Massively parallel assays potentiate both scale and speed of data generation in the biomedical sciences and have proven key to the discovery of antibody, peptide, aptamer leads as well as enzymatic catalysts. While repertoire generation by high-throughput DNA oligonucleotide synthesis is highly developed, and selection strategies (such as phage, yeast & ribosome display) are able to process very large combinatorial (poly)peptide repertoires, these only reveal a highly biased section of the possible genotype / phenotype space.

We have developed deep screening [1], an ultra-high-throughput approach that leverages the power of the Illumina HiSeq platform for massively parallel sequencing, display, and global screening of diverse biomolecular repertoires.

Deep screening enables the real-time examination of both binding interactions and catalysis in repertoires of RNA, XNA (xeno nucleic acids), peptide and nanobody (VHH) and single-chain Fv (scFv) antibody sequences at a depth of up to 109 individual, simultaneous measurements, enabling the discovery of antibodies with picomolar target affinities in a 3-day experiment directly from synthetic repertoires.

The very large genotype-phenotype correlation datasets generated by deep screening combined with transformer machine learning models enable rapid, in silico prediction of novel and highly functional antibody sequences not present in the original repertoires and promise to further accelerate antibody discovery for a wide range of drug targets.

We anticipate many applications of the deep screening platform in particular the accelerated discovery and development of antibodies and aptamers for biotechnology and medicine.

[1] Porebski BT, Balmforth M, Browne G, Riley A, Jamali K, Fürst MJLJ, Velic M, Buchanan A, Minter R, Vaughan T & Holliger P. (2024) Rapid discovery of high-affinity antibodies via massively parallel sequencing, ribosome display and affinity screening. Nature Biomed Eng. 8 : 214-232. doi: 10.1038/s41551-023-01093-3.