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CD47 Targeting Double Antibody in Tumor Immunotherapy
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CD47 Targeting Double Antibody in Tumor Immunotherapy
So far, compared with traditional anti-cancer treatment strategies, immunotherapy is considered to be the most promising systemic tumor treatment method, and it plays an indispensable role in improving the treatment effect.
Emerging cancer immunotherapies include cancer vaccines, CAR-T cell therapy, cytokine therapy, immune checkpoint inhibitors, and tumor-targeting monoclonal antibodies.
Among them, monoclonal antibodies have become a key and effective treatment method in cancer treatment due to their ability to specifically target molecules.
However, due to the complex pathogenesis of tumors, monoclonal antibodies directed against a single target are often insufficient to show sufficient therapeutic effects.
Therefore, bispecific antibodies ( bsAbs ) against multiple targets have emerged, and its development has changed the field of tumor immunotherapy.
CD47 is a glycosylated transmembrane protein, and its expression is generally up-regulated in a variety of malignant tumors.
The CD47/SIRPα axis is considered a new target in tumor immunology, and CD47 plays a major role in tumorigenesis, because its enhanced expression in cancer cells can avoid phagocytosis.
At present, some immunotherapies targeting CD47, including monoclonal antibodies, CAR-T cells, and ADCs, have entered the clinical research stage.
Here we mainly summarize some bsAbs targeting CD47, as well as their possible mechanisms, safety and efficacy.
The structure and function of CD47
CD47 has a molecular weight of 45-55kDa and belongs to the immunoglobulin superfamily.
It is a supramolecular complex composed of integrins, G protein and cholesterol.
The structure of CD47 includes an extracellular variable region that interacts with the corresponding ligand, a transmembrane region formed by a highly hydrophobic transmembrane segment, and a hydrophilic carboxy-terminal intracellular region.
CD47 activation can mediate cell proliferation, migration, phagocytosis, and phagocytosis.
A series of processes such as apoptosis, immune homeostasis and inhibition of NO signal transduction. CD47 ligands include SIRPα, thrombospondin-1 ( TSP-1 ) and integrins ( αvβ3 and α2β1 ).
Cancer cells use CD47’s “don’t eat me” function, and the level of CD47 expressed on the surface is higher than that of non-malignant cells; a large number of studies have shown that CD47 is overexpressed in different types of tumors.
The high expression level of CD47 is related to the treatment response and prognosis of cancer deterioration.
The expression of CD47 is used by macrophages to distinguish between “self” and “non-self”.
CD47 and its ligands not only regulate immune response, but also mediate various pathophysiological processes, such as neutrophil chemotaxis and nervous system development, and play a regulatory role in immune tolerance and T cell activation.
BsAbs targeting CD47
There are currently four bsAbs that target CD47 for the treatment of various cancer patients and are currently undergoing clinical evaluation.
IBI322 is the first bsAb developed by Innovent to inhibit PD-1/PD-L1 axis and CD47/SIRP-α axis at the same time, and is used to treat patients with advanced malignant tumors.
Preclinical studies have shown that IBI322 can effectively block the CD47/SIRP-α interaction and induce macrophages to phagocytize CD47-expressing tumor cells. IBI322 also effectively blocks the binding of PD-1 and PD-L1 and activates CD4+ T lymphocytes.
Because PD-L1 is expressed in tumor cells, IBI322 can selectively bind to tumor cells more effectively than anti-CD47 monoclonal antibodies. , Thereby reducing the possibility of binding to CD47 expressed on red blood cells, thereby ultimately reducing the toxicity associated with anti-CD47 antibodies.
Therefore, IBI322 has stronger anti-tumor activity and higher safety.
The results of preclinical studies show that the efficacy, tumor distribution and safety of IBI322 in the body are higher than those of anti-CD47 monoclonal antibodies.
Compared with the combination therapy of two monoclonal antibodies, bispecific antibodies can provide patients with a lower cost solution.
Therefore, the development of anti-CD47/PD-L1 bsAb will provide patients with a novel, comprehensive, effective and cost-saving option.
IBI322 may benefit more patients in need. IBI322 is currently undergoing phase I dose escalation trials in China ( NCT04328831 ) and the United States ( NCT04338659 ), and there is currently no clinical data report.
In China, CIBI322A101 is a phase 1a/1b clinical study designed to evaluate the efficacy of IBI322 in the treatment of advanced malignant tumors. The Phase 1b study will be used to evaluate the efficacy of IBI322 on lung cancer, cervical cancer, esophageal cancer, head and neck squamous cell carcinoma, and liver cancer.
HX009 is an anti-PD-1/CD47 bsAb developed by Hangzhou HanxBio , which is used to treat patients with advanced solid tumors, including gastric cancer, colorectal cancer and liver cancer.
It is composed of anti-PD-1 IgG4 subtype monoclonal antibody and SIRPα extracellular domain ( ECD ), which inhibits tumor immune escape by simultaneously activating innate and acquired immune responses and releases immunosuppression by blocking immune checkpoints , So as to achieve a synergistic anti-tumor effect.
This form of antibody-receptor fusion can use natural ligands instead of antibodies to save time and cost.
However, due to the relatively low stability of the receptor part, the stability of the antibody-receptor fusion protein may be lower than the BSAb based on two monoclonal antibodies.
Currently, HX009 is undergoing phase I clinical trials in patients with advanced solid tumors ( NCT04097769 ). So far, there is no clinical data report on the safety and effectiveness of HX009.
IMM0306 was developed by Shanghai ImmuneOnco Biopharmaceutical Co., Ltd. It is a bispecific recombinant antibody receptor fusion protein.
It is designed to target CD47 and CD20 on B cells, but to avoid binding to human red blood cells.
IMM0306 activates the phagocytic ability of macrophages and triggers antigen-specific T cells through tumor antigen presentation, which will become a new hot spot for cancer immunotherapy research in the future.
In vitro studies have shown that IMM0306 binds CD47 and CD20, and its affinity is 3-8 times lower than that of a single targeting molecule.
However, it has stronger phagocytic activity on CD47-positive target cells, and even has stronger ADCC activity than rituximab. Interestingly, IMM0306 has no binding activity to human red blood cells at all.
Treatment of SCID mice implanted with tumors with IMM0306 can significantly inhibit tumor growth, and tumor cells in 5 out of 8 mice were eliminated, which is more effective than rituximab.
In addition, in vivo studies have shown that IMM0306 does not bind to human red blood cells, nor does it induce T cell apoptosis.
Lymphoma can be eliminated at a low dose ( 1.5mg/kg ), which shows obvious advantages in terms of safety and clinical development.
Preclinical studies on non-human primates have shown that after single and multiple administrations of different doses, they have good pharmacokinetic characteristics and no obvious hematological toxicity.
IMM0306 is currently undergoing a phase I clinical trial ( NCT04746131 ) to evaluate its safety and efficacy in patients with B-cell non-Hodgkin’s lymphoma.
At the same time, the IMM03061 dose escalation trial ( IND No.CTR20192612 ) in China is being evaluated in patients with refractory or relapsed CD20-positive B-cell non-Hodgkin lymphoma.
So far, there is no clinical data report on IMM0306.
TG-1801 is an anti-CD47/CD19 bsAb that uses a combination of a low-affinity CD47 targeting antibody and a high-affinity anti-CD19 antibody to ensure that the bsAb only blocks CD47 on tumor cells co-expressing the two antigens. It has enhanced Fc-mediated phagocytosis.
TG-1801 is designed to selectively target CD47 on CD19+ B cells, while retaining red blood cells and platelets.
It can avoid off-target toxicity and represents a new immunotherapy strategy that may have synergistic or complementary effects with drugs currently under development.
In addition, the combined targeting of CD47 and CD19 enhances the expected safety and provides a second mechanism of anti-tumor activity by retaining the ADCC effect of its IgG1 Fc region.
Therefore, TG-1801 may play a key role in improving the prognosis of patients with B-cell malignancies.
At the same time, TG treatment proved for the first time that TG-1801 has a synergistic effect with ublituximab ( anti-CD20 monoclonal antibody ) and umbralisib ( PI3K-δ/casein kinase-1ϵ inhibitor ).
The synergistic tumor growth inhibition seems to be mediated by increased immune effector cell infiltration. Guided.
Currently, TG-1801 is undergoing a phase I clinical trial ( NCT03804996 ) to evaluate its safety and effectiveness in the treatment of patients with B-cell lymphoma. So far, there is no clinical data report on TG-1801.
SL-172154 developed by Shattuck Labs Inc. is a new type of fusion protein, which is formed by linking human SIRPα and CD40L ( SIRPα-Fc-CD40L ) through human Fc.
Its purpose is to block the CD47 immune checkpoint, and at the same time activate the CD40 pathway through the dual mechanism of checkpoint blockade and TNF activation.
Existing studies have found that SL-172154 significantly improves the clearance of primary and secondary tumors, similar to PD-1-Fc-OX40L, compared with the use of monoclonal antibodies against CD40 and CD47 alone or in combination.
It is worth noting that SL-172154 stimulated the dose-dependent increase of multiple serum cytokines in cynomolgus monkeys and CD40+B cell edge, without causing hemolysis or thrombocytopenia.
Currently, SL-172154 is being evaluated in a phase 1 trial ( NCT04406623 ) in patients with ovarian cancer . So far, there is no clinical data report on SL-172154.
The safety and future direction of CD47 targeting BsAbs
Due to the widespread expression of CD47, the potential problems of anti-CD47 antibodies as anti-cancer drugs may cause off-target effects, such as anemia.
CD47 is a key regulator of red blood cell renewal. Therefore, some people worry that CD47-targeting antibodies will accelerate red blood cell clearance and cause hemolytic anemia.
For bsAbs that target CD47 in preclinical studies, people are using various methods to try to reduce this targeted cytotoxicity.
For example, NHP studies have shown that a second dose of IBI322 will cause an additional decrease in red blood cell and hematocrit index.
Although the red blood cell count of the two groups began to recover on the 11th day, compared with the Hu5F9 group on the 15th day, the red blood cell count of the IBI322 treatment group increased significantly.
It is reasonable to expect that IBI322 can reduce the side effects mediated by CD47 targeting in patients.
It is worth noting that CD47 targeting agents ( ie Hu5F9-G4 and TTI-621 ) can cause acute anemia and thrombocytopenia in humans, which may also depend on the form of Fc.
Given that anti-CD47 antibodies and SIRPα-Fc fusion proteins can cause this toxicity, and high-affinity SIRPα monomers do not cause such toxicity, the toxicity of anti-CD47 antibodies seems to be Fc-dependent.
Further research should consider optimizing the structure of anti-CD47 bsAbs to avoid toxicity.
In addition, the expression of CD47 on normal tissues may prevent anti-CD47 therapeutic antibodies from reaching tumor cell targets in the body, which also poses problems for anti-CD47 BSAbs.
One strategy to circumvent this problem is to reduce the affinity of bsAbs for CD47, but retain the ability to block the CD47-SIRPα interaction, and increase the affinity for the second tumor antigen.
In future research, more strategies for CD47 and its ligands targeting tumor cells should be considered.
When macrophages or dendritic cells phagocytose cancer cells through CD47 blockade, these phagocytes may present tumor antigens to T cells to induce anti-tumor T cell responses.
Therefore, the regimen combined with T cell checkpoint inhibitors may further enhance T cell response and improve efficacy.
In short, two exclusion conditions must be set during the development of anti-CD47 bsAbs:
1) red blood cell binding and induction of red blood cell agglutination;
2) induction of T lymphocyte apoptosis. If the above factors are not ruled out, it will be difficult to achieve clinical success.
At present, most of the clinical trials targeting CD47 are in phase I clinical trials, mainly for hematological tumors, and its value in solid tumors has yet to be verified
. We look forward to a more extensive and innovative design of immunotherapy for CD47 bsAbs, so as to promote its effectiveness and reduce immune-related adverse reactions, which will bring good news to more patients.
1.Potential Role ofCD47-Directed Bispecific Antibodies in Cancer Immunotherapy. Front Immunol. 2021;12: 686031.
CD47 Targeting Double Antibody in Tumor Immunotherapy
(source:internet, reference only)