Looking for therapeutic antibodies in next-generation sequencing repositories

Abstract

Recently it has become possible to query the great diversity of natural antibody repertoires using nextgeneration sequencing (NGS). These methods are capable of producing millions of sequences in a single experiment. Here we compare clinical-stage therapeutic antibodies to the~1b sequences from 60 independent sequencing studies in the Observed Antibody Space database, which includes antibody sequences from NGS analysis of immunoglobulin gene repertoires. Of 242 post-Phase 1 antibodies, we found 16 with sequence identity matches of 95% or better for both heavy and light chains. There are also 54 perfect matches to therapeutic CDR-H3 regions in the NGS outputs, suggesting a nontrivial amount of convergence between naturally observed sequences and those developed artificially. This has potential implications for both the legal protection of commercial antibodies and the discovery of antibody therapeutics.

Editorial: Next-Generation Sequencing of Human Antibody Repertoires for Exploring B-cell Landscape, Antibody Discovery and Vaccine Development

“…We are delighted to have included an excellent contribution from the Adaptive Immune Receptor Repertoire (AIRR) community (Breden et al), which provides an overview of the founding principles and presents the progress it has made to develop and promote standards and recommendations for best practices and data-sharing protocols. In conclusion, NGS combined with innovative single-B-cell technologies has the potential to yield millions of native human antibody sequences and some of them that could match with therapeutic antibodies (13,14). This suggests a possible implication for data mining in the NGS repositories for discovering therapeutic antibody candidates in future.…”

Data mining patented antibody sequences

“…Successful exploitation of antibodies as therapeutics relies on ever deeper understanding of the biology of these molecules. Many features of therapeutic antibodies can be found in naturally sourced sequences 5 , however effective biotherapeutic requires bespoke engineering for clinical safety and developability 2 . We proposed that such biotherapeutic engineering knowledge could be reflected in patent documents containing antibody sequences.…”

“…Typical timelines involved in bringing these molecules to the market are slow, however more and more molecules are approved in the US and EU each year 1 . Successful exploitation of antibodies by either experimental 2,3 or computational techniques 4 relies on our ability to understand what makes a successful antibody-based therapeutic 5,6 .…”

Computational approaches to therapeutic antibody design: established methods and emerging trends

“…Human antibody repertoires also appear to be constrained structurally, and this includes regions of the antibody that display great variability such as the CDRH3 loop [ 224 ]. Furthermore, many therapeutic CDRH3 loops can be found in naturally sourced NGS datasets, indicating a certain degree of convergence between antibodies raised experimentally and naturally occurring ones [ 225 ]. Studying such convergence of immune repertoires might reveal strategic preferences that have arisen through natural evolution.…”