The emergence of biosimilars has revolutionized the treatment landscape for retinal diseases. While ranibizumab biosimilars have led the way globally over the past few years, the recent FDA and EMA approvals of aflibercept 2 mg biosimilars mark a new chapter in clinical application. However, not all biosimilars are created equal—the secret to their long-term market impact lies in their manufacturing processes.
The Biological Blueprint
To understand the manufacturing differences, one must first look at the molecules themselves. Aflibercept is a complex recombinant human fusion glycoprotein that acts as a “decoy receptor” for VEGF-A, VEGF-B, and placental growth factor. In contrast, ranibizumab is a Fab fragment of a monoclonal antibody, lacking the Fc region found in aflibercept.
Host Cells: E. coli vs. CHO
The most significant divergence occurs in the choice of host cells used for production:
- Ranibizumab (Escherichia coli): Most ranibizumab biosimilars utilize E. coli due to its rapid growth and cost-effectiveness. However, expressing complex proteins in bacteria is technically challenging. E. coli often fails to fold these proteins correctly, leading to inactive protein aggregates known as inclusion bodies. This requires a lengthy and labor-intensive process of solubilization and oxidative refolding, which often results in low protein yields.
- Aflibercept (Chinese Hamster Ovary – CHO cells): Aflibercept is produced using mammalian CHO cells, which offer superior protein folding and proper glycosylation. Because the cells secrete the protein in its active, folded form directly into the culture medium, the process eliminates the need for complex refolding.
Market Implications and Patient Access
The streamlined manufacturing of aflibercept—characterized by high expression levels and straightforward downstream purification—suggests a more cost-effective production model compared to the cumbersome refolding required for many ranibizumab biosimilars. As aflibercept already holds a massive market share among retina specialists, its biosimilar versions are poised to drive significant cost savings through increased competition, ultimately improving affordability and patient access to life-changing anti-VEGF therapies.
Summary: Biosimilars in Ophthalmology
Biosimilars are biological products highly similar to already approved reference medicines, designed to provide more affordable treatment options for retinal conditions like neovascular age-related macular degeneration.
In the field of ophthalmology, ranibizumab biosimilars were the first to establish a global presence. The landscape is currently shifting with the arrival of aflibercept 2 mg biosimilars, which benefit from more efficient mammalian cell manufacturing (CHO cells) compared to the bacterial systems (E. coli) typically used for ranibizumab. These manufacturing nuances are critical because they influence protein yield, quality, and production costs, which directly impact the long-term adoption and sustainability of these therapies in clinical practice.
References
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- **** Sharma A, et al. Biosimilars for Retinal Diseases: An Update. Am J Ophthalmol. 2020;224:36–42.
- **** Sharma A, et al. Approved biosimilar ranibizumab—a global update. Eye. 2022.
- **** Tungekar AA, et al. Understanding in-vivo refolding of antibody fragments (Fab): Biosimilar Ranibizumab a case study. Process Biochem. 2024;146:484–97.
- **** European Medicines Agency. Eylea (aflibercept) Summary of Product Characteristics. 2022.
- **** Sharma A, et al. Aflibercept 2 mg biosimilars-will they lead the Anti-VEGF biosimilar world globally. Eye (Lond). 2025;39:1026–7.
