VEGF-A antibody discovery for next-generation angiogenesis therapies

What is VEGF-A and what is its role in angiogenesis?

Vascular endothelial growth factor A (VEGF-A) is the primary regulator of physiological and pathological angiogenesis. It stimulates the proliferation, migration, and survival of endothelial cells. It also increases vascular permeability. It plays a central role in tumor angiogenesis, retinal angiogenesis, and numerous vascular disorders.

Alternative splicing generates several isoforms of VEGF-A, including VEGF121, VEGF165, VEGF189, and VEGF206. VEGF165 is the predominant biologically active isoform in oncology and ophthalmology.

VEGF-A binds to two tyrosine kinase receptors:

• VEGFR1 (Flt-1), a high-affinity receptor that regulates ligand availability;
• VEGFR2 (KDR/Flk-1), the primary signaling receptor responsible for angiogenesis and vascular permeability.

VEGF-A promotes tissue repair and vascular homeostasis. However, during pathological hypoxia, tumors and ischemic tissues increase VEGF-A production. This leads to uncontrolled neovascularization.

• In oncology, this vascular network supplies the oxygen and nutrients necessary for tumor growth and metastasis.
• In ophthalmology, excess VEGF-A leads to the formation of immature and permeable blood vessels, which are responsible for conditions such as neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME).

Why target VEGF-A in therapy?

Approved indications and therapeutic applications of anti-VEGF-A antibodies

In oncology, anti-VEGF-A monoclonal antibodies such as Bevacizumab (Avastin):

• inhibit tumor angiogenesis;
• normalize tumor vascularization;
• improve the delivery of anticancer treatments.

Anti-VEGF-A therapies are currently used to treat several solid tumors, such as colorectal cancer, non-small-cell lung cancer, renal cell carcinoma, and ovarian cancer.

In ophthalmology, anti-VEGF-A antibodies have become the standard of care for:

• neovascular age-related macular degeneration (wet AMD);
• diabetic macular edema;
• diabetic retinopathy;
• certain retinal vein occlusions.

Drugs such as Ranibizumab (Lucentis), Aflibercept (Eylea), Brolucizumab (Beovu), and Faricimab (Vabysmo) reduce vascular leakage, retinal edema, and pathological neovascularization, thereby helping to preserve vision.

Challenges of VEGF-A antibody discovery

VEGF-A antibody discovery is a competitive field. The goal is to design antibodies that offer added value compared to existing treatments.

The key challenges driving the development of next-generation VEGF-A antibodies are to differentiate them from existing antibodies. Indeed, there are already several approved antibodies on the market. This requires engineering molecules that strike a balance between efficacy, safety, duration of action, and ease of administration.

In ophthalmology, anti-VEGF agents have improved the management of conditions such as neovascular age-related macular degeneration (AMD) and diabetic macular edema. However, despite the excellent results obtained in clinical trials, real-world outcomes are often less favorable. Repeated intravitreal injections are a burden for both patients and healthcare professionals. They lead to reduced adherence and, in the long term, diminished clinical benefits. The development of next-generation VEGF-A antibodies is therefore aimed at prolonging the duration of action and extending the interval between administrations.

In oncology, another challenge lies in the redundancy of angiogenesis mechanisms. Tumors can activate alternative pathways, such as VEGF-C, FGF, or PlGF, limiting the effectiveness of VEGF-A inhibition alone. Some patients also exhibit primary resistance or experience secondary resistance (tachyphylaxis). This underscores the need to develop VEGF-A antibodies that bypass these mechanisms.

Pharmaceutical companies must also address intellectual property challenges. The patent cliff for major biologics, the arrival of biosimilars, and the need to maintain sufficient freedom to operate are driving them to focus on:

• new epitopes;
• bispecific antibodies;
• Fc engineering approaches;
• bio-better strategies.

👉 Explore our pipeline to identify untapped opportunities and competitive positioning.

Overview of VEGF-A antibodies: first generation to next generation

Approved anti-VEGF-A antibodies

Bevacizumab (Avastin), a humanized IgG1 monoclonal antibody, was one of the first anti-VEGF-A monoclonal antibodies to be designed and marketed. It inhibits tumor angiogenesis and neutralizes the main isoforms of VEGF-A. Originally developed for oncology, it is also used in ophthalmology.

Ranibizumab (Lucentis) is a humanized Fab fragment developed for retinal diseases. Its smaller size improves retinal penetration and limits systemic exposure. Its affinity maturation process, achieved through phage display, also gives it a higher binding affinity for VEGF-A than that of the parent molecule from which it was derived.

Aflibercept (Eylea) is a fusion protein that acts as a VEGF trap. It combines domains from VEGFR1 and VEGFR2 with an IgG1 Fc region. In addition to VEGF-A, it also neutralizes VEGF-B and PlGF. Its increased affinity allows for more complete neutralization of the ligand and facilitates longer dosing intervals in clinical practice.

Brolucizumab (Beovu) is a humanized scFv fragment that allows for the delivery of a high concentration of active ingredient in a small volume, although its use is limited by a rare risk of intraocular inflammation.

Finally, faricimab (Vabysmo), the first bispecific antibody approved in ophthalmology, targets VEGF-A and Ang-2 to improve vascular stability. Its Fc region has also been modified to reduce binding to Fc gamma receptors, thereby minimizing the risk of triggering inflammatory effector functions in the eye.

These biologics have revolutionized the treatment of angiogenesis-related diseases. However, they also highlight the need to design molecular engineering strategies aimed at achieving higher affinity, longer duration of action, or additional biological targeting.

Emerging approaches in VEGF-A antibody engineering

Today, strategies for VEGF-A antibody engineering and VEGF-A antibody optimization aim to overcome the limitations of current treatments (duration of action, resistance mechanisms, or clinical differentiation).

Development is now focused on bispecific antibodies, antibody-drug conjugates (ADCs), Fc engineering approaches, as well as sustained-release delivery systems and gene therapies.

In oncology, ADCs and multispecific antibodies aim to overcome resistance mechanisms by targeting multiple signaling pathways. In ophthalmology, the goal is to reduce the frequency of injections by:

• long-acting formulations, such as Eylea HD;
• extended-release delivery systems, such as Susvimo;
• gene therapy approaches.

The patent cliff for major biologics and the arrival of biosimilars are also accelerating the development of bio-better antibodies. These are capable of offering a clinical or commercial advantage over existing treatments.

Future candidates will also need to stand out in terms of their developability, their selection of epitopes, their freedom to operate, and their ability to target new angiogenic pathways, such as VEGF-C, PDGF, or FGF. In the long term, the identification of predictive biomarkers could also enable personalized treatments and improve patient selection.

Why choose MAbSilico for VEGF-A antibody discovery?

MAbSilico’s VEGF-A antibody discovery platform accelerates the discovery of anti-VEGF-A antibodies. It combines artificial intelligence, structural modeling, and experimental data. It enables the identification of new epitopes and the optimization of candidate properties. It also helps you anticipate differentiation and intellectual property challenges from the earliest stages of development.