Five computational developability guidelines for therapeutic antibody profiling
Therapeutic 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 prop...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
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National Academy of Sciences
2019
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| _version_ | 1826283754865295360 |
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| author | Raybould, MIJ Marks, C Krawczyk, K Taddese, B Nowak, J Lewis, AP Bujotzek, A Shi, J Deane, C |
| author_facet | Raybould, MIJ Marks, C Krawczyk, K Taddese, B Nowak, J Lewis, AP Bujotzek, A Shi, J Deane, C |
| author_sort | Raybould, MIJ |
| collection | OXFORD |
| description | Therapeutic 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 in silico 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 cutoffs 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), a 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 opig.stats.ox.ac.uk/webapps/sabdab-sabpred/TAP.php. |
| first_indexed | 2024-03-07T01:03:40Z |
| format | Journal article |
| id | oxford-uuid:8a952eb2-108c-4a19-b181-bb9f89b4727c |
| institution | University of Oxford |
| last_indexed | 2024-03-07T01:03:40Z |
| publishDate | 2019 |
| publisher | National Academy of Sciences |
| record_format | dspace |
| spelling | oxford-uuid:8a952eb2-108c-4a19-b181-bb9f89b4727c2022-03-26T22:32:30ZFive computational developability guidelines for therapeutic antibody profilingJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:8a952eb2-108c-4a19-b181-bb9f89b4727cSymplectic Elements at OxfordNational Academy of Sciences2019Raybould, MIJMarks, CKrawczyk, KTaddese, BNowak, JLewis, APBujotzek, AShi, JDeane, CTherapeutic 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 in silico 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 cutoffs 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), a 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 opig.stats.ox.ac.uk/webapps/sabdab-sabpred/TAP.php. |
| spellingShingle | Raybould, MIJ Marks, C Krawczyk, K Taddese, B Nowak, J Lewis, AP Bujotzek, A Shi, J Deane, C Five computational developability guidelines for therapeutic antibody profiling |
| title | Five computational developability guidelines for therapeutic antibody profiling |
| title_full | Five computational developability guidelines for therapeutic antibody profiling |
| title_fullStr | Five computational developability guidelines for therapeutic antibody profiling |
| title_full_unstemmed | Five computational developability guidelines for therapeutic antibody profiling |
| title_short | Five computational developability guidelines for therapeutic antibody profiling |
| title_sort | five computational developability guidelines for therapeutic antibody profiling |
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