The world's first!

February 18, 2022/eMedClub News/--A few days ago, Immune Onco Biomedical Technology Co.
, Ltd.
announced the successful completion of the world’s first dual-target antibody-receptor recombinant protein drug targeting human CD47 x HER2 (project No.
: IMM2902) The first subject was enrolled and administered
.

The IMM2902 project is a new-generation dual-antibody drug candidate developed based on Immune Onco’s mAb-Trap technology platform with global independent intellectual property rights
.

The project targets the immunoregulatory targets CD47 and HER2, and inhibits tumor cell growth by accelerating the endocytosis and degradation of HER2; by blocking CD47-SIRPα-mediated "don't eat me" signal and activating IgG1Fc-FcγR-mediated "eat me" signal "Signal, thereby stimulating the phagocytosis of tumor cells by macrophages, and presenting the phagocytosed tumor antigens to T cells, thereby exerting a powerful tumor immunotherapy effect
.

The main indications of IMM2902 are advanced solid tumors such as HER2-positive breast cancer, gastric cancer, and lung cancer
.

 The IMM2902 project was previously approved by the China National Medical Products Administration (NMPA) and the U.
S.
Food and Drug Administration (FDA) for clinical trials on June 29 and August 21, 2021, respectively.
The new drug project targeting CD47 has entered the clinical research stage
.

The IMM2902 project successfully completed the first patient enrollment and administration, which is another major milestone for the company! Dr.
Tian Wenzhi, founder, chairman and general manager of Immune Onco, said: "The IMM2902 project enables the drug to preferentially bind to tumor cells through the high affinity of HER2, and at the same time has the ability to not bind to human erythrocytes and avoid "antigen sink".
It is not difficult to see that he is full of confidence in the clinical trial research of IMM2902
.
Exploration begins in the ordinary, but is seen in the subtle.
Immune Onco was established in Zhangjiang Hi-Tech Park, China (Shanghai) Pilot Free Trade Zone in June 2015, focusing on the development and research of anti-tumor immunotherapy products, mainly including new recombinant proteins, bispecific At present, there are many new anti-tumor drugs in the clinical research stage .
The common feature of these products is to stimulate and mobilize the patient's own immune system to exert an anti-tumor effect, and ultimately inhibit the continued growth of tumor cells, reverse a series of malignant symptoms caused by this, and gradually return the patient to a healthy state.
.
Since its establishment, the company has obtained a total of 11 clinical approvals for 5 projects (9 in China and 2 in the United States) .
 ▲ Immune Onco’s CD47-targeting product line (Image source: Immune Onco’s official website) IMM01 is a new generation of tumor immunotherapy products independently developed by Immune Onco with global intellectual property rights.
It has been invented in China, Japan, and the United States.
patent .













The main mechanism of action of the IMM01 product is to block the CD47 target while triggering potent antibody-dependent cellular phagocytosis (ADCP), by activating the phagocytosis of tumor cells by macrophages, and presenting the phagocytosed tumor antigens to T cells, thereby exerting a powerful tumor immunotherapy effect, and at the same time not binding to human erythrocytes, which perfectly solves the core pain point of CD47 target drug development
.

The Phase I clinical trial of the IMM01 product was carried out in the GCP Center of the Hematology Hospital of the Chinese Academy of Medical Sciences, a first-class research institution in the country
.

 IMM0306 is an antibody-receptor recombinant protein targeting both CD47 and CD20.
It belongs to the world's first (First-In-Class) and is a bispecific antibody drug with Immune Onco's completely independent intellectual property rights.
The drug can act on both Targets tumor diseases and modulates the immune system, exerting powerful anti-tumor effects by activating macrophages and NK cells
.

CD47/SIRPα target and HER2 target drug development status ➤ CD47 target integrin-associated protein (IAP, CD47) is an immunomodulatory molecule overexpressed on cancer cells, which is released by cancer cells to avoid being phagocytosed by macrophages The "don't eat me" signal, which binds to the ligand signal regulatory protein alpha (SIRPα) on macrophages, protects tumor cells from immune attack by macrophages and achieves immune escape.
A novel immune checkpoint
.

CD47 is expressed on cells of various solid tumors (eg, ovarian, lung, liver, pancreas, breast, colon, and glioma) and hematological malignancies (eg, acute myeloid leukemia, lymphocytic leukemia, and non-Hodgkin's lymphoma) It is highly expressed, and its expression level is positively correlated with disease progression
.

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
.

 Therapeutic drugs targeting the CD47/SIRPα signaling pathway include the following four categories: CD47 antibody, SIRPα fusion protein, SIRPα antibody, and SIRPγ fusion protein
.

In the past two years, the CD47 target has gone from being questioned by the toxicity of red blood cells to being in full swing now.
It has attracted several domestic and foreign companies to deploy, covering multiple directions such as monoclonal antibody and double antibody
.

➤ On July 21, 2021, Shanghai – Maiwei Bio, an innovative biopharmaceutical company with a full industry chain layout, announced that the clinical trial application for its self-developed anti-CD47/PD-L1 bispecific antibody (R&D code: 6MW3211) was officially approved Approved by the Center for Drug Evaluation (CDE) of the State Drug Administration, clinical trials can be conducted for advanced malignant tumors; on August 20, the clinical trial application of 6MW3211 was officially approved by the US FDA, which can conduct clinical studies on patients with advanced solid tumors ; On September 27, the Phase I clinical study of the project successfully completed the first patient dosing in China
.

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
.

➤ In August 2021, Pfizer and Trillium Therapeutics announced that the two companies have reached a definitive agreement, whereby Pfizer will acquire Trillium, a company focused on developing products targeting the SIRPα-CD47 axis, for $2.
26 billion
.

Since CD47 dominates the balance and clearance of normal red blood cells in the body, severe anemia is still a problem to be overcome by drugs on this target
.

TTI-621 is a novel SIRPαFc fusion protein consisting of the extracellular CD47 binding domain of human SIRPα linked to the Fc region of human IgG1
.

It is a potent bifunctional molecule designed to inhibit CD47 on tumor cells while delivering a strong activation signal to the immune system without the need for additional drug activation
.

TTI-622 shares the same SIRPα domain as TTI-621, but is linked to the Fc region of human IgG4
.

TTI-622 inhibits the CD47 immune checkpoint to the same extent as TTI-621, but delivers a weaker activation signal to the immune system, allowing for higher doses and modulation of the activation signal
.

Importantly, this fusion protein does not bind to CD47 on red blood cells in the body, thus reducing the risk of severe anemia in patients
.

 Currently, the company's two clinical programs, TTI-622 and TTI-621, are in Phase 1b/2 development for multiple indications, with a focus on hematological malignancies
.

 ➤ On January 12, 2022, Zhejiang Borui Biopharmaceutical Co.
, Ltd.
announced that the clinical trial application of its self-developed Class 1 innovative biological product BR105 injection was approved by the NMPA
.

BR105 injection is a humanized monoclonal antibody that targets SIRPα independently developed by BRIO.
It can recognize common genotypes of SIRPα, block the interaction between SIRPα and its ligand CD47, release the "don't eat me" signal, activate Macrophages play a role in tumor phagocytosis and realize anti-tumor immunotherapy
.

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
.

With the deepening of CD47 molecular research, more and more monotherapy and combination therapy targeting CD47/SIRPα have entered the clinical trial stage, and clinical research data show that CD47/SIRPα targeting therapy is effective in acute myeloid leukemia, acute myeloid leukemia, It has shown positive effects on tumors such as lymphoma, head and neck squamous cell carcinoma, and gastric cancer
.

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

 ➤ HER-2 target Human epidermal growth factor receptor 2 (HER2) has a long history and is a long-established oncology target
.

It is expressed in many breast cancer patients, and it also gave birth to the famous HER2 monoclonal antibody Herceptin
.

In addition to breast cancer, the HER2 receptor is also expressed in other cancer types such as gastric cancer
.

In recent years, with the continuous development of technologies targeting HER2, more and more "improved" versions of HER2 have emerged
.

Combination therapy, double antibody, and various antibody-conjugated drugs have all become important research and development directions for HER2 targets
.

They are expected to effectively target tumor cells that do not express high levels of HER2, thereby expanding the range of patients that can be treated
.

 ➤ On July 27, 2020, Carisma announced that its lead HER2-targeting chimeric antigen receptor macrophage (CAR-M) therapy was approved by the US FDA for clinical research, becoming the first CAR-M therapy to enter the clinic
.

In March 2021, CT-0508 completed the first subject dosing
.

In December 2021, Carisma announced CT-0508 in combination with Merck's anti-PD-1 therapy KEYTRUDA for the treatment of HER-2 overexpressing solid tumors
.

 ➤ In June 2021, China's NMPA announced the conditional approval of Rongchang Bio's vedicitumab for injection, a HER2-targeting ADC drug for HER2-overexpressing localized patients who have received at least 2 systemic chemotherapy Treatment of patients with advanced or metastatic gastric cancer
.

The approval of the drug this time means that China has ushered in the first ADC drug independently developed by a Chinese company
.

 ➤ In August 2021, CSPC introduced Corning Jereh HER2 double antibody for RMB 1 billion, and Jinmante Bio, a subsidiary of CSPC, will receive Corning Jereh HER2 double antibody KN026 as a single drug and combined PD-L1/CTLA-4 double antibody Anti-KN046 for the treatment of breast cancer and gastric cancer in China, and will jointly develop other indications of KN026 with Corning Jereh
.

 ➤ In September 2021, clinical-stage biotechnology company Acepodia reported interim data from an active Phase 1 dose-escalation study of its "off-the-shelf" HER2-targeting NK cell therapy ACE1702, demonstrating the therapy's viability in advanced HER2-positive tumors
.

ACE1702 was developed based on Acepodia's proprietary antibody-cell conjugation technology (ACC) and an "off the shelf" NK cell platform (oNK)
.

ACE1702 conjugates Trastuzumab to the surface of NK cells, giving these immune cells the ability to target specific antigens
.

 ➤ In November 2021, Zymeworks announced that it and its partner BeiGene jointly initiated the global Phase 3 clinical trial of Zanidatamab, a bispecific antibody targeting HER2
.

The trial evaluated the efficacy of Zanidatamab in combination with chemotherapy (with or without BeiGene's anti-PD-1-targeting antibody tislelizumab) versus trastuzumab in combination with chemotherapy in HRE2-targeted gastroesophageal adenocarcinoma ( GEA) efficacy and safety in advanced or metastatic patients
.

 ➤ In November 2021, Ambrx Biopharma Inc.
(Ambrx Biopharmaceuticals) announced that its anti-HER2-targeted ADC drug ARX788 successfully completed the first patient with HER2-positive metastatic breast cancer in the global ACE-Breast Phase 2 clinical study
.

Conclusion Cancer treatment has developed rapidly in recent years, and treatment methods have emerged in an endless stream.
We expect that with the update and iteration of technology, the first monoclonal antibody drug targeting CD47 can be launched as soon as possible, bringing hope to more patients, and also hope that there will be more targets.
Drugs with different targets can enter the clinic as soon as possible, providing patients with more treatment options
.

References: 1.
http://cn.
immuneonco.
com/display.
php?id=1352.
Bio-exploration "Pfizer's "Don't Eat Me" target is another success! Trillium Therapeutics for $2.
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