Super hot target CD47/SIRPα!

January 15, 2022/eMedClub News/--Recently, Zhejiang Borui Biopharmaceutical Co.
, Ltd.
(“Borui Bio”) announced its self-developed humanized monoclonal antibody BR105 injection targeting SIRPα The clinical trial application for oncology treatment was approved by the National Medical Products Administration (NMPA)
.

SIRPα is a transmembrane protein expressed on the surface of myeloid cells such as macrophages, monocytes, dendritic cells, and granulocytes
.

In preclinical studies, BR105 can bind to different variants of SIRPα and block the interaction between SIRPα and its ligand CD47.
The in vitro and in vivo pharmacological effects indicate that BR105 can effectively relieve the CD47/SIRPα-mediated phagocytosis inhibitory signal and promote anti-tumor immune response; and BR105 does not affect SIRPγ-involved T cell activation signaling
.

At the same time, in toxicology studies, BR105 can avoid the hematological toxicity caused by targeting CD47, and has better safety
.

In addition, targeting SIRPα can activate the innate immune response by activating myeloid cells, and can bridge innate immunity and adaptive immunity.
Therefore, BR105 has the potential to be combined with T cell immune checkpoint inhibitors such as anti-PD-1 antibody and anti-PD-L1 antibody.
It is expected to solve the drug resistance and non-response problems faced by PD-1/PD-L1 inhibitors in the clinic
.

On the other hand, BR105 can act synergistically with antibodies targeting tumor-associated antigen (TAA) to further enhance the killing effect of immune cells on tumors mediated by TAA antibodies
.

Current Situation of CD47/SIRPα Targeted Drug Development Tumor cells can escape from immunity in various ways.
Among them, one of the mechanisms by which tumor cells evade the innate immune system such as macrophages and other phagocytic cells is to upregulate the CD47/SIRPα signal on the cell surface (also known as for the "don't eat me" signal)
.

Integrin-associated protein (IAP, or CD47) is an important self-signal, which inhibits the phagocytosis of tumor cells by macrophages by binding to the ligand-signaling regulatory protein α (SIRPα) on macrophages
.

Therefore, targeting CD47/SIRPα is an effective strategy to achieve anti-tumor immunotherapy
.

▲ Mechanism of action (Image source: Internet) The CD47/SIRPα signaling pathway was first discovered in 1990, and it is considered to be one of the most promising tumor immunotherapy targets after PD-1/PD-L1
.

Whether at home or abroad, drug development for this target is in full swing
.

➤ In December 2020, Arch Oncology announced that the first patient has been dosed in a Phase 1/2 clinical trial of its innovative fully humanized monoclonal antibody AO-176 targeting CD47 in the treatment of relapsed/refractory multiple myeloma
.

Compared with other antibodies of the same target, AO-176 has highly differentiated characteristics and has the potential to improve its safety and efficacy
.

In addition to the standard mechanism of anti-CD47 antibodies, it binds preferentially to tumor cells over normal cells, and binds tumors more efficiently in an acidic microenvironment
.

In addition, AO-176 can directly kill tumor cells
.

➤ On July 22, 2021, Maiwei Bio, an innovative biopharmaceutical company, announced that its self-developed anti-CD47/PD-L1 bispecific antibody (R&D code: 6MW3211) for clinical trials of advanced malignant tumors was officially approved by the State Drug Administration FDA Center for Drug Evaluation (CDE) approval
.

6MW3211 can simultaneously block the two immunosuppressive signaling pathways of PD-L1/PD-1 and CD47/SIRPα to achieve the combined anti-tumor effect of T cells and macrophages
.

The co-light chain design of this variety makes it have a natural antibody-like structure, which can greatly simplify the production process and ensure product quality
.

In addition, the CD47-binding arm of 6MW3211 only specifically binds to tumor cells and does not bind to human erythrocytes, which reduces the risk of erythrocyte toxicity of CD47 antibodies and avoids the problem of low blood drug concentration due to erythrocyte receptor occupancy
.

The results of preclinical toxicology studies showed that 6MW3211 exhibited good pharmacodynamic effects in a variety of pharmacodynamic models, and had good animal safety
.

➤ In October 2021, Bio-Tech's first clinical trial application for PD-L1/CD47 dual-antibody BAT7104 injection was approved by NMPA, which is intended to be used for the treatment of patients with advanced malignant tumors
.

BAT7104 can effectively inhibit the two signaling pathways of PD-1/PD-L1 and CD47/SIRP-α, thereby mediating T cell activation and triggering the phagocytosis of macrophages
.

As a next-generation anti-PD-L1/CD47 dual antibody, BAT7104 does not bind CD47 on erythrocytes and can preferentially bind to PD-L1-positive tumor cells, thereby reducing the possibility of CD47 antibody toxicity in clinical trials
.

➤ In September 2021, the clinical trials of IBI389 targeting CD3/Claudin 18.
2 and IBI322 targeting CD47/PD-L1 of Innovent Bio were both implicitly licensed by CDE
.

IBI-322 is an anti-CD47/PD-L1 nano-dual antibody.
The approved indications are: single drug or combination for advanced malignant tumors
.

Currently, Phase 1 clinical trials of IBI322 as a single drug are underway in China and the United States
.

IBI-322 is designed to simultaneously inhibit two immunosuppressive signaling pathways, CD47/SIRPα and PD-L1/PD-1
.

By targeting these two pathways, IBI-322 is expected to enhance the body's ability to kill tumor cells
.

Recommended reading: From questioned to full swing: CD47 competition in full bloomYimai Meng broke the news that with the deepening of CD47 molecular research, more and more monotherapy and combination therapies targeting CD47/SIRPα have entered clinical trials Stage, and clinical research data show that CD47/SIRPα targeted therapy has shown positive efficacy in acute myeloid leukemia, lymphoma, head and neck squamous cell carcinoma, gastric cancer and other tumors
.

But so far, there is no monoclonal antibody drug targeting this target on the market globally
.

We look forward to the early launch of the first monoclonal antibody drug targeting this target, bringing hope to more patients
.

Reference: 1.
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