Resources>Blog>Monoclonal Antibody Therapeutics Production in Four Eras
Monoclonal Antibody Therapeutics Production in Four Eras
Biointron2025-01-30Read time: 6 mins
DOI: 10.1007/s41745-018-0061-9
Foundational Discoveries and Challenges (1975–1998)
The development of monoclonal antibody (mAb) therapeutics began in 1975 when Köhler and Milstein developed hybridoma technology, a breakthrough that earned them the Nobel Prize in 1984. The first mAb approved for human use, Orthoclone OKT3 (muromonab-CD3), was licensed in 1986 for preventing kidney transplant rejection. However, early mAbs were derived from murine sources, leading to immunogenicity issues in patients. This challenge spurred the transition to chimeric, humanized, and fully human antibody sequences, improving therapeutic efficacy and safety.1
Manufacturing of mAbs in this era relied on hybridoma cells, often grown in mouse peritoneal cavities, before recombinant DNA technology enabled production in mammalian cell lines such as Chinese hamster ovary (CHO) cells. The first recombinant full-length mAb, Rituxan (rituximab), was launched in 1997, setting a precedent for large-scale bioreactor-based production.
During this period, industry debates centered on purification methods, particularly the use of Protein A chromatography for antibody capture. Concerns over Protein A leaching into final products were mitigated through rigorous purification protocols, leading to its widespread adoption.
The second era of monoclonal antibody production saw a significant rise in demand, with blockbuster drugs like Herceptin (trastuzumab), Humira (adalimumab), and Avastin (bevacizumab) driving industry expansion. The number of licensed mAbs increased significantly, from only a few approvals in the early years to nearly 80 approved therapeutics in this era.
Manufacturing processes became more standardized, with fed-batch CHO cell culture emerging as the dominant platform. This method utilized chemically defined media and optimized upstream processes to boost production culture titers from 1–2 g/L in the early years to 5 g/L or more by the late 2010s.
Purification bottlenecks, once a major concern, were addressed through process improvements such as larger chromatography columns and increased buffer volumes. As confidence in large-scale CHO-based production grew, companies invested heavily in manufacturing infrastructure. Bioreactor sizes expanded from 12,000 L to 25,000 L, with large-scale facilities supporting multiple products simultaneously.
Regulatory agencies also played a role in shaping industry trends. As mAb therapeutics demonstrated consistent safety and efficacy profiles, the approval process for new antibody drugs became more streamlined.
The Acceleration of Monoclonal Antibody Manufacturing (2020–2023)
The COVID-19 pandemic pushed monoclonal antibody manufacturing into an unprecedented phase of rapid scale-up and deployment. mAb therapies from companies such as Eli Lilly, Regeneron, and AstraZeneca were developed, authorized, and manufactured at an extraordinary pace. Production culture titers ranged from 5–8 g/L, reflecting the industry’s ability to leverage cutting-edge cell-line development and bioprocessing technologies.
Despite initial concerns about global manufacturing capacity, the industry demonstrated remarkable agility. Large-scale facilities dedicated to COVID-19 antibody production managed to supply tens of millions of doses, highlighting the robustness of existing monoclonal antibody production infrastructure.
The pandemic reinforced several key principles in biomanufacturing:
Process portability: The ability to transfer manufacturing processes between facilities with minimal changes.
Process simplicity: Streamlining production workflows to reduce complexity and increase efficiency.
Dual-sourcing strategies: Diversifying supply chains for raw materials and manufacturing sites to mitigate disruptions.
The experience also validated the effectiveness of conventional manufacturing methods. Calls for revolutionary changes in mAb production have been tempered by the realization that existing platform technologies can meet high global demand efficiently.
DOI: 10.3389/fimmu.2022.818736
Scaling for Global Access (2024 and Beyond)
The fourth era of monoclonal antibody production presents opportunities for further optimization in both upstream and downstream processing. Industry trends indicate a continued rise in production culture titers, now surpassing 8 g/L, driven by improvements in cell-line engineering, media formulations, and bioreactor control strategies.
Contract research organizations (CROs) such as Biointron are expanding capacity, positioning themselves to handle the growing demand for monoclonal antibodies. This shift suggests that outsourcing to CMOs may become the preferred strategy for many biopharmaceutical companies rather than investing in internal production capacity.
Key considerations for the future include:
Expansion into new therapeutic areas: With improved manufacturing efficiency, mAbs may be increasingly used for chronic conditions such as Alzheimer’s disease, migraines, and cardiovascular diseases.
Cost reduction strategies: Lowering the cost of goods (COGs) to make mAb therapies more accessible to low- and middle-income countries (LMICs).
Innovations in dosing and administration: Efforts to reduce dosing frequency and develop subcutaneous formulations to improve patient compliance.
A notable proposal for the future of mAb manufacturing is the establishment of very large-scale (VLS) facilities dedicated to producing high-demand mAbs, including those for infectious disease prophylaxis. Such a facility could manufacture 10–100 million doses annually, supporting global health initiatives and pandemic preparedness.
Monoclonal antibody therapeutics have come a long way since their inception, evolving through technological advancements, regulatory adaptations, and large-scale commercialization. With continued improvements in bioprocessing and an expanding global manufacturing network, the next era of monoclonal antibody production will likely focus on improving accessibility, reducing costs, and expanding therapeutic applications.
Kelley, B. (2024). The history and potential future of monoclonal antibody therapeutics development and manufacturing in four eras. MAbs, 16(1), 2373330. https://doi.org/10.1080/19420862.2024.2373330
