The rapid growth of more complex monoclonal antibodies (mAbs) creates new challenges for process development teams. Cytiva’s latest findings illustrate just how quickly the landscape is shifting: alongside 357 traditional mAbs, Phase I pipelines already include 169 antibody-drug conjugates (ADCs) and 177 multispecific antibodies.
For scientists working in downstream process development, this diversification introduces a new reality. Different molecular architectures bring different purification behaviours, impurity profiles and manufacturing requirements. This puts greater demands on chromatography, protein purification, bioprocessing and scalable manufacturing strategies and models.
When the Molecule Changes, the Process Must Change Too
Multispecific antibodies can differ considerably in molecular architecture, stability, impurity profiles, and binding characteristics. ADCs introduce an additional layer of complexity by combining an antibody with a cytotoxic payload and linker.
The downstream process must therefore deal not only with recovering the desired molecule, but with maintaining its critical quality attributes while removing increasingly molecule-specific impurities.
Recent scientific literature reflects the same trend: as antibody formats diversify, purification approaches established for conventional mAbs increasingly need to be adapted or supplemented with more tailored strategies.
The First Challenge: Finding the Right Capture Strategy
Protein A affinity chromatography has long been the workhorse of monoclonal antibody capture.
But diversification of antibody structures means that developers need a broader purification toolbox. Depending on molecular architecture and impurity profile, conventional Protein A capture may need to be optimized, while alternative affinities or modified Protein A resins can provide advantages for particular molecules.
This changes the role of process development. Rather than simply applying an established platform, scientists increasingly need to understand the properties of the molecule early and evaluate which capture and polishing technologies provide the best balance of purity, yield, productivity, and scalability.
Cytiva’s portfolio to optimize productivity in mAb capture supports this approach through affinity, ion-exchange, multimodal, and other separation technologies that allow developers to construct purification strategies around the molecule rather than forcing every molecule into the same process.
Polishing Becomes More Challenging
Capture is only the beginning. Complex antibody therapeutics can generate product-related impurities that are particularly difficult to separate because their physicochemical characteristics may closely resemble those of the target molecule. Aggregates, fragments, mispaired species, charge variants, host cell proteins, and other impurities can all create downstream challenges. This places greater demands on polishing.
Ion exchange and multimodal chromatography can provide complementary selectivity after capture, giving process developers additional tools for separating closely related species. Multimodal chromatography, for example, has been investigated for the removal of aggregates, fragments, and other impurities associated with complex antibody formats.
The objective is no longer simply to purify an antibody. It is to design a purification sequence capable of consistently delivering the required product quality for a specific therapeutic molecule.
Process Development Also Needs to Become Faster
There is another challenge: time. Biopharmaceutical developers cannot afford to spend years creating an entirely new downstream process for every candidate entering the pipeline. Process development therefore needs to become both more molecule-specific and more efficient. This is where high-throughput experimentation, Design of Experiments (DoE), mechanistic modelling, and digital process-development tools are becoming increasingly valuable.
Instead of relying primarily on sequential trial-and-error experiments, development teams can use experimental data and modelling to explore a larger process design space, identify influential parameters, and narrow down promising operating conditions earlier.
Research into downstream process development has increasingly highlighted the potential of combining experimental and model-based approaches to reduce experimental effort while building deeper process understanding.
From Chromatography Equipment to a Connected Development Ecosystem
The diversification of antibody therapeutics also changes what laboratories need from their equipment. Nowadays, a chromatography system is an integral part of a broader process-development environment in which scientists need to test conditions, compare resins, collect process data, optimize methods, and eventually transfer those methods towards larger-scale production.
This is where Cytiva’s ÄKTA™ chromatography systems provide an important bridge between research, process development, and scale-up.
Systems such as ÄKTA pure™ support flexible protein purification and method development, while ÄKTA avant™ is designed for process development and scale-up studies.
Together with Cytiva’s extensive chromatography resin portfolio, including MabSelect™ Protein A resins, Capto™ ion exchange and multimodal resins, and other separation technologies, these systems allow developers to investigate different purification strategies within a connected chromatography ecosystem.
The value lies not simply in individual products, but in the ability to move from screening and process development towards scalable purification using technologies designed to work across different stages of development.
Digitalization Is Becoming Part of Downstream Development
As the number of experiments and process variables increases, managing and interpreting process data becomes another challenge. Digital tools can help scientists capture experimental knowledge, compare process conditions, improve method development, and support technology transfer. For complex molecules, this becomes particularly important because historical platform knowledge may provide only part of the answer.
Future downstream development is therefore likely to combine three elements: flexible hardware, adaptable purification technologies, and increasingly sophisticated digital process knowledge. The objective is to enable process developers to make better decisions earlier and build robust processes with greater confidence.
Scalability Must Be Considered from the Beginning
A purification process that performs well at laboratory scale is not automatically suitable for manufacturing. Column dimensions, flow rates, pressure limitations, resin performance, buffer requirements, system configuration, and regulatory expectations all become increasingly important as processes move toward clinical and commercial production.
Considering scalability during early process development can therefore reduce the risk of costly redesign later. This is particularly relevant for emerging antibody modalities, where manufacturing experience may be more limited than for conventional mAbs. Developing with scalable technologies from the beginning creates a more continuous path from discovery to process development and eventually manufacturing.
Conclusion
Perhaps the most important conclusion from the changing antibody pipeline is that there may no longer be one universal model for antibody manufacturing. Traditional mAbs will remain important. But ADCs, bispecific and multispecific antibodies, fragments, and other engineered formats will continue expanding the therapeutic toolbox. Each brings different molecular characteristics. And different molecules require different process decisions.
At The Science Support, we provide Cytiva’s chromatography systems, resins, and bioprocessing technologies to support scientists across protein purification and downstream process development, from early laboratory studies through process optimization and scale-up. View our complete portfolio of comprehensive solutions for your downstream processing and scale-up.