Abstract
Screening for biologics, in particular antibody drugs, has evolved significantly over the last 20 years. Initially, the screening processes and technologies from many years experience with small molecules were adopted and modified to suit the needs of biologics discovery. Since then, antibody drug discovery has matured significantly and is today investing earlier in new technologies that commercial suppliers are now developing specifically to meet the growing needs of large molecule screening. Here, we review the evolution of screening and automation technologies employed in antibody discovery and highlight the benefits that these changes have brought.
Highlights
By the mid 1990s the advent of combinatorial chemistry required pharmaceutical companies to adopt assay miniaturisation, the use of robotics and simple “mix and measure” technologies to facilitate cost effective ultra high throughput screening of every individual small molecule contained within libraries in excess of 1 × 106 compounds.In contrast, combinatorial human antibody libraries made via phage display in E. coli, are significantly larger, containing as many as 1 × 1011 individual compounds [1]
A major step forward in the high throughput screening of biological entities came with the advent of homogeneous time resolved FRET assays such as LANCE ® and HTRF® [8,9] coupled with a tool box of reagents and labelling chemistries, Many of the heterogeneous assay formats used for studying ligand-receptor interactions were adapted to simple mix and measure homogeneous assay formats which could be miniaturised to 384 well format, allowing an increase in throughput
The evolution of assay development and screening for bio-pharmaceuticals has been similar to that found in the world of small molecule discovery
Summary
By the mid 1990s the advent of combinatorial chemistry required pharmaceutical companies to adopt assay miniaturisation, the use of robotics and simple “mix and measure” technologies to facilitate cost effective ultra high throughput screening of every individual small molecule contained within libraries in excess of 1 × 106 compounds. The tremendous power of phage display selection [2] is used to identify a sub-population of antibodies from the 1011 library which are enriched for binding to the target of interest (Figure 1) The techniques available for these ELISAs were manual and in 96-well format only This severely limited the throughput of the discovery process and would often result in failure to identify those antibodies that may be less common in the selected population but have the desired properties. ELISA’s were limited to those antigens which could be purified and immobilised to solid surfaces and retain epitopes that are representative of their native conformation To overcome these inherent problems, and maximise the chances of isolating diverse panels of lead antibodies, it was necessary to adopt screening strategies which facilitated the testing of higher numbers of antibodies from selection outputs. The assays implemented should be more predictive of activity in downstream disease relevant, functional cellular assays
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