![]() This is one of the first steps in discovering antibodies from human donors. When studying repertoires, separating cells of interest by cell sorting is commonly used for isolating natural B cells with a specific phenotype or antigen specificity. 2 B cell sortingĪ repertoire of BCRs refers to a snapshot of all the B cells produced in a given donor at a given time. Given the recent breakthroughs in computational biology, including antibody-specific machine-learning methods ( Akbar et al., 2022), we can expect rapid growth in this area as data generation merges with data analysis in the context of antibody discovery. Although each of these areas are active research topics on their own, the greatest impact on the pharmaceutical industry will come through synthesis into integrated experimental and computational pipelines. Here we review four main areas of innovation: B Cell sorting, BCR sequencing, BCR repertoire analysis, and experimental validation of antigen binding. The Antibody Society currently lists 35 anti-SARS-CoV-2 mAbs or mAb cocktails undergoing clinical trials ( ).Īlthough it is important not to over-generalize the development of anti-SARS-CoV-2 antibodies to other disease areas, the intensity of research on COVID-19 has refocused attention on the technological innovations that enabled the discovery of antigen-specific antibodies from human BCR repertoires so quickly. Due to the overwhelming need for a response to the pandemic, along with the rapid availability of resources for COVID-19 related research, many of the mAbs were quickly tested for safety and efficacy in the clinic. Remarkably, within months of the pandemic, multiple research groups reported the discovery of neutralizing antibodies from the BCR repertoires of COVID-19 patients ( Cao et al., 2020 Hansen et al., 2020 Ju et al., 2020 Pinto et al., 2020 Robbiani et al., 2020 Seydoux et al., 2020 Wang et al., 2020 Zost et al., 2020 Baum et al., 2021). However, the COVID-19 pandemic brought with it an urgent need for creative ways of targeting the SARS-CoV-2 virus quickly. Up to the mid-2000s, mining human B cell receptor (BCR) repertoires for mAbs specific to an antigen of interest was primarily done in academic research labs ( Truck et al., 2015 Wang et al., 2015 Goldstein et al., 2019). In the past decade, a number of technological breakthroughs have enabled the discovery of antigen-specific mAbs directly from human donors ( Pedrioli and Oxenius, 2021). By the mid-2000’s, approximately one-half of therapeutic antibodies were fully human through the use of transgenic mice or phage display platforms utilizing human BCR genes ( Nelson et al., 2010 Ju et al., 2020). Animal-based antibody discovery had a huge impact on the pharmaceutical industry through the 1990’s and motivated the development of new antibody discovery platforms. The first blockbuster therapeutic antibody (anti-CD3 OKT3), which was engineered in this manner, was approved by the FDA in 1986. In this approach, candidate monoclonal antibodies (mAbs) are selected and engineered to minimize immunogenicity in humans, while maintaining target specificity and desired pharmacokinetics. Traditional therapeutic antibody discovery approaches utilized animals, usually mice, to generate polyclonal antibodies against a target antigen. Together with innovations in Deep learning these technologies will contribute to the future discovery of diagnostic and therapeutic antibodies directly from humans. Here we group these innovations into four broad categories: cell sorting allows the collection of cells enriched in specificity to one or more antigens BCR sequencing can be performed on bulk mRNA, genomic DNA or on paired (heavy-light) mRNA BCR repertoire analysis generally involves clustering BCRs into specificity groups or more in-depth modeling of antibody-antigen interactions, such as antibody-specific epitope predictions validation of antibody-antigen interactions requires expression of antibodies, followed by antigen binding assays or epitope mapping. While traditional antibody discovery utilized immunization of animals to generate lead compounds, technological innovations have made it possible to search for antibodies targeting a given antigen within the repertoires of B cells in humans. 3Department Systems Immunology, Immunology Frontier Research Center, Osaka University, Suita, JapanĪntibodies make up an important and growing class of compounds used for the diagnosis or treatment of disease.2Core Instrumentation Facility, Immunology Frontier Research Center, Osaka University, Suita, Japan.1Department of Genome Informatics, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
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