Raybould, M. | bioRxiv Science

bioRxiv2019

Looking for Therapeutic Antibodies in Next Generation Sequencing Repositories

Recently it has become possible to query the great diversity of natural antibody repertoires using Next Generation 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. Of the 242 post Phase I antibodies, we find 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 discovery of antibody therapeutics and the legal protection of commercial antibodies.

bioinformatics↗

bioRxiv2018

The Therapeutic Antibody Profiler (TAP): Five Computational Developability Guidelines

Therapeutic monoclonal antibodies (mAbs) must not only bind to their target but must also be free from 'developability issues', such as poor stability or high levels of aggregation. While small molecule drug discovery benefits from Lipinski's rule of five to guide the selection of molecules with appropriate biophysical properties, there is currently no in silico analog for antibody design. Here, we model the variable domain structures of a large set of post-Phase I clinical-stage antibody therapeutics (CSTs), and calculate an array of metrics to estimate their typical properties. In each case, we contextualize the CST distribution against a snapshot of the human antibody gene repertoire. We describe guideline values for five metrics thought to be implicated in poor developability: the total length of the Complementarity-Determining Regions (CDRs), the extent and magnitude of surface hydrophobicity, positive charge and negative charge in the CDRs, and asymmetry in the net heavy and light chain surface charges. The guideline cut-offs for each property were derived from the values seen in CSTs, and a flagging system is proposed to identify nonconforming candidates. On two mAb drug discovery sets, we were able to selectively highlight sequences with developability issues. We make available the Therapeutic Antibody Profiler (TAP), an open-source computational tool that builds downloadable homology models of variable domain sequences, tests them against our five developability guidelines, and reports potential sequence liabilities and canonical forms. TAP is freely available at http://opig.stats.ox.ac.uk/webapps/sabdab-sabpred/TAP.php.

immunology↗