For decades, full-length monoclonal antibodies (mAbs) have dominated the biopharma landscape, serving as the gold standard for targeted therapeutics. However, a significant paradigm shift is currently underway. As the industry pivots towards smaller indication scopes and moves away from the traditional blockbuster model, production demands are shifting to smaller batch sizes. This makes standard Chinese hamster ovary (CHO) expression systems becoming less attractive for a growing list of products.
Consequently, in fields of oncology, rare diseases, autoimmune and infectious diseases, and as diagnostic/imaging tools, the focus is sharpening on smaller, more agile modalities. Fragment-based formats, including specifically nanobodies (single-domain antibodies or VHHs), Fabs and single-chain variable fragments (scFvs), represent the next frontier in protein engineering. A key advancement driving this transition is the development of multi-domain VHH constructs. By combining multiple VHH units (bivalent or trivalent) into a continuous polypeptide chain, these formats achieve higher avidity and multi-specificity while retaining the stability of classic VHHs. Furthermore, they allow for the seamless integration of functional payloads, such as enzymes or toxins.
This transition is not merely a trend; it is a necessary development driven by the limitations of conventional mAbs and the unique capabilities of these smaller molecules.
The strategic advantage of antibody fragments
The dominance of mAbs has been challenged by their inherent physical limitations, specifically their structural complexity and approximate size of 150kDa. These factors can hinder tissue penetration, particularly within dense solid tumours, and complicate stability profiles.
VHHs and antibody fragments in general offer a compelling alternative. Their reduced size of approximately 15kDa (for single-domain VHHs) allows for exceptional tissue penetration, granting access to epitopes that conventional antibodies cannot reach. Furthermore, their superior stability and high specificity make them powerful tools for next-generation cancer immunotherapies and advanced diagnostic imaging.
However, the therapeutic potential of a molecule is irrelevant if it cannot be manufactured efficiently, safely and at scale needed. This is where the industry faces its most critical challenge: establishing robust production pipelines for these formats.
This is precisely the area in which Richter BioLogics excels, with its extraordinary capabilities, capacities and expertise in producing VHH/nanobodies for clinical and commercial purposes.
Richter BioLogics overcomes manufacturing hurdles with specialised expression systems
Producing complex proteins at high titres without compromising quality requires more than standard manufacturing protocols – it demands a specialised toolbox tailored to the molecule’s unique properties.
As pioneers in this field, having produced single-domain VHH/nanobody molecules years before they became a dominant trend, Richter BioLogics has established and implemented a comprehensive production ecosystem over the last years.
Its experience confirms that a one-size-fits-all approach is insufficient for different molecule types, including antibody fragments. Instead, success relies on leveraging different expression systems that ensure high yields and purity specifically for fragments.
Three platforms have proven essential in our manufacturing strategy for various protein products, including VHH/nanobodies:
- Pichia pastoris (Komagataella phaffii): this yeast-based expression system combines the speed of microbial growth with the ability to perform eukaryotic post-translational modifications. It is particularly effective for producing robust titres of functional antibody fragments.
- The Corynex™ Platform (Corynebacterium glutamicum): through a strategic partnership with Ajinomoto, Richter BioLogics has successfully implemented this Gram-positive non-endotoxic bacterial expression system. The platform is a game changer for VHH production, as it enables active proteins to be secreted directly into the culture medium, simplifying downstream processing.
- Cell-free protein synthesis (CFPS): in collaboration with our partner SUTRO, the technology giver, we can offer industrial-scale CFPS systems at Richter BioLogics. This platform enables the direct synthesis of complex proteins, including antibodies and antibody fragments like VHH/nanobodies, Fab and scFv, without the constraints of living cells. By utilising the CFPS technology, we support production volumes of 1,500L and larger, ensuring a seamless transition from development by SUTRO to large-scale manufacturing by Richter BioLogics.
Crucially, both strategies – Pichia and Corynex™ – eliminate the risk of endotoxin contamination ensuring a safer, cleaner final product essential for pharma applications. With its extensive experience with several expression strategies for protein products, Richter BioLogics offers an established infrastructure for development, manufacture and analysis designed for scalability.
Richter BioLogics: experienced partner CDMO for small antibody assets
The industry’s pivot towards fragments and nanobodies is not speculative; it is visible in hard data, including the company’s own experiences. The PatentScope database shows a clear picture, with more than 1,135 VHH-derived patents that were registered from 2022 until today. Looking at the VHH drug market globally, it keeps expanding according to various analysts, with an expected growth rate of approximately 15% by 2033. Internal analysis over the last four years reveals that antibody fragments constitute 25% of all product sales across the company’s manufacturing sites. Furthermore, Richter BioLogics has observed a 13% growth rate in this category over the last five years.
This trajectory indicates that fragments keep moving from niche applications to becoming a cornerstone of the biopharma pipeline. The demand is driven by partners who recognise that the future of diverse therapeutics lies in the versatility of these smaller formats.
Richter BioLogics offers the perfect prerequisites to support clients’ antibody-based projects. The company operates a large process development facility and three multi-product facilities with two 300L and two 1500L bioreactor capacities. This allows Richter BioLogics to seamlessly guide partners from early clinical phases through to commercial-scale production.
This infrastructure is backed by an undeniable track record:
- Over 35 years of experience in microbial production
- More than eight commercial products with product licence holders holding dossiers worldwide
- More than 1,000 batches successfully produced
- More than eight years of experience in VHH/nanobody production
- Accreditations in all major markets including but not limited to the US Food and Drug Administration (FDA), European Medicines Agency (EMA), Japanese Pharmaceuticals and Medical Devices Agency (PMDA) and Brazilian Agência Nacional de Vigilância Sanitária (ANVISA), ensuring regulatory compliance globally
Conclusion
The era of the single-domain antibody is here. As the industry continues to move towards more targeted, stable and penetrative therapies, the ability to manufacture these molecules with precision will define market leadership.
Richter BioLogics established the blueprint for fragment production years ago and continues to establish new and refine existing platforms and toolboxes that make commercialisation possible.
For biopharma companies looking to bring their fragment-based assets to the clinic or market, the time to secure a partnership with Richter BioLogics, a knowledgeable manufacturing partner and expert for nanobody, VHH, Fab and scFv production, is now.
Get in Touch with us:
Contact our VHH/nanobody experts today via e-mail
businessDevelopment@richterbiologics.eu
References:
1. patentscope.wipo.int
2. datainsightsmarket.com/reports/vhh-antibodydrugs-306596