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Single B-cell technologies have emerged as powerful screening tools to accelerate antibody discovery, offering R&D teams the potential to interrogate millions of individual antibody-secreting cells to find high-value binders of a specific target antigen. However, most methods to date lack the throughput or ease-of-use required to meet the antibody capacity demands of modern drug discovery.
“The xPloration® platform stands out for its throughput and speed,” explains Bob Chen, VP of Discovery Systems at OmniAb®, a biotech company that licenses advanced technologies to enable the discovery of next-generation antibody therapeutics. “We can achieve about 10x more recovery than other available approaches in less time.”
The xPloration platform screens millions of cells for desirable antibodies and uses fully automated, AI-fueled data analysis software, simplifying the selection of positive hits. This is a significant leap forward from early 2020, when many of the current single-cell screening platforms started to be adopted by the broader life science industry.
In the following Q&A, Chen explains how the xPloration platform works and how it can be applied in antibody discovery.
What is the xPloration platform, and how does it work?
The xPloration platform can screen the activity of millions of cells to find those antibody-expressing cells that fit the target product profile our partner might want. Screening occurs on a glass chip with 1.5 million microcapillaries, each about 40 microns in diameter and containing a single B-cell. We can then interrogate the unique antibody secreted by each B-cell loaded on the chip using various imaging assays, including fluorescent or label-free methods.
How is the data from the xPloration instrument analyzed?
As you can imagine, analyzing millions of datapoints to find the clones you want is a massive undertaking. The xPloration platform isn’t just the hardware; it includes the data analysis software, which we are continuously optimizing for our partners’ needs. We’ve developed a fully automated data analysis workflow that uses AI-based ”computer vision,” obviating the need for researchers to manually analyze the million-plus images. The software can look at an image of each of the 1.5 million microcapillaries, analyze it, and determine if it’s a positive hit based on pre-defined criteria and the desired antibody properties. Once we identify a cell that matches the desired hit profile, a laser ejects the sample into a recovery plate, which is then used to sequence the antibody of interest.
What distinguishes the xPloration technology from other single B-cell screening platforms?
The xPloration platform stands out in its throughput, speed, and ease of use. We can interrogate an order of magnitude more single B-cells in less time, and recover an order of magnitude more hits in minutes. The whole process takes only 1 to 3 hours from assay set-up to cell recovery, a big advantage in overall run time.
Most other technologies use tens to hundreds of thousands of pens or wells to isolate single B-cells. We have over a million microcapillaries, so we can screen many more cells and identify rare clones. That’s helpful especially when trying to find specific binders of a difficult target when there are minimal hits.
Touchless and automatic recovery of hits is enabled by a laser that is guided by computer vision. The instrument uses a moving stage to position and laser to recover hits from these single capillaries, up to one per second, allowing us to recover hundreds or thousands of promising B cells quickly. This ability is particularly useful when you have a robust immune response that has yielded an abundance of hits.
What are the benefits of using AI-based data analysis?
Using AI has greatly streamlined and increased scalability of our screening workflows. We’ve seen faster turnaround times as we’ve eliminated many of the manual data analysis steps while also reducing the risk of human error.
We trained the AI models using experimental data from real antibody discovery projects, so they are finely tuned for detecting various binding events. Our scientific team was also deeply involved in the training, providing iterative feedback to refine and validate the outputs. As we collect and access more data, we continue to improve the algorithms and our data analysis.
What types of assays can you perform using the xPloration platform?
With the throughput, speed, and ease-of-use advantages, xPloration can run screens simply. We can perform many of the standard binding and multiplexed assays for assessing monoclonal therapeutic antibodies, and we’re currently working out screening workflows for bi- and multi-specific antibodies. We perform binding assays using live cells or beads, so we can capitalize on the advantages of each method. Screening with live cells enables us to unlock hits against challenging targets, including membrane proteins like GPCRs or ion channels.
With various bead formats, we can detect selective protein or epitope binding with multiplex assays. For example, we can assay selective binding with two proteins at once using different bead formats. Then, using a fluorescent readout and computer vision, we can look for selective binding to the different beads. These positive hits can then be recovered and sequenced.
Because it’s so easy for us to screen, we tend to perform bead-based and cell-based screens in parallel. By collecting complementary datasets, we give our partners the flexibility to decide which hits they want to pursue further. For some purposes, they may only be interested in the cell-specific hits. For others, they may want the dual-positive hits. In addition, they can always go back to the data to re-investigate hits that they didn’t initially pursue or re-analyze the data a different way to test a new hypothesis. In short, the data analysis is fluid and not restricted to a linear screening workflow.
Can you share a success story using the xPloration platform?
Recently, we undertook a bispecific antibody discovery project targeting NKp46, a promising candidate for NK-cell engagement. Using our fixed (or common) light chain transgenic rat discovery platform, OmniFlic®, we immunized three animals, then conducted bead-based and cell-based binding assays. In total, we screened 27.5 million cells and isolated 3024 positive hits, which yielded 1375 unique sequences. Approximately 20% of these unique clones demonstrated KD values below 10 nM.
Beyond the benefits for your customers, how does the xPloration platform fit into OmniAb’s operational efficiency?
The platform is robust and easy to use. Unlike other single-cell screening platforms, xPloration is fluidics-free, which significantly simplifies the system by not having any liquid handling components or any risk of clogging. Even junior lab personnel can turn it on, and it just works. The software is designed to be user-friendly and accessible to even new, inexperienced users. All of the data analysis is outsourced to AI, so you don’t have to be an image analysis expert to generate data and select positive hits.
To learn more about OmniAb and how you can leverage the xPloration platform for your antibody discovery projects, contact us.
