Multispecific Manufacturability Starts With Molecular Design
By Tyler Menichiello, Chief Editor, Bioprocess Online
At the heart of it, biopharma is about pushing the boundaries of medicine. And while this motivation has yielded elegant solutions to some of the most devastating diseases, it can also result in some ambitiously complicated molecules. These molecules and their respective mechanisms of action may seem amazing on paper, but they can prove exceedingly difficult to manufacture reproducibly and at scale.
Therein lies the main challenge of biopharmaceutical development: Balancing cutting-edge science and novel therapeutic approaches with the constraints of modern manufacturing and commercial realities.
When I think about drug development — and more specifically, the people at small- to mid-size biotech companies working to bring these products to market — I picture Sisyphus rolling these extraordinary molecules up the proverbial hill.
While the “hill” of drug development cannot change its grade, there are ways to make this climb a little easier, e.g., rounding out the rock (molecule) to make it roll more efficiently.
This idea of easing development by making slight changes to the molecule was the theme of a recent “Better Biopharma” episode with Jhong-Jhe You, Ph.D., AP Biosciences’ VP of antibody discovery. He talked about how molecular complexity and other aspects of antibody design can influence a product’s manufacturability, and ultimately, its developability.
Below are excerpts from the full podcast episode, which you can find here. Subscribe to hear new episodes every other Wednesday, wherever you get your podcasts!
The following transcription has been edited for clarity.
How do design decisions improve manufacturing outcomes?
You: Design decisions have a very direct and underestimated impact on manufacturing. At a fundamental level, what you define at the protein sequence and format-selection stage essentially determines how the molecule will behave through all of production. Even a relatively small choice such as framework selection, domain orientation, linker design, or specific amino-acid optimization can meaningfully influence expression levels, stability, aggregation risk, and overall product quality.
In general, simpler and more symmetric formats tend to be more robust. They improve chain pairing, increase titer, and simplify purification. The Fc domain and linker design in particular can have a major impact on both a molecule’s expression and stability, while also influencing how cleanly the molecule can be processed downstream.
In many cases, avoiding unnecessary structural complexity is a design advantage because it reduces the risk of heterogeneity and manufacturing failure. Formatting decisions also reflect directly in CMC performance, affecting process consistency, scalability, reliability, and analytical simplicity. So, the impact is not just biochemical; it’s operational and industrial.
A good example is our TQ platform and its IgG-scFv design. It’s built on a symmetric IgG scaffold with an scFv fused to the C-terminal of the heavy chain, which is an old-fashioned design, but it’s well-suited from a functional standpoint to bridge the two different cell types.
From a manufacturing perspective, this format is also highly practical. The intact IgG backbone allows us to leverage the established protein-A based purification workflow without introducing an entirely new downstream system. At the same time, this symmetrical format reduces the heavy-chain/light-chain mispairing, a common challenge in more complex bispecific formats, which in turn improves yield and product homogeneity.
Overall, better-designed molecules are not just biologically more effective, they are also significantly easier to develop, manufacture, and scale. Good molecular design directly reduces the CMC burden and increases the probability that a candidate can successfully become a drug. The final format still has to be aligned with the mechanism of action or therapeutic effect you’re trying to achieve.
The following transcription has been edited for clarity.
What are the key elements of bispecific or multispecific antibody design, and how do these conflict with traditional mAb design?
You: From a design perspective, there are three key elements of multispecific antibodies: biology, drug format, and developability.
From a biological perspective, the target pairing has to make sense. In other words, you need a clear rationale for why these two elements should be engaged at the same time and what kind of functional synergy you hope to achieve. In many complex diseases like oncology and immune-mediated diseases, a single target is often not sufficient. So, the design should always start from a biological hypothesis.
The next question is, how do you physically build this functionality into a single molecule? The binding geometry and valency are as important as the affinity. It’s not only about whether each arm binds, but also how the molecule behaves in space and whether it can bring the right cells or targets into a strong connection.
This pairing strategy, molecular symmetry, and Fc design all play a critical role in expression, purification, and overall manufacturability. For example, our TQ platform uses a symmetric IgG-scFv format, which is designed to efficiently bridge an immune effector cell and a tumor cell. This optimizes the geometry for functional activity rather than just for binding strength. The intended route of administration and the dosing regimen also feed back into format selection.
Developability is often underestimated in the early stages. Even if a molecule looks excellent in vitro, it still has to be stable, manufacturable, and have acceptable pharmacokinetics and safety in vivo. We spend a lot of effort optimizing drug properties like aggregation risk, expression, and half-life early on to make sure [the molecule] can actually become a real drug.