We find ourselves at a singular moment in time and science. The appearance of SARS-CoV-2 at the end of 2019 realigned science throughout the world towards developing vaccines and therapeutics against this horrific and ultimately pandemic virus. Within the context of therapeutics, antibodies have been isolated against the viral spike protein by numerous groups using many different methods. In fact, never in antibody discovery history have so many different groups generated antibodies against a single target. This vast worldwide unplanned experiment has provided a unique opportunity to compare different methods of antibody generation for their efficiency and speed, and the properties of the derived antibodies for their affinities and neutralizing potencies. At the beginning of April 2021, 32 peer reviewed publications describing antibodies generated against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein had been published. The most potent were generated from convalescent patients, while those from naïve libraries were less effective. However, antibodies from immune sources were not equally potent, with different groups reporting different best affinities spanning three orders of magnitude, and only four groups reporting best affinities <100 pM. In contrast, no naïve library publication reported affinities better than 100 pM. IC50’s for live virus neutralization showed a similar trend, with six groups reporting best immune antibodies with IC50’s <10 ng/ml, and no published naïve best antibody with live virus IC50 <10 ng/ml.
In this webinar we will describe how the Specifica Generation 3 platform, a semi-synthetic naïve antibody library that relies on whole natural CDRs for diversity, fared in this global competition: yielding antibodies more similar in their properties to immune, as opposed to naïve, sources. Analysis of 96 picked clones resulted in 31 unique antibodies (falling into 12 sequence clusters), 19 of which had subnanomolar affinities, and three of which had affinities below 100 pM. Eight of ten tested antibodies had IC50’s <10ng/ml, with four having live virus IC50’s <2ng/ml, including one with an IC50 of 1.3 ng/ml. The antibodies showed excellent developability properties, with 95% having one or zero sequence liabilities, and none showing any polyreactive behavior. Expanding the analysis by Next Generation Sequencing using software developed by Specifica increased the number of different specific antibody clusters to over 600.
The qualities of antibodies generated against other targets from the Specifica Generation 3 platform in other campaigns are similar to those obtained against SARS-CoV-2, with 500 to 5,000 different clusters, ~20% subnanomolar antibodies and over 80% of antibodies with no biophysical liabilities.
Key Learning Objectives:
- How do the world’s different antibody discovery platforms perform when tested against the same target?
- Immune libraries generally provide better antibodies in terms of affinity and viral neutralization than naïve libraries
- The Specifica Generation 3 platform performs more like an immune library than a naïve one
- NGS increases the number of unique antibody clusters identified by approximately fifty-fold, compared to random picking
Andrew Bradbury, MD PhD
Chief Scientific Officer
Andrew Bradbury is Chief Scientific Officer of Specifica. He trained in medicine at the universities of Oxford and London and received his PhD from the university of Cambridge at the MRC Laboratory of Molecular Biology under the guidance of Nobel Laureate, Cesar Milstein. He has worked in the fields of phage and yeast display, library generation, antibody engineering and Next Generation Sequencing for up to thirty years. He was a Group Leader at Los Alamos National Laboratory before founding Specifica.
Frank Erasmus, PhD
M. Frank Erasmus is head of bioinformatics at Specifica, Inc. He has over 11 years of experience incorporating both experimental and computational approaches to antibody-based drug discovery. His work has directly contributed to the development of novel therapeutic monoclonal antibodies with implications in leukemia and antibody libraries built exclusively for the biotech community. He is currently focusing on the development of tools for the biopharma industry to extract patterns from next generation sequencing data derived from recombinant display technologies.
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