Drugs like monoclonal antibodies are becoming more sophisticated — and harder to purify JULICHKA/ISTOCK
Inside the bodies of a growing number of cancer patients, a remarkable feat of pharmaceutical ingenuity is playing out: an injection of an engineered antibody that targets two different fronts at once — a feat no natural antibody can achieve.
With one of its molecular arms, the engineered antibody seizes a cancer cell and with the other, an immune cell called a killer T cell. By hauling the two together, the antibody allows the T cell to destroy the cancer cell. But without this forced union, the killer T cell would have missed the cancer cell altogether. Such molecules, known as bispecific antibodies, are transforming cancer treatment. Their dual-targeting powers bring enhanced precision, reduced side-effects and the ability to circumvent cancer’s famously inventive resistance mechanisms. They are now being trained on other complex conditions such as autoimmune disease.
Bispecific antibodies are just one of a new generation of protein-based drugs, or biologics, that are shaping the future of precision medicine. Scientists are aiming for ever-more complex therapeutic targets, with a broader range of drug types. For example, trispecific antibodies that can bind to three antigens are in the works, as well as more sophisticated versions of single-target monoclonal antibodies, which have been in clinical use for decades. With AI helping to generate more options, drug candidates are flooding the pipeline.
However, this vast increase in drug candidate diversity has exposed a critical bottleneck: manufacturing technology hasn’t kept up. “Downstream development, manufacturing and some analytical workflows are not scaling at the same rate as what’s happening in discovery,” says Paul Belcher, business leader at global life sciences company Cytiva. “And that is creating bottlenecks.”
In the long and tortuous path from drug candidate to the clinic, a key stumbling block is purification—separating the active ingredient from the environment in which it is made. Unlike “small molecule” drugs, which are wholly or partly synthesised by chemists, biologics are made in living cells, meaning they have to be extracted from a complex mixture of other biomolecules. What’s more, biologics are large and complex molecules, and must retain their intricate three-dimensional structure to work correctly, without unravelling or clumping together. “This requires an expanded toolbox of purification tools,” says Belcher. And companies are finding that purification considerations must be built into their drug discovery process early on.
Increasing complexity
The stakes are high. Fewer than 1 in 10,000 new drug candidates ever make it to the clinic, says Belcher, a statistic that is worsening as researchers train their sights on increasingly complicated targets. These candidates can fail or be delayed for numerous reasons and purification problems are a growing concern. That means biopharma companies risk losing out on a booming sector that is currently showing double-digit annual growth, says Henrik Ihre, distinguished fellow at Cytiva. For patients, it means missing out on potentially transformative new treatments.
Although purification methods exist for “classic” biologics such as monoclonal antibodies, these may not work well for the new generation of biologics, each of which demands a different approach. “People don’t always know how to make the new molecules,” says Ihre. And this often means there is no obvious way to purify them.
The sheer number of new candidates is an issue too. “There are so many that enter the development pipelines each week that companies have a hard time keeping up with developing purification protocols that purify the molecules well enough to do clinical testing,” says Ihre.
Most biologics are purified using chromatography, where molecules are separated based on properties such as size, charge, hydrophobicity or binding affinity. In many cases, this involves a chromatography resin—a material made up of porous beads functionalised with ligands that selectively bind to impurities or to the target molecule before it is released in a later step.
Shared structures
Over the past 20 years, Cytiva has developed 45 resins for purifying new biologics. The ligands on these resins are usually off-the-shelf molecules because, although each biologic is different, it usually belongs to a class of molecules that have key features in common. These can be targets for resin ligands. Classic monoclonal antibodies, for example, share a structure known as the Fc domain, which is targeted by conventional protein A resins. But monoclonal antibodies are getting more varied and complex — some no longer have an Fc domain — and this has transformed purification. “So we need to come up with new resins,” says Ihre.
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. NEMES LASZLO/ISTOCK
Successful purification means knowing your molecule like the back of your hand, says Ihre. This includes its size, form, 3D shape, hydrophobicity, and whether there are any regions that a resin ligand could bind to. “If you don’t understand your target molecule, your likelihood of being able to manufacture it and purify it will be very low,” he adds. Newer approaches can also have more liabilities, such as being aggregation prone, acidic and temperature sensitive.
That’s why planning ahead is so important – because it reveals which molecules are likely to be hard to purify. “We need to identify these liabilities as early as possible,” says Belcher. This allows companies to reduce the risk of failure as early as possible in the drug development process.
Another key consideration is to have purification processes that work at scale. Paradoxically, approaches that work in the lab don’t always translate to large-scale manufacture. For example, size exclusion chromatagraphy is still used in drugdiscovery but rarely in manufacturing because of its low capacity and slow throughput. Some issues are cost and productivity: a new technique could be scalable in theory, but in practice is too expensive or inefficient, says Ihre.
Purification technology
In a field where scientific innovation is accelerating rapidly, success depends not only on discovering new molecules but on understanding how they can be developed, purified and produced at scale. That requires expertise across the full development journey—from early discovery insights through to manufacturing realities.
By anticipating purification challenges earlier and designing molecules with production in mind, researchers and developers can reduce risk, improve scalability and bring therapies to patients faster. For companies working at the intersection of discovery and manufacturing, closing this gap is becoming essential to turning scientific breakthroughs into real-world impact.
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