and mobilize T Cells and macrophages participate in the elimination of tumor cells
.
In addition, the CD47 binding arm of 6MW3211 has the differentiated feature that it only specifically binds to tumor cells but not human red blood cells, which reduces the risk of red blood cell toxicity of CD47 antibodies and avoids the problem of low blood drug concentration caused by red blood cell receptor occupancy
.
Preclinical pharmacological and toxicological studies have shown that 6MW3211 has shown good animal safety and clear tumor suppressor activity in a variety of solid tumors and hematoma animal models
.
In addition, Maiwei Biologics has also deployed 6MW3411, a bispecific antibody of PD-L1 and NK cell immune checkpoint, which is the first of its kind, and is expected to enter the clinical research phase in 2022
.
6MW3411 can synergistically relieve the tumor microenvironment NK and T cell immunosuppression, has tumor cell T cell bridging function, and enhances the anti-tumor effect
.
Nanobody design is introduced, the production process is simplified, the expression amount is >6g/L, and the product quality is controllable
.
6MW3411 and 6MW3211 echo each other, reflecting the systematic pipeline layout strategy
.
The addition of CD47 is not only a supplement and upgrade to PD-L1 inhibitors, but also a combination of innate and adaptive anti-tumor immune response, and is expected to become a new generation of broad-spectrum anti-tumor therapy
.
A number of clinical trials and real-world studies have shown that blocking PD-L1 alone is not enough to cope with the multiple immune escape mechanisms of the tumor microenvironment.
It needs to be combined with other immune checkpoint antagonists to improve patient benefits
.
However, most of the CD47 targeted drugs under development, whether it is to change the IgG subtype, modify the Fc domain to remove the killing effect, reduce/remove the red blood cell binding ability, the efficacy of the single drug is still very limited or even ineffective, so it is inhibited by PD-L1 The combination of agents is one of the natural choices
.
Taking into account the production cost, specificity, medication compliance and the possibility of multi-drug combination/sequential use in the future, direct development of bispecific antibodies is an efficient strategy in the long run
.
The addition of CD47 not only compensates for the limitations of PD-L1 inhibitors from the mechanism of action, but also combines two types of broad-spectrum targets, and takes into account both innate and adaptive anti-tumor immune responses [4]
.
The double-blocking intervention is actually a mutual achievement under a synergistic effect.
While further reducing the escape of immune checkpoints, it also releases the unique effect of blocking CD47, bridging the innate immune system (phagocytosis of macrophages) and adaptation Sexual immune system (activated macrophages can present tumor antigens to T cells and have anti-tumor immune amplification effects; preclinical data suggests that CD8+ T cells will be activated and release more IFN-γ after blocking CD47)
.
If interventions such as chemotherapy and even oncolytic viruses are used in advance, it is possible to further enhance the efficacy of CD47/PD-L1 dual antibodies
.
Therefore, the CD47/PD-L1 double antibody may not only be an upgraded version of the PD-L1 antibody, but is expected to become a new generation of broad-spectrum anti-tumor therapy
.
Based on the approved 1~3 line anti-tumor usage of the domestic PD1/PD-L1 antibody, combined with the predictions of many institutions, it is estimated that the domestic PD1/PD-L1 core applicable population is more than 2 million people
.
With the reduction of medication costs after medical insurance negotiations and the successive approval of new indications, the actual population of medications is expected to reach more than 700,000
.
A certain proportion of them can be switched to CD47/PD-L1 double antibodies.
The main growth driver is the accumulation of clinical data in solid tumors, which has more possibilities and broad application prospects
.
The existing payment system may be an important limiting factor for the acceptance of new drugs such as double antibodies
.
References: [1]Ca Sey SC, Tong L, Li Y, et al.
MYC regulates the antitumor immune response through CD47 and PD-L1.
Science, 2016.
[2]Shih-Hsun Chen, Pawel K Dominik, Jessica Stanfield et al.
Dual checkpoint blockade of CD47 and PD-L1 using an affinity-tuned bispecific antibody maximizes antitumor immunity.
J Immunother Cancer, 2021.
[3] Maiwei Biological Prospectus.
[4] Gao Xiangzheng, Liang Keying, Mei Shengsheng, etc.
.
Anti-tumor research progress of combined targeted immune checkpoint CD47 and PDL1.
Chinese Journal of Cell Biology, 2021.