Biological drugs take after nature. Often called biologics for short, these therapeutics are made of proteins, sugars, nucleic acids, viruses, and even whole cells or tissues. Biologics treat a wide range of conditions such as autoimmune diseases and cancers, or they act as vaccines that prevent sickness.

Yongchao Su, a Senior Principal Scientist at Merck, studies the molecular intricacies of biologics to create better drug products. Drawing on his training as a structural biophysicist, Su seeks to bridge basic science and pharmaceutical science. He focuses on the formulation of biologics and the analytical functions of peptide and protein drug products. 

On Su’s first day at Merck over a decade ago, his manager emphasized the influence of their work on human health. To this day, Su carries that sense of purpose with him as he teams up with his colleagues to improve the stability, bioavailability, efficacy, and delivery efficiency of biologics.

Why do you study biologic drugs?

My passion for biologics comes from my inherent appreciation of the beauty of proteins. In structural biophysics, we see beautiful 3D structures, and it’s amazing that Mother Nature made these proteins to perform valid functions. When we compare naturally occurring proteins and human-made therapeutic compounds that we use as drugs, we see that even though their functions are totally different from each other, they share similar structures. It’s very exciting to get to study and appreciate the beauty of proteins and how biological drugs can help human health.

If we look at the current modern medicine market, biologics and small molecule drugs are becoming the primary drugs on the market. Compared to small molecule drugs, biologics have larger molecular weights. That carries opportunities because they better target different sites for therapeutic purposes, and they can be more selective than small molecule drugs, which means less toxicity. But that also brings complexity.  

Biologics include monoclonal antibodies, fusion proteins, antibody drug conjugates, mRNA vaccines, and cell and gene therapies. The route of delivery is also diverse, as it includes intravenous, subcutaneous, intramuscular and oral delivery. Working in this space, how can we design all those drugs with different molecular properties and formulation processes? 

How have you advanced the molecular understanding of peptide and protein drugs?

We studied glucagon, which is a peptide drug for treating hypoglycemia that’s been on the market since it was approved in 1960 (1). To this day, glucagon drug products are provided in a lyophilized powder formulation. They don’t have liquid formulations because glucagon can aggregate and fibrilize in solution, especially in acidic solutions. When a drug molecule starts to aggregate, it can lose its therapeutic function and the quality that regulatory agencies require. So, even though glucagon has been such an important drug in the past more than half a century, the community still faces challenges with developing a stable liquid formulation, which is more convenient to administer. 

In 2019, our team published a paper in Nature Structural & Molecular Biology describing the mechanism that causes glucagon to aggregate (2). We used an advanced technology, solid-state nuclear magnetic resonance (NMR), to determine the mechanism. We found that similar to other peptide and protein drugs, glucagon exhibits intermolecular interactions in solution that lead to the formation of aggregates or fibrils. 

Our paper serves as an example that in pharmaceutical science, we need to bring fundamental analytical tools and structural biophysics methodology to understand the molecular mechanisms needed for modifying drugs and overcoming challenges.

How will applying new structural biophysics tools further biologic drug development?

We analyze our drug particles to ensure the size of the particles, for example, but that's not enough because having the same particle size doesn't mean the same internal structure. Our team has been advancing NMR as a biophysical tool to understand the structural properties of biologics that modulate their stability and delivery. One example is our recent article reporting a novel NMR method for probing the internal structure of lipid nanoparticles, which is largely inaccessible by routine laboratory tools (3).

Our paper serves as an example that in pharmaceutical science, we need to bring fundamental analytical tools and structural biophysics methodology to understand the molecular mechanisms needed for modifying drugs and overcoming challenges. 
– Yongchao Su, Merck

This is important to me because there's a gap in our mechanistic understanding of biologics, particularly in unraveling the molecular details of how these drugs are stabilized and delivered. Filling this gap is crucial as it provides the structural basis for the design of peptide and protein drugs. By applying NMR, I'm using my training as a structural biophysicist, and I'm also using my network between the biophysical community and the pharmaceutical community to hopefully bring awareness and eventually bring interest from others to fill that gap.

How have you and your team approached finding new ways to study biologics?

We understand that a protein drug often exists in a combination drug product, which means that there are interactions with different parts of a device. How do we know that they get along with each other? We can put together the formulation and wait for a long time. Then we conduct a shelf life stability study where we test whether the formulation is stable at the end of two years. 

A faster way of answering that question is to do a stress condition study, where we put together a formulation and add a stress condition like high temperature. That's one way that we try to understand long-term stability from a short-term study. Yet, we still need innovation and creativity at every step of the formulation design process.

We recently came up with another way to stress the formulation. We connected two syringes through a needle and pushed the syringes back and forth. In that case, the proteins actually experience the interaction because we are mixing them. It’s only another way to agitate, but it is a better way because we are going through the delivery device itself. We published that paper in the Journal of Pharmaceutical Sciences (4). The goal was to enhance awareness that we need to be creative in the way we do things and also to share the knowledge with the community. 

What does the future hold for biologic drugs?

We are in an era of pharmaceutical science where we will keep advancing biologics for unmet medical needs. We're going to see more interdisciplinary collaborations and advancements than we have thought about before.

The complexity will continue to grow as well. We always pick the lower hanging fruit first. In this case, it is picking molecules that are stable and then making the overall process simpler. But once we get to more difficult molecules, things will become even more challenging. 

This interview has been condensed and edited for clarity.

References

1. Story, L. H. & Wilson, L. M. New Developments in Glucagon Treatment for Hypoglycemia. Drugs  82, 1179–1191 (2022).
2. Gelenter, M. D. et al. The peptide hormone glucagon forms amyloid fibrils with two coexisting β-strand conformations. Nat Struct Mol Biol  26, 592–598 (2019).
3. Schroder, R. et al. Probing Molecular Packing of Lipid Nanoparticles from ³¹P Solution and Solid-State NMR. Anal Chem  96, 2464–2473 (2024).
4. Du, Y. et al. Design of a Reciprocal Injection Device for Stability Studies of Parenteral Biological Drug Products. J of Pharm Sci  113, 1330–1338 (2024).