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How advances in antibody discovery platforms are essential for driving precision medicine.
Precision medicine represents a new era for healthcare: tailoring treatment decisions to individual patients improves outcomes and prevents treatment that would be inappropriate or ineffective for a patient’s condition.
Advancement of the antibody tools themselves is a key factor in progressing precision medicine.
Precision medicine relies on diagnostic tests to help healthcare professionals assess whether a treatment is appropriate for a patient. These tests are frequently based on antibodies specific to treatment response biomarkers and, consequently, advancement of the antibody tools themselves is a key factor in progressing precision medicine.
Antibody discovery platforms have come a long way since target-specific monoclonal antibodies were developed using a hybridoma technique, wherein a single cell is cloned to yield a cell line that produces the monoclonal antibody1. While hybridoma technology has proven itself extremely useful, more advanced techniques are now available for the production antibodies for diagnostics assays.
Complex biomarker targets
One apparent successor to traditional hybridoma methods is in vitro recombinant technology. Production of recombinant antibodies by in vitro methods has enormous advantages for developing therapeutics and diagnostics. The use of highly diverse, synthetically produced immunogen libraries can deliver antibodies for almost any desired antigen, including conformational variants or low immunogenic antigens that may not elicit an immune response when using traditional hybridoma techniques2. As such, diagnostics using recombinant antibody technology can be developed for a wide range of biomarkers including those with sequence variations.
A significant advance in recombinant technology was the development of phage display, a technology that uses bacteriophage to display an antibody protein of interest by incorporating the gene for that protein into the phage, which then displays the protein on its coat. Phage display makes selection and screening of recombinant antibodies much more efficient: development of a new recombinant monoclonal antibody by phage display can be achieved in approximately two months from start to finish2. Once the antibody sequence is known, phage display is readily automatable, and so it can be used for high-throughput antibody development4.
Rapid antibody production is essential in the race to get a diagnostic made, patented, and into the clinic.
The development of new state-of-the-art display platforms, such as AxioMx used at Abcam, has sped the in vitro display process up even more. AxioMx is a high-throughput phage display antibody development platform that reduces recombinant antibody production time down from months to a few weeks. It uses high-diversity libraries of antibody single-chain variable fragments (scFvs) fused to the coat protein of a bacteriophage. This combined with improved library screening, and affinity maturation methods make AxioMx a much more elegant approach to recombinant antibody production compared to traditional phage display5.
Sequencing antibody repertoires is a powerful new technology that can significantly boost our understanding of the immune response and revolutionize the speed and accuracy to which we can design specific and consistent monoclonal antibodies for use in diagnostic tests.
High-throughput next-generation sequencing (NGS) technology allows the most critical antibodies and clonal families generated during an immune response to be pinpointed, allowing for a greater chance of discovering the antibody that best binds a target of interest. Bioinformatic analysis of the immune repertoire identifies those antibodies contributing to a functional immune response6, including the paired human heavy and light chain repertoire from isolated naïve and antigen-specific B cells, T cell receptors, and antibody display repertoires7.
Sequencing of large-scale immune repertoires is also paving the way for future advancements in antibody technology. The datasets generated from sequencing antibody repertoires, combined with our understanding of antibody-antigen binding, is anticipated to enable computational modeling of antibody-antigen structure-binding, allowing prediction of antibody specificity6.
Looking to the future
What does the future hold for these technologies? Synergy between these technologies will provide the most significant steps forward in antibody production for diagnostic development. Combining the consistency of recombinant antibodies with the speed of output from AxioMx and the antibody sequence prediction from NGS provides everything needed to push the boundaries of antibody-based diagnostics and produce high-quality, reliable antibodies for any target, quickly and efficiently.
The synergy between existing technologies and future developments has the potential to advance precision medicine to new levels of patient care.
Antibodies designed from computer models could be engineered to bind the desired antigen and contain all the desired traits to make it perfect for a diagnostic test. It is also possible that we could use our technologies in conjunction with artificial intelligence (AI) engines to analyze big data sets emanating from NGS. This would mean that more data sets can be analyzed speeding up the entire antibody development process and subsequently improving the rate and efficiency of antibodies moving from conceptualization to production.
1. Köhler G, Milstein C. (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 256(5517):495–497
2. Hentrich C, Ylera F, Frisch C, Ten Haaf A, Knappik A. (2018) Chapter 3 – Monoclonal Antibody Generation by Phage Display: History, State-of-the-Art, and Future. Handbook of Immunoassay Technologies. p47-80.
3. Kennedy, P. J., Oliveira, C., Granja, P. L., Sarmento, B., Kennedy, P. J., Oliveira, C., … Sarmento, B. (2017). Critical Reviews in Biotechnology Monoclonal antibodies : technologies for early discovery and engineering. Critical Reviews in Biotechnology, 0(0), 1–15. https://doi.org/10.1080/07388551.2017.1357002
4. Konthur Z, Hust M, Dübel S. (2005) Perspectives for systematic in vitro antibody generation. Gene. 2005 Dec 30;364:19-29.
5. Interview with Michael Weiner for Nature inside https://www.nature.com/advertorials/insideview/pdf/ivabcammar2017.pdf
6. Robinson, W. H. (2014). — diagnostic and therapeutic discovery. Nature Publishing Group, 1–12. https://doi.org/10.1038/nrrheum.2014.220
7. Rouet R, Jackson KJL, Langley DB, Christ D. Next-Generation Sequencing of Antibody Display Repertoires. Front Immunol. 2018;9:118. Published 2018 Feb 2. doi:10.3389/fimmu.2018.00118