Dual Signaling Inhibition

Bispecific antibodies are synthetic antibody molecules that can simultaneously recognize and bind two different antigens or targets. They have high specificity and affinity and can effectively regulate the interaction between the immune system and tumor cells. The research on bispecific antibodies began in the 1980s. After years of development and improvement, a variety of bispecific antibody drugs have been clinically approved or are in different stages of clinical trials. Compared with traditional monospecific antibodies, bispecific antibodies have higher therapeutic effects and lower side effects, but they also face challenges in terms of stability, half-life, and production costs. The mechanism of action of bispecific antibodies is to achieve bidirectional regulation between the immune system and tumor cells by simultaneously binding to two or more targets, thereby enhancing the effect of tumor immunotherapy. The classification of bispecific antibodies is mainly divided according to their structure and function, one of which is bispecific antibodies with dual-target signaling pathway inhibitory functions, which can simultaneously block two or more signals inside or outside tumor cells pathway, thereby inhibiting the growth, invasion, metastasis, and drug resistance of tumor cells.

Features of Bispecific Antibodies for Dual Signaling Inhibition

• The main feature of bispecific antibodies that inhibit dual-target signaling pathways is that they can simultaneously block two or more signaling pathways, thereby achieving multi-faceted inhibition of tumor cells. This type of bispecific antibody has the following advantages:
• Due to the high heterogeneity and plasticity of tumor cells, they are often able to escape the inhibition of single targets or develop drug resistance by activating other signaling pathways. Dual-target signaling pathway inhibitory bispecific antibodies can simultaneously act on two or more related or complementary signaling pathways, thereby effectively blocking tumor cell survival and proliferation signals, and reducing the possibility of tumor cell escape and drug resistance.
• Dual-target signaling pathway inhibitory bispecific antibodies can simultaneously act on two or more interacting or regulated signaling pathways, thereby producing a synergistic or additive effect, making its therapeutic effect greater than that of single-target inhibition. For example, a bispecific antibody against EGFR and HER2 can simultaneously inhibit the activation of two growth factor receptors, thereby enhancing the killing effect on tumor cells.Dual-target signaling pathway inhibitory bispecific antibodies can selectively recognize and bind two or more targets, reducing the impact on normal cells and improving treatment safety. For example, a bispecific antibody against CD3 and CD20 was able to induce T cell-mediated B cell killing by simultaneously binding T cells and B cells, thereby avoiding adverse reactions to other CD3-positive cells.

Application of Dual Signaling Inhibition

The scope of application of dual-target signaling pathway inhibitory bispecific antibodies in tumor therapy mainly depends on the selection and combination of their targets. Currently, various dual-target signaling pathway inhibitory bispecific antibodies have been clinically tested or approved in different tumor types. Some representative target combinations and indication areas are as follows:

• EGFR and HER2: Both targets are members of the epidermal growth factor receptor family, which are overexpressed or mutated in a variety of solid tumors, leading to proliferation, invasion, and metastasis of tumor cells. Bispecific antibodies against EGFR and HER2 can simultaneously inhibit the activation of two growth factor receptors, thereby enhancing the killing ability of tumor cells. Currently, a bispecific antibody called ZW25 has been clinically tested in various EGFR or HER2-positive solid tumors such as breast cancer, gastric cancer, and ovarian cancer, and has shown good safety and efficacy.
• CD3 and CD20: These two targets are marker molecules on the surface of T cells and B cells, respectively, playing an important role in various hematological tumors. Bispecific antibodies against CD3 and CD20 can effectively eliminate malignant B cells by inducing T cell-mediated B cell killing through simultaneous binding of T cells and B cells. Currently, a bispecific antibody called blinatumomab has been clinically approved in various CD20-positive hematological tumors such as acute lymphoblastic leukemia and non-Hodgkin's lymphoma, showcasing significant therapeutic effects.
• PD-1 and LAG-3: These two targets are immune checkpoint molecules expressed by tumor cells or immune cells in the tumor microenvironment, resulting in the suppression or exhaustion of T cell function. Bispecific antibodies against PD-1 and LAG-3 can simultaneously block the signaling of two immune checkpoint molecules, thereby restoring T cell activity and persistence. A bispecific antibody called relatlimab has been clinically tested in a variety of refractory solid tumors such as melanoma, renal cell carcinoma, and squamous cell carcinoma of the head and neck, demonstrating superior objective response rates compared to the drug targeting a single immune checkpoint.

References

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