We continue last week’s trek into the IPO wilderness to explore the technology of Molecular Partners (Zurich, Switzerland). What they are in search of is a new class of small protein therapeutics, referred to by their acronym: DARPins.
DARPins inherently share some of the same advantages monoclonal antibodies (mAbs) have over small molecule drugs. DARPins go a step further and offer possible upsides to some known mAb downsides.
The potential of DARPins—the driving force behind Molecular Partners—shows promise enough for a planned fourth quarter debut on the Swiss SIX exchange. Let’s strap on our hiking boots and unearth the science behind DARPin technology.
DARPins can be better understood in the context of a primer on proteins. Proteins are complex, three-dimensional formations built up from intermediate layers of structure. The most basic level of protein structure is the primary structure, or the linear sequence of the amino acid building blocks that make up the protein:
The next level, secondary structure, consists of highly regular three-dimensional structures formed by interactions between neighboring amino acids. Two common types of secondary structure are alpha helices and beta sheets:
Regions of secondary structure may be grouped together to form a motif. Motifs are patterns found in several different proteins.
The compact globe-shaped configuration formed by the interactions of alpha helices and beta sheets is called the tertiary structure. In many functional proteins, the final formation consists of two or more tertiary structures that fit together to form one protein, termed the quaternary structure.
WELCOME TO THE LAND OF DARPINS
The moniker DARPin stands for Designed Ankyrin Repeat Protein. An ankyrin repeat is a motif that consists of two helices separated by a loop, as shown below. The number of helix-loop-helix repeats can vary, ranging from four to thirty-four.
In nature, the ankyrin repeat motif mediates a wide variety of protein-to-protein interactions. The number of repeats influences the final configuration of the motif and this final shape determines which target protein the ankyrin repeat domain will influence.
Using genetic engineering, scientists at Molecular Partners are creating a large library of ankyrin repeat proteins, hence the design aspect of Designed Ankyrin Repeat Proteins. These DARPins are screened for their ability to interact with and modulate a variety of drug targets, with the prospect of being used in future therapies.
DARPINS VS. MONOCLONAL ANTIBODIES
All of this talk about DARPin technology begs the question: how exactly do these small proteins compare to today’s biotech darling: mAbs? It is no accident that seven out of the top ten best selling drugs are mAbs, also known as large molecule drugs—their target specificity mitigates disease with few adverse reactions.
What is obvious when comparing the monoclonal antibody to the DARPin is size and complexity of structure. MAbs are large and complex and as the following table illustrates, small and simple may be an advantage.
CLINICAL TRAILS: DARPINS
The first DARPin therapeutic, Molecular Partners’ Abicipar, has ascended up the FDA mountain to Phase III clinical trials for wet age-related macular degeneration (AMD).
Wet AMD is caused by excessive blood vessel growth to the retina, potentially leading to retinal detachment. Abicipar binds to and inhibits the growth factor, known as vascular endothelial cell growth factor (VEGF), that activates the excessive blood vessel growth.
Molecular Partners continues to expand its territory with a multi-VEGF/PDGF DARPin in preclinical development. This DARPin targets both VEGF and a second growth factor: platelet-derived growth factor (PDGF), also implicated in wet AMD. Scouting reports predict the ability to target two different growth factors will lead to even greater efficacy in clinical trials. Both wet AMD therapies are being developed with support from Allergan (Irvine, CA).
On an encouraging endnote, other DARPins developed by Molecular Partners show preclinical and early clinical success against solid tumors. We will be keeping watch on the field of DARPins as they make their way along the drug development trail.
Emily Burke, PhD has worked in biopharma for 20 years, gaining science writing experience at The Scripps Research Institute and Ionis Pharmaceuticals. As a Ph.D. molecular biologist, she is passionate about advancing the public’s understanding of science. In addition to being a self-proclaimed “science geek,” she is regularly asked to speak at international scientific meetings. When not teaching and writing the WEEKLY for Biotech Primer, Dr. Burke swims with her swim club and performs regularly on the improv circuit in San Diego.