Bispecific Antibodies Targeting VEGF and ANG2

Introduction to VEGF

VEGF is an acronym for vascular endothelial growth factor, also known as vascular permeability factor. VEGF is a signaling protein secreted by various cells, belonging to a subfamily of the platelet-derived growth factor family, which includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placenta growth factor. VEGF mainly acts by binding to tyrosine kinase receptors on the surface of endothelial cells, such as VEGFR-1, VEGFR-2, and VEGFR-3, activating downstream signaling pathways. VEGF is a key regulator of angiogenesis, stimulating endothelial cell proliferation, migration, differentiation, and survival, as well as increasing vascular permeability. VEGF plays an important role in normal physiological processes such as embryonic development, wound healing, the female reproductive cycle, and more. At the same time, VEGF is also associated with various diseases such as cancer, diabetic retinopathy, age-related macular degeneration, ischemic heart disease, and more. Therefore, VEGF is a potential target for the treatment of many diseases.

Fig.1 VEGFs and VEGF receptors (VEGFRs) (Rauniyar K, 2018)

Introduction to ANG2

ANG2 is an acronym for angiopoietin-2, also known as the tumor-specific growth factor. ANG2 is a specific angiogenic stimulator, belonging to the angiopoietin family, which includes ANG1, ANG2, ANG3, ANG4, and more. ANG2 mainly acts by binding to the tyrosine kinase receptor Tie-2 on the surface of endothelial cells, modulating its signaling transduction. ANG2 can act as an antagonist or a partial agonist of Tie-2, depending on its expression level and ligand competition. ANG2 can regulate the connection between endothelial cells and the matrix, affecting the stability and plasticity of blood vessels. ANG2 can induce endothelial cells to secrete matrix metalloproteinases, degrade the matrix, and make blood vessels unstable and prone to remodeling. ANG2 can also synergize with the VEGF signaling pathway, enhancing vascular permeability and inflammation. ANG2 plays a role in normal physiological processes such as embryonic development, inflammation response, immune regulation, and more. At the same time, ANG2 is also associated with various diseases such as cancer, atherosclerosis, pulmonary arterial hypertension, sepsis, and more. Therefore, ANG2 is also a potential target for the treatment of many diseases.

Fig.2 Schematic representation of the Ang2 effect on the vascular bed in normal conditions, inflammation, and cancer (Akwii RG, 2019)

Signaling Pathways Involved in Bispecific Antibodies Targeting VEGF and ANG2

Bispecific antibodies are a novel class of therapeutics that can simultaneously recognize and bind to two different antigens or epitopes, offering high specificity and affinity. Targeting VEGF and ANG2 with bispecific antibodies can simultaneously block two important angiogenic signaling pathways, thereby achieving a synergistic inhibition of angiogenesis. VEGF signaling pathway mainly involves the binding of VEGF to VEGFR, activating downstream Ras/Raf/MEK/ERK, PI3K/Akt/mTOR, PLCγ/PKC, and other pathways, promoting endothelial cell proliferation, migration, differentiation, and survival, as well as increasing vascular permeability. Bispecific antibodies can bind to VEGF, blocking its interaction with VEGFR, and thus inhibiting these signaling pathways. ANG2 signaling pathway mainly involves the binding of ANG2 to Tie-2, modulating downstream Akt, ERK, p38 MAPK, and other pathways, affecting the connection between endothelial cells and the matrix, as well as synergizing with VEGF signaling pathway. Bispecific antibodies can bind to ANG2, blocking its interaction with Tie-2, and thus inhibiting these signaling pathways. By simultaneously targeting VEGF and ANG2, two key factors, bispecific antibodies can effectively inhibit angiogenesis, and may have stronger and more durable effects than monospecific antibodies targeting VEGF or ANG2 alone.

Clinical Status of Bispecific Antibodies Targeting VEGF and ANG2

Currently, there is only one bispecific antibody targeting VEGF and ANG2 that has been approved for marketing, namely faricimab-svoa (Vabysmo™, Genentech, San Francisco, CA). This drug received FDA approval in January 2022 for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). This drug is the first bispecific antibody that simultaneously targets and inhibits VEGF-A and Ang-2, and has shown longer and more effective treatment effects than monospecific antibodies targeting VEGF-A alone in clinical trials.

In addition to faricimab-svoa, there are some other bispecific antibodies targeting VEGF and ANG2 that are in clinical trial stages.

Table 1. Bispecific antibodies targeting VEGF and ANG2 in clinical trails

A study showed that nintedanib, a tyrosine kinase inhibitor (TKI) targeting the VEGF pathway, combined with a bispecific anti-VEGF/Ang-2 nanobody (BI836880) could selectively prevent brain metastases of lung adenocarcinoma cells in a mouse model. Ang-2-VEGF-A CrossMab is a novel bispecific human IgG1 antibody that blocks VEGF-A and Ang-2 functions simultaneously. It has shown potent antitumor, antiangiogenic, and antimetastatic efficacy in various syngeneic mouse tumors and human tumor xenografts. BI836880 is another bispecific nanobody that targets VEGF and Ang-2. It has been evaluated in two nasopharyngeal carcinoma patient-derived xenograft models, and showed significant tumor growth inhibition.

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