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Abstract
As a result of the SARS-CoV-2 pandemic numerous scientific groups have generated antibodies against a single target: the CoV-2 spike antigen. This has provided an unprecedented opportunity to compare the efficacy of different methods and the specificities and qualities of the antibodies generated by those methods. Generally, the most potent neutralizing antibodies have been generated from convalescent patients and immunized animals, with non-immune phage libraries usually yielding significantly less potent antibodies. Here, we show that it is possible to generate ultra-potent (IC50 < 2 ng/ml) human neutralizing antibodies directly from a unique semisynthetic naïve antibody library format with affinities, developability properties and neutralization activities comparable to the best from hyperimmune sources. This demonstrates that appropriately designed and constructed naïve antibody libraries can effectively compete with immunization to directly provide therapeutic antibodies against a viral pathogen, without the need for immune sources or downstream optimization.
Highlights
As a result of the SARS-CoV-2 pandemic numerous scientific groups have generated antibodies against a single target: the CoV-2 spike antigen
The HCDR3s were directly amplified from the mRNA of B cells purified from the LeukoPaks of ten donors, while the remaining “naturally replicated” CDRs were identified from nextgeneration sequencing (NGS) of 40 donors and synthesized on arrays after eliminating those containing sequence liabilities, speculating that a library in which the replicated natural CDRs were informatically purged of sequence liabilities would provide antibodies with superior biophysical properties
We describe a panel of antibodies against the SARS-CoV2 spike protein directly selected from this naïve library platform, with neutralizing IC50s comparable to the best obtained with more time-consuming strategies dependent on immune B cells, demonstrating that naïve libraries of this kind are a viable alternative to immune cells as antibody sources for viral pathogens and possibly additional targets as well
Summary
As a result of the SARS-CoV-2 pandemic numerous scientific groups have generated antibodies against a single target: the CoV-2 spike antigen. We show that it is possible to generate ultra-potent (IC50 < 2 ng/ml) human neutralizing antibodies directly from a unique semisynthetic naïve antibody library format with affinities, developability properties and neutralization activities comparable to the best from hyperimmune sources. We describe a panel of antibodies against the SARS-CoV2 spike protein directly selected from this naïve library platform, with neutralizing IC50s comparable to the best obtained with more time-consuming strategies dependent on immune B cells, demonstrating that naïve libraries of this kind are a viable alternative to immune cells as antibody sources for viral pathogens and possibly additional targets as well
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