“Delivering a novel approach for protein design can be challenging, but the potential is huge” - BioInnovation Institute

“Delivering a novel approach for protein design can be challenging, but the potential is huge”

“Delivering a novel approach for protein design can be challenging, but the potential is huge”

As part of a collaboration between BioInnovation Institute (BII) and the Institute for Protein Design (IPD) at the University of Washington School of Medicine, we spoke with Lance Stewart, Interim Project Director of ‘MODULATE’, a translational research project in BII’s Bio Studio program. Lance has more than 27 years of experience in protein and drug discovery research, life sciences partnering, and entrepreneurial start-up activities. He also manages IPD’s Translational Investigator Research program, has co-founded several biotechnology companies, and is an active angel investor.

We asked him what he expects from the project and its commercial potential based on the exceptional science spun out from the Baker Lab headed by Professor David Baker, Director of IPD, and Howard Hughes Medical Institute Investigator at the University of Washington.

What is the overall purpose of the project?

It is a platform-based project using de novo protein design to generate binders to integral membrane proteins like GPCRs and ion channels, which are a high-value class of receptors that have traditionally been difficult to target with antibodies in a directed manner.  De novo protein design is a new technology enabling the creation of novel biological medicinal proteins that target precisely defined sites on disease-relevant proteins. If this platform works, there will be a great opportunity to deliver a new class of medications.

What problem in drug development and drug discovery are you solving?

Around 50% of all the drugs today target integral membrane proteins, but biologics in this space are really lacking because the antibody pipeline technology largely breaks down for this target class. Everything is more challenging, from purifying the target proteins for immunization and display to finding high-affinity antibodies to binding the right epitope to activate or inhibit the target. In drug development, you mostly focus on small molecules and antibodies, but we are working on constructing a completely new class of drug molecules that combine the properties of both to offer a compelling alternative to the pharmaceutical industry.

What are the advantages of minibinders/designer proteins?

Minibinders created through protein design are fifty times smaller than a traditional antibody. But they’re extremely well-folded proteins that can be encoded in genes and synthesized by cells. This allows for low-cost manufacturing since you can deploy a well-established fermentation process for production. These minibinders have several other features that make them superior to small molecules as well. The binding interface to the target is designed with sub-angstrom accuracy, so minibinders can achieve high selectivity, avoiding off-target effects. Minibinders also offer outstanding stability to proteases and heat. You can boil them, and they stay folded and functional, which comes in handy with regard to formulation and international shipping where you often struggle with coating issues and long-term stability. Additionally, the minibinders are highly soluble and can be concentrated without losing their activity, meaning you can provide a person with a bigger dose of the drug in a smaller volume. Furthermore, they are modular and can be combined or configured in ways you just couldn’t with natural protein biologics because we have a thorough understanding of their sequence-structure relationship thanks to de novo design.

What are the challenges when it comes to scalability?

We have several minibinder proteins making their way to the clinic. Some have already proven to be safe in animal studies and in Phase 1 human safety trials. One example from the IPD is an antiviral minibinder formulated as a nasal spray to combat COVID-19. The technology was developed over the last five years and things are moving fast.

The biggest risk that people ask about has to do with immunogenicity, where the concern is centered around whether the body will accept the minibinder or will consider it as a foreign element and mount an immune response to it. In all our preclinical animal studies for three or four different minibinders to date we have not seen any significant immune response to the drug candidates, and recently one of our IPD spinout companies, Neoleukin Therapeutics, reported no significant immune responses in Phase I human clinical study where people received multiple doses of a de novo-designed mimetic of cytokine IL-2. Nevertheless, this will still have to be tested in the clinic since human and animal immune systems are very different from one another.

What do you need to primarily focus on in the Bio Studio program?

The project will focus on building a platform for improving the design of minibinders to target a very challenging high-value class of drug targets. Thus, it will be key to demonstrate the reproducibility of our technology and put all the membrane proteins through a screening platform to ensure validation. Once this task is finished, we will approach the large-scale platform for the discovery of new minibinders to target these proteins.

What will be crucial to make this project a commercial success?

Getting the platform running will be a success since it can yield candidates to target. But when you start to pick specific candidates, you really need to understand the potential value, the competitive landscape, the indications that you would be treating, and how you can go about developing a molecule for that. So, over time this project will be picking targets where we have traction with minibinders and then at a later stage, we will dig deeper to figure out exactly where the commercial opportunities exist and what value those opportunities represent.

How does the competitive landscape look regarding minibinders – are there many others looking in this direction?

The field is moving very rapidly! We are clearly the de facto leader as we are the only ones who not only published the computational design methods but also experimentally and structurally validated many different minibinders. Even though we have reproduced our results on a scale that no one else has achieved, competition is increasing as many people show interest in applying machine learning approaches for protein structure prediction and we have observed that the area of deep learning receives a large flow of capital.

Why is the Bio Studio program a unique opportunity for a project like this?

Being a part of BII’s Bio Studio program offers a tremendous opportunity for the Institute for Protein Design to expand our translational research program internationally. So far, our focus has mostly been on sparking innovation in the Seattle area, and over the last ten years we spun out 12 companies there. But the beautiful thing about having been successful is that people are now calling the Institute for Protein Design from all over the world, and we see our participation in this unique program as a great chance for us to expand our international activities in the field of protein design.

Is it a challenge from a commercial perspective that you are presenting something completely novel compared to an adjustment to something already existing?

The completely novel approach has its risks, but it also holds huge potential and impact, so people need to balance this when assessing our project. I believe our advantage is that we can design every aspect of our proteins to solve the problem at hand, whether it’s binding to challenging targets or getting the ideal delivery route and pharmacokinetics. Nevertheless, we are aware of the many risks that relate to product development which go well beyond those known at the design stage.

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