Significant advances have been made over the last three decades in the field of antibody therapeutics. Improved engineering techniques have increased their safety, specificity, and efficacy. Innovation in antibody platforms and library design, including recent developments in artificial intelligence and machine learning, have improved the rate of biotherapeutic discovery and enabled a diversity of indications to be targeted. The need for speed was heightened during the COVID-19 pandemic. Industry, government, and academia rallied; impressive steps were taken to develop and deploy vaccines and therapies at a pace previously thought impossible. This illustrates the potential, but we can and should do more. Biologic drug discovery remains costly, time-consuming, and risky, with a failure rate of over 90% . These and other complexities negatively impact patient access across the developed world and acutely limit it for those in developing countries.
We believe that innovation and competition will continue to push the boundaries of what is possible, leading to improved discovery timelines, lower costs, expanded access, and making it economically feasible to develop cures for more orphan diseases. At Carterra, we are developing tools that will drive the next wave of biotherapeutic discovery. Our instruments provide high-resolution binding data in high throughput, which enables better decision making early in the discovery process.
Understanding the mechanism of action and binding epitope
When seeking to identify effective therapeutic mAb candidates, understanding binding properties is critical, especially the mechanism of action (MOA) and epitope. Characterizing these early in an antibody screening campaign can vastly improve the likelihood of success.
Generating high-resolution data on the binding kinetics, affinities, and epitopes of large libraries of mAbs can be challenging using traditional end-point screening assays or low-throughput techniques such as Surface Plasmon Resonance (SPR). Carterra’s pioneering LSA instrument combines advanced microfluidic technology with gold standard High-Throughput Surface Plasmon Resonance (HT-SPR) to enable mAb characterization at up to 100 times the throughput of traditional SPR instruments.
The LSA enables high-throughput screening of binding kinetics and affinity. However, it can also carry out epitope mapping and binning of up to 384 ligands against 384 analytes in a single run with only a few micrograms per antibody. Understanding a therapeutic mAb’s epitope is critical, as the epitope is an innate characteristic that cannot be enhanced by engineering, whereas affinity can be improved via rational design. Combining epitope binning with affinity at the screening stage yields much richer information from which to select optimal candidates.
Carterra’s LSA technology has been deployed in a variety of biotherapeutic drug discovery workflows and we have a growing global customer base that includes 17 of the top 20 biopharmaceutical companies. We recently celebrated our 100th installation of the LSA at Genovac’s Fargo, North Dakota location. Genovac is a leading contract research and manufacturing organization that discovers, develops, and manufactures antibodies for therapeutic, diagnostic, and research purposes. The LSA has also been featured in several recent high-profile, peer-reviewed publications. Below are some highlights showcasing the power of the LSA platform.
Accelerating the development of COVID-19 therapeutics
The COVID-19 pandemic prompted an unprecedented international effort to produce antibody-based therapeutics and vaccines against the SARS-CoV-2 virus. With the help of the LSA platform, therapeutic mAbs were developed in a matter of months rather than the typical timeframe of years. A good illustration of this success came from Eli Lilly who, in collaboration with AbCellera, was able to advance the world’s first COVID-19 therapeutic into clinical trials in just 90 days.
At Lilly, the LSA platform was utilized to identify antibodies that disrupted the binding of the virus to the ACE2 receptor and displayed potent viral neutralization . The LSA platform was used at different stages of the discovery and characterization processes in the development of the first COVID therapeutic bamlanivimab (LY-CoV555), enabling researchers to obtain affinities, epitope binning, and ACE2 blocking data in days instead of months.
Further work using the LSA identified another COVID-19 antibody (LY-CoV1404) which shows no loss of potency against the Delta and Omicron variants, with broad neutralizing activity and epitopes that are highly conserved, giving it strong potential for use as a therapeutic agent .
Characterizing emerging COVID-19 variants
LSA technology has also been invaluable in tracing COVID-19 variants and the development of variant-related therapeutics. This is highlighted in a 2021 study published in Science , undertaken by a global CoVIC consortium funded by the Gates Foundation, Wellcome and Mastercard, and spearheaded by the La Jolla Institute for Immunology. Carterra’s LSA instrument and epitope binning software enabled the consortium to define and structurally illustrate seven different receptor-binding domain (RBD)–directed antibody communities with distinct footprints and competition profiles. This gave a comprehensive picture of the antigenic landscape of the SARS-CoV-2 RBD and crucially helped to determine antibodies that maintained neutralization activity against emerging SARS-CoV-2 variants. With LSA technology, this study provided a framework for selecting effective antibody treatment cocktails and for understanding how viral variants might affect antibody therapeutic efficacy.
In another COVID-19 study, it was demonstrated that antibodies characterized using the LSA platform had affinities, developability properties, and neutralization activity enabling potential new drug candidates . The ability of the LSA to process large datasets showed that appropriately designed synthetic antibody libraries can effectively compete with immune B cell-dependent pathways to directly provide therapeutic antibodies without the need for immune sources or downstream optimization.
With the rapid pace of innovation in antibody engineering and the rise of artificial intelligence and machine learning, the future of biologics is bright. We are pleased to see our Carterra LSA platform play a role in ground-breaking drug discovery efforts around the world. In years to come, we hope many more therapeutic mAbs will be developed with the LSA to improve patient outcomes for a wide range of health conditions.
- Hay, M. et al. (2014). Clinical development success rates for investigational drugs. Nature Biotechnol., https://doi.org/10.1038/nbt.2786.
- Jones, B. E. et al. (2021). The neutralizing antibody, LY-CoV555, protects against SARS-CoV-2 infection in nonhuman primates. Science Translational Medicine, 13 https://www.science.org/doi/epdf/10.1126/scitranslmed.abf1906.
- Westendorf, K. et al. (2022). LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants. Cell Reports, 39 110812. https://www.cell.com/cell-reports/fulltext/S2211-1247(22)00583-6.
- Hastie, K. M. et al. (2021). Defining variant-resistant epitopes targeted by SARS-CoV-2 antibodies: A global consortium study. Science, 374(6566), 472–478. https://doi.org/10.1126/science.abh2315
- Ferrara, F. et al. (2022). A pandemic-enabled comparison of discovery platforms demonstrates a naïve antibody library can match the best immune-sourced antibodies. Nature Communications, 13(1), 2097. https://www.nature.com/articles/s41467-021-27799-z.
Editor’s Note: Josh Eckman, is the Chief Executive Officer of Carterra. Since founding Carterra (formerly Wasatch Microfluidics) in 2005, Mr. Eckman has been instrumental in securing funding, attracting key employees and advisors, developing strategic partnerships, designing Carterra’s proprietary flexible manufacturing process, securing international distributorships, and building out the sales channels for current products. Mr. Eckman previously worked with the Lassonde New Venture Development Center, moving university technologies into the marketplace. Mr. Eckman graduated summa cum laude in Business Administration and Asian Studies from the University of Utah. At graduation, he was awarded the Outstanding Scholar in Business Administration and the Honors Baccalaureate Award. Mr. Eckman also received a M.S. in Mechanical Engineering (microfluidics focus) from the University of Utah.