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How to Reduce Lead Synthesis Bottlenecks in Antibody Discovery

June 9, 2023

What is Therapeutic Antibody Discovery and Why is it Important?

Antibody therapeutics have tremendous research and clinical value having the potential to combat different diseases such as cancers, HIV, autoimmune, hereditary, and more. The technologies used to discover these antibody-based drug candidates have transformed the way we use biology in both academia and labs globally. Antibody discovery requires biologics developers to rapidly generate, build and screen large numbers of candidate antibodies to maximize workflow efficiency and innovation. Scientists have more pressure than ever to simultaneously meet quality, throughput, and timeline pressures. Antibody discovery programs now require increasing levels of biological diversity in terms of the species and cell types that are screened for therapeutics against harder-to-hit targets, such as GPCRs and ion channels. High-throughput screening methods that analyze multiple antibody candidates quickly and effectively are critical to a successful discovery campaign. Emerging technologies, enhanced methodologies, and higher efficiencies are all required to support demanding development projects.

Antibody Discovery Advancements

Single-cell Characterization Platforms

Shortly after the development of next-generation sequencing, researchers began exploring the possibility of sequencing individual cells. For the first time, endogenous pairing of heavy and light chain variable sequences in a given B-cell repertoire became possible. Advances in microfluidic handling technology rapidly led to the development of optofluidic platforms capable of profiling single cells with relevant phenotypic, genotypic, and imaging information.

The impact of this development on the field cannot be overstated. In fact, the central role that single-cell analysis platforms, such as 10X Genomics Chromium or Berkeley Lights Beacon instruments, have come to play in current antibody development can trace a direct line back to these developments.

Genetically Engineered Hyperimmune Mouse Models

Transgenic humanized mice strains have been developed which can produce chimeric human-mouse monoclonal antibodies comprised of fully human Fab regions and mouse Fc regions. These animals can deliver robust and diverse immune responses, significantly improving the efficiency in which lead candidate antibodies can be obtained that meet difficult target specificity profiles.

High-throughput Biophysical Characterization Platforms

Advances in liquid handling automation have ushered in a new era of high-throughput lead candidate antibody characterization. Essential kinetic and affinity analysis, epitope binning, titer and concentration assessments can all be completed at a scale and pace that meets the challenging demands of current antibody development timelines.

Discovery Workflow Synergy

Thanks to these new tools, a high-throughput workflow has emerged which addresses the increased pressure on discovery pipelines to identify and validate high quality lead candidates for new therapeutics. Antibody discovery programs can now rapidly generate large numbers of lead candidate antibodies directed against complex membrane-bound targets by leveraging transgenic humanized mice. Paired heavy and light chain variable sequences from murine B cell repertoires can then be readily characterized and sequenced. Further downstream in this new workflow, bulk kinetic and binding analyses of expressed antibodies can be rapidly accomplished.

Break through to a new pace of discovery

Break through to a new pace of discovery

To achieve high throughput required to meet development timelines, antibody discovery labs now must grapple with long wait times from synthetic biology service providers or hands-on, labor-intensive protocols often involving bacterial cultures, DNA extraction processes and quality control to build heavy and light chain constructs and amplify them before they are ready for expression. The optimal synthetic biology solution should help seamlessly connect high-content sequencing data from B cell discovery platforms to downstream high-throughput antibody screening and characterization workflows ensuring consistent and high throughput is maintained throughout the discovery process.

Fortunately, advances in automation technologies can transform a cumbersome and labor-intensive process, significantly increasing productivity for researchers. By automating manual processes that normally require expert personnel input, it allows researchers to find the information they need to make timely, well-informed decisions, and research projects proceed on schedule. This new workflow produces fewer errors and dramatically increases throughput. We believe that workflow optimization leveraging our technology can help address the throughput gap in antibody discovery head on.

Enabling Efficiencies in Antibody Discovery

optimization of metabolic pathway and enzyme engineering figure

Telesis Bio Solutions Address Key Bottlenecks in Antibody Discovery:

  • Antibody cloning completed in days, not weeks: By optimizing synthetic biology workflows, the end-to-end time for heavy and light chain variable region cloning can be reduced from multiple weeks to a few days.
  • Reduced process steps: Cell-free DNA amplification supplants tedious manual process steps associated with cloning, transformation, and E. coli culture and harvest during plasmid production.
  • Workflow efficiency gains: By implementing the BioXp® system to provide hands-free, automated assembly of DNA sequences, cloning, and amplification in a single overnight run, antibody discovery programs can produce transfection-ready plasmids in a fraction of the time previously required.

Like this blog? Make sure to check out white paper on how you can accelerate antibody engineering timelines significantly.

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