Bispecific Antibodies Face a Manufacturing Bottleneck as Drug Pipelines Surge
Key Insights
Bispecific antibodies (search) are transforming cancer (search) and autoimmune disease (search) treatment by binding two targets simultaneously, offering enhanced precision and the ability to overcome drug resistance.
The surge in complex biologic drug candidates has exposed a critical manufacturing bottleneck, with purification technology failing to keep pace with discovery.
Fewer than 1 in 10,000 new drug candidates reach the clinic, and purification challenges are a growing contributor to this high attrition rate.
Inside the bodies of a growing number of cancer (search) 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. Such molecules, known as bispecific antibodies (search), 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 (search).
Yet as drug candidates flood the pipeline — including trispecific antibodies (search) that bind three antigens and increasingly sophisticated monoclonal antibodies (search) — a critical bottleneck has emerged: manufacturing technology has not 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 (search). "And that is creating bottlenecks."
The Purification Problem
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 must be extracted from a complex mixture of other biomolecules. What is 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.
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 (search). For patients, it means missing out on potentially transformative new treatments.
One Size Does Not Fit All
Although purification methods exist for "classic" biologics such as monoclonal antibodies (search), 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 compounds the issue. "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. Over the past 20 years, Cytiva (search) 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.
Classic monoclonal antibodies (search), for example, share a structure known as the Fc domain (search), which is targeted by conventional protein A (search) 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.
Know Your Molecule
Successful purification means knowing your molecule intimately, 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 is 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 do not always translate to large-scale manufacture. For example, size exclusion chromatography is still used in drug discovery 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.
Designing for Purification from the Start
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.